HPN 2020 April-May

HOSPITAL PROFESSIONAL NEWS IRELAND

HPN April/May 2020 Issue 73 HOSPITALPROFESSIONALNEWS.IE

Ireland’s Dedicated Hospital Professional Publication

IN THIS ISSUE:

While we must stay apart We stand together supporting you

NEWS: Irish Doctors answer calls home Page 6 REPORT: Medicine Shortages in Hospitals Page 18 CPD: Vitamin-D Deficiency Page 23 FEATURE: COVID-19 within the Irish context Page 32 NEWS: Covid-19 impact on lungs largely 'unknown' Page 36 EDUCATION: Effects of COVID-19 on Mental Health Page 38

THE FLEXIBILITY OF Q3W OR Q6W DOSING ACROSS MONOTHERAPY INDICATIONS1

KEYTRUDA® (pembrolizumab) ABRIDGED PRODUCT INFORMATION Refer to Summary of Product Characteristics before prescribing. PRESENTATION KEYTRUDA 25 mg/mL: One vial of 4 mL of concentrate contains 100 mg of pembrolizumab. INDICATIONS KEYTRUDA as monotherapy is indicated for the treatment of advanced (unresectable or metastatic) melanoma in adults. KEYTRUDA as monotherapy is indicated for the adjuvant treatment of adults with Stage III melanoma and lymph node involvement who have undergone complete resection. KEYTRUDA as monotherapy is indicated for the first-line treatment of metastatic non-small cell lung carcinoma (NSCLC) in adults whose tumours express PD-L1 with a ≥50% tumour proportion score (TPS) with no EGFR or ALK positive tumour mutations. KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of metastatic non-squamous NSCLC in adults whose tumours have no EGFR or ALK positive mutations. KEYTRUDA, in combination with carboplatin and either paclitaxel or nab-paclitaxel, is indicated for the first-line treatment of metastatic squamous NSCLC in adults. KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic NSCLC in adults whose tumours express PD-L1 with a ≥1% TPS and who have received at least one prior chemotherapy regimen. Patients with EGFR or ALK positive tumour mutations should also have received targeted therapy before receiving KEYTRUDA. KEYTRUDA as monotherapy is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL) who have failed autologous stem cell transplant (ASCT) and brentuximab vedotin (BV), or who are transplant-ineligible and have failed BV. KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic urothelial carcinoma in adults who have received prior platinum-containing chemotherapy. KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic urothelial carcinoma in adults who are not eligible for cisplatin-containing chemotherapy and whose tumours express PD L1 with a combined positive score (CPS) ≥ 10. KEYTRUDA as monotherapy or in combination with platinum and 5-fluorouracil (5-FU) chemotherapy, is indicated for the first-line treatment of metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) in adults whose tumours express PD-L1 with a CPS ≥ 1. KEYTRUDA as monotherapy is indicated for the treatment of recurrent or metastatic HNSCC in adults whose tumours express PD-L1 with a ≥ 50% TPS and progressing on or after platinum-containing chemotherapy. KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of advanced renal cell carcinoma (RCC) in adults. DOSAGE AND ADMINISTRATION See SmPC for full details. Therapy must be initiated and supervised by specialist physicians experienced in the treatment of cancer. The recommended dose of KEYTRUDA as monotherapy is either 200 mg every 3 weeks or 400 mg every 6 weeks administered as an intravenous infusion over 30 minutes. The recommended dose of KEYTRUDA as part of combination therapy is 200 mg every 3 weeks administered as an intravenous infusion over 30 minutes. KEYTRUDA must not be administered as an intravenous push or bolus injection. When administering KEYTRUDA as part of a combination with intravenous chemotherapy, KEYTRUDA should be administered first. Treat patients until disease progression or unacceptable toxicity. Atypical responses (i.e., an initial transient increase in tumour size or small new lesions within the first few months followed by tumour shrinkage) have been observed. Recommended to continue treatment for clinically stable patients with initial evidence of disease progression until disease progression is confirmed. For the adjuvant treatment of melanoma, KEYTRUDA should be administered until disease recurrence, unacceptable toxicity, or for a duration of up to one year. KEYTRUDA, as monotherapy or as combination therapy, should be permanently discontinued (a) For Grade 4 toxicity except for: endocrinopathies that are controlled with replacement hormones; or haematological toxicity, only in patients with cHL in which KEYTRUDA should be withheld until adverse reactions recover to Grade 0-1; (b) If corticosteroid dosing cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks; (c) If a treatment-related toxicity does not resolve to Grade 0-1 within 12 weeks after last dose of KEYTRUDA; (d) If any event occurs a second time at Grade ≥ 3 severity. Patients must be given the

Patient Alert Card and be informed about the risks of KEYTRUDA. Special populations Elderly: No dose adjustment necessary. Data from patients ≥ 65 years are too limited to draw conclusions on cHL population. Data from pembrolizumab monotherapy in patients with resected Stage III melanoma, from pembrolizumab in combination with axitinib in patients with advanced RCC, and from chemotherapy combination in patients with metastatic NSCLC, and from pembrolizumab (with or without chemotherapy) in patients receiving first line treatment for metastatic or unresectable recurrent HNSCC ≥ 75 years are limited. Renal impairment: No dose adjustment needed for mild or moderate renal impairment. No studies in severe renal impairment. Hepatic impairment: No dose adjustment needed for mild hepatic impairment. No studies in moderate or severe hepatic impairment. Ocular melanoma: Limited safety and efficacy data exist. Eastern Cooperative Oncology Group (ECOG) performance status score ≥ 2: Patients with ECOG performance status score ≥ 2 were excluded from the clinical trials of melanoma, NSCLC, cHL, and HNSCC. Paediatric population: Safety and efficacy in children below 18 years of age not established. CONTRAINDICATIONS Hypersensitivity to the active substance or to any excipients.

PRECAUTIONS AND WARNINGS Assessment of PD-L1 status When assessing the PD-L1 status of the tumour, it is important that a well-validated and robust methodology is chosen to minimise false negative or false positive determinations. Immune-related adverse reactions Immune-related adverse reactions, including severe and fatal cases, have occurred in patients receiving pembrolizumab. Most immune-related adverse reactions occurring during treatment with pembrolizumab were reversible and managed with interruptions of pembrolizumab, administration of corticosteroids and/or supportive care. Immune-related adverse reactions have also occurred after the last dose of pembrolizumab. Immune-related adverse reactions affecting more than one body system can occur simultaneously. See SmPC for full details. Immune-related pneumonitis: Patients should be monitored for signs and symptoms of pneumonitis. Suspected pneumonitis should be confirmed with radiographic imaging and other causes excluded. Refer to SmPC for information on management of immune-related pneumonitis. Immune-related colitis: Patients should be monitored for signs and symptoms of colitis, and other causes excluded. Consider the potential risk of gastrointestinal perforation. Refer to SmPC for information on management of immune-related colitis. Immune-related hepatitis: Patients should be monitored for changes in liver function (at the start of treatment, periodically during treatment and as indicated based on clinical evaluation) and symptoms of hepatitis, and other causes excluded. Refer to SmPC for information on management of Immune-related hepatitis. Immune-related nephritis: Patients should be monitored for changes in renal function, and other causes of renal dysfunction excluded. Refer to SmPC for information on management of immune-related nephritis. Immune-related endocrinopathies: Severe endocrinopathies, including adrenal insufficiency, hypophysitis, type 1 diabetes mellitus, diabetic ketoacidosis, hypothyroidism, and hyperthyroidism have been observed with pembrolizumab treatment. Long-term hormone replacement therapy may be necessary in cases of immune-related endocrinopathies. Hypophysitis has been reported in patients receiving pembrolizumab. Patients should be monitored for signs and symptoms of adrenal insufficiency and hypophysitis (including hypopituitarism) and other causes excluded. Patients should be monitored for hyperglycaemia or other signs and symptoms of diabetes. Thyroid disorders, including hypothyroidism, hyperthyroidism and thyroiditis, have been reported in patients receiving pembrolizumab and can occur at any time during treatment. Hypothyroidism is more frequently reported in patients with HNSCC with prior radiation therapy. Patients should be monitored for changes in thyroid function (at the start of treatment, periodically during treatment and as indicated based on clinical evaluation) and clinical signs and symptoms of thyroid disorders. Refer to SmPC for information on management of immune-related endocrinopathies. Immune-related skin adverse reactions: Patients should be monitored for suspected severe skin reactions and other causes should be excluded. Based on the severity of the adverse reaction, pembrolizumab should be withheld or permanently discontinued, and corticosteroids should be administered. Cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients

(pembrolizumab) Injection 25mg/ml FEWER INFUSIONS WITH Q6W DOSING The flexible dosing regimen with KEYTRUDA is an opportunity to reduce the frequency of treatments for your patients

Q6W dosing means as few as 8 infusions per year

CHOOSE THE APPROPRIATE DOSING REGIMEN FOR YOUR PRACTICE AND PATIENTS

3

Weeks

OR

Every

6

Weeks

200 mg

400 mg

Short-interval Dosing

Long-interval Dosing

receiving pembrolizumab. For signs or symptoms of SJS or TEN, pembrolizumab should be withheld and the patient should be referred to a specialised unit for assessment and treatment. If SJS or TEN is confirmed, pembrolizumab should be permanently discontinued. Caution should be used when considering the use of pembrolizumab in a patient who has previously experienced a severe or life-threatening skin adverse reaction on prior treatment with other immune- stimulatory anticancer agents. Other clinically significant immune-related adverse reactions: The following additional clinically significant, immune-related adverse reactions, have been reported in clinical trials or in post-marketing experience: uveitis, arthritis, myositis, myocarditis, pancreatitis, Guillain-Barré syndrome, myasthenic syndrome, haemolytic anaemia, sarcoidosis and encephalitis. Refer to SmPC for information on management of significant immune-related adverse reactions. Solid organ transplant rejection has been reported in the post-marketing setting in patients treated with PD-1 inhibitors. The benefit of treatment with pembrolizumab versus the risk of possible organ rejection should be considered in these patients. Complications of allogeneic Haematopoietic Stem Cell Transplant (HSCT): Allogeneic HSCT after treatment with pembrolizumab: Cases of graft-versus-host-disease (GVHD) and hepatic veno-occlusive disease (VOD) have been observed in patients with classical Hodgkin lymphoma undergoing allogeneic HSCT after previous exposure to pembrolizumab. Until further data become available, careful consideration to the potential benefits of HSCT and the possible increased risk of transplant-related complications should be made case by case. Allogeneic HSCT prior to treatment with pembrolizumab: In patients with a history of allogeneic HSCT, acute GVHD, including fatal GVHD, has been reported after treatment with pembrolizumab. Patients who experienced GVHD after their transplant procedure may be at an increased risk for GVHD after treatment with pembrolizumab. Consider the benefit of treatment with pembrolizumab versus the risk of possible GVHD in patients with a history of allogeneic HSCT. Infusion-related reactions: For severe infusion reactions including hypersensitivity and anaphylaxis, stop infusion and permanently discontinue pembrolizumab. With mild or moderate infusion reactions, infusion may continue with close monitoring. Premedication with antipyretic and antihistamine may be considered. Overdose: There is no information on overdose with pembrolizumab. In case of overdose, monitor closely for signs or symptoms of adverse reactions and treat appropriately. INTERACTIONS No formal pharmacokinetic drug interaction studies have been conducted with pembrolizumab. No metabolic drug-drug interactions are expected. The use of systemic corticosteroids or immunosuppressants before starting pembrolizumab should be avoided because of their potential interference with the pharmacodynamic activity and efficacy of pembrolizumab. Corticosteroids can be used as premedication, when pembrolizumab is used in combination with chemotherapy, as antiemetic prophylaxis and/or to alleviate chemotherapy-related adverse reactions. FERTILITY, PREGNANCY AND LACTATION Women of childbearing potential Women of childbearing potential should use effective contraception during treatment with pembrolizumab and for at least 4 months after the last dose of pembrolizumab. Pregnancy No data on use in pregnant women. Do not use during pregnancy unless the clinical condition of the woman requires treatment with pembrolizumab. Breast-feeding It is unknown whether pembrolizumab is secreted in human milk. A risk to newborns/ infants cannot be excluded. Fertility No clinical data available. SIDE EFFECTS Refer to SmPC for complete information on side effects.

Pembrolizumab is most commonly associated with immune-related adverse reactions. Most of these reactions resolved with appropriate medical treatment or withdrawal of pembrolizumab. The most serious adverse reactions were immune-and infusion-related adverse reactions. Monotherapy: Very Common: anaemia, hypothyroidism, decreased appetite, headache, dyspnea, cough, abdominal pain, nausea, vomiting, constipation, musculoskeletal pain, arthralgia, asthenia, oedema, pyrexia, diarrhoea, rash, pruritus, fatigue. Common: pneumonia, thrombocytopaenia, lymphopaenia, hyponatraemia, hypokalaemia, hypocalcaemia, insomnia, neuropathy peripheral, lethargy, dry eye, cardiac arrhythmia (including atrial fibrillation), hypertension, hyperthyroidism, insomnia, dizziness, dysgeusia, pneumonitis, colitis, dry mouth, severe skin reactions, vitiligo, dry skin, alopecia, eczema, dermatitis acneiform, erythema,

➜

over 30 minutes

myositis, pain in extremity, arthritis, influenza like illness, chills, AST and ALT increases, hypercalcaemia, increase in blood alkaline phosphatase, blood bilirubin increased, blood creatinine increased, infusion related reaction. Frequency not known: solid organ transplant rejection Combination with chemotherapy: Very Common: anaemia, neutropaenia, thrombocytopaenia, hypokalaemia, decreased appetite, dizziness, neuropathy peripheral, dysgeusia, headache, dyspnoea, cough, abdominal pain, alopecia, diarrhoea, nausea, vomiting, constipation, rash, pruritus, musculoskeletal pain, arthralgia, pyrexia, fatigue, asthenia, oedema, blood creatinine increased. Common: pneumonia, febrile neutropaenia, leukopaenia, lymphopaenia, infusion related reaction, hypothyroidism, hyperthyroidism, hyponatraemia, hypocalcaemia, insomnia, lethargy, dry eye, cardiac arrhythmia (including atrial fibrillation), hypertension, pneumonitis, colitis, dry mouth, severe skin reactions, erythema, dry skin, myositis, pain in extremity, arthritis, nephritis, acute kidney injury, chills, influenza-like illness, hypercalcaemia, ALT increase, AST increased, blood alkaline phosphatase increased.

Combination with axitinib: Very Common: hyperthyroidism, hypothyroidism, decreased appetite, headache, dysgeusia, hypertension, dyspnoea, cough, dysphonia, diarrhoea, abdominal pain, nausea, vomiting, constipation, palmar-plantar erythrodysaesthesia syndrome, rash, pruritus, musculoskeletal pain, arthralgia, pain in extremity, fatigue, asthenia, pyrexia, alanine aminotransferase increased, aspartate aminotransferase increased, blood creatinine increased. Common: pneumonia, anaemia, neutropaenia, leukopaenia, thrombocytopaenia, infusion related reaction, hypophysitis, thyroiditis, adrenal insufficiency, hypokalaemia, hyponatraemia, hypocalcaemia, insomnia, dizziness, lethargy, neuropathy peripheral, dry eye, cardiac arrhythmia (including atrial fibrillation), pneumonitis, colitis, dry mouth, hepatitis, severe skin reactions, dermatitis acneiform, dermatitis, dry skin, alopecia, eczema, erythema, myositis, arthritis, tenosynovitis, acute kidney injury, nephritis, oedema, influenza like illness, chills, blood alkaline phosphatase increased, hypercalcaemia, blood bilirubin increased PACKAGE QUANTITIES KEYTRUDA 25 mg/mL: 4 mL of concentrate in a 10 mL Type I clear glass vial. Legal Category: POM. Marketing Authorisation numbers EU/1/15/1024/002 Marketing Authorisation holder Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands. Date of revision: November 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 D18 X5K7 or from www.medicines.ie. Date of Preparation: April 2020.

11065_11080 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) Reference 1. Keytruda Summary of Product Characteristics, April 2020, available at www.medicines.ie.

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

IE-KEY-00261

Every

Both dosing options are administered as an intravenous infusion

THANK YOU

To the Hospital Pharmacists, Hospital Pharmacy Technicians, Consultants, Specialist Clinicians, Suppliers, Wholesalers and all Healthcare Workers at the frontline of the COVID-19 Pandemic

5

April/May Issue Issue 73

Contents

Foreword

Irish Doctors return home from Australia P6

Editor Leading the news for this issue, Medicines for Ireland (MFI), the Irish pharmaceutical trade association, has welcomed the co-ordinated approach agreed by European Union leaders for the procurement of medicines, medical devices and protective equipment in light of the growing number of Covid-19 cases around Europe.

Industry's contribution to finding a vaccine P8 All Ireland Breast Cancer Conference P16

“The focus by EU leaders to coordinate their public health responses better, including medicine supply, is hugely welcomed by the MFI members. As the coronavirus has no boundaries and is not restricted by boarders, it is important that not only a national, but a transnational approach is taken to ensure the continued supply of medicines and medical devices," says David Delaney, Chair of MFI. Turn to page 7 for the full story.

7

Changing landscape of Medicine Shortages P18 Hospital Pharmacists respond to COVID-19 battle P14 14

University Hospital Galway harnesses use of technology P41

Ireland is not unique in this regard. According to the HSE, medicine shortages are “happening more often worldwide”.

REGULARS

According to the 2019 Medicines Shortages Survey from the European Association of Hospital Pharmacists (EAHP), the results of which were released in early April, in 2018 almost 92 per cent of hospital pharmacists reported medicine shortages. This jumped to 95 per cent last year.

CPD: P27 18

Feature - COVID-19: P32 Feature Muchenne Dystrophy: P34

The survey found that antimicrobial agents, above other areas, frequently experience shortages. It proposed that deficits be tackled “through a mix of reactive and proactive measures."

Educational Mental Health: P38

Turn to page 16 to read the full report.

38

Clinical Profiles: P45 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.

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

All rights reserved by Hospital Professional News. All material published in Hospital Professional News is copyright and no part of this magazine may be reproduced, stored in a retrieval system of transmitted in any form without written permission.

IPN Communications Ltd have taken every care in compiling the magazine to ensure that it is correct at the time of going to press, however the publishers assume no responsibility for any effects from omissions or errors.

siobhan@hospitalprofessionalnews.ie

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

In our Special Report for this issue, Niamh Cahill take a closer look at the medicines shortage landscape. The problem of medicine shortages in Ireland is worsening. According to the Irish Pharmacy Union (IPU), pharmacists are spending up to seven hours a week trying to resolve shortfalls for patients.

MARKETING MANAGER Siobhan Buchanan-Johnston EDITORIAL editorial@hospitalprofessionalnews.ie

ACCOUNTS Rachel Wilson cs.ipn@btconnect.com CONTRIBUTORS Niamh Cahill Sarah Jane Doyle Dr Diana Hogan Murphy Marie Slevin Karen O'Connor

DESIGN DIRECTOR Ian Stoddart Design HOSPITALPROFESSIONALNEWS.IE

@HospitalProNews HospitalProfessionalNews

In other news, Dr Diana Hogan Murphy writs an exclusive article on 'Emerging evidence on use of remdesivir in COVID-19.' Remdesivir is one of several experimental agents undergoing clinical trials worldwide to evaluate its safety and efficacy in coronavirus disease 2019 (COVID-19). This investigational nucleotide analog inhibits the action of RNA polymerases and terminates RNA transcription. It has broad-spectrum antiviral activity both in vitro and in vivo in animal models against multiple viral pathogens, including Ebola, Marburg virus disease, Middle East respiratory syndrome (MERS), and severe acute respiratory syndrome (SARS). In vitro testing has demonstrated activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19.

Turn to page 32 for the full article.

We welcome all contributed clinical articles and news stories here at Hospital Professional News. Send us an email at: editorial@hospitalprofessionalnews.ie Stay Safe

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

6 News Medicines Shortages – the problem continues to grow New figures have revealed that 95% of hospital pharmacists have reported that medicines shortages are a current problem compared to 91.8% in 2018.

The news comes as the European Association of Hospital Pharmacists (EAHP) released the results of its 2019 Medicines Shortages Survey, which showed that the number of hospital pharmacists reporting shortages to be a problem in their hospital increased compared to data published by EAHP in 2014 and 2018.

COVID-19 pandemic but because it has already been persisting for over 10 years. The survey on the causes of medicines shortages, to be prepared by the European Commission in 2020, is the first step towards targeted pan-European action.

Given that medicines shortages are impacting patient care in all Member States, a strong EU commitment is very much needed to adequately address certain causes of medicines shortages.

The measures at European level should be supported by national action."

Joan Peppard, Chief II Pharmacist at Midland Regional Hospital in Tullamore, and a former President of EAHP told Hospital Professional News, "For hospital pharmacists, it is now time to act. The problem should not only be tackled since it will further increase during the

For the first time, EAHP also reached out to patients, nurses, physicians and other healthcare professionals to gather their impressions. EAHP’s data collection aimed at obtaining more information on reasons for and management of medicines

shortages as well as details on their impact on patients.

The survey was open between November 2019 and mid-January 2020 and therefore did not take into account the availability problems that are currently arising due to the COVID-19 pandemic.

More than half of the participating hospital pharmacists indicated that they had experienced shortages having an impact on patient care in their hospital. A similar response rate was observed for physicians and other healthcare professionals. Delays in care or therapy, suboptimal treatment, including inferior efficacy, and cancellation of care were most frequently communicated.

Hospital pharmacists, physicians and nurses named antimicrobial agents as the type of medicine mostly in shortages, while other healthcare professionals noticed

more frequent shortages for oncology medicines.

When comparing the percentage of hospital pharmacists disclosing that medicines shortages are a problem for delivering the best care to patients, it was observed that this figure rose between 2018 and 2019. While in 2018 91.8% of hospital pharmacists stressed that shortages are a problem in hospitals, 95% of hospital pharmacists had this impression in 2019. Feedback from the other professions differed, with 89% of healthcare professionals taking the survey agreeing that medicines shortages are a problem, while only 62% of nurses and 71% of physicians shared this view.

Turn to page 18 for our exclusive report on medicines shortages and the scale of the problem in Ireland.

Irish Doctors return to the Frontline Some 95 medics were among 170 citizens who touched down in a deserted Dublin Airport after flying home from Perth.

They packed up their lives on the other side of the world in a matter of days to answer the Government’s call to return to their homeland and help tackle the killer Coronavirus.

And they weren't able to see their families for 14 days as they selfisolated before hitting the frontline in Irish hospitals.

Pictured are a group of Doctors who recently returned from Australia to Ireland to support the team at St Vincent’s University Hospital, Dublin in the fight against COVID-19.

workers who have radically changed their plans and made big sacrifices to help us all in the fight against this pandemic. It makes a big difference.

They responded to a call out for healthcare workers at the beginning of the COVID-19 outbreak. Professor Paddy Mallon, Consultant in Infectious Diseases said, “ A huge thanks to these doctors and to all healthcare

"We continue to invite expressions of interest from healthcare workers looking for full time or part time positions – to meet the rising demand in a number of areas following the national outbreak of COVID-19."

APRIL/MAY 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

Pic Robbie Reynolds

News

7

Welcome for Medicines Procurement David Delaney, Chairperson, Medicines for Ireland, European director of policy and market access at Mylan

Pharmacy Technicians Conference 2020 Medicines for Ireland (MFI), the Irish pharmaceutical trade association, has welcomed the co-ordinated approach agreed by European Union leaders for the procurement of medicines, medical devices and protective equipment in light of the growing number of Covid-19 cases around Europe.

Commenting, chairperson of Medicines for Ireland, David Delaney said, “The focus by EU leaders to coordinate their public health responses better, including medicine supply, is hugely welcomed by the MFI members.

As the coronavirus has no boundaries and is not restricted by boarders, it is important that not only a national, but a transnational approach is taken to ensure the continued supply of medicines and medical devices. This will help ensure patient access and

The discussion around medicine supply formed part of wider emergency talks by European Union leaders via video conference, as they worked to coordinate a Europe-wide response to the coronavirus epidemic.

to address challenges arising from Covid-19. Our members are committed to working within their own companies to ensure stability of supply to all patients and are engaged directly with the Government and State agencies to ensure continuity of supply for medicines to patients in Ireland.

This remains the current twin-track focus for MFI.

Mr Delaney continued, “As the supplier of the majority of medicine in Ireland to the HSE and patients directly, we welcome the coordinated approach led by the Department of Health. MFI is continuing to work directly with the Health Products Regulatory Authority (HPRA), community pharmacists, wholesalers, the Government, the Department of Health and other key stakeholders

“It’s important to emphasise that no medicine shortages currently impacting on the Irish market are a result of Covid-19. Irish consumers should be reassured that there will be a continuity of supply of medicines and should be encouraged to talk to their pharmacists and GPs, and not to seek supplies of medicines over and above their normal requirements.”

should include joined up thinking by national Governments across Europe, European Union leaders and the EU Commission.”

The National Hospital Pharmacy Technicians Association has announced that their annual conference is now re-scheudled for Saturday 17th of October. This will go to plan depending on the current restrictions.

Registration and early bird will remain open until a later date.

Visit www.nahpt.ie for further information.

Calls for Investment of 'historic proportions' The Covid-19 crisis must lead to an investment programme in the country’s health services of “historic proportions”, according to the President of the Irish Medical Organisation (IMO).

Dr Padraig McGarry was speaking to mark the fact that the IMO’s AGM was scheduled to take place in Killarney but was postponed due to the Covid-19 crisis.

Dr McGarry said that the IMO was very conscious that at the time when IMO doctors would have been debating health service issues, the fragility of those services is being exposed as never before due to the crisis. Dr McGarry said we must never again

allow our health services to be so underfunded and understaffed.

them to do their jobs to the best of their abilities.”

“We have over 1,100 newly qualified doctors coming into our health services in the next few weeks. We welcome our new colleagues and assure them of the support of all experienced doctors to help them through what will be a particularly challenging start to their careers in medicine. These young people are the future and will be amongst the leaders of the profession in the years ahead. We owe it to them to provide them with every support and assistance we can. We know just how vital their role will be in the years ahead. Let us make sure we equip

Dr. McGarry said, “The simple fact is we have far too few doctors right across our public health services; in our hospitals, in General Practice and in our public health structures. It is not enough to thank people for their efforts, Government must actually support a proactive recruitment programme and financially support a fast track programme for additional beds and services.”

Priorities for the IMO would include: • Increasing the capacity of the public hospitals

• Investment to recruit and retain doctors to work in the health service here, including targeted measures to address our unprecedented number of Consultant vacancies.

• Investment programme for General Practice which has proven its pivotal position in the frontline of the public health response to Covid-19.

• Investing in and supporting our public health doctors and recognising their invaluable contribution to national health policy and the well-being of the nation.

HOSPITALPROFESSIONALNEWS.IE | HPN • APRIL/MAY 2020

8 News

How is Industry tackling COVID-19?

As COVID-19 spreads, biopharmaceutical innovators are at the heart of the fightback against the pandemic. The industry’s efforts are global.

In Ireland, the focus is in four main areas: 1. Ensuring the secure and continued supply of medicines to patients; 2. Securing business continuity in medicines manufacturing; 3. Helping the Government to manage the response through information-sharing; and, 4. Contributing to the search for a vaccine and a treatment.

Globally, biopharmaceutical innovators are searching for a vaccine and a treatment. A vaccine would protect people from the virus in the future. A treatment would help people who have it to get better. Usually, a vaccine takes an average of 2.5 years to develop.

But the industry is working hard to have one much sooner than that.

Vaccines save up to 3 million lives every year. They protect people from often fatal diseases such as polio, measles, diphtheria, thyphoid and rubella. They have even eradicated smallpox. We want to add COVID-19 to that list.

Scientists are investigating three main types of drugs: antivirals to stop the virus from replicating; anti-inflammatories that treat the lungs after the immune system is overwhelmed; and antibody-based treatments for seriously ill patients.

Here is a snapshot of how some companies are supporting efforts in the detection, prevention and treatment of COVID-19.  Pfizer, in partnership with BioNTech SE, is aiming to accelerate the development of BioNTech’s potential first-inclass COVID-19 mRNA vaccine programme, BNT162, which is expected to enter clinical testing by the end of April. In Italy, Pfizer pledged to make available for free medicines worth around ¤2.5 million.  GSK is donating US$10 million to the WHO and the UN Foundation’s COVID-19 Solidarity Response Fund to help prevent, detect and manage the pandemic. The company is expanding vaccines collaborations and evaluating existing medicines to determine whether any could be used beyond current indications.  Johnson & Johnson is searching

for a vaccine, making existing antivirals available for testing, collaborating with industry partners to screen a library of antiviral molecules, working with health authorities and institutions on research platforms, and providing tools and personal equipment where it can.  MSD has donated a supply of interferon beta-1a (Rebif) to the French Institut National de la Santé et de la Recherche Médicale following a request for use in a clinical trial. The company has supported China’s fight against COVID-19 with multiple donations in cash and in kind to local charities.  Novartis is providing US$20 million in grants to support public health initiatives that help communities manage the pandemic. The company is involved in collaborative research efforts, as well as making available compounds from its libraries that are suitable for in-vitro antiviral testing.  Eli Lilly has partnered with AbCellera Biologics to co-develop antibody products for the treatment and prevention of SARS-CoV-2, the virus that causes COVID-19.  AstraZeneca is donating 9 million face masks to support healthcare workers around the world as they respond to COVID-19.

The company is accelerating the development of diagnostic testing capabilities to scale up screening while research and development teams are working to identify monoclonal antibodies to progress towards clinical trial evaluation.  Bayer has partnered with other manufacturers in the COVID-19 Therapeutics Accelerator Initiative, initiated by the Bill and Melinda Gates Foundation, to find and develop effective novel compounds against the virus.  AbbVie donated US$2 million worth of Aluvia to Chinese heath authorities as an experimental option to help tackle the outbreak there. The company is working with the World Health Organisation on a coordinated global response effort.  Sanofi Pasteur, the vaccines global business unit of Sanofi, is leveraging previous development work for a SARS vaccine as part of efforts to unlock a pathway for developing a COVID-19 vaccine.

Sanofi is using its recombinant DNA platform to produce a novel COVID-19 vaccine candidate.

APRIL/MAY 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

 Roche and Genentech, part of Roche, are providing scientific expertise and research and development advice to the WHO and other stakeholders.

The company is working with Chinese health authorities and the government to help provide screening and health care, including supporting local health officials and hospitals in the Hubei Province.  Takeda is initiating the development of a plasmaderived therapy, designated TAK-888, with the potential to

treat hospitalised COVID-19 patients and to prevent infection in frontline healthcare workers.  Boehringer Ingelheim is working to develop neutralising antibodies against the SARSCoV-2 spike protein. It is investigating existing pipeline and in-market compounds, as well as compounds from former HIV and HCV research activities.

The company has a joint fasttrack call for project submissions to develop therapies and diagnostic tools initiated by the Innovative Medicines Initiative.

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 post-marketing 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 4.5% and 0.7% 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%) Grade ≥3 adverse reactions of palbociclib were

PP-IBR-IRL-0286 | Date of preparation: March 2020

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.

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 hormonereleasing hormone; m BC = m et a s t atic b re a s t c a n ce r ; SmPC = summary of product characteristics.

Last revised: 11/2019 Ref: IB 7_0

10 EAHP News Hospital Pharmacist Resources for COVID-19 The novel coronavirus is rapidly spreading across Europe.

Healthcare professionals, such as hospital pharmacists, need to be provided with up-to-date information to adequately manage the situation.

• Collaborating with other healthcare professionals in providing patient care and support

On the following pages we detail a number of resources that can be used by hospital pharmacists and other healthcare professionals. These range from information provided by specialised agencies, such as the World Health Organisation (WHO) or the European Centre for Disease Prevention and Control (ECDC), to information shared by governments and professional societies in different countries.

• Informing and counselling

Hospital pharmacies in outbreakaffected and unaffected areas play an important role in: • Ensuring adequate storage and supply of appropriate stocks of relevant medicines and other medical products and devices to supply the demand, including masks, thermometers, goggles and other necessary equipment. Ensuring these products are adequately supplied if not managed by the hospital pharmacy.

• Promoting hospital prevention and infection control

• Ensuring the responsible use of the pharmaceutical products supplied. For example, ensuring that healthcare professionals wear their masks appropriately and know how to take them off correctly to avoid contamination.

• Pharmacovigilance and monitoring treatment outcomes.

During the pandemic, in addition to community pharmacies and the COVID-19-related roles, hospital pharmacies provide an essential service to patients (both inpatients and outpatients) and health care teams through the supply of medicines and pharmaceutical care. Ensuring the continuity of these services is essential.

The European Association of Hospital Pharmacists (EAHP) is closely monitoring developments linked to the novel coronavirus (COVID-19) across its member countries. To assist its member

associations and individual hospital pharmacists in this critical time with the provision of the best possible care for patients, EAHP has decided to gather and make available information on COVID-19 relevant for the hospital pharmacy profession. The collected information has been included in EAHP’s COVID-19 Resource Centre accessible via the Association’s website.

This seeks to ensure that hospital pharmacists are provided with up-to-date information and guidance on protection measures, surveillance and treatment options for patients infected with the disease. EAHP is encouraging hospital pharmacists to submit useful resources via the following email: covid19@eahp.eu.

Just recently, the European Association of Hospital Pharmacists together with other European health professionals and their students’ organisations issued a Joint Statement calling on the European Commission and the governments to support and protect healthcare professionals fighting COVID-19.

As Europe has become the global centre of the COVID-19 pandemic,

healthcare professionals are working hard to contain the spread of the virus, putting themselves at risk to protect the communities.

Despite the unprecedented efforts to stop the pandemic, healthcare professionals are at the front line without adequate personal protective equipment (PPE).

The number of infections and deaths of the healthcare staff is increasing every day. Even in times of crisis, adequate working conditions must be ensured. Staff must have breaks and time off between shifts, to be able to carry on in what could be a long-term global crisis. The working time Directive should apply. Working in such conditions takes its toll on the psychological health of staff, so appropriate support services must also be put in place.

European healthcare professional organisations call on the European Commission to open a permanent line of communication with European health professionals to share experience and best practices across Europe and to ensure that the European Commission’s support measures focus on operational priorities on the ground.

Beaumont key staff Pin Photos to PPE Beaumont medics print pics to wear on front of PPE to lift patients’ spirits amid Covid-19

“The initial feedback from patients, seeing a face, was really positive.

You could see the light in their eyes and it lifted their spirits, without a doubt.”

Dr. Clíona Ní Cheallaigh, consultant in general medicine and infectious diseases at St James's Hospital in Dublin said Irish hospitals are in a "fantastic" position, but social distancing measures must continue.

Hospital Consultants at Dublin's Beaumont Hospital have stuck their pictures to the front of their personal protective equipment to help patients feel at ease amid the Covid-19 outbreak.

picture taped onto the front of their PPE, as well as their name written on their gowns in marker.

They said their move to adapt PPE has been lifting patients' spirits.

“We have been wearing PPE for a number of days now, but it obviously meant that our patients couldn't see our faces behind our masks.

Beaumont Doctor Laura Durcan posted a picture showing six healthcare workers with their

Dr Ross Morgan says, “We want to provide the best possible environment for our patients.

“So yesterday I took a photo on my phone, printed it out and we stuck it on.

APRIL/MAY 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

“I was on a call yesterday with all the infectious diseases consultants from across Ireland and one after the other, as each person reported from their hospitals they were saying they hadn't seen the surge they expected, that the measures are working.

“It's just a fantastic position to be in. I think we had been very scared that we would be completely overwhelmed and that hasn't happened yet.”

EAHP News 11 PREVENTION IS KEY FOR CANCER PATIENTS Patients with a cancer diagnosis should closely follow official advice on coronavirus (COVID-19) to reduce their chances of infection in the coming weeks and months according to a leading medical oncologist.

The oncology community across the country has come together to prepare for an expected increase in coronavirus cases in Ireland said Cork University Hospital medical oncologist, Professor Roisin Connolly.

However, experts still do not know for certain how coronavirus will affect patients who may have a weaker immune system due to cancer or cancer treatment.

“From an oncology perspective this is very, very new for everyone. It is becoming clear from recent international experience that we need to consider that certain patients with cancer may be more at risk from this virus than the general population,” Prof Connolly, who is also the Professor Gerald O’Sullivan Chair in Cancer Research at UCC. “One of the other messages we’re getting across is that people should be calling their GP or oncology or radiology department if they’re feeling unwell.”

“What we don’t want is people arriving unwell as this may increase spread of the virus if that person has it. Hospitals can minimise spread of the virus to other patients and healthcare staff when they are given advanced notice.”

Cancer treatments for some patients may need to be postponed as hospitals come under strain in the weeks ahead, but Professor Connolly says patient safety is always the number one factor when weighing up what will be done.

“Every patient is different and the pros and cons of treatment may need to be considered in each case. We want to consider what is safest for each individual patient depending on what is happening at the hospitals in the coming weeks.”

Ireland issues general surgery guidance on COVID-19 This updated guidance is subject to further amendment in the light of new national recommendations in relation to PPE and aerosolgenerating procedures, says the RCSI who issued it.

It should be noted that current advice from Public Health England in relation to positive flow ventilation in theatres should be followed and the previous text related to this issue has been removed.

Surgeons will continue to care for patients in the current crisis, especially emergencies. Patient care will be affected if staff become sick and leave work. These recommendations update recent guidance for general surgery now further information has emerged from government, Italy and China.

Consider COVID-19 infection possible in every patient. We must follow guidelines and also apply common sense to at risk clinical environments.

It will be reviewed as regularly as possible but there will remain a great deal of uncertainty regarding the pandemic and you should update yourself from government and hospital resources also.

1. Acute patients are our priority.

COVID-19 should be sought in any patient needing emergency surgery: use history, COVID-19 testing, recent CT chest (last 24h) or failing

that CXR. Any patient undergoing abdominal CT scan should also have CT chest. Current tests for COVID-19 may be false negative.

2. Any patient currently prioritised to undergo urgent planned surgery must be assessed for COVID-19 as above and the current greater risks of adverse outcomes factored into planning and consent. Consider stoma formation rather than anastomosis to reduce need for unplanned post-operative critical care for complications.

3. All theatre staff should use PPE during all operations under general anaesthetic whether by laparoscopy or laparotomy and infection control practices should be followed, as determined by local and national protocol.

4. Laparoscopy is considered to carry some risks of aerosoltype formation and infection and considerable caution is advised.

The level of risk has not been clearly defined and it is likely that the level of PPE deployed may be important. Advocated safety mechanisms (filters, traps, careful deflating) are difficult to implement. Consider laparoscopy only in selected individual cases where clinical benefit to the patient substantially exceeds the risk of potential viral transmission in that particular situation.

Where non-operative management is possible (such as for

early appendicitis and acute cholecystitis) this should be implemented. Appropriate non-operative treatment of appendicitis and open appendicectomy offer alternatives.

5. In theatre: Minimum number of staff in theatre Appropriate PPE for all staff in theatre depending on role and risk Smoke evacuation for diathermy/ other energy sources Team changes will be needed for prolonged procedures in full PPE Higher risk patients are intubated and extubated in theatre – staff immediately present should be at a minimum.

6. Only emergency endoscopic procedures should be performed.

No diagnostic work to be done and BSG guidance followed. Upper GI procedures are high risk AGPs and full PPE must be used.

7. Consider the diagnosis and risk of COVID-19 in other situations in Emergency General Surgery settings and act accordingly.

Presentations with intestinal symptoms occur and COVID-19 may present initially as an apparent post-operative complication. Nasogastric tube placement may be an aerosol generating procedure (AGP). AGPSs are high risk and full PPE is needed. Consider carrying out in a specified location.

Students join Frontline Effort More than two dozen medical students have been drafted in to work alongside frontline healthcare workers in Beaumont and Connolly hospitals as the numbers of cases of Covid-19 continues to rise.

Students from the Royal College of Surgeons of Ireland University of Medicine and Health Sciences have been trained in prone positioning - turning intubated

patients to lie on their front to make breathing overnight easier – with 26 young people working in the ICUs of the two hospitals in recent weeks.

Recently Beaumont hospital had the largest number of Covid-19 cases followed by St James’ and the Mater hospitals. Dublin has the highest number of coronavirus cases in the State with 5,006

confirmed cases in the capital as of midnight on Saturday, April 11th.

There are now 10,647 known coronavirus cases in the State, and 365 people have died from the virus.

Gordon Treacy, a second year graduate medicine student, was posted to Connolly hospital as a team lead after responding to a callout from RCSI’s head of medicine for volunteers. “It wasn’t an easy decision to volunteer because you’re putting yourself at an increased risk but there was no doubt in my mind that it was the right thing to do.”

RCSI students volunteering in Beaumont ICU during Covid-19 pandemic. From left: Patrick Kennelly, Sarah Kelly, Adam Lynch, Aliya Hiridjee, Brian Fox and Evelyn Flynn. Photograph: Sarah Kelly

HOSPITALPROFESSIONALNEWS.IE | HPN • APRIL/MAY 2020

12 EAHP News

Irish Hospitals set up Heroes Appeal

A group of Hospitals from across Ireland have joined forces at this time of great uncertainty for our country andare asking the public to support Our Hospital Heroes and to thank them for the amazing job that they are doing for the country.

conditions such as cancer and heart disease who also need to be cared for in these difficult times for everyone.

Over the coming weeks and months they will treat large numbers of Covid-19 patients.

Many of them may contract Covid-19 and become ill themselves as they care for patients.

Hospital, St James's Hospital,

They need the public to donate to ‘Our Hospital Heroes’ so that they can give them what they need to care for Covid-19 patients and other patients with life threatening

University Hospital, Waterford

The hospitals benefiting from this appeal are: The Mater Misericordiae University Beaumont Hospital, Tallaght Hospital, Connolly Hospital Blanchardstown, St Vincent's University Hospital, Mercy University Hospital Cork, Cork University Hospital, Limerick University Hospital, Cavan General Hospital.

Funds raised will also help to support the hospitals and enable them to provide essential comforts to staff as they work on the frontline and also to help the hospitals to invest in the things that they will need to meet the needs of their patients in the future.

“It’s time to think with our heads as well as our hearts and to unite as one in the fight against Covid-19.

Every little will help!” They state. https://www.ourhospitalheroes.ie/

Accord launch Hi-Tech Medicine

Accord Healthcare is delighted to announce the launch of another Hi-Tech medicine to their extensive range of Hi Tech medicines, Cinacalcet Accord 30 mg, 60 mg and 90 mg film-coated tablets in pack size of 28.

This medicine is indicated for the treatment of secondary

hyperparathyroidism (HPT) in adult patients with endstage renal disease (ESRD) on maintenance dialysis therapy.

Cinacalcet Accord may be used as part of a therapeutic regimen including phosphate binders and/or Vitamin D sterols, as appropriate. It is also indicated for the reduction of hypercalcaemia

APRIL/MAY 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

in adult patients with parathyroid carcinoma or primary HPT for whom parathyroidectomy would be indicated based on serum calcium levels, but is not clinically appropriate or is contraindicated.

Please refer to the Summary of Product Characteristics (SPC) for further information. The SPC will

be available from the launch date at www.hpra.ie and for Healthcare Professionals at www.accord-healthcare.ie.

For further information please contact Accord in Cork on 021-461 9040 or visit www.accord-healthcare.ie

Fresenius Kabi FFresenius resenius KKabi a b i your partner partner in the the Fresenius Kabi your in y o u r p artner iCOVID-19 fight against COVID-19 n t h D-19 against e your partner in the fight against COVID-19 fight against COVID-19

Further Further information information is is available availableupon uponrequest request Prescription Only Medicine Prescription Only Medicine Fresenius Kabi of of preparation: April 2020 Date of preparation: 2020 Date FreseniusApril KabiIreland Ireland Date preparation: April 2020 Unit Park Job code: IV/ONCO/004/2020 Job code: IV/ONCO/004/2020 Unit3B, 3B,Fingal FingalBay BayBusiness Business Park Job code: IV/ONCO/004/2020 Balbriggan, Ireland Balbriggan,Co. Co.Dublin, Dublin,K32 K32X065, X065, Ireland Phone: Phone:+353 +353(0) (0)1 841 1 8413030 3030 Email: Email:FK-enquiries.Ireland@fresenius-kabi.com FK-enquiries.Ireland@fresenius-kabi.com www.fresenius-kabi.com/ie www.fresenius-kabi.com/ie

14 News

Keeping Pharmacy Spirits up during Covid

Aseptic St James pic - The team from the Pharmacy Aseptic Unit at St James Hospital

Pharmacy Department across Ireland have been working under immense pressure during the COVID-19 pandemic, alongside allied key frontline workers.

University Hospital Limerick caption: The Pharmacy Department team members from the University Hospital Limerick

However what they are all demonstrating are examples of rallying around each other in ways never seen before as the battle against coronavirus continues.

Many hospital workers are off due to self-isolation or being unwell and thus the health service is facing increasing pressures.

However, keen to keep a smile on their faces, they have been finding

Tallaght caption for both pics: The pharmacy team at Tallaght Hospital practising safe distancing and enjoying homemade treats from visiting patients in appreciation of their work and efforts ways to maintain team spirit with a smile on their faces whilst also enjoying gifts of appreciation from patients and community workers.

for themselves and their family members, they are showing a dedicated team spirit during this highly challenging time.

It has been reported to Hospital Professional News that whilst many staff are anxious and worried

Pictured here are some of those captured making the absolute best of the situation.

Irish Virologist refutes Testing myths The polymerase chain reaction (PCR) swab test used to detect the novel Coronavirus can effectively detect the virus for at least 10 days after a swab is taken, Dr Cillian De Gascun, Consultant Virologist and Director of the National Virus Reference Laboratory (NVRL) has told Hospital Professional News.

Commenting on the falsehood that Covid-19 samples have a short shelf life and expire quickly, Dr De Gascun said he was unsure where the untruth had arisen.

“I’ve seen people tweeting, to my mind irresponsibly that, if it’s not tested in 72 hours, then it’s not valid. That’s completely inaccurate…and it’s coming from professional people who should know better,” Dr De Gascun said.

“We have a good seven to 10 days from the time the sample is taken for the sample to be tested.

I say seven to 10 days because we have evidence up to that point.

It is quite possible that they last longer but we don’t necessarily have the evidence for that.

“We don’t want to grow this virus – all we need is for the RNA [ribonucleic acid] to be present and detectable. Does the RNA deteriorate over time? Yes, we know that happens but it certainly doesn’t happen to any significant degree.

“There’s huge amounts of virus present, that’s why the RNA is detectable for a long time.”

Commenting on myths surrounding testing, Dr De Gascun said to date there had been no significant issue with expired Covid-19 swabs.

“People will say the swabs are expiring and the next day they’ll say the virus lives on surfaces for

APRIL/MAY 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

a week. You can’t have it both ways. Either the virus is robust, which we believe it is, and what people don’t appreciate is that we don’t need the virus to be alive for 10 days, we just need the RNA to be detectable for 10 days. In our experience to date is, we’ve had no significant issue with expired swabs or swabs that have not been suitable for testing. I am not sure where that story has arisen.”

Around 100 patients tested for Covid-19 were wrongly told they had tested negative for the virus, the HSE recently admitted. Anecdotally, there have been unconfirmed reports of patient samples being mixed up and/or lost.

He admitted there had been delays for some patients in receiving test results and expressed sympathy for those awaiting results. There are anecdotal reports of patients waiting up to three weeks for results.

“We need to have a very streamlined and efficient, real time testing and contact system, those two things go hand in hand. We want to see the numbers come down. For the numbers we do have, we want to be able to test them in real time and contact trace in real time.”

“I am sympathetic to people waiting on results. That is not a nice situation to be in and it is something we want to address,” said Dr De Gascun.

Dr De Gascun said that efforts to “streamline” the entire testing process were now underway to help reduce waiting times.

16 News

Touchpoint Meeting on Breast Cancer Professor Janice Walshe, Consultant Medical Oncologist in St Vincent's University Hospital and Tallaght University Hospital; Professor Ann O'Doherty, Consultant Radiologist as St. Vincent's University Hospital

Dr Patrick Morris, Beaumont Hospital, Dublin

The 2020 All Ireland Conference on the Clinical Management of Breast Cancer took place in Barberstown Castle on Friday 28th and Saturday 29th February and was the largest to date with over 130 delegates in attendance over the two days.

Attendees were from the faculties of pathology, oncology, radiation oncology, radiology and surgery.

This meeting marked the 11th national breast meeting of its kind.

The event provides healthcare professionals an opportunity to collaborate on several key issues related to the area of breast cancer in Ireland.

The meeting agenda included several national experts including Ms Liz Connolly, Consultant Breast Surgeon, St James’s Hospital, Dr Lillian Smyth, Consultant Medical Oncologist, St Vincent’s University Hospital, Professor Maccon Keane, Consultant Medical Oncologist, Galway University Hospital, Professor Roisin Connolly, Consultant Medical Oncologist, Cork University Hospital and Dr Mark Knox, Consultant Radiologist, St James’s Hospital, Dublin.

The conference attendees were also honoured to hear presentations from a number of international experts including Dr Neelima Denduluri, Associate Chair, US Oncology Breast Committee and Past Chair of ASCO Guideline Committee, Dr Karen Cadoo, Consultant

Medical Oncologist, MSKCC, New York, Professor Emiel Rutgers, Surgical Oncologist, Netherlands Cancer Institute, Amsterdam, Dr Elena Provenzano, Lead Breast Histopathologist, Addenbrooke’s Hospital, Cambridge and Dr Lisa Carey, Richardson and Marilyn Jacobs Preyer Distinguished Professor in Breast Cancer Research, University of North Carolina.

Professor Janice Walshe, Consultant Medical Oncologist, St Vincent’s University Hospital and Chair of the All Ireland Breast Cancer Meeting stated, “The All Ireland Conference on the Clinical Management of Breast Cancer has grown from strength to strength in the last 24 years and we are delighted to see this year’s meeting achieved record attendance. This meeting acts as an important touchpoint for healthcare professionals working in disciplines related to breast cancer and offers them the opportunity to share information, results and future areas of research which may have an impact on how we move forward as a discipline. We look forward to the continued growth and evolvement of the meeting in the years to come.”

The 2020 meeting was sponsored

by Roche Products (Ireland) Limited, Novartis, MSD, Pfizer, Exact Sciences and Astra Zeneca / Daiichi Sankyo.

Pics: Damien Eagers

Dr Deirdre O'Mahony, Bon Secours Hospital, Cork, Dr Neelima Denduluri, US Oncology Breast Committee, Professor Janice Walshe, St Vincent's University Hospital

APRIL/MAY 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

Professor Cecily Quinn, St Vincent's University Hospital, Dr Elena Provenzano, Addenbrooke's Hospital, Cambridge

Dr Neelima Denduluri, US Oncology Breast Committee

Bayer is a Life Sciences company with a presence in Ireland for over

50 years.

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18 Report

Pharmacy Landscape of Medicine Shortages during COVID-19 The IPU publishes a list of medicine shortages in Ireland every month. The April list details over 300 products usually available via the GMS where supply issues have arisen.

Separately, the Health Products Regulatory Authority (HPRA) highlights out of stock human medicines and documents when supply concerns have been resolved.

Before the outbreak of Covid-19, pharmacists and doctors reported that the problem of medicine shortages in Ireland was worsening. Now that SARS CoV-2 is here to stay (at least until a vaccine is found), will medicine shortages deteriorate further?

The problem of medicine shortages in Ireland is worsening.

According to the Irish Pharmacy Union (IPU), pharmacists are spending up to seven hours a week trying to resolve shortfalls for patients.

Ireland is not unique in this regard.

According to the HSE, medicine shortages are “happening more often worldwide”.

A recent European report added weight to the Irish experience, with 95 per cent of hospital pharmacists in 2019 reporting that medicines shortages are a “current problem”.

In 2016 the World Health Organisation reported: “Shortages of essential drugs are becoming increasingly frequent globally, burdening health systems with additional costs and posing risks to the health of patients who fail to receive the medicines they need.”

They added: “Medicines shortages pose risks for patient health as a result of non-treatment, undertreatment and possible medication errors from attempts to substitute missing medicines.”

The Authority is responsible for coordinating the management of shortages of medicines on the Irish market and works with manufacturers, wholesale distributors, marketing authorisation holders, healthcare professionals, the HSE, patients and representative groups to respond to potential drug shortages and reduce their impact on patients.

In 2018, it launched the “Medicine Shortages Framework” as part of these efforts.

The framework states: “Medicine shortages are recognised as a global problem by the World Health Organisation. Whilst medicine shortages have been a global issue for some time, they have increasingly affected Ireland and other European countries with significant impact on patient care and total healthcare costs”.

Both the IPU and HPRA medicine shortage notices illustrate the ongoing challenges faced here.

Unexpected increases in demand, manufacturing delays, product recalls and quality issues are some of the factors that result in supply chain issues.

When a drug is unavailable, pharmacists are forced to seek an alternative drug for the patient, or in some cases, to provide a product not licensed for a patient’s particular condition, but which has shown to be effective. On occasion, however, there is no substitute available.

EU According to the 2019 Medicines Shortages Survey from the European Association of Hospital Pharmacists (EAHP), the results of which were released in early April, in 2018 almost 92 per cent of hospital pharmacists reported medicine shortages. This jumped to 95 per cent last year.

The survey found that antimicrobial agents, above other areas, frequently experience shortages. It proposed that deficits be tackled “through a mix of reactive and proactive measures”.

“Hospital pharmacists, physicians and nurses named antimicrobial agents as the type of medicine mostly in shortages, while other healthcare professionals noticed more frequent shortages for oncology medicines”, the results showed.

The survey also gathered the views of healthcare professionals on the reasons for medicine shortages.

Among the highest ranked problems noted by hospital pharmacists surveyed was the global shortage of an active pharmaceutical ingredient, as well as manufacturing and supply chain problems.

“Physicians included the pricing of a medicine, supply chain problems and issues related to parallel export as the leading reasons for medicines shortages,” the report outlined.

Dr Nuala O'Connor, ICGP GP Lead HSE Antimicrobial Resistance and Infection Control Team

APRIL/MAY 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

19 “Several patients that participated in the data collection activity stressed their dissatisfaction with how their problem was handled since they desired the provision of more detailed reasons behind not receiving the prescribed treatment.”

effects and to make sure that co-amoxiclav remains available for those who need it”.

The Association believes that “only a comprehensive communication strategy on shortages targeting all European states will ensure that all supply chain actors, including hospital pharmacists, receive adequate information on the shortage of medicines in their country”.

By mid-April, sufficient supplies of the product had resumed. A spokesperson for the HPRA said: “It is expected that sufficient stocks of co-amoxiclav medicines will continue to be available to enable patients to be treated in line with antimicrobial prescribing guidelines”.

According to results from the Pharmaceutical Group of the European Union (PGEU) Medicine Shortages Survey 2019, the time pharmacy staff spends dealing with shortages has jumped from 5,6 hours per week (2018) to 6,6 hours per week on average.

Separately, frusemide/amilorise has been unavailable in Ireland recently. According to the IPU, “it will be back in stock shortly”.

Responding to the survey, released in February, Darragh O’Loughlin, General Secretary of the IPU, said the results shows the problem is getting worse.

“In Ireland, we have experienced significant shortages of medicines in the last year and the situation continues to get worse. Patients can sometimes wait for weeks to get a new supply of a common drug. Not only is this putting their health at risk but it is causing undue stress, fear and anxiety for patients. Instead of directing their efforts and professional expertise towards the needs of patients, pharmacists are spending nearly seven hours a week resolving medicines shortages and firefighting on behalf of our patients.”

Professor Michael Barry, National Clinical Lead, HSE Medicines Management Programme

A HPRA spokesperson said: “In relation to the combination of furosemide and amiloride, there are no supply issues in relation to Frumil 40mg / 5mg Tablets which are available to order in the normal manner. There has been a temporary shortage of Frumil Low Strength 20mg / 2.5mg Tablets (which was not related to COVID-19) but supply of that strength is expected to resume shortly.”

Covid-19 The recent survey from the EAHP was open between November 2019 and mid-January 2020 and therefore did not take into account the “availability problems that are currently arising due to the COVID-19 pandemic”.

Shortages

The outbreak has generated concern among countries about the future availability of medicines and agencies globally are stepping up efforts to mitigate the risks posed by the pandemic.

On 20 March the HSE wrote to all GPs, community pharmacists and community nursing units advising of “critically low stock levels” of co-amoxiclav 625mg tablets.

There have been warnings in the US that the coronavirus outbreak will lead to even greater drug shortages there, especially antibiotics.

“In the context of preparedness work for the COVID-19 National Public Health Emergency we have identified that stocks of co-amoxiclav 625mg tablets are critically low,” Prof Martin Cormican, HSE National Clinical Lead for HCAI/AMR (Healthcare Associated Infections/ Antimicrobial Resistance) and Dr Nuala O’Connor, ICGP GP Lead HSE Antimicrobial Resistance and Infection Control Team, advised.

According to the European Medicines Agency (EMA), EU authorities recently agreed measures to support the availability of medicines during the pandemic.

The letter went on to state the specific indications the drug should be reserved for and suggested alternative medications to help “protect patients from avoidable antibiotic related side-

“These include medicines used in intensive care units such as certain anaesthetics, antibiotics and muscle relaxants as well as medicines used off-label for COVID-19. EU authorities

In a statement, the agency said some countries in the EU had already begun to see shortages of some medications used for patients with the virus, or were anticipating shortages soon.

are therefore putting in place additional measures to mitigate the impact of the pandemic on the supply chain of medicines in a coordinated manner.

“The number of shortages of medicines has increased in the past few years and the issue is aggravated in this pandemic by many different factors, e.g. lockdown in factories due to quarantine, logistical issues caused by border closures, export bans, lockdowns in third countries [countries outside the EU and EEA] supplying medicines to the EU, increased demand due to the treatment of COVID-19 patients, stockpiling in certain hospitals, but also individual stockpiling by citizens as well as at Member State level. To avoid shortages due to stockpiling, some member states have imposed restrictions on the number of packs that can be prescribed to patients or purchased by citizens.”

Because of this, the EMA is establishing an industry single point of contact system to help fast track the communication of medicine shortages. An EU Executive Steering Group on Shortages of Medicines Caused by Major Events has also been set up.

The system will allow pharmaceutical companies to report directly to the EMA anticipated shortages or current shortages of critical medicines required for patients with COVID-19.

Furthermore, the EMA advised “mitigation measures are currently under consideration, such as regulatory actions to support increased manufacturing capacities, e.g. through speeding up the approval of a new manufactu ring line or site.

Discussions are also ongoing with the pharmaceutical industry to increase production capacity for

all medicines used in the context of COVID-19, and in particular for medicines potentially at risk of supply shortages”.

The EU Executive Steering Group is considering areas where regulatory rules could be applied with “greater flexibility” during the pandemic to secure supply.

In Ireland, authorities here have pointed out that to date there is no threat to the supply of medicines due to the outbreak and that measures are being put in place in the event shortages arise.

The HPRA is a member of the National Public Health Emergency Team (NPHET), which is coordinating the management of, and response to Covid-19 (SARSCoV-2) in Ireland.

“There is no evidence to suggest that Ireland is likely to face general medicines supply issues, now or in the near future, as a result of any potential delays in the supply chain caused by COVID-19 related issues,” according to a HPRA spokesperson.

“Ireland is unlikely to face general medicine supply issues, and is well placed to deal with these as they arise. However, this is very much based on normal use of medicines.”

The IPU has said there has been no direct impact on general medicines availability as a result of Covid-19, but, like the HPRA, cautioned the public against stockpiling medicines.

“Throughout the ongoing Covid-19 situation, the IPU has issued several calls urging the public not to stockpile medicines. Covid-19 has not caused any supply shortages and there are additional stocks of medicines routinely built into the medicine supply chain; stockpiling is completely

HOSPITALPROFESSIONALNEWS.IE | HPN • APRIL/MAY 2020

20 Report Dr Ray Walley, Dublin GP

“Since the Covid-19 situation it has got a bit better in my experience, strangely enough.”

The IPU is gravely concerned about the increase in medicine shortages here in recent years, according to its spokesperson.

“Even before the current pandemic, we consistently heard from pharmacists that the problem of medicine shortages was worsening.

unnecessary and, in fact, could itself hamper the availability of medicines for other patients.”

The Department of Health said medicines shortages inevitably arise from time to time and are “a feature of health systems around the world”.

Authorities remain vigilant to supply issues and Ireland will “continue to work with authorities at a European and International level to closely monitor the situation and ensure that all appropriate steps are taken to facilitate continuity of care and treatment”, a spokesperson confirmed.

“Work is also ongoing to ensure that there are additional supplies of medicines used in the treatment and care of Covid-19 patients.

“The potential future shortage of any specific medicine will be managed through the existing Medicine Shortages Framework to prevent the shortage from occurring where possible or, where it does occur, to manage the impact in terms of identifying alternative treatments.”

Hydroxychloroquine

to consider alternatives when prescribing the drug for patients in the community with rheumatoid and lupus conditions.

“Hydroxychloroquine has an important role in the on-going management of rheumatoid and lupus conditions of many individuals. Stocks of this medicine are being managed to ensure these individuals will continue to have access to their regular medication in the normal manner. This management is premised on the recommendations of the national guideline that hydroxychloroquine will only be prescribed for COVID-19 positive in-patients by a hospital clinician on a hospital prescription only.

“I would ask you in this COVID-19 Public Health Emergency that you would carefully consider alternative therapies before initiating new patients on longterm hydroxychloroquine for rheumatoid and lupus conditions to support continuity of supply, where such alternatives are available,” he wrote.

On 14 April, further guidance was issued by the HSE to GPs and pharmacists regarding the antibiotic azithromycin.

On 30 March Professor Michael Barry, National Clinical Lead, HSE Medicines Management Programme wrote to pharmacy contractors regarding the “conservation” of the drug Hydroxychloroquine.

It advised that prescriptions for azithromycin should not be offered in the community for the management of patients with COVID-19 in the home.

The medication is used for the treatment of rheumatoid and lupus conditions, but has been shown to have “some antiviral activity” against Covid-19.

According to Tomas Conefrey, Community Pharmacist, medicine shortages are a “big problem in Ireland”.

Because of efforts to preserve stock of the medication for hospital patients with the virus, Mr Barry asked prescribers

However, following the outbreak of Covid-19 here, in his view they have alleviated somewhat since the pandemic.

Ireland

APRIL/MAY 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

“Pharmacists will always make every effort to ensure that their patients receive the medicines they need, including sourcing medicines from abroad when not available in Ireland. Nevertheless, pharmacists report that the amount of time they spend on trying to resolve shortages has increased hugely, amounting to several hours per day, and that, despite their efforts, it frequently impacts on their patients.

“Obviously, it can be very distressing for patients when supply problems arise, but it is important to know that Irish community pharmacists are doing all they can to support patients directly in their own communities.”

Dublin GP and former president of the Irish Medical Organisation (IMO) Dr Ray Walley is increasingly concerned by the growth in the number of medicines in short supply here.

He believes more should be done to raise awareness of and tackle the issue. He also maintains that shortages are a serious threat to patient safety.

The current frusemide/amilorise has impacted “a significant number of patients”, he said, and has, worryingly, not yet been resolved.

Dr Walley is First Vice President of the Standing Committee of European Doctors. On 3 April 2020, the CPME Executive Committee adopted the “CPME Policy on Medicine Shortages.”

The policy states that “medicine shortages are a growing public health threat with a serious impact on health care systems and public health. They can severely limit doctors’ ability to provide appropriate treatment. Medicine shortages have an unquestionable impact on public health.”

It outlines several ways in which shortages can be addressed at EU level, including improved communication, identifying the root causes, strengthened cooperation, increasing diversification of supply sources and reducing Europe’s reliance on external manufacturing.

It claims that “the current overreliance on manufacturing sites located in third and remote countries for the production of active pharmaceutical ingredients and medicines constitutes a real threat to the secure and stable supply in the EU”.

“Currently, the majority of Active Pharmaceutical Ingredients (API) and medicines are produced outside of Europe in limited number of manufacturing sites.

Distant location of factories makes it more difficult to inspect them and results in longer, less transparent and fragile supply chains . Unforeseen disruptions or quality and production problems have far-reaching consequences.”

The EU should explore “regulatory measures or financial incentives to shift the production of essential medicines back to Europe,” the policy adds.

The HPRA medicine shortage list, updated on 7 April, shows, to give just one example, that manufacturing delays have led to a deficit of a number of products with the active ingredient fentanyl, an opioid used in the treatment of severe pain.

The shortage was notified on 22 January this year and an expected product return date is still awaited.

In another example, the HPRA website states that “HRT shortages have impacted multiple countries over the past year and are not restricted to Ireland. While there are shortages of some specific brands, alternatives are available to meet patient need.

The suppliers have stated that the causes of the shortages relate to both active substance availability and manufacturing delays”.

The examples clearly illustrate that supply disruptions are having a direct impact on the health of Irish patients.

But could Covid-19 turn the tide on medicine shortages? The pandemic has succeeded in bringing the issue of medicine shortages to the fore, both here and internationally.

In light of the grave threat posed to public health, the critical importance of adequate medicine stock is now foremost in the minds of governments as they seek to protect their citizens.

As efforts continue to ensure critical medications needed in the response to Covid-19 are available, there is hope, therefore, the crisis will mobilise authorities to finally do more to dramatically reduce ongoing shortages.

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Ultibro® Breezhaler® ABBREVIATED PRESCRIBING INFORMATION Please refer to Summary of Product Characteristics (SmPC) before prescribing Presentation: Ultibro Breezhaler 85mcg / 43mcg inhalation powder hard capsules containing indacaterol maleate and glycopyrronium bromide respectively and separate Ultibro Breezhaler inhaler. Indications: A maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). Dosage and administration: Recommended dose is the inhalation of the content of one capsule once daily, administered at the same time of the day each day, using the Ultibro Breezhaler inhaler. Capsules must not be swallowed. No dose adjustment required in elderly patients, for patients with mild and moderate hepatic impairment or for patients with mild to moderate renal impairment. No data available for use in patients with severe hepatic impairment and should only be used in patients with severe renal impairment or end-stage renal disease requiring dialysis if the expected benefit outweighs the potential risk. No relevant use in the paediatric population. Contraindications: Hypersensitivity to the active substances or to any of the excipients. Warnings/Precautions: Not to be administered concomitantly with medicinal products containing other LABA’s or LAMA’s. Asthma: ♦ULTIBRO BREEZHALER SHOULD NOT BE USED FOR TREATMENT OF ASTHMA. Acute use: ♦Not indicated for treatment of acute episodes of bronchospasm.

Hypersensitivity: ♦Immediate hypersensitivity reactions have been reported after administration of indacaterol or glycopyrronium. If signs suggesting allergic reactions occur (in particular, angioedema, difficulties in breathing or swallowing, swelling of the tongue, lips and face, urticaria or skin rash), treatment should be discontinued immediately and alternative therapy instituted. Paradoxical bronchospasm: ♦If paradoxical bronchospasm occurs, Ultibro Breezhaler should be discontinued immediately and alternative therapy instituted. Anticholinergic effects related to glycopyrronium: ♦To be used with caution in patients with narrowangle glaucoma and in patients with urinary retention. Patients with severe renal impairment: ♦Should only be used in patients with severe renal impairment, including those with end-stage renal disease requiring dialysis, if the expected benefit outweighs the potential risk. These patients should be monitored closely for potential adverse reactions. Cardiovascular effects: ♦To be used with caution in patients with cardiovascular disorders (coronary artery disease, acute myocardial infarction, cardiac arrhythmias, hypertension), in patients with known or suspected prolongation of the QT interval or patients treated with medicinal products affecting the QT interval and in patients with unstable ischaemic heart disease, left ventricular failure, history of myocardial infarction, arrhythmia (excluding chronic stable atrial fibrillation), a history of long QT syndrome or whose QTc (Fridericia method) was prolonged. ♦LABA’s may produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, blood pressure, and/or symptoms, ECG changes. In case such effects occur, treatment may need to be discontinued. Hypokalaemia: ♦LABA’s may produce significant hypokalaemia in some patients, which has the potential to produce cardiovascular effects.

In patients with severe COPD, hypokalaemia may be potentiated by hypoxia and concomitant treatment which may increase the susceptibility to cardiac arrhythmias. Hyperglycaemia: ♦Inhalation of high doses of LABA’s may produce increases in plasma glucose. Upon initiation of treatment with Ultibro Breezhaler plasma glucose should be monitored more closely in diabetic patients therefore caution and appropriate monitoring are advised in such patients. ♦Ultibro Breezhaler has not been investigated in patients for

Date of Preparation: January 2020 IE02/ULT19-CNF027a

whom diabetes mellitus is not well controlled. General disorders: ♦To be used with caution in patients with convulsive disorders or thyrotoxicosis, and in patients who are unusually responsive to LABA’s. Excipients: ♦This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine. Pregnancy and Lactation: ♦Ultibro Breezhaler should only be used during pregnancy if the expected benefit to the patient justifies the potential risk to the foetus. ♦Not known whether indacaterol, glycopyrronium and their metabolites are excreted in human milk. Use of Ultibro Breezhaler by breast-feeding women should only be considered if the expected benefit to the woman is greater than any possible risk to the infant. Interactions: ♦Concomitant use is not recommended with beta-adrenergic blockers, anticholinergics or sympathomimetics. ♦Concomitant hypokalaemic treatment with methylxanthine derivatives, steroids, or non-potassium-sparing diuretics may potentiate the possible hypokalaemic effect of beta2-adrenergic agonists, therefore use with caution. ♦Inhibition of the key contributors of indacaterol clearance, CYP3A4 and P-gp, does not raise any safety concerns given the safety experience of treatment with indacaterol. ♦No clinically relevant drug interaction is expected when glycopyrronium is co-administered with cimetidine or other inhibitors of the organic cation transport. Adverse reactions: ♦Very common: upper respiratory tract infection. ♦Common: nasopharyngitis, urinary tract infection, sinusitis, rhinitis, hypersensitivity, hyperglycaemia and diabetes mellitus, dizziness, headache, cough, oropharyngeal pain including throat irritation, dyspepsia, dental caries, bladder obstruction and urinary retention, pyrexia, chest pain. ♦Uncommon: angioedema, insomnia, glaucoma, ischaemic heart disease, atrial fibrillation, tachycardia, palpitations, paradoxical bronchospasm, dysphonia, epistaxis, gastroenteritis, dry mouth, pruritus / rash, musculoskeletal pain, muscle spasm, myalgia, pain in extremity, oedema peripheral and fatigue. ♦Please refer to SmPC for a full list of adverse events for Ultibro Breezhaler.

Legal Category: POM. Pack sizes: Cartons containing 10 capsules (1x10 capsule blister strips) and one Ultibro Breezhaler inhaler or 30 capsules (3x10 capsule blister strips) and one Ultibro Breezhaler inhaler. Marketing Authorisation Holder: Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland.

Marketing Authorisation Numbers: EU/1/13/862/007 & 003. Full prescribing information is available on request from Novartis Ireland Ltd, Vista Building, Elm Park Business Park, Dublin 4. Tel: 01 2601255 or at www.medicines.ie Date of Revision of API Text: June 2019.

REFERENCES: 1. Ultibro Breezhaler Summary of Product Characteristics. www.medicines.ie. Accessed on January 2020. 2. Donohue JF, et al. Int COPD 2017;12:367-381. 3. Miravitlles M, et al. Clin Invest (Lond) 2014;4(12);1095-1111.

ADVERSE EVENT REPORTING Reporting suspected adverse reactions of the medicinal product is important to Novartis and the HPRA. It allows continued monitoring of the benefit/risk profile of the medicinal product. All suspected adverse reactions should be reported via www.hpra.ie or email to medsafety@hpra.ie.

Adverse events could also be reported to Novartis preferably via www.report.novartis.com or by email: drugsafety.dublin@novartis.com or by calling 01 2080 612.

22 News

Time is Dragging - Clarity is Needed say Consultants During the last month, the Irish Hospital Consultants Association (IHCA) has engaged with the Health Service Executive (HSE) on the issue of working arrangements for the provision of care to all patients during the COVID-19 emergency.

Patients and consultants, including the 600 full-time private practice consultants, are understandably seeking clarification that care can continue to be provided.

They have also sought to agree a

timeframe and related provisions for such arrangements.

An understanding had been reached on 8 April 2020 between the parties which provided for both existing patients of full-time private practice consultants and new referrals necessitated by the COVID-19 emergency to be cared for on an agreed basis, including the continued operation of consulting rooms.

However, this did not materialise in the written updated draft contract

circulated by the HSE on 10 April 2020. If this proposed version was to apply, consultants would be liable for costs which would likely exceed their income thereby forcing the closure of consulting rooms needed to provide timely outpatient care.

for agreement on the proposed contract without further delay. But patients and consultants need certainty as the current impasse is untenable.

In a statement they say, "Our fulltime private practice consultant members will continue, voluntarily, to deliver urgent inpatient care and continue to provide time critical essential care from consulting rooms to permit an opportunity

“We remain available to engage and are urging all parties to intensify efforts in a spirit of realism and understanding.

The COVID-19 crisis and wider provision of healthcare for all patients deserves no less.”

“Time is dragging on. Patients and consultants need clarity. We are all mindful of the bigger picture.

NEXIUM COMPLETION OF TRANSFER Grünenthal Pharma Ltd have announced the completion of the transfer of the Marketing Authorization for Nexium (esomeprazole magnesium trihydrate) to Grünenthal Pharma Ltd on March 20th 2020.

The transfer is part of a US$ 922m deal between AstraZeneca and Grünenthal whereby Grünenthal acquired the European rights to Nexium and the global (ex US and Japan) rights to Vimovo (naproxen 500mg /esomeprazole 20mg).

Grünenthal provides Nexium in Ireland in three presentations: Nexium 20mg gastro-resistant multi-unit pellet system (Nexium MUPS™) tablets Nexium 40mg gastro-resistant multi-unit pellet system (Nexium MUPS™) tablets Nexium I.V. 40mg powder for solution for injection / infusion Nexium (esomeprazole magnesium trihydrate) is used to treat gastroesophageal reflux disease, ulcers, and Zollinger-Ellison syndrome. It is also used for the prevention and treatment of gastric ulcers induced by pain-relieving non-steroidal anti-inflammatory drugs (NSAIDs). It is a member of the drug class of proton pump inhibitors (PPIs), which reduce the production of stomach acid by binding to and inhibiting acid pumps in parietal cells lining the stomach wall which helps to heal erosions in the oesophagus or ulcers in the stomach and duodenum.

For specific details on Nexium approved uses in adults and children, and contraindications please see the Summary of Product Characteristics on www.medicines.ie Please direct any enquiries by telephone to: + 44 870 351 8960 or via e-mail to GeneralenquiriesIE@grunenthal.com M-NIU-IE-04-20-0001 – April 2020

UHG introduces new ICU FamilyLink University Hospital Galway (UHG) has introduced a new video call system known as ICU FamilyLink which will enable contact between families, patients and the clinical teams providing care. This is particularly important as currently visitors are not permitted in the hospital, due to the COVID-19 pandemic.

When the visiting restrictions were introduced in early March, the Intensive Care Unit (ICU) team in Galway appreciated that it was going to be very difficult to keep families and patients in the ICU updated and connected, particularly where family members may be in physical isolation in different locations. In an effort to address these challenges, the ICU team at UHG reached out to its academic partners in NUI Galway, who in turned reached out to industry contacts in Galway and beyond.

NUI Galway, Cisco and IBM assembled a team to answer the call and working closely with the ICU and Clinical Engineering teams in UHG, have rapidly developed a state-of-the-art video call system specifically for the ICU setting.

The systems runs on the hospital’s Cisco Enterprise Wireless Network using Cisco Webex Meetings software and Cisco Webex Devices donated from Cisco’s software development office in Oranmore.

The secure system is designed for easy setup where close family members are invited by the nurse looking after the patient, to see and speak to their loved one. ICU FamilyLink also enables staff to advise the family and discuss medical and treatment issues that arise.

The project is supported by a team of IBM volunteers who are available by phone to family members to offer any technical support. The system is complemented by

APRIL/MAY 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

UHG staff Frank Kirrane, Medical Physical and Clinical Engineering Dept and Leonie Cullen, Clinical Nurse Manager 2 with the ICU FamilyLink video call unit which is being used to connect family members with patients and staff in the ICU

Apple iPads to facilitate staff-tostaff Webex video calls. All the equipment and expertise required to get this system operational has been kindly donated by the collaborators and a wider set of supportive organisations.

Commenting Chris Kane, Hospital Manager said, “We are very grateful

to everyone who has given their time and expertise to support the delivery of such an important project in such a short timeframe.

The last number of weeks have been very difficult for patients in ICU and their families; the staff recognised this and wanted to do something to support them.”

Preterm Child 23

Attention and Sensory Challenges for the Preterm Child Written by Marie Slevin, Clinical Psychologist, Department of Neonatology, National Maternity Hospital, Dublin; Karen 0'Connor, Specialised Speech & Language Therapist

Marie Slevin, clinical psychologist, Department of Neonatology, National Maternity Hospital, Dublin

Karen O'Connor, Specialised Speech and Language Therapist

Research has shown that children born preterm have a higher rate of attention problems and learning difficulties at school age when compared to term infants.

sound therapy from The Child Development Centre, Furbo, Galway in a joint randomized control trial (ISRCTN ref no: 99326699/ Slevin M, O'Connor K, Segurado R, Murphy JFA, 'Therapeutic Listening for Preterm Children with Sensory Dysregulation, Attention and Cognitive Problems' - Ir Med J 2020:113;4-12 (IMJ S-6976/ PMID 32298558) to look at using Therapeutic Listening as a possible treatment option for children born preterm presenting with the attention and sensory regulation issues mentioned above. Karen is a trained therapeutic listening therapist with 20 years’ experience treating children with a wide range of developmental challenges and has had very successful outcomes using this method of treatment. The fact that this intervention can take place in the child’s home as a daily therapy was also very appealing.

They are at increased risk of below average levels of executive functioning, even when their general IQ is normal.1 Attention and sensory processing are two notable challenges that I have observed for the preterm child who has had a good outcome but who is not achieving their potential in terms of their language development, learning and quality motor development.

These are children who are unable to attend appropriately or sustain attention levels sufficiently to complete the tasks they have been set to do / who cannot sit still/have a constant need to move/ who struggle with maintaining sustained periods of play/attention to learn / who have poor eye-contact and rapport while being assessed / who don’t tune in / listen or respond to their environment or name being called. They are very active/ find it difficult to look at a book /pictures /become easily frustrated / continually searching for something to appease them – when they get that toy or object

they seek, it is immediately dropped in search for another.

These children are struggling because they can’t self- regulate or pull themselves together in order to attend and learn, hence experience difficulty exploring and attending to their environment.

They are missing out on crucial aspects of their language and cognitive development as a consequence of their inability to self- regulate. Some children will mange to overcome this inattention but others will need therapeutic support.

We know from the research that 46% of preterm infants born with a median age = 26 wks gestation1 and 39% of preterm infants born < 32 wks gestation2 can have atypical auditory, tactile and vestibular processing which can impact on their future learning.

Early intervention is essential for the child who is unable to cope and who is struggling in this regard.

Therapeutic Listening as a Treatment Option for Attention and Sensory Regulation Issues I coordinated with Karen O'Connor, Specialised Speech and Language Therapist with advanced training in

What is Therapeutic Listening and How does it Work?

Therapeutic Listening3 is an auditory intervention programme that was developed by Sheila Frick Occupational Therapist in the United States. It uses music specifically designed to

support children who experience challenges with sensory processing, listening, attention and communication. It is designed to tap into the orienting response to prime approach behaviour which is the gateway to attention4.

The treatment effect is attributed to electronic modifications and qualities within the music to trigger attention and activate body movement4. In the context of auditory interventions, the music is processed using alternating high/ low pass filter, sliding highpass filter, spatial enhancement and binaural beat. The high/low filter set at 1,000hz is the optimal range for eliciting the orienting response3. It is hypothesized to trigger mechanisms involved in selective attention through triggering the orienting response and activating the middle ear mechanism to contract to focus on higher sounds nearby and to relax to monitor stimuli that trigger a shift in focus. The sliding pass filter is hypothesized to enhance processing of higher ranges of sound and sustained attention for refined discrimination. Spatial enhancement is hypothesized to increase the listener’s spatial awareness needed to access the environment. A binaural beat is hypothesized to lead to subconscious entrainment of the listener’s brainwaves to the neural alpha state, thereby regulating the listener’s arousal level and promoting a calm alert state3.

Alternating between low-pass and high-pass filters trains the ear to shift back and forth between focal and ambient processing and sharpens the parts of sound signals that assist in the perception of time and space. They create a flow between focusing to listen and taking a break (subconscious monitoring) between tuning in and tuning out4.

When designing a Therapeutic Listening programme, the treatment goals of the child influence the choice of music, the manner in which the music has been altered, the duration and frequency of the listening sessions. A variety of music

HOSPITALPROFESSIONALNEWS.IE | HPN • APRIL/MAY 2020

24 Preterm Child Example of Therapeutic Listening

"This is the first study to use Therapeutic Listening as a home

Improvement was minimal in terms of motor outcome. In our study, both groups demonstrated low levels of functioning on the test battery at 3-4 years of age.

Pre-assessment results showed that all 18 children (Intervention and Controls) had poor motor development, all performing below peer group standards.

No child in either group reached normal Total Motor Quotient scores. Motor deficits are noted to persist for some preterm children.8

intervention programme for children born preterm"

Our Conclusion

selections may be used (classical, jazz or contemporary) varying in tone, rhythm, melody, harmony and timbre. Optimum listening duration ranges from 20-30 minutes twice per day. This decision is guided by clinical judgement factoring in the child’s age, level of sensitivity, developmental needs, and response to previous musical selections - ‘just right fit or just right challenge’. Each child receives the amount of listening that their nervous system requires to optimise function Our Study This is the first study to use Therapeutic Listening as a home intervention programme for children born preterm. The primary goal was to establish domains which may respond to the intervention, and to estimate outcome instrument characteristics in this population to permit design of future trials.

The study group we looked at were preterm infants who were born with a birthweight of <1500g (from the National Maternity Hospital, Dublin) aged 3-4 years who had presented with concerning (low average scoring, sensory/behavioural challenges) Bayley-lll performances when they were assessed at 2 years corrected age. The children were randomly assigned to an Intervention Group (therapeutic listening) and Control Group

(no intervention). The children were assessed pre and post intervention using the same battery of tests to assess intervention outcomes for sensory processing / attention/ language / cognitive and motor development.

The children in the Intervention group listened to modified music3 using specialised headphones for 5 consecutive days per week (usually Monday – Friday), for a period of 6 months. The children could continue normal daily activities while listening to the music. A time interval of 3 hours was advised between listening times. The programme was reviewed every 6 weeks (5 reviews) by Karen the intervention therapist and adjusted to the next level according to each child’s needs.

Our Findings Two key findings stood out - improvement in sensory processing and in attention.

The Intervention Group (n=9) showed better improvement in sensory processing, compared to the Control Group (n=9) (6.4 fold improvement in sensation seeking; 5.0 in auditory processing; 4.0 in tactile processing). Six children in the Intervention group (67%) improved in vestibular processing.

Attention level improved by two levels (two years) for 7 (78%) out of the 9 children in

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the Intervention Group and by one level (one year) for 2 (22%) children. In the Control Group, attention level improved by two levels (two years) for 2 (22%) children and by one level (one year) for 5 (56%) children. The outcomes on this scale linked in with improved sensory profiles for the intervention group. The children in the intervention group were listening better and were more focused. They went from being “very busy kids” to “quieter kids”.

Scores reflecting language and cognitive ability showed either mild advantage, or a mixed picture, indicating that improving these abilities may be challenging for this group of children. No benefits from Therapeutic Listening were encountered in receptive/expressive communication. Our Intervention and Control Groups scored poorly on the Renfrew Action Picture Test (RAPT) indicating their challenges with language.

Adequate attention is required in order for language to occur.

The differences in expressive language between preterm and full term children becomes evident around the end of their second year.6 A stronger Low Registration pattern - flat or dull “affect” is related to delayed early cognitive development including dampened responses to the environment, potentially affecting developmental opportunities in areas such as language.7

We showed that Therapeutic Listening is a feasible intervention for preterm children to improve attention levels and sensory processing skills. The processing and regulation of sensory information at a basic level of the nervous system lays the foundation for development and regulation of attention skills which are foremost in terms of acquiring later skills of motor development, speech and language development, social skills and academic learning.

Therapeutic Listening improved the Intervention group’s ability to regulate or modulate sensory information more than the control group as evidenced by their improved sensory profile results, attention and parental reports.

This enabled them to be more regulated and calmer triggering the orientating response4 thus improving their attention and focus. When a child can regulate their attention levels, their sensory processing improves5.

This sensory modulation process appears to work across the spectrum of senses from auditory to vestibular to oral with the vestibular sense showing the greatest benefit. This is consistent with an optimisation of learning potential as per Williams and Schellensberger’s Pyramid of Learning model5.

The music in sound therapy turns on and enhances the connections between brain areas that process positive award and the insula, a cortical area of the brain that is involved in ‘paying attention’9.

25 Analyses of daily living experiences reported by parents in response to parent review questionnaires which were completed during each review session Levels of arousal /emotional tone

More animated/relaxed/affectionate/independent; improved empathy/happier/more mature and assertive/calmer/more regulated

Social skills

Improved eye-contact/social engagement

Attention Skills

Improved attention/focus and concentration

Motor Skills

Improved coordination/balance; better at running/using the scooter/jumping; improved drawing; now seeking painting/drawing/play doh activities;

Language Skills

Increase in sound production/variety of sounds; more speech imitation; better at listening/following instructions; improved expressive language; improved articulation; making efforts to talk more; increasing vocabulary/sentences; louder more confident expressions; more chat

General Observations

Better at sleeping /eating/completing tasks; improved play skills/independent dressing/increased energy levels; Changed from being “very busy kids to quieter kids”.

Stimulating the vestibular system with music and movement therapy causes it to send signals to another subcortical area, the basal ganglia, which is part of the attention circuit. The vagus system is also stimulated, which turns on the parasympathethic nervous system to calm children down10 and stimulates the “smart vagus”11 to allow children to pay close attention, communicate and get ready to learn. Children are often presented with a complex environment of information. It is important that they can selectively attend to that which they need and to ignore or filter that which is unimportant to the task at hand in order to learn.

Poor sensory processing affects motor, language and cognitive development. 46%1 and 39%2 of the preterm populations studied have been reported as having sensory sensitivities. This perspective is beneficial12, as in the case of sensory processing, it is the subjective experiences of the child and family that impact quality of life. (See Table above).

Therapeutic Listening could be an effective treatment option for sensory sensitive preterm children. As a home programme it facilitates more intensive intervention than conventional treatment methods, with less therapist input than clinic based treatment programmes. It is cost and time efficient. We observed a good response and motivation to engage from parents.

Author Bio Marie Slevin is a clinical psychologist at the Department of Neonatology, National Maternity Hospital, Dublin. She specialises in the neurodevelopmental assessment, follow-up and research of preterm infants and term infants with neonatal encephalpathy. She has specialised skills in the administration of the Bayley Scales. Recently she has been exploring sensory problems associated with being born preterm and the application of therapeutic listening as a treatment option for these children presenting with sensory dysregulation, attention and cognitive challenges.

Karen 0'Connor is a specialised speech and language therapist with over 20 years experience working with children with complex communication needs.

Her specialism is in combining speech and language therapy with up to the minute sensory integrative sound techniques.

References 1. Crozier SC, Goodson JZ, Mackey ML, Synnes AG, Grunau RE, Miller SP, Zwicker JG. Sensory processing patters in children born very preterm. Am J Occup Ther 2016; 70: 7001220050p1-77.

2. Wickremasinghe AC, Rogers EE, Johnson BC, Shen A, Barkovich AJ, Marco EJ.

Children born prematurely have atypical sensory profiles.

J Perinatol 2013; 33:631-5 3. Frick SM, Young S. Listening with the whole body: Clinical concepts and treatment guidelines for Therapeutic Listening. 2nd ed. Madison, USA: Vital Links 2009 4. Cook, E. W. III., & Turpin, G. Differentiating orienting, startle and defense responses: The role of affect and its implications for psychopathology. In P. J. Lang, R. F. Simons, & M. T. Balaban (Eds.), Attention and orienting: Sensory and motivational processes (pp.137-164). Hillsdale, NJ: Erlbaum 5. Williams MS, Shellengberger S. “How does your engine run?”. A leaders’s guide to the alert program for selfregulation. Albuquerque, USA: Therapy Works Inc. 1996 6. Sansavini A, Guarini A, Savini S, Broccoli S, Justice L, Alessandroni R,Faldella G. Longitudinal trajectories of gestural and linguistic abilities in very preterm infants in the second year of life. Neuropsychologia 2011; 49(13): 3677-88 7. Eeles AL, Anderson PJ, Brown NC, Lee KJ, Boyd RN, Spittle AJ, Doyle LW. Sensory profiles of children born less than <30 weeks’ gestation at 2 years of age and their environmental and biological

predictors. Early Hum Dev 2013; 89: 727-732 8. MacKayTL, Jakobson LS, Ellemberg D, Lewis TL, Maurer D, Casiro O. Deficits in the processing of local and global motion in very low birthweight children. Neuropsychologia 2005; 43(12):1738-48 9. Menon V, Levitin D. The rewards of Music Listening: Response and Physiological Connectivity of the Mesolimbic Sysytem.

Neuroimage 2005;28:175-84 10. Minson R, Pointer AW. Integrated Listening Systems: A Multisensory approach to Auditory Processing Disorders.

Auditory Processing Disorders:Assessment, Management, and Treatment, in Geffner D, Ross-Swaine D, eds., 2nd ed.(San Diego: Plural,) 2012: pp.757-71 11. Porges SW. The Polyvagal Theory: Neurophysiological Foundations of Emotions, Attachment, Communication, and Self- Regulation.

WW.Norton and Company.

New York. NY 2011.416 12. Eeles AL, Anderson PJ, Brown NC, Lee KJ, Boyd RN, Spittle AJ, Doyle LW. Sensory profiles obtained from parental reports correlate with independent assessments of development in very preterm children at 2 years of age.

Early Human Development 2013; 89: 1075-1080

HOSPITALPROFESSIONALNEWS.IE | HPN • APRIL/MAY 2020

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Adverse events should be reported to Mylan Ireland Pharmacovigilance Tel: +44 (0) 800 1218267 Email: UKPharmacovigilance@mylan.com You can also report side effects directly via the national reporting system: HPRA Pharmacovigilance, Earlsfort Terrace, Dublin, Ireland Tel: +353 1 6764971 Fax: +353 1 6762517 Web: www.hpra.ie Email: medsafety@hpra.ie REFERENCES 1. Desunin® 800IU Summary of Product Characteristics. 2. Desunin® 4000IU Summary of Product Characteristics.

Mylan IRE Healthcare Ltd, Newenham Court, Northern Cross, Malahide Road, Dublin 17, Ireland. www.mylan.ie Job code: DES-2019-0012 Date of preparation: July 2019

CPD 65: VITAMIN D Continuing Professional Development

CPD

27

AUTHORS: Dr Eamon Laird & Professor Rose Anne Kenny The Irish Longitudinal Study on Ageing On behalf of the TILDA team The Irish Longitudinal Study on Ageing, Trinity College Dublin Dublin 2 Tel: +353 1 896 2509 Email: tilda@tcd.ie Website: www.tilda.ie ISBN: 9781-907894-30-5 https://www.doi. org/10.38018/TildaRe.2020-05

Dr Eamon Laird

Professor Rose Anne Kenny

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.

Vitamin D Deficiency in Ireland Implications for COVID-19 In this report, we aim to describe the importance of vitamin D for immune function, the prevalence of vitamin D deficiency and vitamin D supplement use in Ireland by age group, gender, geographic location and by obesity and lung disease (particularly vulnerable to COVID-19), describe those most at risk of deficiency and the best sources of vitamin D and recommendations to improve status. By compiling this report, we hope the information given can help in the mitigation of the negative health consequences of COVID-19.

Frailty is a dynamic process that changes over time and can be viewed on a continuum. An older person can transition in either direction between the different states of frailty, namely robustness, pre-frailty (an intermediate state) and frailty(9). Robust older people may have some health problems, but in general these problems are being well managed. Older people with pre-frailty are at an increased risk of adverse outcomes but are coping. Individuals living with frailty generally require some support for instrumental and/ or basic activities of daily living, have increased susceptibility to infection, take longer to recover from infections and are less likely

to recover to previous levels of functional independence. For older adults living with frailty, exposure to a stressor such as infection significantly increases the risk of disability, hospital admission, longer in-patient length of stay, transition to long-term care and death(10). It is highly likely that individuals living with frailty who contract COVID-19 are at greatest risk for admission to hospital, admission to critical and intensive care units and death. Identifying people living with frailty provides an opportunity to prevent this at-risk group from contracting COVID-19 in the community and proactively to develop healthcare service planning and delivery for our medically vulnerable population aged 70+ years(11).

1.1 Vitamin D and immune function Vitamin D is essential for older adults to help maintain bone and muscle health, plays a key role in the prevention and the treatment of falls and fractures and helps the absorption of calcium from the gut(2). Recent research has also highlighted that it may have an important function within the immune system(3).

With increased age, there is a shift in the immune response to

a more pro-inflammatory state which may lead to chronic low level inflammation and a slow accumulation of damage, with subsequent progression to chronic disease. This age related proinflammatory state is referred to as ‘inflamm-aging’(4). This can be particularly important in periods of metabolic stress such as infection - the body is already pre-set to a higher level of inflammation and the necessary immune response to the infection may be impaired.

Experiments and research has shown that vitamin D can alter the immune system response through its influence on the production and manufacturing of immune molecules known as cytokines(5).

Vitamin D has been shown to help signal the increased production of ant-inflammatory molecules and decrease the production of pro-inflammatory molecules(6,7).

This switch in immune response in theory may have some potential benefit in cases of ‘cytokine storm’ – a massive release of proinflammation (which has been observed in those infected with COVID(8)) which can cause acute respiratory distress syndrome(9).

Importantly, in a large crosssectional clinical trial (n = 18,883) the risk of respiratory infection increased with lower blood vitamin

D levels and the effect was even stronger in those with underlying lung conditions(10). Many casecontrol studies have also reported associations between low vitamin D and increased risk of infection(11) while in a trial supplementing patients at risk of respiratory infection with 1,000 International units (IU) of vitamin D a day for a year, supplement use reduced both symptoms and antibiotic use(12).

Recently, a large meta-analysis (data analysis of a large collection of previous studies) of 10,933 people from 25 trials conducted in 15 countries investigated whether taking a vitamin D supplement helped to prevent colds, flu and chest infections (acute respiratory infections - ARIs)(13). Vitamin D had a significant protective effect when it was given daily or weekly to people with lowest vitamin D levels: the risk of having at least one ARI was reduced from 60% to 32% in these people. Overall, vitamin D supplements reduced the risk of having at least one ARI. The study authors concluded that taking a vitamin D supplement was safe and can help protect against ARIs, particularly if baseline levels are low. In 2019, a newer analysis using 21,000 participants from across eight studies showed that

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CPD 65: VITAMIN D

KEY MES 1. Why is Vitamin D important?

• Vitamin D is essential for bone and muscle health • Vitamin D may help prevent respiratory infections in those who have low vitamin D levels • Vitamin D is seasonal and cannot be made during the winter-time while the amount in summer time is subject to sunshine, weather and other factors 2. What are the rates of deficiency in older adults in Ireland*1?

• 47% of all adults aged >85 are deficient in winter (31,480) • 27% of the over 70s who are ‘cocooning’ are likely to be deficient (115,536) • 1 in 8 (13%) adults over 55 are deficient (149,049) all year 3. Who is at risk of Vitamin D deficiency in Ireland?

• People who are housebound/confined, little sun exposure and/or eat inadequate amounts of fortified foods • People who don’t take vitamin D supplements - currently over 91% of older adults 55+ do not take a supplement during the winter (1,038,752).

Only 4% of men and 15% of women take a supplement those with a low blood vitamin D level had a 64% increased risk of communityacquired pneumonia(14).

Therefore, maintaining a sufficient vitamin D status in the adults is beneficial in prevention of ARI and may therefore be of benefit in the COVID-19 pandemic.

Vitamin D Status of Older Adults in Ireland in Winter During the winter period, 21.3% (244,209) of adults aged >55

years were vitamin D deficient.

The highest rates of deficiency were observed for those aged 80-84 years (29.6%; 23,987) and those aged >85 years (46.6%; 31,480). For those aged >70 years, the deficiency rates were 27.1% (115,536). Across all ages, deficiency rates were similar for both men and women though with men tending to have slightly higher deficiency rates overall.

Similar high rates of deficiency

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were observed when examined by province of residence. Again, those aged >85 years had the highest rates of deficiency regardless of province. However, those aged 85+ in the Connacht & Ulster area had the highest deficiency rate (59.5%; 8,738). For those aged >70 years, the Munster region had the highest deficiency rate (31.8%; 39,410) vs the Leinster region (21.4%; 46,231). Overall, Leinster had the lowest rate of deficiency

(17.6%; 103,615) compared to those residing in either Munster (25.3%; 83,615) or Connacht & Ulster (24.5%; 55,690).

In winter, only 9.4% (107,773) of those aged 55+ and 11.5% (49,028) of those aged 70+ reported taking a vitamin D supplement. A much higher proportion of women (14.6%; 87,181) compared to men (3.8%; 20,877) took a supplement. This sex difference was consistent

29 1919

SSAGES

Figure 6. Vitamin D deficiency in older adults in Ireland with obesity by age (winter) Figure 6.Vitamin VitaminDDdeficiency deficiency in in older older adults age (winter) adultsininIreland Irelandwith withobesity obesitybyby age (winter)

• People who are obese, physically inactive, have asthma or chronic lung disease 4. Where is Vitamin D found • Vitamin D is made in the skin from 10-15 minutes 7.Vitamin VitaminDDdeficiency deficiency in in older older adults age (summer) per day of sun exposureFigure adultsininIreland Irelandwith withobesity obesitybyby age (summer) Figure 7. Vitamin D deficiency in older adults in Ireland with obesity by age (summer) in Ireland only made from late March to late September • Vitamin D is available in oily fish (salmon, mackerel etc.), eggs, liver, fortified foods such as cereals and dairy products 5. How much Vitamin D should be taken to prevent deficiency?

• 10 ug (400 IU) is the Figure 7. Vitamin D deficiency in older adults in Ireland with lung conditions (winter) by age VitaminDDdeficiency deficiency in older adults (winter) byby age adults ininIreland Irelandwith withlung lungconditions conditions (winter) age minimum recommendedFigure 7.Vitamin daily during the winter time • Between 15 -20 ug (800-1,000 IU/day) recommended for most at risk groups *1 For further information see: Laird E, O’Halloran AM, Carey D, Healy M, O’Connor D, Moore P, Shannon T, Molloy AM, Kenny RA. The prevalence of vitamin D deficiency and the determinants of 25 (OH) D concentration in older Figure 7.Vitamin VitaminDDdeficiency deficiency in older adults (summer) byby ageage adults ininIreland Irelandwith withlung lungconditions conditions (summer) Irish adults: Data from The Figure 7. Vitamin D deficiency in older adults in Ireland with lung conditions (summer) by age Irish Longitudinal Study on Ageing (TILDA). The Journals of Gerontology: Series A. 2018 73(4):519525. https://academic.oup. com/biomedgerontology/ article/73/4/519/4103040

2020

when examined by age as for instance, in those aged 85+ only 5.6% (1,291) of men vs 17.7% (7,875) of women reported taking a supplement.

Vitamin D Status of Older Adults in Ireland in Summer During the summer period (optimum period for making vitamin D from sunlight), 8.4% (96,308) of adults aged >55 years were vitamin D deficient while

for those aged 70+, the rate of deficiency was 12.1% (51,586).

The highest rates of deficiency were observed for those aged 85+ years (30.7%; 20,739). Similar age defined rates were observed for both men and women though with women having slightly higher deficiency rates overall.

Similar rates of deficiency were observed when examined by province of residence. Again, those aged >85 years had the highest rates of deficiency regardless of province. However, those aged 85+ in the Connacht & Ulster area had the highest deficiency rate (48.3%; 7,093) followed by Munster area (41.1%;

7,826) and then Leinster (20.7%; 7,002). Overall, Leinster again had the lowest rate of deficiency (6.8%; 40,033) compared to those residing in either Munster (9.5%; 31,397) or Connacht & Ulster (10.0%; 22,731). For those aged 70+, those residing in Munster had a deficiency rate of 15.9% (19,705) vs 10.3% (22,252) in Leinster.

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CPD 65: VITAMIN D

In summer, 10.3% (118,092) of those aged 55+ reported taking a vitamin D supplement. Again, a much higher proportion of women (14.6%; 87,181) compared to men (5.5%; 30,217) took a supplement. For those aged 70+, only 14.2% (60,539) took a vitamin D supplement.

Risk factors for deficiency The largest negative predictors included smoking, geographic location (living in the North and West compared to the East of the country), winter season, physically inactivity, and older age. The largest positive predictor of vitamin D was vitamin D supplement use followed by being female.

Vitamin D status by obesity and respiratory lung conditions Overall, obese older adults had much higher rates of vitamin D deficiency both in winter and summer (Figures 6-7).

During winter, rates of vitamin D deficiency in the obese were 27.3% for those aged 55+ and 35.3% for those aged 70+ compared to 20.8% and 27.0% respectively for those not obese.

Similar trends were also observed during summer.

In those reporting chronic lung disease (such as chronic bronchitis or emphysema), the prevalence of vitamin D deficiency was significantly higher than those not reporting disease across the age groups both in winter and summer.

For instance in those aged >55 years, the prevalence in winter of deficiency was 33.8% in those with lung conditions vs 22.7% with no conditions. Similar trends were observed in 70+ age group where rates were 32 vs 29.9% in winter and 16.9 vs 12.3% in summer.

of supplements, many of this vulnerable group could be at very high risk of deficiency. This of key importance given the usefulness of vitamin D for immune function particularly at this time.

Discussion

Of particular concern we have observed very high levels of vitamin D deficiency in those who are obese and those with pre-existing lung conditions both of which have been observed to make individuals particularly vulnerable to COVID-19 and complications from the virus(15,16).

This report demonstrates that of those aged 55+ years in Rep. of Ireland, 1 in 5 are vitamin D deficient during the winter and 1 in 12 during the summer. Of particular concern is that nearly 30% of those aged 70+ and 47% of those aged 85+ are deficient in vitamin D. These are the age groups who are considered to be ‘extremely medically vulnerable’ to the adverse health outcomes of COVID-19 and have been advised to participate in ‘cocooning’ during the COVID-19 public health emergency. Of extra concern is the fact that only 10.5% of those aged 70+ actually report taking a vitamin D supplement – because of ‘cocooning’ many may now lack the opportunity for sun exposure and given the low use

Ireland does not have any formal vitamin D food policy – we practice a voluntary but not mandatory food fortification policy where food manufacturers can decide to fortify (or not) their food products with vitamin D. The vitamin D status of those in Ireland is lower than either the United States or Canada who have systematic (mass) vitamin D food fortification. However, vitamin D deficiency is not inevitable in older adults in Ireland and the ability to have sufficient vitamin D status year round is an achievable goal that many countries meet.

For example, another European country - Finland (which is at a much higher latitude and therefore receives less sunshine than Ireland) has virtually eliminated vitamin D deficiency in its population with

APRIL/MAY 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

rates <1%(17). This is due in part to a successful food fortification and vitamin D supplement policy and educating the public and medical practitioners on the importance of vitamin D. This vitamin D success story demonstrates what could be achieved in Ireland.

Here we outline the main sources of vitamin D and what are the intake recommendations.

Vitamin D sources There are three main sources of vitamin D – sunlight, food and supplements. Due to Ireland’s far latitude geographic location, vitamin D synthesis by sunlight is only during the months of late March to late September. This is 10-15 minutes exposure to sunlight (before application with sun-protection at a time period between 12-4 pm). However, even during the summer, the amount of vitamin D that can be made is affected by cloud cover, use of skin creams, clothing, obesity and age(18). Foods rich in this micronutrient include oily fish (tinned or fresh salmon, mackerel etc.), egg yolks, liver and vitamin D fortified foods such as cereals and dairy products. Regular consumption of vitamin D rich foods is recommended to help prevent deficiency, particularly in the winter months and those

not exposed to sunshine in the summer time.

Vitamin D Intake recommendations During the winter-period at least 10 ug/day (400 IU) from the diet is required (due to the lack of sunlight for vitamin D synthesis).

Recent data has shown that the average intakes from diet are significantly below this level and therefore a 10 ug (400 IU) vitamin D supplement maybe be required during the winter. For those who are housebound (due to illness or quarantine for an extended period) an upper supplement of 15-20 ug/day (600800 IU) maybe required due to the lack of sunshine exposure. In persons over 70 years, 20-25 ug/day (800100IU) is recommended.

Conclusion Our people aged 70 and over are the fabric of our society(19) and we must use all available tools to facilitate the reduction and transmission of COVD-19. Vitamin D is a potent immune modifying micronutrient and if vitamin D status is sufficient, it could benefit vulnerable adults in particular those 70+ years and older who are ‘cocooning’ during the COVID-19 outbreak.

References on Request

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Dosage and administration: Altavita D3 1,000 IU soft capsules are suitable for daily supplementation.

Paediatric posology: Doses of up to 1,000 IU/day may be required to prevent deficiency in some children. Treatment of deficiency 10-18 years 2,000 IU/day for 6 weeks, followed by maintenance therapy of 400-1,000 IU/day (such as one 1,000 IU soft capsule per day or one 7,000 IU soft capsule per week). Pregnancy and breastfeeding: Doses of 1,000 – 2,000 IU/day may be required to prevent deficiency in some women. Adults: Prevention of vitamin D deficiency: 1,000 IU/day. As an adjunct to specific therapy for osteoporosis: 1,000 IU/day. Treatment of deficiency: 1,000 IU – 4,000 IU/day for up to 12 weeks, followed by maintenance therapy of 1,400 – 2,000 IU/day (such as two 1,000 IU soft capsules per day) Altavita D3 7,000 IU soft capsules: Suitable for weekly supplementation, which should be taken into consideration and dosage should be established by a physician. The dose of 1,000 IU/day is considered equivalent to 7,000 IU/week. Pregnancy and breastfeeding: Doses of 1,000 – 2,000 IU/day may be required to prevent deficiency in some women (see below). Even higher doses may be required during breast-feeding if women choose not to give the infant a vitamin D supplement. Adults - prevention of vitamin D deficiency 1,000 IU/day. As an adjunct to specific therapy for osteoporosis: 1,000 IU/day. Treatment of deficiency: 1,000 IU – 4,000 IU/day for up to 12 weeks, followed by maintenance therapy of 1,400 – 2,000 IU/day, such as two 7,000 IU soft capsules per week). Altavita D3 25,000 IU soft capsules: Children aged 10-18 years: Prevention of deficiency, 25,000 IU (1 capsule) every 6 weeks. Treatment of deficiency, 25,000 IU (1 capsule) once every 2 weeks for 6 weeks followed by maintenance therapy of 400 – 1,000 IU/day, such as 1 capsule per month. Pregnancy and breastfeeding: The high strength formulation is not recommended. Altavita D3 25,000 IU soft capsules and Altavita 25,000 IU oral

solution: Adults: Prevention of deficiency, 25,000 IU/month (1 capsule or single dose oral solution); higher doses and monitoring of serum 25(OH)D may be required in populations at high risk of vitamin D deficiency (* see below) Adjunct to specific therapy for osteoporosis, 25,000 IU/month (1 capsule or single dose oral solution).

Treatment of deficiency (<25 nmol/L), 50,000 IU/week (2 capsules or single dose oral solution) for 6-8 weeks followed by maintenance therapy 1,400 – 2,000 IU/day, may be required such as 2 capsules or oral solutions per month; follow-up 25(OH)D measurements should be made approximately 3-4 months after initiating maintenance therapy to confirm that the target level has been achieved. Altavita 25,000 IU oral solution: Paediatric posology: Prevention of deficiency 0-1 years 25000 IU (1 single dose oral solution) every 8 weeks, Prevention of deficiency 1-18 years 25,000 IU (1 single dose oral solution) every 6 weeks. Treatment of deficiency 0-18 years 25,000 IU (1 single dose oral solution) once every 2 weeks for 6 weeks, followed by maintenance therapy of 400-1000 IU/day (such as 1 25,000 IU single dose oral solution per month). *Altavita D3 1,000 and 7,000 IU soft capsules, Altavita D3 25,000 IU soft capsules and Altavita 25,000 IU oral solution: Populations at high risk of vitamin D deficiency include those who are institutionalised or hospitalised, dark skinned, obese, being evaluated for osteoporosis, with limited effective sun exposure due to protective clothing or consistent use of sun screens, using certain concomitant medication e.g. anticonvulsants or glucocorticoids, with malabsorption, including inflammatory bowel disease and coeliac disease and recently treated for vitamin D deficiency, and requiring maintenance therapy. Special populations: Altavita D3 25,000 IU soft capsules and oral solution should not be used in combination with calcium in patients with severe renal impairment. Administration to Adults: Altavita D3 should be taken orally – the capsules should be swallowed whole with water, for the oral solution the full contents of the single dose oral solution should be either emptied into the mouth and swallowed orally, or emptied onto a spoon and taken orally. AltavitaD3 can also be taken by mixing with a small amount of cold or lukewarm food immediately prior to use. Patients should be advised to take Altavita D3 25,000 IU preferably with a meal. Administration to children: In children, Altavita D3 oral solution can be mixed with a small amount of children’s foods, yogurt, milk, cheese or other dairy products. Parents should be warned not to mix Altavita D3 oral solution into a bottle of milk or container of soft foods in case the child does not consume the whole portion, and does not receive the full dose. They should ensure that their child takes the entire dose. For children who are not being breast-fed, the prescribed dose should be administered with a meal. Contraindications: Altavita D3 1,000 IU soft capsules, Altavita D3 7,000 IU soft capsules, Altavita D3 25,000 IU soft capsules and AltaVita 25,000 IU oral solution: Hypersensitivity to the active substance or to any of the excipients; hypercalcaemia and/or hypercalciuria; nephrolithiasis and/or nephrocalcinosis; hypervitaminosis D. Pregnancy and breastfeeding: Due to lack of clinical data Altavita D3 25,000 IU is not recommended. Warnings and precautions: Use with caution in impaired renal function; monitor effect on calcium and phosphate levels.

Consider the risk of soft tissue calcification. Exercise caution in patients receiving treatment for cardiovascular disease as concomitant administration of vitamin D with

drugs containing digitalis and other cardiac glycosides may increase risk of digitalis toxicity and arrhythmia; strict medical supervision is needed, with serum calcium concentration and electrocardiographic monitoring if necessary. Use with caution in patients with sarcoidosis due to possible increase in vitamin D metabolism; monitor serum and urinary calcium levels in these patients. Allow for the total dose of vitamin D where patients consume treatments and / or foodstuffs enriched with vitamin D and for the patient’s level of sun exposure. Possible risk of renal stones, especially with concomitant calcium supplementation; consider the need for additional calcium supplementation for individual patients. Calcium supplements should be given under close medical supervision. For a full list of interactions see the full SmPC. Altavita D3 1,000 IU soft capsules and 25,000 IU soft capsules contain Allura Red AC (E129).

Altavita D3 7,000 IU soft capsules contain Sunset Yellow FCF (E110). These excipients may cause allergic reactions. Undesirable effects: Not known (cannot be estimated from the available data): Hypersensitivity reactions such as angio-oedema or laryngeal oedema Uncommon (>1/1,000, <1/100): Hypercalcaemia and hypercalciuria.

Rare (>1/10,000, <1/1,000): pruritus, rash, urticaria. Price: Altavita D3 1,000 IU soft capsules: GMS reimbursed at €3.28 per pack of 28 capsules Altavita D3 7,000 IU soft capsules: GMS reimbursed at €3.28 per pack of 4 capsules. Altavita D3 25,000 IU soft capsules: GMS reimbursed at: €6.00 per pack of 3 capsules. Altavita D3 25,000 IU oral solution: GMS reimbursed at €5.25 per pack of 3 x 1ml single dose oral solution. Legal Classification: POM. MA number: Altavita D3 1,000 IU soft capsules PA 1876/5/1 Altavita D3 7,000 IU soft capsules PA 1876/5/2 Altavita D3 25,000 IU soft capsules: PA1876/004/0033, Altavita D3 25,000 IU oral solution PA1876/002/002. Marketing Authorisation Holder: Consilient Health Limited, 5th Floor, Beaux Lane House, Mercer Street Lower, Dublin 2, Ireland. Further information is available on request from Consilient Health Ltd. Block 2A, Richview Office Park, Clonskeagh, Dublin 14 Ireland, 01 2057760 or drugsafety@consilienthealth.com. Date of preparation of prescribing information: June 2019.

Healthcare professionals are asked to report any suspected adverse reactions.

To report an adverse event or a product complaint about a Consilient Health medicine, please contact Consilient Health at drugsafety@consilienthealth.com or 01 2057766 Adverse events and product complaints may also be reported to the Health Products Regulatory Authority. Reporting forms and information can be found at www.hpra.ie then click on “report an issue”.

Code: IE-ALT-145 Date of preparation: September 2019

32 Educational

Emerging evidence on use of remdesivir in COVID-19 Dr Diana Hogan-Murphy, Antimicrobial Pharmacist University Hospital Galway and Clinical Lead Health Innovation Hub Ireland NUI Galway

of any duration and at least one of the following: radiographic infiltrates by imaging; oxygen saturation (SpO2) <=94% on room air; requirement for supplemental oxygen; or requirement for mechanical ventilation. The trial enrolled 1063 patients in a 1:1 ratio to receive intravenous remdesivir 200mg on day 1 followed by 100mg for 9 days or placebo. The primary clinical endpoint was time to recovery within 28 days after randomisation. A total of 68 sites joined the study, 47 in the United States and 21 in Europe and Asia.

Findings

Remdesivir is one of several experimental agents undergoing clinical trials worldwide to evaluate its safety and efficacy in coronavirus disease 2019 (COVID-19). This investigational nucleotide analog inhibits the action of RNA polymerases and terminates RNA transcription.

It has broad-spectrum antiviral activity both in vitro and in vivo in animal models against multiple viral pathogens, including Ebola, Marburg virus disease, Middle East respiratory syndrome (MERS), and severe acute respiratory syndrome (SARS). In vitro testing has demonstrated activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19.

Available data to date on its safety and efficacy include three phase 3 randomised clinical trials for COVID-19 patients, compassionate use programmes in patients with COVID-19, and clinical trials in healthy volunteers and subjects with Ebola virus disease.

Evidence from NCT04257656 clinical trial This is the first phase 3 randomised, double-blind, placebo-controlled, multicenter study to evaluate the safety and efficacy of remdesivir in hospitalised adult patients with severe COVID-19. The trial was published in The Lancet on 29 April 2020, funded by Chinese agencies, and carried out in 10 hospitals in the province of Hubei in China. Eligibility included adult patients entering the study within 12 days of symptom onset,

pneumonia confirmed by chest imaging, and oxygen saturation <=94% on room air. Patients were randomly assigned in a 2:1 ratio to intravenous remdesivir 200mg on day 1 followed by 100mg for 9 days or the same volume of placebo infusions for 10 days. Concomitant use of lopinavir/ritonavir, interferons, and corticosteroids was permitted.

The primary endpoint was time to clinical improvement up to day 28, defined as the time from randomisation to the point of a decline of two levels on a six-point ordinal scale of clinical status from hospital discharge to death. Clinical improvement was defined as at least a two point improvement compared to a patient's admission status.

237 patients were enrolled and randomly assigned to a treatment group, 158 to remdesivir and 79 to placebo.

Findings Remdesivir use was not associated with a difference in time to clinical improvement.

No significant differences were noted between the groups in duration of oxygen support, length of hospital stay, or time to discharge or death. Treatment with remdesivir did not result in significant reductions in viral load or detection of the virus in the upper or lower respiratory tract compared with placebo. Although not statistically significant, patients receiving remdesivir had a numerically faster time to clinical improvement than those receiving placebo among patients with symptom duration <=10 days. There was no difference

APRIL/MAY 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

in adverse events between the groups, 66% of remdesivir recipients vs 64% of placebo recipients, with the most common in the remdesivir group being constipation, hypoalbuminaemia, hypokalaemia, anaemia, thrombocytopenia, and increased total bilirubin. Patients with serious adverse events tended to be lower in the remdesivir group than in the placebo group, 18% vs 26%. However, more patients in the remdesivir group discontinued treatment because of adverse events including gastrointestinal symptoms (anorexia, nausea, vomiting), aminotransferase or bilirubin increases, and worsened cardiopulmonary status, 12% vs 5%. Interpretation of findings is limited as the study was stopped early after investigators were unable to recruit the anticipated 453 patients due to a steep decline in cases in China resulting in insufficient power to detect differences in clinical outcomes.

Restrictions on bed availability also resulted in most patients being enrolled later in the disease course leading to inadequate assessment of clinical benefit in early treatment. This trial is now terminated.

Evidence from NCT04280705 clinical trial A phase 3 randomised, doubleblind, placebo-controlled Adaptive COVID-19 Treatment Trial (ACTT) by the National Institute of Allergy and Infectious Diseases (NIAID) in the United States evaluated the safety and efficacy of remdesivir for the treatment of COVID-19 in hospitalised adult patients.

Inclusion criteria included illness

In a preliminary analysis released on 29 April 2020 by the National Institute of Health of the primary endpoint performed after 606 recoveries were attained, patients who received remdesivir had a 31% faster time to recovery than those who received placebo. The median time to recovery was 11 days in the remdesivir group vs 15 days in the placebo group.

Results also suggested a survival benefit, with a mortality rate of 8% in the remdesivir group vs 12% in the placebo group. More comprehensive data results will be available in a forthcoming report. This trail is ongoing and currently recruiting patients.

Evidence from NCT04292899 clinical trial Another phase 3 randomised, open-label multicenter clinical trial (SIMPLE) by remdesivir manufacturers Gilead Sciences evaluated the safety and efficacy of 5 day and 10 day dosing regimens of remdesivir in hospitalised patients with severe COVID-19. The initial phase of the study randomised 397 patients in a 1:1 ratio to receive remdesivir 200mg on the first day, followed by remdesivir 100mg daily until day 5 or 10, in addition to standard of care. Patients were required to have evidence of pneumonia and reduced oxygen levels not requiring mechanical ventilation at the time of study entry. The primary endpoint was clinical improvement of two or more points from baseline on a predefined seven-point ordinal scale ranging from hospital discharge to increasing levels of oxygen support to death at day 14. Patients achieved clinical recovery if they no longer required oxygen support or were discharged from hospital.

33 Findings Initial study results announced on 29 April 2020 by Gilead Sciences found patients receiving a 5 day treatment course of remdesivir had similar improvement in clinical status compared with those receiving a 10 day treatment course. Time to clinical improvement for 50% patients was 10 days in the 5 day treatment group and 11 days in the 10 day treatment group. At day 14, observed rates between the 5 day and 10 day treatment groups were 65% vs 54% for clinical improvement, 70% vs 59% for clinical recovery, and 8% vs 11% for mortality. No new safety signals were identified with remdesivir across either treatment group. The most common adverse events in >10% patients in either group were nausea and acute respiratory failure.

Alanine aminotransferase (ALT) test elevations occurred in 7% of patients, with 3% discontinuing treatment due to elevated liver function tests. An expansion phase of the study recently added will enrol an additional 5600 patients including those requiring mechanical ventilation in 180 trial sites around the world inclusive of the United States, China, France, Germany, the Netherlands, Italy, Spain, Switzerland, Sweden, the United Kingdom, Hong Kong, Japan, Korea, Singapore, and Taiwan.

Evidence from compassionate use experience with COVID-19 In 163 compassionate use patients with severe COVID-19, liver function test abnormalities were reported in 12% of cases.

Time to onset from first dose ranged from 1-16 days with 4% of patients having serious abnormal liver function tests and 2% discontinuing remdesivir with elevated transaminases occurring on day 5. One serious adverse event of elevated blood bilirubin was identified in a critically ill patient with septic shock and multi-organ failure.

Evidence from clinical trials in healthy volunteers and subjects with Ebola virus disease Four phase 1 studies, GSUS-399-1812, GS-US-399-1954, GS-US-399-4231, and GSUS399-5505, found transient graded elevations in ALT and aspartate aminotransferase (AST) tests at repeated once daily doses of remdesivir in 138 healthy adult volunteers. A phase 2-3, open label, randomised, parallel group PALM study NCT03719586 assessed the safety and efficacy of remdesivir in 175 randomised

patients with Ebola virus disease.

No serious adverse events of transaminase elevations or hepatic events were reported.

Preliminary results from another double-blinded, randomised, viral persistence study NCT02818582 in male Ebola survivors indicated no serious side effects of transaminase elevations in the 20 subjects that received remdesivir.

Other Trials Multiple additional clinical trials are ongoing to generate more data on the safety and efficacy of remdesivir as a treatment for COVID-19. A second phase 3 SIMPLE trial NCT04292730 is evaluating the safety and efficacy of 5 day and 10 day dosing durations of remdesivir in patients with moderate manifestations of COVID-19, compared with standard of care. Results from the first 600 patients of this study are expected end of May 2020.

The World Health Organization (WHO) phase 2-3 Solidarity trial is evaluating the clinical efficacy and safety of four treatment options against standard of care for hospitalised adults with Covid-19 comprising remdesivir, lopinavir/ ritonavir, lopinavir/ritonavir with interferon beta, and chloroquine or hydroxychloroquine. Over 70 countries including Ireland have confirmed they will contribute to the trial, with many more in the process of joining.

Main secondary endpoints include duration of hospital stay and time to first receiving ventilation or intensive care.

Additionally, INSERM in France has initiated a multi-centre, adaptive, randomised phase 3 trial DisCoVeRy 2020-00093623 evaluating the safety and efficacy of potential treatments in hospitalised adults with Covid-19 using a WHO master protocol.

Investigational therapies include remdesivir, lopinavir/ritonavir, lopinavir/ritonavir and interferon beta, and hydroxychloroquine with the primary endpoint clinical status at day 15. The study is being carried out in France, Belgium, Germany, Luxembourg, the Netherlands, Spain, Sweden, and the United Kingdom.

Access to remdesivir Remdesivir is available as part of several ongoing clinical trials or from the manufacturer Gilead Sciences for treatment of severe COVID-19. The company has transitioned the provision of emergency access from individual compassionate use, limited due to supply issues to pregnant women or patients <18 years with confirmed COVID-19 and severe manifestations of disease, to

expanded access programmes to manage the volume of requests, expedite the delivery of remdesivir for patients, and enable the gathering of evidence-based data. This programme is currently available at two sites in Ireland.

seven calendar days from onset of the event. Over time, the expanded access programme in the United States will wind down as the EUA will enable more readily accessibility of remdesivir for appropriate patients.

In response to serious supply issues to date, Gilead Sciences has now shortened the lead time through process refinements and supplemented internal manufacturing with additional capacity from partners in the United States, Europe, and Asia.

More patients may also have access based on initial results from the SIMPLE NCT04292899 clinical trial demonstrating similar efficacy with 5 day vs 10 day dosing durations.

Researchers are also evaluating the potential for developing inhaled and oral dosage forms of the agent as alternative routes of administration.

Based on similar evidence and in recognition of the urgent need to treat critically ill patients with limited options available, on 7 May 2020 the Japanese Ministry of Health, Labour and Welfare granted regulatory approval for remdesivir, trade name Veklury®, as treatment for severe COVID-19 under an exceptional approval pathway.

Response to evidence on use of remdesivir for COVID-19 Based on emerging evidence, on 1 May 2020 the Unites States Food and Drug Administration (FDA) issued a temporary Emergency Use Authorisation (EUA) to permit the emergency use of remdesivir for treatment of suspected or laboratory confirmed COVID-19 in both adults and children hospitalised with severe disease. This authorisation is temporary and does not take the place of a formal new drug application submission, review, and approval process. Remdesivir remains an investigational drug and has not been approved by the FDA. Severe disease is defined as patients with SpO2 ≤ 94% on room air, or patients requiring supplemental oxygen or mechanical ventilation or extracorporeal membrane oxygenation (ECMO). A treatment course of 10 days is recommended for patients requiring mechanical ventilation and/or ECMO and 5 days for patients not requiring mechanical ventilation and/or ECMO. Given the limited experience with remdesivir at the recommended dose and duration, patients are required to have appropriate clinical and laboratory monitoring to support early detection of potential adverse events, inclusive of renal and liver function tests prior to initiation and daily during therapy, and serum chemistries and haematology daily during therapy. Healthcare providers and/or their designee are responsible for mandatory FDA reporting of all medication errors and serious adverse events or deaths considered potentially attributable to remdesivir within

On 8 May 2020 a rapid evidence review of clinical evidence for use of antivirals in the treatment of COVID-19 (v6) was published in Ireland inclusive of results from the remdesivir clinical trials. No update to the current Irish guidance on antivirals (v3) published on 24 April 2020 is required which states if access to remdesivir is possible, either through a clinical trial or through an emergency treatment request from Gilead Sciences, it is recommended for treatment of hospitalised patients with severe or critical disease that meet set clinical criteria. The stated dose is 200mg on day 1 followed by 100mg for 9 days.

On 11 May 2020 the European Medicines Agency (EMA) recommended expanding compassionate use of remdesivir to include treatment of hospitalised patients requiring supplemental oxygen, noninvasive ventilation, high-flow oxygen devices, or ECMO based on preliminary results from the NCT04280705 ACTT clinical trial.

In addition, treatment duration of 5 days has been introduced alongside the 10 day course, based on preliminary results from the NCT04292899 SIMPLE clinical trial. These recommendations will enable more patients with severe COVID-19 to access remdesivir while the EMA evaluate data on its benefits and risks and make a recommendation on marketing authorisation.

Results to date facilitate a clearer understanding of how treatment with remdesivir may be optimised if proven safe and effective. More evidence from ongoing clinical trials and emergency access programmes are needed to better understand whether this antiviral agent can provide meaningful clinical benefit. Depending on emerging data for its use, rapid access to remdesivir will be paramount to treat those in most need.

HOSPITALPROFESSIONALNEWS.IE | HPN • APRIL/MAY 2020

34 Feature

Duchenne Muscular Dystrophy (DMD): Current Pharmacological Management & Emerging Therapies

more exons occur in 11% of cases while small mutations (nonsense or frameshift) are noted in 20% of patients5.

general practitioner(s) and pharmacist(s). With increasing numbers of clinical trials and expanded access programmes the clinical pharmacist’s involvement in the management of DMD has greatly increased, making them a key member of the MDT.

Symptoms and Diagnosis

Pharmacological Management

DMD is not commonly diagnosed at or prior to birth unless there is a confirmed familial link. Traditionally, DMD is suspected in patients presenting with abnormal muscle function, elevated serum creatine kinase and elevated aspartate aminotransferase and alanine aminotransferase1. DMD is most frequently diagnosed between the ages of 4-5. However, it can be suspected much earlier in patients presenting with a significant delay in motor milestones. E.g. delayed walking. Genetic screening for the absence of the dystrophin gene is necessary to confirm a diagnosis of DMD.

Pharmacological treatment options for DMD maybe divided into genetic and non-genetic therapies.

Sarah-Jane Doyle M.P.S.I.

Introduction The term muscular dystrophies refers to a group of inherited genetic disorders which are characterised by progressive muscle weakening and atrophy which in turn leads to increasing levels of disability. Duchenne muscular dystrophy (DMD), is the most diagnosed muscular dystrophy. DMD is a clinically heterogeneous, severe and rare X-linked recessive neuromuscular childhood disorder1. While females maybe carriers or mildly affected DMD is predominantly diagnosed in males2. It occurs in approximately 1 in every 3600– 6000 live male births1. To date there is no published Irish data detailing the incidence of DMD. However, experts claim there are about 100 boys in Ireland under 18 with a DMD diagnosis.

The DMD or dystrophin gene is the largest known human gene containing 79 exons and spanning >2,200kb, approximately 0.1% of the entire genome3. It is responsible for providing the necessary instructions to make the protein dystrophin. Dystrophin is located predominantly in the skeletal and cardiac muscles works within a protein complex (the dystrophin complex) to strengthen muscle fibres4. It is also found to a lesser extent within the nerve cells of the brain and in the retina. A high pathogenic variant rate underlies the large variation of mutations which has been identified in DMD patients5. The pathogenic variant most frequently observed in DMD patients is a single or multiple out-of-frame exon deletion(s), accounting for approximately 68% of diagnoses5.

Large deletions are observed predominantly from exon 45 to exon 553. Duplications of one or

Signs and symptoms typically observed in DMD patients include2: - Difficulty from sleeping or sitting position - Walking on toes - Waddling gait - Increased incidence of falls - Large calf muscles - Muscle pain and stiffness - Cognitive delay / learning disabilities - Delayed growth Later complications of DMD include scoliosis, heart failure, respiratory insufficiency, long bone and vertebral fractures due to osteoporosis and eventual death6.

Management DMD is a multi-systemic, progressive disease1 which requires multidisciplinary team (MDT) collaboration in its management to improve ambulation, independence, quality of life and delay disease - related complications7.

Healthcare professionals involved in the MDT include (but are not limited to): consultant paediatric neurologist(s), consultant paediatrician(s), non-consultant hospital doctors (NCHDs), nurse specialist(s), occupational therapist(s), physiotherapist(s), social worker(s), dietician(s),

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Non-Genetic Therapies Glucocorticoids For decades glucocorticoids (i.e. prednisolone and deflazacort) have been the standard of care for DMD. They have been shown to prolong ambulation, slow the decline in muscle strength and delay the onset of secondary cardiac, pulmonary complications and scoliosis and prolong life expectency1.

How oral glucocorticoids impact DMD disease progression has been widely investigated.

Many hypotheses exist, some of which include: - Reduction in muscle necrosis and inflammation8.

- Enhancement of the proliferation of myogenic precursor stem cells or myoblasts and thereby increase muscle regeneration and growth due to their anabolic effect9.

- Improvement in muscle mass via inhibition of proteolysis (protein metabolism)10.

Initiation of glucocorticoid therapy usually occurs when the patient reaches the plateau phase. The plateau phase refers to the stage in disease progression where the patient’s motor skill progression begins to level off, halt or ‘plateau.’

This usually occurs between 4-6 years of age.

Steroid choices include prednisolone (0.75mg/kg/d) daily or alternative daily (e.g. 10 days on, 10 days off, or daily deflazacort (0.9mg/kg/d). While the summary of product characteristics for oral prednisolone advises alternate day dosing due to the increased risk of growth retardation in children10, daily dosing is preferred amongst experts as alternate day dosing does not necessarily reduce the incidence of adverse effects11. Therefore, the

recommended starting dose of prednisolone is 0.75mg/kg/day1.

Incremental increases in dose are recommended to accommodate patient growth to a maximum weight of 40kg1 (i.e. dose of 30mg/kg/day).

The drawback of glucocorticoid use is the unfavourable side effect profile. A dosing regimen of prednisolone 0.75mg/kg/ day is potentially associated with a ‘significant risk of weight gain, hirsutism, osteopenia/ osteoporosis, steroid induced cataracts and the development of features related to Cushing’s syndrome’12. If adverse effects are becoming problematic for the patient prednisolone 0.3mg/ kg/day is a suitable alternative regimen. This regimen is associated with less adverse effects but is less efficacious12.

Table 1 Recommendations to counteract glucocorticoid adverse effects illustrates practical steps recommended to counteract some commonly experienced side effects. If these measures prove ineffective and the patient’s quality of life is severely affected a review of glucocorticoid therapy is warranted.

Treatment of secondary cascades The PolarisDMD study is a Phase III, global study to evaluate the efficacy and safety of edasalonexent in paediatric patients with a genetically confirmed diagnosis of DMD13.

Male patients from 4-7 years of age maybe enrolled. NF-κB is a multifunctional transcription factor that controls gene expression and is involved in cellular responses to stress, modulating immune and inflammatory responses as well as skeletal muscle development and protein homeostasis14. NF-κB is activated in skeletal muscles of DMD patients due to the loss of sarcolemmal dystrophin14. Chronic activation of NF-κB is a key driver of muscle degeneration in DMD15. Edasalonexent is an orally administered anti-inflammatory agent which inhibits NF-κB. In animal studies NF-κB inhibition has demonstrated improved histology, function, and muscle regeneration14.

Vamorolone Vamorolone (VBP15) is a synthetically generated steroid designed specifically for use in

35 DMD patients. Its aim is to slow DMD disease progression.

A phase IIa multi-centre, open-label, sequential multiple ascending dose study evaluating the safety, pharmacokinetics, pharmacodynamics, and exploratory efficacy following oral administration of vamorolone 0.25, 0.75, 2.0,and 6.0 mg/kg/ day for two weeks, with two-week follow-up off drug, in boys ages 4–< 7 years of age with DMD16.

The study demonstrated positive safety outcomes in comparison to standard glucocorticoid therapy.

Use of vamorolone resulted in a reduction of insulin resistance, beneficial changes in bone turnover and a reduction in adrenal suppression16.

Enrolment is underway for phase IIb of the study. This study aims to compare the effect and side effect profile of vamorolone versus placebo and daily prednisolone to determine whether vamorolone improves muscle strength and function compared to placebo and whether it has fewer side effects compared with prednisolone17.

Cardioprotective agents DMD disease progression often results in a significant strain on

cardiac muscle with many patients developing cardiomyopathy. Early introduction of a cardioprotective agent e.g. beta-blocker or ACE inhibitor may significantly delay cardiomyopathy progression15.

Genetic Therapies At present, three genetic therapies are commercially available (Ataluren approval by EMA and Eteplirsen and Golodirsen approval by FDA). Numerous other genetic therapies are being rigorously assessed in clinical trials to determine their safety and efficacy. Like glucocorticoid therapy the following therapies aim to slow disease progression in DMD patients. However, unlike glucocorticoid treatment genetic therapies work by increasing dystrophin expression.

Nonsense suppression therapy As aforementioned small mutations are observed in some DMD patients. A nonsense mutation in the DMD gene is observed in approximately 10-15% of patients18. This mutation installs a premature stop codon in the dystrophin mRNA thus preventing the production of a fully functional dystrophin protein14.

Ataluren (Translarna) is currently licensed for the treatment of DMD resulting from a nonsense mutation in the dystrophin gene, in ambulatory patients aged 2 years and older. For some time, Irish patients could access ataluren solely via an expanded access programme operated by the drug’s manufacturer PTC Therapeutics.

However, in May 2019 a significant change occurred in the access to and reimbursement of ataluren in Ireland19. The HSE approved ataluren for reimbursement under the High-Tech Arrangement for ambulatory DMD patients aged 5 years and older. From the summer of 2019 approved prescribers could prescribe ataluren via the High-Tech Hub (HTH) for all eligible patients. Patients in the 2 to 5-year age bracket are reviewed on an individual basis and may still avail of ataluren via the expanded access programme as agreed by the HSE and PTC therapeutics.

Ataluren acts by enabling ribosomal readthrough of mRNA containing such a premature stop codon, resulting in production of a full-length protein20. Ataluren is indicated for oral administration in three daily doses (morning, midday and evening). The total daily dose

recommended is 40mg/kg/day which is divided up 10mg/kg in the morning and at midday followed by 20mg/kg in the evening20.

Adverse events observed with ataluren treatment include increased serum lipids (cholesterol & triglycerides) and a small increase in serum creatinine20.

Regular monitoring of bloods is recommended.

Exon Skipping Eteplirsen and Golodirsen are phosphorodiamidate morpholino oligomers (PMOs) designed to skip exons 51 and 53 respectively.

These RNA based technologies have received license for commercial use through the FDA. Eteplirsen received a negative approval through the EMA and is therefore not currently available in Europe commercially. Other exon skipping therapies are currently in various stages of pre-clinical and clinical development. Exon skipping works by restoring the dystrophin reading frame, thereby promoting the synthesis of a shorter dystrophin protein with the intention to slow the decline of ambulation and mobility seen in DMD patients21.

Gene Therapy: Microdystrophin

Table 1: Recommendations to counteract glucocorticoid adverse effects1 Adverse Effects

Issue

Recommendations

Immune system suppression and adrenal insufficiency

Minor illnesses are potentially fatal in the immunocompromised patient10.

Consult with infectious disease specialist should severe infection occur. The varicella vaccine does not currently form part of routine vaccination programme in Ireland Therefore, vaccination should be offered to DMD patients prior to glucocorticoid commencement. Switch to an intravenous alternative (e.g. hydrocortisone) to ensure treatment continuity should patient be nil-by-mouth.

Cushingoid features & Obesity

Significant weight gain

Provision of education on appropriate diet prior to commencement of treatment. Emphasise that glucocorticoid therapy is often linked with an increase in appetite.

Behavioural disorder

e.g. Low mood, attention deficit hyperactivity disorder (ADHD)

Consult with psychiatric specialist RE: management options. e.g. cognitive vs pharmacological

Gastro-oesophageal Reflux Disease (GORD) / Peptic Ulcer Disease (PUD)

Aggravated by corticosteroid use – heartburn and reflux

Consider addition of an antacid, proton-pump inhibitor (PPI) or H2-antagonist to treatment regime. If the patient tolerably swallows tablets offer an enteric-coated, gastroresistant prednisolone product.

Growth retardation

Growth plateaus

Refer to endocrinology

Glucose intolerance

Urine positive for glucose

Recommend regular pre & post-prandial glucose monitoring. Dietician lead diet modifications. Consider referral to endocrinology.

Demineralisation of bone.

Biannual DEXA scans. Annual monitoring of vitamin D blood levels. Vitamin D supplementation. Dietician advice on increasing dietary intake of vitamin D. Consult with endocrinology and consider bisphosphonate therapy.

Increased bone fractures

The addition of a synthetic dystrophin protein to replace the defunct or absent protein is not feasible due to its large size.

However, researchers have found it is possible deliver a synthetic DNA that encodes information for the cell to make a smaller dystrophin protein called microdystrophin22 The synthetic DNA is inserted into muscle cells by a viral carrier (vector) adeno-associated virus (AAV). A direct injection of the AAV vector has produced highlevel and persistent gene transfer in muscle23. Clinical trials are underway and are demonstrating encouraging results.

Conclusion There has been a significant increase in commercially available therapies for DMD within the last 5 years. Pharmaceutical companies continue to invest significant funding into DMD treatment research. Many novel therapies are emerging which could potentially have a significant impact on prolonging ambulation and improving life expectancy for DMD patients.

Sarah-Jane Doyle M.P.S.I. With special thanks to Dr Declan O’Rourke, Consultant Paediatric Neurologist, CHI at Temple Street.

References available on request

HOSPITALPROFESSIONALNEWS.IE | HPN • APRIL/MAY 2020

36 Feature

COVID lung damage 'largely unknown' Dr Cillian De Gascun, Consultant Virologist and Director of the National Virus Reference Laboratory (NVRL)

“If we look at the other human coronaviruses, which cause the common cold, obviously SARS is more severe, but people get lots of colds and they get better. Very occasionally some people get very sick.”

Individuals who suffer significant lung damage due to contracting Covid-19 and who recover from the virus may not return to full health, a leading virologist has warned.

There is currently no evidence that people who suffer mild to moderate effects of the virus will have any lasting negative impact on health, according to Dr Cillian De Gascun, consultant virologist and Director of the National Virus Reference Laboratory (NVRL).

But because the virus only “crossed over the species barrier in November”, with the first notification of the virus emerging from China on 31 December, Dr De Gascun says it is, as yet, largely unknown what the long-term consequences on health will be.

“Generally speaking, with respiratory viruses, they shouldn’t really have a long-term impact.

They tend to be fairly short lived infections. People either get better or they don’t,” he says.

However, in people who are hospitalised with the virus, for instance, and who suffer more severe symptoms, the repercussions on health could be long-lasting, says Dr De Gascun.

“If people end up in intensive care and they have a severe lung infection that can damage the lungs and lead to significant inflammation and scar tissue, then obviously that can have a longterm impact.

“I think that’s probably what we would most expect to see in the coming months and years; that

those individuals who have had very significant pulmonary disease may have reduced lung function in the future compared to what they would have had if they had not been infected with SARS CoV 2 [Covid-19].

“If somebody gets admitted to intensive care and has a significant infection or damage to their lungs then assuming they get out of intensive care and get back to an otherwise normal life they may well struggle to recover. Some of the older individuals, maybe people who smoke previously, those type of individuals, would probably struggle to get back to baseline if they have significant lung damage as a result of Covid-19.

“But for the majority of people in the community who have mild to moderate infection at this stage there is no reason to think they will have significant, long-term health morbidities. There is no real evidence to suggest they would have a long-term negative impact on their health as a result of having SARS CoV 2.”

Direct Healthcare Professional Communications published on Direct Healthcare Professional Communications on the HPRA website since the the HPRA website since the last published Drug Safety Newsletter last Drug Safety Newsletter PRODUCT

SAFETY ISSUE

Esmya

Esmya 5mg Tablets (Ulipristal acetate) for uterine fibroids not to be used during ongoing review of liver injury risk

Xeljanz

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Picato

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Increlex

Risk of benign and malignant neoplasia of INCRELEX 10mg/ml Solution for Injection (mecasermin)

Methotrexate

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Cyproterone acetate*

Restrictions in use of cyproterone acetate due to risk of meningioma

** Due Dueto to unprecedented logistical as aCOVID-19 result ofpandemic the current COVID-19 haveholder’s impacted the the unprecedented logistical limitations as a limitations result of the current which have impacted onpandemic the marketingwhich authorisation (MAH –on i.e. the company which holds a licence for aholder’s medicine) capacity print the and distribute the Direct Healthcare Communication (DHPC) for cyproterone acetate the marketing authorisation (MAH –to i.e. company which holds aProfessional licence for a medicine) capacity to print and in hard copy format to healthcare professionals at this time, a copy of the full text is appended to this DSN, with a link to the electronic version available on the HPRA distribute the Direct website at the above link. Healthcare Professional Communication (DHPC) for cyproterone acetate in hard copy format to healthcare professionals at this time, a copy of the full text is appended to this DSN, with a link to the electronic version available on the HPRA website at the above link.

APRIL/MAY 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

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Abbreviated prescribing Information 3 Refer to -full Summary of Product Characteristics before prescribing. stoma output 2 Simple to use, low volume stoma output of magnesium may Because of increased magnesium losses, a dose adjustment Name: Magnaspartate 243 mg powder for oral solution Presentation: Each - Suitable gastric, duodenal be necessary when taking the following substances: for Aminoglycoside antibiotics, box contains 10 sachets. Each sachet of powder3 contains magnesium aspartate - Suitable for gastric, duodenal Twice daily cisplatinum and ciclosporin A, Diuretics (such as thiazide and furosemide), EGFdihydrate -equivalent to 243 mg (10dosing mmol) of magnesium. Indication: Treatment and nasal feeding 3 inhibitors receptor antagonists (such as cetuximab and erlotinib), proton pump and prevention of magnesium deficiency, as diagnosed by a doctor. Dosage and and nasal feeding (such as omeprazole and pantoprazole) and viraltoDNA administration: Adults (> 18 years) 1-2 sachets daily; Children and adolescents 10 - Simple use,polymerases-inhibiting low volume foscarnet, pentamidine, rapamycin and -amphotericin B. to 18 years: 1 sachet daily; Children 4-10 years: One level 5ml spoon daily (109 mg) Simple to use, low volume3 Twice daily dosing or One sachet daily (243 mg); Children 2 to 4 years: One level 5ml spoon daily (109 Side-effects: Uncommonly, Soft stools or diarrhoea following high 3dosage and mg). For oral use after solution in water, tea or orange juice. Contraindications: - Twice daily dosing 1

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3

References: 1. Kora Healthcare & Costello, S. Evaluation of solubilities of various Magnesium compounds. 2013; Report 1-5 and response to questions 2. Turner, P., Mishra, V., and Marks, E.M.C. Effect of magnesium-l-aspartate supplementation on the plasma magnesium levels in patients with short bowel syndrome. Conference Abstract 2007 3. Magnaspartate® SmPC https://www.medicines.ie/medicines/magnaspartate-243-mg-powder-for-oral-solution-34759/smpc (accessed 26/11/2019)

Hypersensitivity to the active substance or to any of the excipients. Severe renal impairment, Disorders of Cardiac conduction (bradycardia).

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very rarely fatigue if used long-term. MA: PA 1748/002/001. MA Holder: Kora Corporation Ltd t/a Kora Healthcare, Swords Business Park, Swords Co. Dublin, Ireland Legal category: POM. Price: €8.70 Date of text: April 2019, PR_MAGIE_041901

Special warnings and precautions: In the case of confirmed magnesium Adverse events should be reported. Reporting forms and information deficiency, concomitant hypocalcaemia and hypokalaemia should be suspected and can be found at HPRA Pharmacovigilance, Earlsfort Terrace, Dublin 2, corrected if confirmed since magnesium deficiency is frequently secondary to those Ireland. Tel: +353 1 6764971 Fax: +353 1 6762517 Website: www.hpra.ie conditions. Contains sucrose. Patients with rare hereditary problems of fructose Prescribing information medsafety@hpra.ie. Adverse events should also be reported to intolerance, glucosegalactose malabsorption or sucrase-isomaltase insufficiency is available at e-mail: the Kora Healthcare on 01-8900406 or medinfo@korahealthcare.com should not take this medicine. Frequent and long-term use of Magnaspartate 243

01-8900406

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Prescribing information

supplementation for treatment and prevention of magnesium diagnosed by a doctor.

2. Turner, P., Mishra, V., and Marks, deficiency E.M.C. asEffect of magnesium-l-aspartate supplementation on the plasma magnesium levels in patients

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References: 1. Kora Healthcare & Costello, S. Evaluation of solubilities of various Magnesium compounds. 2013; Report 1-5 and response to

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€8.70 Box of 10 sachets

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with short bowel syndrome. Conference Abstract 2007 PA 1748/002/001 is available at the MAH: Kora3.

Corporation Ltd, t/a Kora Healthcare Magnaspartate® SmPC https://www.medicines.ie/medicines/magnaspartate-243-mg-powder-for-oral-solution-34759/smpc Swords Business Park, Swords, Co. Dublin, Ireland (accessed 26/11/2019) company stand

PR_MAGIE_022001 Date of preparation: February 2020

www. korahealthcare.com

38 Mental Health

Coping With Coronavirus How To Stay Calm and Protect your Mental Health: A Psychological Toolkit Professor Brendan Kelly, Consultant Psychiatrist, Tallaght University Hospital, Professor of Psychiatry, Trinity College Dublin

Dealing with Feelings Coronavirus, or Covid-19, generates anxiety and panic in the minds of virtually everyone who hears about it. This extract from my new book, “Coping with Coronavirus” (Merrion Press), focuses on managing our feelings, with a view to helping us to become more aware of our emotions and recognising when feelings rather than logic are governing our behaviour. There is nothing wrong with emotions shaping what we do, but it is useful to recognise when this is happening and to be more aware of the interplay between logic and emotion in our thoughts and actions. This matters, now more than ever.

Don’t forget that emotions can disguise themselves as behaviours or facts - and can therefore mislead us The problem with much of the advice about managing our emotions is that our emotions do not always present themselves as emotions. Often, they manifest as behaviours that we poorly understand (even in ourselves), ‘facts’ that upset us (and likely are not true) or a general sense of confusion about what is going on (and how we are feeling). This is especially true when someone is diagnosed as ill or is asked to do something that suggests that, while they are not yet ill, they might soon be (e.g. self-isolation

APRIL/MAY 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

or limited social interaction).

These situations feel mid-way between wellness and illness. You are well, but you are being treated as if you are ill. So, how, exactly, are you supposed to feel? Well or ill?

The first step in dealing with these peculiar and distressing situations is to recognise that we can have several conflicting emotions at the same time or in quick succession. The rules of logic apply loosely, if at all. Much of what we feel might not make sense, at least at first glance.

Recognising this is important. We like to think that our emotions and inner lives have a certain reason to them, but sometimes we need

to acknowledge the existence of a tangle of emotions that we simply cannot figure out. There they are.

So be it.

The second step in this situation is to practice simply sitting with uncomfortable emotional states – tolerating distress without trying to understand it fully. An activity like meditation helps greatly with this. To try this, find a quiet spot where you are unlikely to be disturbed. You will never find a place that is entirely secluded but do try to find one that minimises disturbances and distractions.

Having calmed your body gently and centred your thoughts in the moment, focus on your breath. To begin, silently count ten breaths

39 direct your thoughts back to your breathing. This is a skill that takes time. If it does not work out today, try again tomorrow. If it does not work out tomorrow, try the next day. And so on.

Meditation is often described as ‘a practice’. This is very true.

Even the meditation masters, after decades of contemplation, are still ‘practicing’.

Do talk to others about your feelings (but label them clearly as feelings rather than facts) It is helpful to talk to other people about how you are feeling. It is equally helpful to listen to others who are often experiencing the same emotions as you are but might express them differently.

Take time to let them explain.

Once you listen properly, you will see how similar we all are.

explore these distractions in your head. Simply try to sit with them and observe how quickly such passing thoughts and emotions disappear once we deny them the oxygen of our attention.

When expressing your emotions, be sure to label them as feelings rather than facts. It can help to write down how you feel beforehand. It is not helpful for you or others to express feelings through anonymous, hysterical speculation on social media. The Buddhist concept of ‘right speech’ is relevant here. This is one of the key tenets of the ‘Noble Eightfold Path’ of Buddhism. It centres on avoiding harsh words against others, only saying what is true, speaking in a way that promotes understanding, using a reasonable tone of voice and ensuring that our speech is honest and truthful. This is also known as ‘mindful speech’.

This is not easy to achieve, so do not be dismayed if you get distracted. Simply try again.

Commit to trying this for ten minutes. Do not berate yourself each time you get distracted.

Practice self-compassion. Gently

It is sometimes difficult to adhere to right speech, particularly when we are upset. But right speech is especially important when we are distressed and at times of threat, illness or personal loss.

These issues are clearly relevant

Professor Brendan Kelly (photo credit Ruth Medjber)

on the in-breath. Then count ten breaths on the out-breath.

Then count ten breaths on the turning of the breath. And then start again.

As you try to do this, a variety of thoughts will inevitably enter your head. Emotions will come to the surface and you will get distracted. The work of meditation lies in observing these thoughts, emotions and distractions but not engaging with them. So, try not to

in the context of coronavirus.

For some people, personal losses might include loss of hope or loss of health and, for others, bereavement. Direct, truthful communication is vital in these circumstances. We need to remember that discussing emotions is central to honest communication, once we are just as willing to listen as we are to speak.

In other words, if you want to be heard, listen.

Brendan Kelly is Professor of Psychiatry at Trinity College Dublin and author of “Coping with Coronavirus. How to Stay Calm and Protect your Mental Health: A Psychological Toolkit” (Merrion Press). The e-book costs ¤1 and royalties will go to charities assisting with the global response to coronavirus: https://www.amazon.co.uk/ gp/product/B0869TH43N/ ref=dbs_a_def_rwt_bibl_vppi_i0

COVID-19 Psychological Survey - First Wave Researchers from the Trinity Centre for Global Health have released the first wave of the Irish COVID-19 Psychological Survey; a multi-wave study running throughout the COVID-19 outbreak to better understand how people are responding, understanding, and coping with the pandemic.

The Trinity research team collaborated with researchers from Maynooth University, Ulster University, Edinburgh Napier University, and University of Sheffield.

Over 1,000 adult citizens of the Republic of Ireland completed the survey, which was launched on

31 March; 31 days after the first confirmed case of COVID-19 was reported in the Republic of Ireland.

The survey was launched 19 days after An Taoiseach Leo Varadkar announced sweeping restrictions on the movement of people, and two days after Irish residents were required to stay at home.

Participants answered questions about their current circumstances of the COVID-19 pandemic, their mental health, and their views on COVID-19 vaccination.

Initial results suggest that mental health problems are common; 41% of people reported feeling lonely, 23% reported clinically meaningful levels of depression,

20% reported clinically meaningful levels of anxiety, and 18% reported clinically meaningful levels of post-traumatic stress.

Dr Frédérique Vallières, Director of Trinity College’s Centre for Global Health further added, "Despite encouraging results in terms of people’s knowledge on COVID-19, we further found that attitudes towards the uptake of a potential COVID-19 vaccine to be worryingly low, with only 65% of people indicating that they would accept a vaccine for themselves and their children. One-in-four people did say however that they might accept a vaccine for themselves and their child, compared to one-

in-ten people who said they would not. A better understanding of why people might be hesitant to accept a COVID-19 vaccine, if and when it is developed is required."

The second wave of the COVID-19 Psychological Survey is scheduled to commence prior to May 5th 2020. The research team will examine what effect prolonged quarantine and physical distancing measures have on people’s mental health and well-being, and what can be done to safeguard the mental health of the nation during this and any future health emergency. The research team seek to understand more about COVID-19 vaccine hesitancy.

HOSPITALPROFESSIONALNEWS.IE | HPN • APRIL/MAY 2020

40 News Early Planning needed for Flu Warning that such an ambitious programme will not be without challenge President, Irish Medical Organisation, Dr Padraig McGarry

The President of the Irish Medical Organisation (IMO), Dr Padraig McGarry, has said that the Government’s plans for a total population flu vaccine programme will require urgent and detailed planning now if it is to be successful.

Dr McGarry said that the IMO fully supported the announcement

(this morning) by the Minister for Health that he was seeking a total population flu vaccine scheme.

Dr. McGarry said that such a population wide scheme was critically important this year in the context of Covid-19; “Covid-19 changes the flu challenge completely. We simply can’t have the double-whammy of a Flu and

Covid-19 crisis this winter. We have to up our game in respect of flu vaccinations and a total population approach is the way to do it.”

However Dr McGarry warned that such an ambitious programme would not be without challenge; “If this is to work as it must, we have to invest

immediately in detailed planning to get it right. The key will be to vaccinate people as early as possible. The IMO will work with the Government to agree an ambitious programme and we look forward to an early engagement on the issue.”

Dr McGarry also warned that the Government can not assume that people will be enthusiastic for a broad vaccination programme; “the sad reality is that the authorities have lost some ground to fringe movements of anti-vaxers. We have to redouble our efforts to educate people about the necessity and the safety of vaccination and we must not concede any ground to reactionaries or fringe commentators who are only interested in stoking fear.”

Dr McGarry also stressed the importance of a GP focussed vaccination programme; “we’ve seen previously that patients are most likely to take up vaccinations on the advice of their GP. At this time in particular, continuity of care is vital and GPs are best placed to deliver this.”

Minister Harris addresses WHO Minister for Health Simon Harris TD has recently addressed the World Health Organisation’s annual World Health Assembly.

Normally held in Geneva, this year’s Assembly took place virtually over video conference technology, with an agenda focusing almost exclusively on the COVID-19 response.

Minister Harris said, "Though the pandemic prevents us from meeting in the traditional format,

this meeting will be an important opportunity for the WHO and its Member States to collectively address the single most pressing global health issue in a moment of crisis.

“It is essential we continue to work collectively to confront this global threat.

“It is also an opportunity for Ireland to show its support for the World Health Organisation.

“In this time of great crisis, we need unity, not division. We cannot allow the politicisation of this pandemic. Ireland stands shoulder to shoulder with the WHO.” WHO Director-General Tedros Adhanom Ghebreyesus addressed delegates on the COVID-19 pandemic preparedness and response, followed by statements from health ministers.

Minister Harris paid tribute to healthcare workers, and

underlined the importance of ensuring equitable access to vaccines, diagnostics, therapeutics and equipment in the COVID-19 context.

Member States are expected to adopt a global resolution on the COVID-19 response which calls for an intensification of cooperation and collaboration at all levels to contain, control and mitigate the COVID-19 pandemic.

New Approval from Clonmel Clonmel Healthcare is delighted to announce the launch of Cinacalcet Clonmel 30mg, 60mg and 90mg Film-coated Tablets.

disease (ESRD) on maintenance dialysis therapy.

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APRIL/MAY 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

therapy in whom secondary HPT is not adequately controlled with standard of care therapy.

Please contact Clonmel Healthcare on 01-6204000 if you require any additional information.

Full prescribing information is available on request or alternatively please go to www.clonmel-health.ie. Product is subject to medical prescription.

PA 126/306/001-003. PA Holder: Clonmel Healthcare Ltd., Clonmel, Co. Tipperary. Date prepared: April 2020. 2020/ADV/CIN/034H

News 41

Harnessing Technology for Cystic Fibrosis The Adult Cystic Fibrosis Team at University Hospital Galway who are using technology to replace face-toface appointments and minimise staff and patient interactions as part of social distancing measures

The Adult Cystic Fibrosis Team at University Hospital Galway is using online video conferencing to replace face-to-face outpatient appointments during the COVID-19 outbreak.

Dr Michael O’Mahony, Adult Cystic Fibrosis Physician explains, “We were successful in obtaining Sláintecare Integration Funding at the start of the year for a telemedicine project which will involve delivering a Physiotherapy Service via online video link to our patients to increase our level of physiotherapy input into their care between their scheduled outpatient appointments.

“We were lucky to have the set-up in place so that when social distancing became a necessity at the hospital and most outpatient appointments were cancelled, we turned to this technology.

“Our patients now have a video consultation with the team here in the hospital. We talk to the patients individually about their care in terms of our different specialties.

Patients get to speak to myself, the Clinical Nurse Specialist, the Dietitian, the Physiotherapist and our Psychologist as required, via the video link. Each of the team can access the video link in different consultation rooms which means that we are able to observe social distancing as well.

“The video consultation covers everything that the patient would normally get from a consultation in the hospital apart from spirometry testing and measuring vital signs but we are planning to roll out further technology-based solutions to record this physiological data from the patient’s home going forward, as part of a pilot study.

“As we deal with the COVID-19 outbreak, I urge everyone to comply with all the public health advice to keep yourself and others protected. Hand hygiene, cough etiquette and staying at home are all very important if we want to slow down the spread of this disease and save lives.”

1

1. Dr Michael O’Mahony, Adult Cystic Fibrosis Physician 2. Mary Connolly, Dietitian with the Adult Cystic Fibrosis Team 3. Stephen Bradish, Physiotherapist with the Adult Cystic Fibrosis Team

2

4. Orela Ryan-Fox, Clinical Nurse Specialist with the Adult Cystic Fibrosis Team

3

4 HOSPITALPROFESSIONALNEWS.IE | HPN • APRIL/MAY 2020

42 News

FIP Guidance for Hospital Pharmacists Jane Dawson, Chair, International Pharmaceutical Federation

 Modes of transmission and incubation period  Pharmacy operations and facilities: ensuring safety and continuity of service  Preventive measures, including the use of masks  Pharmacy interventions and patient counselling Guidance for pharmacists in hospital and clinical biology on coronavirus/COVID-19 has been updated by the International Pharmaceutical Federation (FIP) and is released today.

The document replaces FIP’s first coronavirus guidance issued last month. “The situation has developed rapidly and an urgent update was necessary as, around the world, we are learning more

about this new virus,” said Mrs Jane Dawson, chair of FIP’s Emergency Taskforce, who is also secretary of FIP’s Military and Emergency Pharmacy Section and director of health policy for the New Zealand Defence Force.

The updated guidance document takes into account newly available evidence and recommendations. In particular, around:

 Treatment guidelines and medicines that may need to be stocked  Progress in medicines and vaccines development  Laboratory testing for COVID-19 in suspected human cases  Cleaning and disinfection products and procedures  Travel advice

The guidance also addresses opinions on the safety of the use of ibuprofen, ACE inhibitors, angiotensin receptor blockers and corticosteroids during the coronavirus/COVID-19 pandemic, which suggest an increased risk of infection or increased severity of disease. FIP has issued a position statement on this issue today, available on the federation’s website.

“Since COVID-19 was declared a pandemic by the World Health Organization just over a week ago, and with some countries going into lockdown, we have seen an even greater reliance on pharmacists as the first point of contact with the health system. FIP has been hearing from colleagues around the world who have been stepping up to get their communities through this challenging time for our health services. We thank them for the amazing work that they are doing under increased pressure and hope that this updated guidance will support them in their practice,” Mrs Dawson said.

FIP’s Coronavirus Emergency Taskforce is made up of experts from several countries, including China, and representing different regions around the world. FIP is collaborating with its member organisations and other partners to make this guidance available in different languages for maximal dissemination and use.

SVUH take part in global research efforts to tackle pandemic St. Vincent’s University Hospital has started to enrol ICU patients in COVID-19 trial as part of global research efforts to tackle the pandemic The new clinical trial began enrolling COVID-19 patients at the start of April and will test interventions for COVID-19 in critically ill patients, capture the outcomes and analyse data across an international network* in a global effort to reduce the impact of COVID 19 in Intensive care settings. Rapid data sharing will ensure findings relevant to the COVID-19 outbreak are shared quickly with others working in the area to inform decision making.

Consultant Anaesthetist, Professor Alistair Nichol, St Vincent’s University Hospital and University College Dublin, who is

the Irish lead on the trial, explains how it will work and why it is so important.

‘In the 2009, H1N1 pandemic many groups tried to conduct trials in a timely manner, however, our groups and others couldn’t establish a clinical trial in time to respond to the pandemic. So, we designed a new trial called REMAP CAP to recruit in “peacetime” but to be able to convert rapidly in the event of a pandemic, such as COVID-19. This trial will now allow a rapid response which is ready to enrol Irish patients in intensive care units in the first weeks of such a pandemic. This means we can rapidly generate evidence to guide doctor’s decisions on the best treatment for critically ill patients with COVID-19.’

Researchers in Ireland led by Prof

APRIL/MAY 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

Nichol will work with local network of Clinical Research Facilities and other partners across academia and hospitals to start assessing these potential interventions as quickly as possible. The COVID-19 aspect of the trial will commence in ICUs in St Vincent’s University Hospital and University Hospital Galway in the next week.

Beaumont Hospital have signed contracts and the following hospitals are preparing to be involved soon: Cork University Hospital and University Hospital Limerick as well as the Royal Victoria Hospital in Belfast, with others to will follow.

Professor Peter Doran, Director of Research, St. Vincent’s Healthcare Group said: “This trial continues our tradition of research and scholarship and is a sign of our commitment to improving

patient outcomes. The study also reinforces the global impact of UCD and St Vincent’s University Hospital who by working together and engaging in robust appraisal of different treatments will help to enhance knowledge of Covid-19 and play our part in the global effort to overcome this devastating pandemic.”

The additional interventions that have been proposed for Covid-19 trials, are prioritised by experts brought together by the World Health Organisation in midFebruary, and these Covid-19 trial interventions will be rolled out across the international network. *The international network involves research teams in UK, Ireland, Netherlands, Germany, Belgium, Singapore, New Zealand, Australia and Canada.

News 43

Bayer Contributes to Fight Against COVID Dr Mike Devoy, Member of the Executive Committee of Bayer AG's Pharmaceuticals Division and Chief Medical Officer

Bayer is undertaking a number of initiatives to support the fight against COVID-19 both globally and here in Ireland.

Firstly, Bayer employees around the world have taken the necessary measures to ensure the continuity of the operations.

Supplying hospitals, doctors, patients and consumers with our products and services on a sustainable basis is a key priority.

Secondly, the company is using its knowledge and resources to combat the virus.

Bayer has announced it will partner with the Canadian Population Health Research Institute (PHRI) in launching a major clinical research programme aimed at identifying potential treatments against COVID-19.

The two studies will evaluate the safety and efficacy of different combination therapies including Bayer’s chloroquine and interferon beta-1b. “Treatments against COVID-19 are urgently needed as no validated options are currently available,” said Dr. Mike Devoy, Member of the Executive Committee of Bayer AG's Pharmaceuticals Division and Chief Medical Officer. “We want to contribute to the global fight against the coronavirus through our products and expertise and look forward to partnering with the PHRI.” Bayer is making a

financial commitment of CAD 1.5 million (approx. ¤1 million) towards the studies and will supply study drugs to support the research.

help with their energy needs and Bepanthen to help protect faces from the marks caused by wearing masks and to nourish dry hands.

In addition, as part of joining the COVID-19 Therapeutics Accelerator, initiated by the Bill & Melinda Gates Foundation, Bayer will open its compound library to find and develop effective novel compounds.

Bayer is also supporting patients by contributing towards the establishment of services that are being set up by some patient group associations here in Ireland to assist during this pandemic. This includes support for the Irish Heart Foundation who have established a service for patients who have had a stroke. Many stroke nurses in hospitals are being redeployed to care for COVID-19 patients, so are no longer able to undertake important follow up checks with stroke patients after discharge. At the request of the HSE, the IHF is now providing this vital service and complimentary supports to stroke patients in the community for a five-month period.

Since the outbreak of the COVID-19 crisis, Bayer has donated money, medicines, protective equipment and medical devices worth approximately ¤11 million worldwide. It has donated ¤1 million each to various health care institutions in the European countries badly affected by the pandemic - Italy, Spain and France; and is currently preparing to make a further donation of around ¤1 million to fight the pandemic in Brazil.

At the Pharmaceuticals Division's Berlin headquarters, Bayer set up its own test laboratory, where specially assigned employees perform up to 1,000 COVID-19 tests every day.

Here in Ireland, Bayer is making a product donation to the HSE for front line healthcare workers to support them at this challenging time. The donation comprises of Berocca, a supplement to

About Bayer Bayer is a global enterprise with core competencies in the life science fields of health care and nutrition. Its products and services are designed to benefit people by supporting efforts to overcome the major challenges presented by a growing and aging global population. At the same time, the Group aims to increase its earning power and create value through innovation

and growth. Bayer is committed to the principles of sustainable development, and the Bayer brand stands for trust, reliability and quality throughout the world. In fiscal 2019, the Group employed around 104,000 people and had sales of 43.5 billion euros. Capital expenditures amounted to 2.9 billion euros, R&D expenses to 5.3 billion euros. For more information, go to www.bayer.com.

Forward-Looking Statements This release may contain forward-looking statements based on current assumptions and forecasts made by Bayer management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the actual future results, financial situation, development or performance of the company and the estimates given here. These factors include those discussed in Bayer’s public reports which are available on the Bayer website at www.bayer.com. The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments.

HOSPITALPROFESSIONALNEWS.IE | HPN • APRIL/MAY 2020

44 News

RCSI develop Covid Buffer

Nubeqa® EU approval

Over the weekend, a team at RCSI made an essential buffer for COVID-19 testing called viral lysis buffer. This buffer breaks open the coronavirus and extracts RNA. Once more of the key reagent (guanidine thiocyanate) is received next week, another batch will be produced for testing sites in our associated hospitals, Beaumont and Connolly Hospitals. Thanks to Profs Donal O’Shea, Steve Kerrigan, Drs Sudipto Das, Emmet Campion and Richard Carroll for carrying out this vital piece of work to assist with the testing of COVID-19.

Bayer has announced that the European Commission has granted marketing authorisation in the European Union (EU) for Nubeqa® (darolutamide), an oral androgen receptor inhibitor (ARi). The compound, which is developed jointly by Bayer and Orion Corporation, is indicated for the treatment of men with non-metastatic castrationresistant prostate cancer (nmCRPC), who are at high risk of developing metastatic disease. Bayer is responsible for global commercialisation, with a co-promotion of Bayer and Orion Corporation in certain European markets.

Nubeqa has a distinct chemical structure which inhibits the growth of prostate cancer cells while limiting the burden of side effects on patients’ everyday lives. The EU approval is based on the pivotal Phase III ARAMIS trial data evaluating the efficacy and safety of darolutamide plus androgen deprivation therapy (ADT) compared to placebo plus ADT.

Galway Research Leaders

Dr Akke Vellinga, NUI Galway

Professor Gary Donohue, NUI Galway

Professor Gary Donohoe, Established Professor of Psychology at NUI Galway and Director of the NUI Galway Center for Neuroimaging, Cognition and Genomics, and Dr Akke Vellinga, Epidemiologist and Senior Lecturer in the School of Medicine, have been named as two of five new Research Leaders by the Health Research Board.

Each Research Leader has developed strong partnerships with different parts of the health sector to conduct research programmes that will deliver evidence to directly inform changes in health policy and practice. Professor Donohoe is aiming to provide psychosocial supports for young people with severe mental health challenges, while Dr Vellinga will provide

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actionable research to reduce infections and the use of antibiotics.

informing implementation of best practice and new discoveries in routine care.”

Professor Donohoe’s award is in the area of youth mental health, in collaboration with the National Early Intervention for Psychosis Service. The overarching aim of this research program is to build capacity for evaluating and implementing psychological treatments in young people with mental health difficulties. 75% of all mental health difficulties first occur between 15-25 years of age, but despite this young people have the poorest access to treatment and supports. The more severe of these disorders, including schizophrenia and other psychotic disorders, are ranked by the World Health Organisation as a top five cause of years lived with disability.

Dr Vellinga was named as Health Research Board Research Leader for her Collaboration to reduce Antibiotic use and Resistance and identify opportunities for improvement and Awareness (CARA) project. In Europe, about 33,000 people die each year as a direct consequence of an infection due to bacteria resistant to antibiotics.

Commenting on the award, Professor Donohoe said: “This is a tremendous opportunity to lead a collaboration with key figures in the Health Service Executive providing early psychosis services, and international experts in youth mental health research. This award recognises the critical need for research-informed services focused on youth mental health,

Dr Vellinga said: “Superbugs cause resistant infections which are difficult to treat and pose a serious threat to human health.

This programme will combine, link and analyse data from multiple already existing databases about infection, antibiotic prescribing antibiotic resistance and other healthcare- information. The CARA data-infrastructure will be set up with dashboards for other researchers, clinicians, and healthcare workers to visualise relevant and linked data. Using data visualisation, we will be able to identify opportunities to reduce infections and antibiotic use and improve health care.”

Clinical R&D 45 Global Kevzara® (sarilumab) clinical trial programme The first patient outside of the U.S. has been treated as part of a global clinical program evaluating Kevzara® (sarilumab) in patients hospitalized with severe COVID-19. The global clinical program has now been initiated in Italy, Spain, Germany, France, Canada, Russia and the United States – all countries that have been impacted by COVID-19.

This is the second multi-center, double-blind, Phase 2/3 trial as part of the Kevzara COVID-19 program, and the companies are continuing to work with health authorities around the world to secure initiation at additional sites. This follows Sanofi and Regeneron's announcement earlier this month of the initiation of the first trial, which is U.S.-based.

"Sanofi and Regeneron are relentlessly working to rapidly initiate trials around the world that will help determine whether Kevzara has the potential to play a role in addressing the COVID-19 global health crisis. These trials will provide important data to determine whether Kevzara ameliorates the life-threatening complications of COVID-19 infections by counteracting the overactive inflammatory responses in the lungs when damaged by the virus. In these unprecedented times, we are deeply grateful for the daily collaboration with health authorities that are enabling us to conduct this clinical work so quickly," said John Reed, M.D., Ph.D., Sanofi's Global Head of Research and Development. "In addition to this clinical trial aiming to help critically ill COVID-19 patients, our work continues to bring forth a vaccine for disease prevention, along with efforts to provide other important Sanofi medicines that may help patients impacted by COVID-19."

Kevzara is a fully-human monoclonal antibody that inhibits the interleukin-6 (IL-6) pathway by binding and blocking the IL-6 receptor.

IL-6 may play a role in driving the overactive inflammatory response in the lungs of patients who are severely or critically ill with COVID-19 infection. The role of IL-6 is supported by preliminary data from a single-arm study in China using another IL-6 receptor inhibitor.

"Data from a single-arm study in China suggest that the interleukin-6 pathway may play an important role in the overactive inflammatory response in the lungs of patients with COVID-19. Despite this encouraging finding, it's imperative to conduct a properly designed, randomized trial to understand the true impact of Kevzara, which we are now doing through this global clinical trial program," said George D. Yancopoulos, M.D., Ph.D., Co-founder, President and Chief Scientific Officer of Regeneron. "In addition to the Kevzara program, Regeneron continues to rapidly advance a novel antibody cocktail for the prevention and treatment of COVID-19."

under a global collaboration agreement. Kevzara is a fully-human monoclonal antibody. Kevzara binds specifically to the IL-6 receptor, and has been shown to inhibit IL-6-mediated signaling.

IL-6 is an immune system protein produced in increased quantities in patients with rheumatoid arthritis and has been associated with disease activity, joint destruction and other systemic problems.

Kevzara is being investigated for its ability to reduce the overactive inflammatory immune response associated with COVID-19 based on evidence of markedly elevated levels of IL-6 in severely ill patients infected with coronaviruses.

The trial outside of the U.S. will assess the safety and efficacy of adding a single intravenous dose of Kevzara to usual supportive care, compared to supportive care plus placebo. The trial has an adaptive design with two parts and is anticipated to enroll approximately 300 patients.

The trial will recruit hospitalised patients from several countries who are severely or critically ill with COVID-19 infection.

Sanofi receives positive CHMP opinion for Sarclisa® (isatuximab)

Scientists have preliminary evidence that IL-6 may play a key role in driving the inflammatory immune response that causes acute respiratory distress syndrome (ARDS) in patients critically ill from COVID-19. In an initial, nonpeer-reviewed case series from China, a 21-patient cohort of COVID-19 patients experienced rapidly reduced fevers and 75% of patients (15 out of 20) reduced their need for supplemental oxygen within days of receiving another IL-6 receptor antibody (tocilizumab).

Based on these results, China updated its COVID-19 treatment guidelines and approved the use of that IL-6 inhibitor to treat patients with severe or critical disease.

The use of Kevzara to treat the symptoms of COVID-19 is investigational and has not been evaluated by any regulatory authority.

Kevzara is currently approved in multiple countries to treat adults with moderately to severely active rheumatoid arthritis who have not responded to or tolerated previous therapy.

Kevzara was jointly developed

by Sanofi and Regeneron

The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion for Sarclisa® (isatuximab). The CHMP recommends Sarclisa in combination with pomalidomide and dexamethasone (pomdex) for the treatment of adult patients with relapsed and refractory multiple myeloma (MM) who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on the last therapy.

The European Commission (EC) will review the CHMP recommendation and a final decision on the Marketing Authorisation Application for Sarclisa in the E.U. is expected in the coming months. Sarclisa has not been approved for commercial use in the E.U. Sarclisa was approved in the US on March 2 in combination with pomalidomide and dexamethasone (pom-dex) for the treatment of adults with RRMM who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.

"Relapsed and refractory multiple myeloma is a complicated disease that continuously develops resistance to treatment, creating a significant need for continued innovation," said John Reed, M.D., Ph.D., Sanofi's Global Head of Research & Development. "This positive CHMP opinion for Sarclisa

brings us closer to our ambition to deliver a new treatment option for patients in Europe with relapsed and refractory multiple myeloma."

The CHMP positive opinion is based on data from ICARIAMM, the first randomized Phase 3 trial to evaluate an anti-CD38 monoclonal antibody (mAB) in combination with pom-dex. In the ICARIA-MM study, Sarclisa added to pom-dex (Sarclisa combination therapy; n=154) demonstrated a statistically significant improvement of progression free survival (PFS) with a median PFS of 11.53 months compared to 6.47 months with pom-dex alone (n=153; HR 0.596, 95% CI: 0.44-0.81, p=0.0010). Sarclisa combination therapy also demonstrated a significantly greater overall response rate compared to pom-dex alone (60.4% vs. 35.3%, p<0.0001).

In additional analyses, Sarclisa combination therapy compared to pom-dex alone showed a treatment benefit consistent across select subgroups reflective of real-world practice, including patients with high risk cytogenetics, those aged 75 years and older, patients with renal insufficiency, and patients who were refractory to lenalidomide.

The most common adverse reactions (all grades occurring in 20% or more of patients) in patients who received Sarclisa combination therapy were neutropenia (96%), infusionrelated reactions (39%), pneumonia (31%), upper respiratory tract infection (57%) and diarrhea (26%).

Serious adverse reactions that occurred in more than 5% of patients who received Sarclisa combination therapy included pneumonia (25.3%) and febrile neutropenia (12.3%). Permanent discontinuation of Sarclisa combination therapy due to an adverse reaction (Grades 3-4) occurred in 7% of patients, and 3% of patients discontinued due to an infusion-related reaction.

First Patient Treated in Pivotal Phase III Clinical Trial Abeona Therapeutics Inc. (Nasdaq: ABEO), a fullyintegrated leader in gene and cell therapy, have announced that investigators at Stanford University Medical Center have treated the first patient in the pivotal phase III VIITAL™ study evaluating EB-101, the Company's gene-corrected cell

HOSPITALPROFESSIONALNEWS.IE | HPN • APRIL/MAY 2020

46 Clinical R&D therapy for recessive dystrophic epidermolysis bullosa (RDEB).

"Treating the first patient in our pivotal Phase III VIITAL™ study is an important achievement for the EB-101 program, now the most advanced gene therapy program in RDEB," said João Siffert, M.D., Chief Executive Officer. "This achievement confirms that Abeona can deliver EB-101 in a study setting that closely parallels its potential real-world application.

We remain confident that VIITALTM will replicate results from the Phase I/II trial demonstrating that EB-101 treatment resulted in sustained and durable wound healing with a favorable safety profile."

The VIITAL™ Phase III study is a multi-center, randomized clinical trial assessing EB-101 in up to 15 RDEB patients, with approximately 30 large, chronic wound sites treated in total.

The primary outcome measure is wound healing, comparing treated with untreated wound sites on the same patient.

Secondary endpoints include the assessments of pain, as well as other patient reported outcomes. Investigators at Stanford University Medical Center are currently enrolling eligible patients into the VIITALTM study and preparations for an additional clinical site initiation are ongoing. Additional information about the trial is available at abeonatherapeutics. com/clinical-trials/rdeb.

Abeona is producing EB-101 for the VIITALTM study at the Elisa Linton Center for Rare Disease Therapies, its fullyfunctional gene and cell therapy manufacturing facility centrallylocated in Cleveland, OH. The 26,000 ft2 center is housing large-scale cGMP capacity for AAV gene therapy and EB-101 cell therapy manufacturing, and state-of-the-art laboratories to support CMC development for process and analytics, all of which is validated and governed by comprehensive quality systems and overseen by experienced staff.

About EB-101 EB-101 is an autologous, gene-corrected cell therapy in late-stage clinical development for the treatment of recessive dystrophic epidermolysis bullosa (RDEB), a rare connective tissue disorder without an approved therapy.

Treatment with EB-101 involves using gene transfer to deliver COL7A1 genes into a patient's own skin cells (keratinocytes and its progenitors) and transplanting them back to the patient to enable normal Type VII collagen expression and facilitate wound healing.

Data from a Phase I/IIa clinical trial conducted by Stanford University evaluating EB101 showed that the genecorrected cell therapy provided durable wound healing for RDEB patients lasting 2+ to 5+ years, including for the largest, most challenging wounds that affect the majority of the RDEB population. In the U.S., Abeona holds Regenerative Medicine Advanced Therapy, Breakthrough Therapy, and Rare Pediatric designations for EB-101 and Orphan Drug designation in both the U.S. and EU.

"We believe that by pairing Pfizer's development, regulatory and commercial capabilities with BioNTech's mRNA vaccine technology and expertise as one of the industry leaders, we are reinforcing our commitment to do everything we can to combat this escalating pandemic, as quickly as possible."

Pfizer and BioNTech to Co-develop Potential COVID-19 Vaccine

The companies will begin collaborating immediately.

They will finalize details of the agreement regarding financial terms, and all activities related to development, manufacturing and potential commercialization over the next few weeks.

Pfizer Inc. (NYSE: PFE, "Pfizer") and BioNTech SE (Nasdaq: BNTX, "BioNTech) haveannounced that the companies have agreed to a letter of intent regarding the co-development and distribution (excluding China) of a potential mRNA-based coronavirus vaccine aimed at preventing COVID-19 infection. The companies have executed a Material Transfer and Collaboration Agreement to enable the parties to immediately start working together.

The collaboration aims to accelerate development of BioNTech's potential first-inclass COVID-19 mRNA vaccine program, BNT162, which is expected to enter clinical testing by the end of April 2020. The rapid advancement of this collaboration builds on the research and development collaboration into which Pfizer and BioNTech entered in 2018 to develop mRNA-based vaccines for prevention of influenza.

"We are proud that our ongoing, successful relationship with BioNTech gives our companies the resiliency to mobilize our collective resources with extraordinary speed in the face of this worldwide challenge," said Mikael Dolsten, Chief Scientific Officer and President, Worldwide Research, Development & Medical, Pfizer.

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"This is a global pandemic, which requires a global effort. In joining forces with our partner Pfizer, we believe we can accelerate our effort to bring a COVID-19 vaccine to people around the world who need it," said Ugur Sahin, Co-Founder and CEO of BioNTech.

The companies expect to utilize multiple research and development sites from both companies, including in the United States and Germany, to house the activities identified by the collaboration agreement.

On March 13, 2020, Pfizer issued a five-point plan calling on the biopharmaceutical industry to join the company in committing to unprecedented collaboration to combat COVID-19.

EMA recommends temporary suspension and recall of uterine fibroids medicine ulipristal acetate 5mg The European Medicines Agency (EMA) has recommended, as a precautionary measure, that women should stop taking 5-mg ulipristal acetate (Esmya and generic medicines) for uterine fibroids while a safety review on the risk of serious liver injury is ongoing.

The EMA is starting its review following a recent case of liver injury, which led to liver transplantation in a patient taking the medicine. Cases of serious liver injury have been reported, including 5 that led to transplantation, out of over 900,000 patients who have been treated with ulipristal acetate for fibroids since its authorisation in 2012. A 2018 EMA review concluded that there is a risk of rare but serious liver injury with ulipristal acetate medicines for the treatment of

uterine fibroids, and measures were implemented to minimise the risk. However, as the new case of serious liver injury occurred in spite of adherence to these measures, the EMA has started a new review.

To protect patients’ health, the EMA is recommending the temporary suspension of the medicine ‘s marketing authorisation in the EU and a recall of batches from pharmacies and patients while the safety review is completed.

Ulipristal acetate is also authorised as a single-dose medicine for emergency contraception. This review does not affect the single-dose ulipristal acetate emergency contraceptive (ellaOne and other trade names) and there is no concern about liver injury with these medicines.

Positive results from Swedish study with DiviTum in metastatic breast cancer Biovica, active in cancer diagnostics, have announced that results from a study by researchers at Lund University have been published in the well renowned journal Scientific Reports, a journal from Nature.

The results support that the blood test DiviTum can be used as a prognostic tool for evaluating treatment outcomes in metastatic breast cancer.

The study evaluated thymidine kinase activity in 142 women with newly diagnosed metastatic breast cancer as a tool for first-line prognosis and monitoring. Activity was measured by Biovica's DiviTum test at diagnosis and after 1, 3 and 6 months of treatment.

The patients in the study received standard therapy such as hormonal therapy, chemotherapy and HER2targeted therapy.

The results show that measurement of levels of thymidine kinase activity with DiviTum predicts patient outcomes and is clinically valuable in improving prognosis and monitoring of treatment of newly diagnosed metastatic breast cancer patients.

Decreasing levels of thymidine kinase activity correlate with prolonged time to disease progression and survival.

“Our study shows that DiviTum can provide additional information on prognosis and therapy efficacy in women with

Clinical R&D 47 metastatic breast cancer treated with today's standard therapies.

For me as an oncologist, this means that I can get complementary information on the development of the disease that can influence treatment decisions with the goal of better outcome and quality of life for the patient. We are interested in continuing to evaluate DiviTum for women with metastatic breast cancer in larger studies,” said Anna-Maria Larsson, MD, oncologist and lead investigator in the study at Skåne University Hospital in Lund and Lund University.

patient enrollment continued as planned notwithstanding the increasing difficulties experienced by the hospitals to organize the proper treatment and follow-up. Over the past two weeks, ERYTECH has observed a reduction in enrollment rate due to the COVID-19 pandemic and now believes new patient enrollment will be below plan in the coming months. The Company currently expects a delay of 3 to 4 months in completion of patient enrollment, bringing the time of complete enrollment to the fourth quarter of this year.

“The study is a strong confirmation of previous studies in metastatic breast cancer.

DiviTum has been used in seven published studies in more than 1,000 breast cancer patients.

The study in Lund shows that DiviTum can be used as an independent prognostic tool in this indication. The goal for Biovica is for DiviTum to become a standard tool for evaluating treatment efficacy in patients with metastatic breast cancer,” said Anders Rylander, CEO of Biovica.

With more than 75% of the patients enrolled in the trial, the Company believes that the planned interim superiority analysis, to be conducted by an IDMC when two-thirds of the total death events have been reached, will not be significantly affected by the expected delay in enrollment. However, based on recent tracking of the total death events in the trial, the average time to event appears longer than originally anticipated. As a result, the Company now expects to report the interim analysis around year-end 2020 and the final analysis in the second half of 2021.

Update on the TRYbeCA-1 Phase 3 Clinical Trial of Eryaspase in Second Line Pancreatic Cancer ERYTECH Pharma (Nasdaq & Euronext: ERYP), a clinicalstage biopharmaceutical company developing red blood cell-based cancer therapeutics, has provided an update on the pivotal Phase 3 clinical trial for advanced metastatic pancreatic cancer (TRYbeCA-1), which is evaluating the efficacy and safety of ERYTECH's lead product candidate eryaspase in combination with chemotherapy as second-line therapy.

The independent data monitoring committee (IDMC) has reviewed the safety data for the first 320 patients enrolled and treated in the TRYbeCA-1 trial. In line with the two earlier safety reviews, no safety issues were identified and the IDMC recommended to continue the trial as planned.

To date, more than 75% of the approximately 500 patients to be enrolled in the trial have been randomized. Various measures have been put in place to facilitate compliance with the study schedule and to preserve study data integrity.

Through March 2020, new

Study detects presence of disease-causing E.coli in recreational waters, including in bathing waters rated excellent under EU criteria New research due to be presented at this year’s European Congress on Clinical Microbiology and Infectious Diseases (ECCMID)* has revealed the presence of disease-causing E.coli in recreational waters, including from beaches rated excellent under EU criteria. The study is led by Professor Dearbháile Morris and Dr Louise O’Connor at the School of Medicine, NUI Galway.

E.coli are part of the normal gut flora of humans and animals, but not all E. coli are exactly the same. Some E. coli can produce toxins that can cause serious infection in humans.

Shiga -toxigenic E. coli (STEC) are pathogenic E. coli that can cause severe intestinal infection and potentially renal failure and death. Ireland has had the highest incidence rate for human infection with STEC among EU member states for many years, reporting 10 times the EU average in

2017. This research looked at recreational waters for the presence of STEC. Seawater, river and lake samples were collected around Ireland between December 2018 and October 2019 and examined for genetic markers of STEC. Of the 75 samples tested, 49 (65%) were positive for the presence of STEC genetic markers, including 29/52 (56%) seawater samples, 14/15 (93%) river samples and 6/8 (75%) lake samples.

Professor Morris says: “To our knowledge this is the first investigation of recreational waters across Ireland for the presence of STEC. There was a high occurrence of genetic markers for STEC in the samples tested, highlighting the need for further investigation to establish the scale of the problem, not only in Ireland but globally. It is worth noting that all of the bathing waters tested were designated as of good or excellent quality based on current EU bathing water quality monitoring criteria. Bathing water quality is assessed based on estimating the total number of E. coli in a 100ml sample over a defined time-period (May to September). Bathing waters in Europe and elsewhere are not routinely monitored for the presence of STEC. This study highlights the limitations of only assessing the total number of E. coli present as an indicator of water quality without taking into consideration the potential pathogenicity of some variants.”

Sanofi to present Phase 2 detailed results of its brainpenetrant BTK inhibitor in relapsing multiple sclerosis Sanofi will host a scientific session to present detailed data from their Phase 2b trial evaluating its investigational BTK (Bruton's tyrosine kinase) inhibitor (SAR442168), an oral, brain-penetrant, selective small molecule. In February, the company reported that the study's primary endpoint was met, demonstrating that the BTK inhibitor significantly reduced disease activity associated with multiple sclerosis (MS) as measured by magnetic resonance imaging.

impact our potential brainpenetrant BTK inhibitor could have on the lives of people living with this disease," said John C. Reed, M.D. Ph.D. Sanofi's Global Head of Research & Development. "Our virtual session will provide the opportunity for an important scientific exchange and a forum for sharing the recent clinical results obtained with our brainpenetrant BTK inhibitor for multiple sclerosis."

Sanofi is hosting this scientific session as a result of the cancellation of the live American Academy of Neurology (AAN) annual meeting due to the COVID-19 pandemic.

Audio webcast and conference call will be open to healthcare professionals and healthcare media. It will include presentations followed by Q&A session and live access to the speakers including: Daniel Reich, MD, PhD, Senior Investigator at NIH and Chief of the Translational Neuroradiology Section in the National Institute of Neurological Disorders and Stroke; Ross Gruber, PhD, Principal Scientist at Sanofi Genzyme; and Anthony Traboulsee, MD, Professor and Research Chair of the MS Society of Canada at the University of British Columbia in Vancouver, Canada Topics to be highlighted which were planned to be presented at AAN: • BTK inhibitor mechanism of action and preclinical data • Phase 2b trial design • Phase 2b efficacy and safety results In the US and Europe, there are approximately 1.2 million people diagnosed with MS, an unpredictable, chronic disease that attacks the central nervous system. Despite current treatments, many people with MS continue to accumulate disability, and one in four suffer from progressive forms of the disease with limited or no treatments available.

The efficacy and safety of Sanofi's BTK inhibitor has not been confirmed by any regulatory authority.

"During these unprecedented times we remain committed to sharing results that allow us to advance the understanding of multiple sclerosis and the HOSPITALPROFESSIONALNEWS.IE | HPN • APRIL/MAY 2020

(pembrolizumab) Injection 25mg/ml KEYTRUDA®: HELPING TO REDEFINE OVERALL SURVIVAL EXPECTATIONS for more patients with mNSCLC1-4 PD-L1 <1% or unknown

PD-L1 1-49%

PD-L1 >50%

NONSQUAMOUS

√

√

√

1st line Combination** Therapy3

SQUAMOUS

√

√

√

1st line*** Monotherapy4

NON-SQUAMOUS AND SQUAMOUS

X

X

√

Line

Histology

1st line Combination* Therapy2

* KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of metastatic non-squamous NSCLC in adults whose tumours have no EGFR or ALK positive mutations. ** KEYTRUDA, in combination with carboplatin and either paclitaxel or nab-paclitaxel, is indicated for the first-line treatment of metastatic squamous NSCLC in adults. *** KEYTRUDA, as monotherapy, is indicated for the first-line treatment of metastatic non-small cell lung carcinoma (NSCLC) in adults whose tumours express PD-L1 with a≥ 50% tumour proportion score (TPS) with no EGFR or ALK positive tumour mutations. skin adverse reaction on prior treatment with other immune- stimulatory anticancer agents. Other clinically significant immune-related adverse reactions: The following additional clinically significant, immune-related adverse reactions, have been reported in clinical studies or in post-marketing experience: uveitis, arthritis, myositis, myocarditis, pancreatitis, Guillain-Barré syndrome, myasthenic syndrome, haemolytic anaemia, sarcoidosis and encephalitis. For Grades 3 or 4 myocarditis, encephalitis or Guillain Barré syndrome, pembrolizumab should be permanently discontinued. Refer to SmPC for information on management of significant immune-related adverse reactions. Solid organ transplant rejection has been reported in the post-marketing setting in patients treated with PD-1 inhibitors. The benefit of treatment with pembrolizumab versus the risk of possible organ rejection should be considered in these patients.

Complications of allogeneic Haematopoietic Stem Cell Transplant (HSCT): Allogeneic HSCT after treatment with pembrolizumab: Cases of graft-versus-host-disease (GVHD) and hepatic veno-occlusive disease (VOD) have been observed in patients with classical Hodgkin lymphoma undergoing allogeneic HSCT after previous exposure to pembrolizumab. Until further data become available, careful consideration to the potential benefits of HSCT and the possible increased risk of transplant-related complications should be made case by case. Allogeneic HSCT prior to treatment with pembrolizumab: In patients with a history of allogeneic HSCT, acute GVHD, including fatal GVHD, has been reported after treatment with pembrolizumab. Patients who experienced GVHD after their transplant procedure may be at an increased risk for GVHD after treatment with pembrolizumab. Consider the benefit of treatment with pembrolizumab versus the risk of possible GVHD in patients with a history of allogeneic HSCT. Infusion-related reactions: For Grades 3 or 4infusion reactions including hypersensitivity and anaphylaxis, stop infusion and permanently discontinue pembrolizumab. With Grades 1 or 2 infusion reactions, infusion may continue with close monitoring. Premedication with antipyretic and antihistamine may be considered.

Overdose: There is no information on overdose with pembrolizumab. In case of overdose, monitor closely for signs or symptoms of adverse reactions and treat appropriately. INTERACTIONS No formal pharmacokinetic drug interaction studies have been conducted with pembrolizumab. No metabolic drug-drug interactions are expected. The use of systemic corticosteroids or immunosuppressants before starting pembrolizumab should be avoided because of their potential interference with the pharmacodynamic activity and efficacy of pembrolizumab. Corticosteroids can be used as premedication, when pembrolizumab is used in combination with chemotherapy, as antiemetic prophylaxis and/or to alleviate chemotherapy-related adverse reactions. FERTILITY, PREGNANCY AND LACTATION Women of childbearing potential. Women of childbearing potential should use effective contraception during treatment with pembrolizumab and for at least 4 months after the last dose of pembrolizumab. Pregnancy. No data on use in pregnant women. Do not use during pregnancy unless the clinical condition of the woman requires treatment with pembrolizumab. Breast-feeding. It is unknown whether pembrolizumab is secreted in human milk. A risk to newborns/ infants cannot be excluded. Fertility. No clinical data available.

SIDE EFFECTS Refer to SmPC for complete information on side effects. Pembrolizumab is most commonly associated with immune-related adverse reactions. Most of these reactions resolved with appropriate medical treatment or withdrawal of pembrolizumab. The most serious adverse reactions were immune-and infusion-related adverse reactions. Monotherapy: Very Common: anaemia, hypothyroidism, decreased appetite, headache, dyspnea, cough, abdominal pain, nausea, vomiting, constipation, musculoskeletal pain, arthralgia, asthenia, oedema, pyrexia, diarrhoea, rash, pruritus, fatigue. Common: pneumonia, thrombocytopaenia, lymphopaenia, hyponatraemia, hypokalaemia, hypocalcaemia, insomnia, neuropathy peripheral, lethargy, dry eye, cardiac arrhythmia (including atrial fibrillation), hypertension, hyperthyroidism, insomnia, dizziness, dysgeusia, pneumonitis, colitis, dry mouth, severe skin reactions, vitiligo, dry skin, alopecia, eczema, dermatitis acneiform, erythema, myositis, pain in extremity, arthritis, influenza like illness, chills, AST and ALT increases, hypercalcaemia, increase in blood alkaline phosphatase, blood bilirubin increased, blood creatinine increased, infusion related reaction. Frequency not known: solid organ transplant rejection. Combination with chemotherapy: Very Common: anaemia, neutropaenia, thrombocytopaenia, hypokalaemia, decreased appetite, dizziness, neuropathy peripheral, dysgeusia, headache, dyspnoea, cough, abdominal pain, alopecia, diarrhoea, nausea, vomiting, constipation, rash, pruritus, musculoskeletal pain, arthralgia, pyrexia, fatigue, asthenia, oedema, blood creatinine increased. Common: pneumonia, febrile neutropaenia, leukopaenia, lymphopaenia, infusion related reaction, hypothyroidism, hyperthyroidism, hyponatraemia, hypocalcaemia, insomnia, lethargy, dry eye, cardiac arrhythmia (including atrial fibrillation), hypertension, pneumonitis, colitis, dry mouth, severe skin reactions, erythema, dry skin, myositis, pain in extremity, arthritis, nephritis, acute kidney injury, chills, influenza-like illness, hypercalcaemia, ALT increase, AST increased, blood alkaline phosphatase increased. Combination with axitinib: Very Common: hyperthyroidism, hypothyroidism, decreased appetite, headache, dysgeusia, hypertension, dyspnoea, cough, dysphonia, diarrhoea, abdominal pain, nausea, vomiting, constipation, palmar-plantar erythrodysaesthesia syndrome, rash, pruritus, musculoskeletal pain, arthralgia, pain in extremity, fatigue, asthenia, pyrexia, alanine aminotransferase increased, aspartate aminotransferase increased, blood creatinine increased. Common: pneumonia, anaemia, neutropaenia, leukopaenia, thrombocytopaenia, infusion related reaction, hypophysitis, thyroiditis, adrenal insufficiency, hypokalaemia, hyponatraemia, hypocalcaemia, insomnia, dizziness, lethargy, neuropathy peripheral, dry eye, cardiac arrhythmia (including atrial fibrillation), pneumonitis, colitis, dry mouth, hepatitis, severe skin reactions, dermatitis acneiform, dermatitis, dry skin, alopecia, eczema, erythema, myositis, arthritis, tenosynovitis, acute kidney injury, nephritis, oedema, influenza like illness, chills, blood alkaline phosphatase increased, hypercalcaemia, blood bilirubin increased. PACKAGE QUANTITIES KEYTRUDA 25 mg/mL: 4 mL of concentrate in a 10 mL Type I clear glass vial. Legal Category: POM. Marketing Authorisation numbers: EU/1/15/1024/002.

Marketing Authorisation holder: Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands. Date of revision: March 2020. © Merck Sharp & Dohme B.V. 2020. All rights reserved. Further information is available on request from: MSD, Red Oak North, South County Business Park, Leopardstown, Dublin 18, D18 X5K7 or from www.medicines.ie. Date of Preparation: May 2020.

R081.

Adverse events should be reported. Reporting forms and information can be found at www.hpra.ie.

Adverse events should also be reported to MSD (Tel: 01-2998700) References 1. Keytruda Summary of Product Characteristics, September 2019, available at www.medicines.ie.

2. Gandhi L, et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med. 2018;378:2078-2092.

3. Paz-Ares L, et al. Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. N Engl J Med. 2018;379:2040–2051.

4. Reck, M et al. Pembrolizumab versus chemotherapy for PDL1 positive-non-small cell lung cancer, N Eng J Med 2016, 375(19)1823-1833.

ALK=anaplastic lymphoma kinase; EGFR=epidermal growth factor receptor; mNSCLC=metastatic non–small cell lung carcinoma; PDL1=programmed death ligand 1.

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

IE-KEY-00268

KEYTRUDA® (pembrolizumab) ABRIDGED PRODUCT INFORMATION Refer to Summary of Product Characteristics before prescribing. PRESENTATION KEYTRUDA 25 mg/mL: One vial of 4 mL of concentrate contains 100 mg of pembrolizumab. INDICATIONS KEYTRUDA as monotherapy is indicated for the treatment of advanced (unresectable or metastatic) melanoma in adults. KEYTRUDA as monotherapy is indicated for the adjuvant treatment of adults with Stage III melanoma and lymph node involvement who have undergone complete resection. KEYTRUDA as monotherapy is indicated for the first-line treatment of metastatic non-small cell lung carcinoma (NSCLC) in adults whose tumours express PD-L1 with a ≥50% tumour proportion score (TPS) with no EGFR or ALK positive tumour mutations. KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of metastatic non-squamous NSCLC in adults whose tumours have no EGFR or ALK positive mutations. KEYTRUDA, in combination with carboplatin and either paclitaxel or nab-paclitaxel, is indicated for the first-line treatment of metastatic squamous NSCLC in adults. KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic NSCLC in adults whose tumours express PD-L1 with a ≥1% TPS and who have received at least one prior chemotherapy regimen. Patients with EGFR or ALK positive tumour mutations should also have received targeted therapy before receiving KEYTRUDA. KEYTRUDA as monotherapy is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL) who have failed autologous stem cell transplant (ASCT) and brentuximab vedotin (BV), or who are transplant-ineligible and have failed BV. KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic urothelial carcinoma in adults who have received prior platinum-containing chemotherapy. KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic urothelial carcinoma in adults who are not eligible for cisplatin-containing chemotherapy and whose tumours express PD L1 with a combined positive score (CPS) ≥ 10. KEYTRUDA as monotherapy or in combination with platinum and 5-fluorouracil (5-FU) chemotherapy, is indicated for the first-line treatment of metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) in adults whose tumours express PD-L1 with a CPS ≥ 1. KEYTRUDA as monotherapy is indicated for the treatment of recurrent or metastatic HNSCC in adults whose tumours express PD-L1 with a ≥ 50% TPS and progressing on or after platinum-containing chemotherapy. KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of advanced renal cell carcinoma (RCC) in adults. DOSAGE AND ADMINISTRATION See SmPC for full details. Therapy must be initiated and supervised by specialist physicians experienced in the treatment of cancer. The recommended dose of KEYTRUDA as monotherapy is either 200 mg every 3 weeks or 400 mg every 6 weeks administered as an intravenous infusion over 30 minutes. The recommended dose of KEYTRUDA as part of combination therapy is 200 mg every 3 weeks administered as an intravenous infusion over 30 minutes. KEYTRUDA must not be administered as an intravenous push or bolus injection. When administering KEYTRUDA as part of a combination with intravenous chemotherapy, KEYTRUDA should be administered first. Treat patients until disease progression or unacceptable toxicity. Atypical responses (i.e., an initial transient increase in tumour size or small new lesions within the first few months followed by tumour shrinkage) have been observed. Recommended to continue treatment for clinically stable patients with initial evidence of disease progression until disease progression is confirmed. For the adjuvant treatment of melanoma, KEYTRUDA should be administered until disease recurrence, unacceptable toxicity, or for a duration of up to one year. KEYTRUDA, as monotherapy or as combination therapy, should be permanently discontinued (a) For Grade 4 toxicity except for: endocrinopathies that are controlled with replacement hormones; or haematological toxicity, only in patients with cHL in which KEYTRUDA should be withheld until adverse reactions recover to Grade 0-1; (b) If corticosteroid dosing cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks; (c) If a treatment-related toxicity does not resolve to Grade 0-1 within 12 weeks after last dose of KEYTRUDA; (d) If any event occurs a second time at Grade ≥ 3 severity. Patients must be given the Patient Alert Card and be informed about the risks of KEYTRUDA. Special populations. Elderly: No dose adjustment necessary. Data from patients ≥ 65 years are too limited to draw conclusions on cHL population. Data from pembrolizumab monotherapy in patients with resected Stage III melanoma, from pembrolizumab in combination with axitinib in patients with advanced RCC, and from chemotherapy combination in patients with metastatic NSCLC, and from pembrolizumab (with or without chemotherapy) in patients receiving first line treatment for metastatic or unresectable recurrent HNSCC ≥ 75 years are limited. Renal impairment: No dose adjustment needed for mild or moderate renal impairment. No studies in severe renal impairment. Hepatic impairment: No dose adjustment needed for mild hepatic impairment. No studies in moderate or severe hepatic impairment. Paediatric population: Safety and efficacy in children below 18 years of age not established. CONTRAINDICATIONS Hypersensitivity to the active substance or to any excipients. PRECAUTIONS AND WARNINGS Assessment of PD-L1 status. When assessing the PD-L1 status of the tumour, it is important that a well-validated and robust methodology is chosen to minimise false negative or false positive determinations. Immune-related adverse reactions. Immune-related adverse reactions, including severe and fatal cases, have occurred in patients receiving pembrolizumab. Most immune-related adverse reactions occurring during treatment with pembrolizumab were reversible and managed with interruptions of pembrolizumab, administration of corticosteroids and/or supportive care. Immune-related adverse reactions have also occurred after the last dose of pembrolizumab. Immune-related adverse reactions affecting more than one body system can occur simultaneously. See SmPC for full details. Immune-related pneumonitis: Patients should be monitored for signs and symptoms of pneumonitis. Suspected pneumonitis should be confirmed with radiographic imaging and other causes excluded. Refer to SmPC for information on management of immune-related pneumonitis. Immune-related colitis: Patients should be monitored for signs and symptoms of colitis, and other causes excluded. Consider the potential risk of gastrointestinal perforation. Refer to SmPC for information on management of immune-related colitis. Immune-related hepatitis: Patients should be monitored for changes in liver function (at the start of treatment, periodically during treatment and as indicated based on clinical evaluation) and symptoms of hepatitis, and other causes excluded. Refer to SmPC for information on management of Immune-related hepatitis. Immune-related nephritis: Patients should be monitored for changes in renal function, and other causes of renal dysfunction excluded. Refer to SmPC for information on management of immune-related nephritis. Immune-related endocrinopathies: Severe endocrinopathies, including adrenal insufficiency, hypophysitis, type 1 diabetes mellitus, diabetic ketoacidosis, hypothyroidism, and hyperthyroidism have been observed with pembrolizumab treatment. Long-term hormone replacement therapy may be necessary in cases of immune-related endocrinopathies. Hypophysitis has been reported in patients receiving pembrolizumab. Patients should be monitored for signs and symptoms of adrenal insufficiency and hypophysitis (including hypopituitarism) and other causes excluded. Patients should be monitored for hyperglycaemia or other signs and symptoms of diabetes. Thyroid disorders, including hypothyroidism, hyperthyroidism and thyroiditis, have been reported in patients receiving pembrolizumab and can occur at any time during treatment. Hypothyroidism is more frequently reported in patients with HNSCC with prior radiation therapy.

Patients should be monitored for changes in thyroid function (at the start of treatment, periodically during treatment and as indicated based on clinical evaluation) and clinical signs and symptoms of thyroid disorders. Refer to SmPC for information on management of immune-related endocrinopathies. Immune-related skin adverse reactions: Patients should be monitored for suspected severe skin reactions and other causes should be excluded. Based on the severity of the adverse reaction, pembrolizumab should be withheld for Grade 3 skin reactions until recovery to Grade ≤ 1or permanently discontinued for Grade 4 skin reactions, and corticosteroids should be administered. Cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving pembrolizumab. For suspected SJS or TEN, pembrolizumab should be withheld and the patient should be referred to a specialised unit for assessment and treatment. If SJS or TEN is confirmed, pembrolizumab should be permanently discontinued. Caution should be used when considering the use of pembrolizumab in a patient who has previously experienced a severe or life-threatening