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HOSPITAL PROFESSIONAL NEWS IRELAND

HPN October 2020 Issue 77 HOSPITALPROFESSIONALNEWS.IE

Ireland’s Dedicated Hospital Professional Publication

IN THIS ISSUE:

NOW AVAILABLE CONVENIENT

ONCEDAILY FORMULATION XELJANZ 11 mg Once-Daily XELJANZ (tofacitinib) in combination with methotrexate (MTX) is indicated for the treatment of moderate to severe active rheumatoid arthritis (RA) in adult patients who have responded inadequately to, or who are intolerant to one or more diseasemodifying antirheumatic drugs. Tofacitinib can be given as monotherapy in case of intolerance to MTX or when treatment with MTX is inappropriate.1

XELJANZ® (tofacitinib) Prescribing Information Please refer to the Summary of Product Characteristics (SmPC) before prescribing XELJANZ 5 mg or 10 mg film-coated tablets or XELJANZ 11 mg prolonged release tablets. Presentation: Film-coated tablet containing tofacitinib citrate, equivalent to 5 mg or 10 mg tofacitinib. Prolonged-release tablets containing tofacitinib citrate, equivalent to 11 mg tofacitinib. Indications: All presentations: In combination with methotrexate (MTX) for the treatment of moderate to severe active rheumatoid arthritis (RA) in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying antirheumatic drugs. Can be given as monotherapy in case of intolerance to MTX or when treatment with MTX is inappropriate. 5 and 10 mg film coated tablets: In combination with MTX for the treatment of active psoriatic arthritis (PsA) in adult patients who have had an inadequate response or who have been intolerant to a prior disease modifying antirheumatic drug (DMARD) therapy. For the treatment of adult patients with moderately to severely active ulcerative colitis (UC) who have had an inadequate response, lost response, or were intolerant to either conventional therapy or a biologic agent. Dosage: Treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of the condition for which tofacitinib is indicated. Tofacitinib is given with or without food. RA: The recommended dose is 5 mg orally twice daily or 11 mg once daily which should not be exceeded. Patients treated with tofacitinib 5 mg film coated tablets twice daily may be switched to tofacitinib 11 mg prolonged release tablets once daily on the day following the last dose of tofacitinib 5 mg film coated tablets. Patients treated with tofacitinib 11 mg prolonged-release tablets once daily may be switched to tofacitinib 5 mg film coated tablets twice daily on the day following the last dose of tofacitinib 11 mg prolonged-release tablets. PsA: The recommended dose is 5 mg administered twice daily, which should not be exceeded. UC: The recommended dose is 10 mg given orally twice daily for induction for 8 weeks. For patients who do not achieve adequate therapeutic benefit by week 8, the induction dose of 10 mg twice daily can be extended for an additional 8 weeks (16 weeks total), followed by 5 mg twice daily for maintenance. Tofacitinib induction therapy should be discontinued in any patient who shows no evidence of therapeutic benefit by week 16. The recommended dose for maintenance treatment is tofacitinib 5mg given orally twice daily. Tofacitinib 10 mg twice daily for maintenance treatment is not recommended in patients with UC who have known venous thromboembolism (VTE) risk factors, unless there is no suitable alternative treatment available. For patients with UC who are not at increased risk for VTE, tofacitinib 10 mg orally twice daily may be considered if the patient experiences a decrease in response on tofacitinib 5 mg twice daily and failed to respond to alternative treatment options for ulcerative colitis such as tumour necrosis factor inhibitor (TNF inhibitor) treatment. Tofacitinib 10 mg twice daily for maintenance treatment should be used for the shortest duration possible. The lowest effective dose needed to maintain response should be used. Dose interruption: Tofacitinib treatment should be interrupted if a patient develops a serious infection until the infection is controlled. Interruption of dosing may be needed for management of dose-related laboratory abnormalities including lymphopenia, neutropenia, and anaemia. It is recommended not to initiate dosing in patients with an absolute lymphocyte count (ALC) less than 0.75 x 109/l, an absolute neutrophil count (ANC) less than 1x10 9 /l or in patients with haemoglobin less than 9 g/dL. Renal impairment: No dose adjustment is required in patients with mild or moderate renal impairment. Patients with severe renal impairment the dose should be reduced to 5 mg once daily when the indicated dose in the presence of normal renal function is 5 mg twice daily or 11 mg prolonged release tablet once daily. Dose should be reduced to 5 mg twice daily when the indicated dose in the presence of normal renal function is 10 mg twice daily. Patients with severe renal impairment should remain on a reduced dose even after haemodialysis. Hepatic impairment: No dose adjustment is required in patients with mild hepatic impairment. Patients with moderate hepatic impairment dose should be reduced to 5 mg once daily when the indicated dose in the presence of normal hepatic function is 5 mg twice daily or 11 mg prolonged release tablet once daily. Dose should be reduced to 5 mg twice daily when the indicated dose in the presence of normal hepatic function is 10 mg twice daily. Tofacitinib should not be used in patients with severe hepatic impairment. Elderly: No dose adjustment is required in patients aged 65 years and older. Use with caution as increased risk and severity of adverse events. In patients over 65 years of age tofacitinib should only be considered if no suitable alternative treatment is available. Drug–drug Interactions: Tofacitinib total daily dose should be reduced by half in patients receiving potent inhibitors of cytochrome (CYP) P450 3A4 (e.g., ketoconazole) and in patients receiving 1 or more concomitant medicinal products that result in both moderate inhibition of CYP3A4 as well as potent inhibition of CYP2C19 (e.g., fluconazole). Coadministration of XELJANZ with potent CYP inducers (e.g., rifampicin) may result in a loss of or reduced clinical response. Coadministration of potent inducers of CYP3A4 with XELJANZ is not recommended. Contraindications: Hypersensitivity to any of the ingredients, active tuberculosis (TB), serious infections such as sepsis, or opportunistic infections, severe hepatic impairment, pregnancy and lactation. Warnings and Precautions: Patients treated with tofacitinib should be given a patient alert card. There was a higher incidence of adverse events for the combination of tofacitinib with MTX versus tofacitinib as monotherapy in RA clinical studies. Tofacitinib should be avoided in combination with biologics and potent immunosuppressants such as azathioprine, 6-mercaptopurine, ciclosporine and tacrolimus. Venous thromboembolism (VTE): Serious VTE events including pulmonary embolism (PE), some of which were fatal, and deep vein thrombosis (DVT), have been observed in patients

PP-XEL-IRL-0554 | Date of preparation:August 2020

taking tofacitinib. Tofacitnib should be used with caution in patients with known risk factors for VTE, regardless of indication and dosage. Tofacitinib 10 mg twice daily for maintenance treatment is not recommended in patients with UC who have known VTE risk factors, unless there is no suitable alternative treatment available. Promptly evaluate patients with signs and symptoms of VTE and discontinue tofacitinib in patients with suspected VTE, regardless of dose or indication. Infections: Serious and sometimes fatal infections have been reported in patients administered tofacitinib. Rheumatoid arthritis patients taking corticosteroids may be predisposed to infection. Patients should be closely monitored for infections, with prompt diagnosis and treatment. Treatment should be interrupted if a serious infection develops. As there is a higher incidence of infections in the elderly and in the diabetic populations in general, caution should be used when treating the elderly and patients with diabetes. Tuberculosis: Patients should be evaluated for both active and latent TB prior to being treated with tofacitinib, patients who test positive for latent TB should be treated with standard antimycobacterial therapy before administering tofacitinib. Viral Reactivation: In clinical studies viral reactivation and cases of herpes zoster have been observed. Screening for viral hepatitis should be performed in accordance with clinical guidelines prior to starting therapy with tofacitinib. The impact on chronic viral hepatitis is not known. Vaccinations: Prior to initiating tofacitinib, it is recommended that all patients be brought up to date with all immunisations in agreement with current immunisation guidelines. Live vaccines should not be given concurrently with tofacitinib. Malignancy: Lymphomas and other malignancies have been observed in patients treated with tofacitinib. Patients with highly active disease may be at higher risk than the general population. The effect of tofacitinib on the development and course of malignancies is not known. NMSCs have been reported, the risk of NMSC may be higher in patients treated with tofacitinib 10 mg twice daily than in patients treated with 5 mg twice daily. Periodic skin examination is recommended in patients at increased risk. Interstitial lung disease: Caution is recommended in patients with a history of chronic lung disease as they may be more prone to infection. Asian patients are known to be at higher risk of ILD, caution should be exercised with these patients. Gastrointestinal perforations: Tofacitinib should be used with caution in patients who may be at increased risk e.g. diverticulitis or concomitant use of corticosteroids or NSAIDs. Cardiovascular risk: Risk factors should be managed as part of usual standard of care. Hypersensitivity: Cases of drug hypersensitivity associated with tofacitinib administration have been reported. Allergic reactions included angioedema and urticaria; serious reactions have occurred. If any serious allergic or anaphylactic reaction occurs, tofacitinib should be discontinued immediately. Laboratory Parameters: Increased incidence of lymphopenia and neutropenia have been reported and decreases in haemoglobin and should be monitored in accordance with the SmPC. Monitor ANC and haemoglobin at baseline, 4-8 weeks and 3 monthly, ALC at baseline and 3 monthly. Tofacitinib has been associated with increases in lipid parameters, maximal effects are observed at 6 weeks. Monitoring should be performed 8 weeks after initiation and managed according to hyperlipidemia guidelines. Increases in liver enzymes greater than 3x ULN were uncommonly reported, use caution when initiating with potential hepatotoxic medicinal products. Gastrointestinal obstruction with a non-deformable prolonged-release formulation: Caution should be used when administering tofacitinib 11 mg prolonged release tablets to patients with pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic). Pregnancy & Lactation: Use of tofacitinib during pregnancy and breast-feeding is contraindicated. Side Effects: RA: The most common serious adverse reactions were serious infections; pneumonia, cellulitis, herpes zoster, UTIs, diverticulitis, appendicitis and opportunistic infections. The most commonly reported adverse reactions during the first 3 months in controlled clinical trials were headache, upper respiratory tract infections, nasopharyngitis, diarrhoea, nausea and hypertension. UC: The most commonly reported adverse reactions in patients receiving tofacitinib 10 mg twice daily in the induction studies were headache, nasopharyngitis, nausea, and arthralgia. Commonly reported adverse reactions (≥1/100 to <1/10), were pneumonia, influenza, herpes zoster, urinary tract infection, sinusitis, bronchitis, nasopharyngitis, pharyngitis, anaemia, headache, hypertension, cough, abdominal pain, vomiting, diarrhoea, nausea, gastritis, dyspepsia, rash, arthralgia, pyrexia, oedema peripheral, fatigue, blood creatine phosphokinase increased. 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 Number: EU/1/17/1178/003 – 5 mg (56 film-coated tablets); EU/1/17/1178/007 – 10 mg (56 film-coated tablets); EU/1/17/1178/012 – 11 mg (28 prolonged-release tablets). Marketing Authorisation Holder: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium. For further information on this medicine please contact: Pfizer Medical Information on 1800 633 363 or at medical.information@ pfizer.com. For queries regarding product availability please contact: Pfizer Healthcare Ireland, Pfizer Building 9, Riverwalk, National Digital Park, Citywest Business Campus, Dublin 24 + 353 1 467 6500. ˱This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 of the SmPC for how to report adverse reactions. Last revised: 06/2020. Ref: XJ 9_0. References: 1. XELJANZ prolonged release tablets summary of product characteristics.

News: IMO accuses HSE of Hypocrisy Page 4 Report: The Sexual Health & HIV Landscape within Ireland Page 10 Perspectives: Moving from Community to Hospital Pharmacy Page 12 Feature: Statins for primary prevention of cardiovascular disease Page 22 CPD: Cancer Associated Thrombosis; clinical challenges and therapeutic advances Page 24 Educational: Celebrating World Psoriasis Day in an Era of New Treatments Page 30 Congress: European Society of Radiology Online Congress Page 42


A new option in HIV-1

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

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 of the SPC for how to report adverse reactions. ABRIDGED PRODUCT INFORMATION Refer to Summary of Product Characteristics before prescribing. PRESENTATION Pifeltro: film-coated tablet containing 100 mg doravirine. Delstrigo: film-coated tablet containing 100 mg doravirine, 300 mg lamivudine and 300 mg tenofovir disoproxil fumarate, equivalent to 245 mg of tenofovir disoproxil. INDICATIONS Pifeltro: For use in combination with other antiretrovirals, for the treatment of HIV-1 without past or present evidence of resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI). Delstrigo: For the treatment of HIV-1 without past or present evidence of resistance to NNRTIs, lamivudine or tenofovir. DOSAGE AND ADMINISTRATION Therapy should be initiated by a physician experienced in HIV infection management. Pifeltro: One 100 mg tablet once daily. Delstrigo: One 100/300/245 mg tablet once daily. Pifeltro and Delstrigo: If co-administered with rifabutin or other moderate CYP3A inducers, increase doravirine dose to 100 mg twice daily (12 hours apart). Pifeltro: Elderly: No dose adjustment necessary. Renal impairment: No dose adjustment necessary. Hepatic impairment: mild to moderate: no dosage adjustment required; severe: use with caution. Delstrigo: Elderly: Special care advised. Renal impairment: estimated creatinine clearance (CrCl) ≥ 50 mL/min: no dose adjustment necessary; estimated CrCl <50 mL/min: not recommended. Hepatic impairment: mild to moderate: no adjustment required; severe hepatic: use with caution. CONTRAINDICATIONS Hypersensitivity to the active substance or excipients Co-administration with strong CYP3A inducers. PRECAUTIONS AND WARNINGS A residual risk of sexual transmission of HIV-1 cannot be excluded and precautions should be taken in accordance with national guidelines. Use with CYP3A inducers may reduce the exposure of doravirine. Autoimmune disorders (such as autoimmune hepatitis) and immune reactivation syndrome have been reported in patients treated with combination antiretroviral therapy which may require investigation and treatment. Contains lactose monohydrate. Delstrigo: Post-treatment exacerbation of HBV (including hepatic decompensation and liver failure) have been reported in patients co-infected with HIV-1 and HBV following discontinuation of lamivudine or tenofovir disproxil. Monitor patients co-infected with HIV-1 and HBV after discontinuation of Delstrigo and if appropriate initiate anti-HBV therapy. Renal impairment, including acute renal failure and Fanconi syndrome have been reported with tenofovir disoproxil. Assess estimated CrCl prior to initiation and during therapy. In patients at risk of renal dysfunction, serum phosphorus, urine glucose, and urine protein should also be assessed. Discontinue therapy if estimated CrCl declines below 50 mL/min. Avoid with concurrent or recent use of nephrotoxic medicinal products (e.g. high-dose or multiple NSAIDs). Evaluation of renal function is recommended for persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness. Assessment of bone mineral density should be considered for patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms. Doravirine/lamivudine/tenofovir disoproxil must not be co-administered with other medicinal products containing lamivudine, tenofovir disoproxil, or tenofovir alafenamide or with adefovir dipivoxil. Doravirine/lamivu-

dine/tenofovir disoproxil should not be administered with doravirine unless needed for dose adjustment (e.g. co-administered with rifabutin). Drug interactions: Refer to SmPC for full information on drug interactions. Pifeltro and Delstrigo: Doravirine is metabolized primarily by CYP3A. Do not co-administer with strong CYP3A enzyme inducers. If co-administration with rifabutin or other moderate CYP3A inducers cannot be avoided, increase doravirine dose to 100 mg twice daily (taken 12 hours apart). Use with caution when co-administering doravirine with medicinal products that are sensitive CYP3A substrates that have a narrow therapeutic window (e.g., midazolam, tacrolimus and sirolimus). Delstrigo: Do not administer with other antiretroviral medicinal products. Co-administration of doravirine/lamivudine/tenofovir disoproxil with medicinal products that reduce renal function or compete for active tubular secretion may increase serum concentrations of lamivudine. Co-administration of doravirine/lamivudine/tenofovir disoproxil with medicinal products that reduce renal function or compete for active tubular secretion via OAT1, OAT3 or MRP4 may increase serum concentrations of tenofovir. Avoid with concurrent or recent use of nephrotoxic medicinal products. Pregnancy and Lactation: Pifeltro and Delstrigo: Avoid use during pregnancy. An Antiretroviral Pregnancy Registry has been established. Breastfeeding is not recommended. SIDE EFFECTS Refer to SmPC for complete information on side-effects.Pifeltro and Delstrigo: Common: abnormal dreams, insomnia, headache, dizziness, somnolence, nausea, diarrhoea, abdominal pain, flatulence, vomiting, rash, fatigue alanine aminotransferase increased. Uncommon: hypophosphataemia, nightmare, depression, suicidal ideation, paraesthesia, asthenia. Rare: hypomagnesaemia, blood creatine phosphokinase increased. Delstrigo: Common: cough, nasal symptoms, alopecia, muscle disorders, fever. Uncommon: neutropenia, anaemia, thrombocytopenia, pancreatitis, rhabdomyolysis, proximal renal tubulopathy (including Fanconi syndrome), aspartate aminotransferase increased. Rare: lactic acidosis, hepatitis, angioedema, myopathy, acute renal failure, renal failure, acute tubular necrosis, nephritis (including acute interstitial) and nephrogenic diabetes insipidus. Very Rare: pure red cell aplasia, peripheral neuropathy (or paraesthesia). PACKAGE QUANTITIES Bottle of 30 tablets. Legal Category: POM. Marketing Authorisation numbers: Pifeltro: EU/1/18/1332/001, Delstrigo: EU/1/18/1333/001. Marketing Authorisation Holder: Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands. Date of revision: September 2019. © Merck Sharp & Dohme Ireland (Human Health) Limited 2019. All rights reserved. Further information is available on request from: MSD, Red Oak North, South County Business Park, Leopardstown, Dublin 18, D18 X5K7 or from www.medicines.ie. Date of Preparation: June 2020. IB/0007/0008. References: 1. DELSTRIGO Summary of Product Characteristics, December 2019. 2. PIFELTRO Summary of Product Characteristics, November 2019. Adverse events should be reported. Reporting forms and information can be found at www.hpra.ie. Adverse events should also be reported to MSD (Tel: 01-2998700)

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

IE-DOV-00016

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


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October Issue Issue 77

Contents

Foreword

Patients could be ignoring life-threatening risk, says leading Consultant P5

Editor Professor Alan Irvine, Consultant Dermatologist at Children’s Health Ireland at Crumlin has been elected as President of the Irish Hospital Consultants Association (IHCA).

New President for Irish Hospital Consultants Association P6 The HIV landscape in Ireland P10

According to Professor Irvine, the IHCA continues to advocate strongly for an improved, sustainable health system that delivers timely access to care for all patients – both in the ongoing Covid-19 environment and the longer term. The Association has warned health leaders that action must be taken now to address hospital capacity deficits before the winter months.

5

Hospital Pharmacist Barry O’Sullivan on making the transition from community P12

Turn to page 6 to read more about their causes for concern.

Celebrating World Psoriasis Day in an Era of New Treatments P30 12

Marking Osteoporosis Day with launch of new drug P40

“In both sectors of pharmacy there are commonalities and transferrable skills. Clear communication, evidence-based decision making and team playing will aid greatly in problem solving. The centre of what we do as Pharmacists is the patient, and we always strive to do our best for them,” he reflects.

Breakthrough trial in Motor Neurone Disease P44 REGULARS Feature: The evolving role of liquid biopsy in lung cancer P16

Elsewhere in this issue we have plethora of contributed clinical articles, including, the evolving role of liquid biopsy in lung cancer, emerging evidence in breast cancer, statins within cardiovascular disease and new drug treatments within psoriasis and osteoporosis.

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Educational: Statins for primary prevention of cardiovascular disease P22 CPD Thrombosis P24 44

Clinical R&D 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. All rights reserved by Hospital Professional News. All material published in Hospital Professional News is copyright and no part of this magazine may be reproduced, stored in a retrieval system of transmitted in any form without written permission. IPN Communications Ltd have taken every care in compiling the magazine to ensure that it is correct at the time of going to press, however the publishers assume no responsibility for any effects from omissions or errors.

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

On page 10, Barry O’Sullivan, Senior Pharmacist with Mater Private Hospital in Cork, urges readers not to be afraid of change. In this article, Barry gives an insightful overview into his transition from community to hospital pharmacy.

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

Natasha Lynch

In other news, The European Association of Hospital Pharmacists (EAHP) has launched a survey to collect information on the lessons learned from the Covid-19 pandemic. To better understand the impact on the profession, EAHP’s survey gathers on the one hand details on the medicines for which shortages were experienced. On the other hand, it takes stock of the experiences made in hospitals during the first few months of the crisis and explores suggestions for improving the future crisis preparedness of hospital pharmacies. World Thrombosis Day is acknowledged on October 13th, and on page 28 we take a look at the condition in more detail. One in 4 Irish people will die of causes related to thrombosis and it has now become the number one cause of preventable death in Irish hospitals.

editorial@hospitalprofessionalnews.ie

Thrombosis patient Ann-Marie O’Neill talks about founding the charity Thrombosis Ireland, an organisation which directly represents the views and responds to the needs of people with Thrombosis.

ACCOUNTS Rachel Wilson cs.ipn@btconnect.com

You can visit www.eahp.eu to take part in the survey, which is open until December 23rd.

CONTRIBUTORS

I hope you enjoy the issue.

Natasha@hospitalprofessionalnews.ie

EDITORIAL

Barry O'Sullivan | Dr David McMahon Dr Dearbhaile Collins | Dr Paula Byrne Dr John Quinn | Dr Jamie O'Sullivan Professor Janice Walshe Dr Claire Comerford | Dr Viviana Marzaioli Professor Anne-Marie Tobin

DESIGN DIRECTOR Ian Stoddart Design HOSPITALPROFESSIONALNEWS.IE

@HospitalProNews

HospitalProfessionalNews

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


4 News “Hypocrisy” claims to HSE The Irish Medical Organisation (IMO) has accused the HSE and the Department of Health of hypocrisy for praising the expertise of Public Health specialists on the one hand even while denying them Consultant status on the other. Despite their expertise, Public Health Specialists – who are on the frontline of the fight against Covid-19, work on “Specialist Contracts” and are not allowed to be employed on “Consultant Contracts”. This impacts on their pay and conditions. There are 60 Public Health Specialists in this position currently. However last month (September) the IMO met with the HSE and Department of Health on the issue. This is the latest in a series of

At the most recent meeting the IMO was told that the Department of Expenditure and Reform is effectively blocking the development by withholding approval for the revised terms of the new consultant contract and stalling progress on the required legislative changes.

their status by granting them longpromised consultant contracts, they refuse. This is not only unfair on the hard working specialists who are battling Covid 19 at the moment, it will directly discourage future doctors from considering a career in Public Health Medicine. Even as we speak our Public Health Specialists are being actively recruited as Consultants in other jurisdictions. That will accelerate when they see that their reasonable expectations are being ignored in their own country.”

Dr Ina Kelly, Chairman of the Public Health Committee of the IMO, said, “Politicians have been falling over themselves to praise the work of Public Health specialists for the past six months but when it comes to recognising

The argument for public health specialists to be awarded consultant posts has long been accepted in many Government commissioned reports, including recent reports from Crowe Howarth and the Scally report on

meetings which began last year. It follows comments from the Minister for Health to the COVID 19 Committee indicating progress would be made.

Cervical Check - yet little or no progress has been made. Dr Kelly said it was significant that the Government was able to move with speed to facilitate required legislation to raise the salaries for three “super-junior” Ministers in the new Government but couldn’t show the same resourcefulness when it came to helping frontline workers. Dr Kelly warned, “Our colleagues have stepped up to the plate, taken on duties that are not covered by contract, worked continuously without proper time off to manage outbreaks and I know they will be completely devastated by the inaction of Government on this matter. Ireland needs a consultant led public health system and it needs it now.”

World Pharmacists Day As designated in 2009 by the FIP Council in Istanbul, Turkey, 25 September marks the annual World Pharmacists Day. Hospital Pharmacists are encouraged to use this day to organise activities that promote and advocate for the role of the pharmacist in improving health in every corner of the world. “Transforming global health” is the theme of this year’s World Pharmacists Day. This year sees the 10th World Pharmacists Day. The World Pharmacists Day theme this year is an opportunity to communicate how pharmacists are transforming health through a variety of health services in their communities, including advising on healthy living, vaccinating to prevent disease, and ensuring that medicines are taken correctly, thereby managing diseases well and improving quality of life. It also covers how pharmaceutical scientists transform and prolong people’s lives by developing safe and effective medicines and vaccines. On the education front, pharmacy educators are transforming outcomes by ensuring that there are enough qualified and competent pharmacists and scientists to meet the growing needs of our societies.

Consultant Develops ‘Clinical Pass’ A University Hospital Galway Medical Consultant has developed a “Clinical Pass” smartphone app to allow healthcare students across the region to undertake clinical placement. Professor Derek O’Keeffe Consultant Physician University Hospital Galway, working with colleagues in the College of Medicine, Nursing and Health Sciences in NUI Galway and Renville Informatics has developed a smartphone based Clinical Pass App to facilitate clinical placement for health care students.

Saolta medical students and staff demonstrate the Clinical Pass App: Jack Kelly, Medical Student; Professor Timothy O’Brien, Dean of College of Medicine, Nursing and Health Sciences NUI Galway; Sinead Corcoran, Medical Student and Professor Derek O’Keeffe, Consultant Physician at University Hospital Galway

OCTOBER 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

Commenting, Prof Derek O’Keeffe said, “Clinical placement training is a critical part of healthcare student education but reintroducing students into a clinical environment with COVID-19 is challenging and has to be done in a carefully controlled manner to ensure everyone remains safe. This Clinical Pass App is a powerful example of how digital health initiatives can improve patient care by ensuring that the next generation of clinicians can safely get appropriate clinical experience.”


News

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Lessons learned – Future crisis preparedness of hospital pharmacies The European Association of Hospital Pharmacists (EAHP) has launched a survey to collect information on the lessons learned from the Covid-19 pandemic. The survey on the future crisis preparedness of hospital pharmacies targets EAHP’s members from 35 different European countries. For hospital pharmacists frequent shortages of medicines which impact patient care are not a new phenomenon. EAHP has worked on this issue for 10 years. Research conducted by the Association

in 2014, 2018 and 2019 showed that the impact that shortages have on patient outcomes and the working time of hospital pharmacists’ needed to solve them has significantly increased. Due to reports about the shortages of medicines used for patients in intensive care units these problems seemed to have worsened during the Covid-19 pandemic. To better understand the impact on the profession, EAHP’s survey gathers on the one hand details on the medicines for which shortages were experienced. On the other

hand, it takes stock of the experiences made in hospitals during the first few months of the crisis and explores suggestions for improving the future crisis preparedness of hospital pharmacies. Ahead of the launch, EAHP President Petr Horák highlighted the importance of analysing and using the knowledge gained after the COVID-19 outbreak: “To respond adequately to further coronavirus infection waves or similar crisis situations that will severely test the European

health systems it is crucial to understand what worked and what did not work during the first wave. Consequently, I invite my fellow colleagues to share their experience and best practises to help all European hospital pharmacists improve their crisis preparedness.” The EAHP Survey on the future crisis preparedness of hospital pharmacies will be open from 16th September to 23rd December 2020. Besides the English version, 12 different translations are available.

Leading heart specialist warns of "life-threatening risk" A leading cardiologist has warned that thousands of patients could be ignoring the signs and symptoms of a potentially lifethreatening heart issue due to fear of attending healthcare providers during the Covid-19 pandemic.

Director of Cardiology at Mater Private and Chair of Cardiovascular Research at RCSI, Professor Robert Byrne

Recent figures published by the National Treatment Purchase Fund (NTPF) reveal a decline of over 300,000 outpatient appointments in Ireland between March and April this year compared to the same period in 2019. According to Director of Cardiology at Mater Private, Professor Robert Byrne, this decline suggests that thousands of patients may have postponed seeking expert care during the Covid-19 pandemic, which could result in potentially life-threatening issues. The warning to Irish patients comes as Mater Private launches the ‘Listen to Your Heart’ campaign, encouraging people to educate themselves about the signs and symptoms of heart disease during Irish Heart Health Month, and to seek medical advice if heart issues are a concern. In Ireland, approximately 10,000 people die from cardiovascular disease every year. Statistics show that Irish men and women have the highest rate of death before the age of 65 from coronary heart disease in Europe.

Additional data from the NTPF reveals that there are almost 700 fewer patients on the 0-3 month wait list for cardiology treatments or procedures compared to the same period in 2019, which suggests that fewer patients were seeking referral in the months of April, May, and June this year. Commenting, Director of Cardiology at Mater Private and Chair of Cardiovascular Research at RCSI, Professor Robert Byrne said, “Over the course of the Covid-19 pandemic, there has been an evident decline in the number of people presenting to

hospitals with symptoms of heart-related illness or disease. This decline in numbers is greatly concerning. “Ten thousand Irish men and women die from heart disease every year. This problem has not gone away, and the correlation between the reduced numbers and the peak of the pandemic in Ireland suggests that Covid fears might be causing patients to avoid GPs or hospitals. “It is crucial that patients present to a medical professional if they have any potential cardiac symptoms, problems or concerns.

Symptoms of a cardiac issue can include chest pain, shortness of breath, pain or weakness in the leg or arm, or sudden and unexplained pain in the neck or jaw. Others warning signs can include a racing or slow heartbeat, light-headedness, fatigue, or easily tiring during exercise or activity. “For many people, cardiovascular disease is not diagnosed until they have a heart attack, angina, stroke, or heart failure, so it is important that we raise awareness and encourage people to recognise these symptoms.”

HOSPITALPROFESSIONALNEWS.IE | HPN • OCTOBER 2020


6 News Professor Irvine to continue to ‘advocate strongly’ Professor Alan Irvine, newly elected President, Irish Hospital Consultants Association

72,695 people have now been added to various National Treatment Purchase Fund (NTPF)* waiting lists in 2020, as the latest figures (for August 2020) show: 841,459 people on some form of NTPF waiting list in August, an increase of 9,016 (1%) in one month and 72,695 (9.5%) since the start of the year;

Professor Alan Irvine, Consultant Dermatologist at Children’s Health Ireland at Crumlin, has been elected as President of the Irish Hospital Consultants Association (IHCA). The change in leadership at the IHCA comes at a time where around 500 permanent consultant posts are currently either vacant or filled on a temporary basis in our acute public hospitals, and almost one million people in Ireland find themselves on some form of waiting list for treatment or to see a hospital consultant. The effect of the widespread consultant and capacity deficit has only been amplified during

the Covid-19 pandemic. With the latest figures on hospital waiting lists due to be released later today (Friday) consultants expect to see further increases in the number of people waiting to see a specialist or receive treatment. According to Professor Irvine, the IHCA continues to advocate strongly for an improved, sustainable health system that delivers timely access to care for all patients – both in the ongoing Covid-19 environment and the longer term. The Association has warned health leaders that action must be taken now to address hospital capacity deficits before the winter months.

of Health to outline steps being taken to brace this country’s health service for the coming months is a cause for concern. We still do not have a winter plan and it remains unclear what increased public hospital capacity will be provided. “We know what the problems are, and we know what it takes to fix them: fill the 500 vacant permanent consultant posts, open up the required number of beds and ensure they are resourced and staffed. Yet there is no clear commitment to doing this from the HSE or Government.

610,996 outpatients nationally are waiting to be seen by a consultant, an increase of 9,634 (1.6%) on July’s figures and 57,562 (10.4%) during 2020;

“Our health service, hospital management and clinical teams need fully funded plans in place with cross government backing to fill the vacant consultant posts and increase hospital capacity.

77,620 now wating for inpatient/ day case treatment, an increase of 11,057 (16.6%) since the start of 2020; with 89% (+8,127) more patients now waiting over 12 months for inpatient/day case treatment compared with the start of the year.

“If the Government adopts the same approach as other years and significantly increased capacity is not urgently provided to prepare for the extraordinary winter surge due to COVID-19 and other demand increases, then it will simply be too late.”

The latest waiting list figures come as the familiar reports of growing trolley figures appear across the media, with over 200 admitted patients** left waiting on a trolley for a hospital bed on Tuesday of this week – a worrying trend this early in September, according to the IHCA. Commenting Professor Irvine, said, “This latest rise in patient waiting times comes the same day NPHET warns of the high likelihood of insufficient staffing levels to respond to service demands. “The persistent lack of clear action from the HSE and Department

Representing over 90% of Ireland’s hospital consultants, the officers elected to lead the representative body are: • Vice President – Dr. Gabrielle Colleran, Consultant Radiologist, Children’s Health Ireland at Temple Street. • Treasurer – Prof. Clare Fallon, Consultant in Geriatric Medicine, Regional Hospital Mullingar. • Membership Secretary – Dr. Conor O’Riordan, Consultant Radiologist, St Luke’s Hospital, Kilkenny.

First report on accidental or unintended medical exposures The Health Information and Quality Authority (HIQA) has published an overview report on the lessons learned from notifications of significant incident events arising from accidental or unintended medical exposures in 2019. This report provides an overview of the findings from these notifications and aims to share learnings from the investigations of these incidents. In 2019, HIQA received 68 notifications of significant events

of accidental or unintended medical exposures to patients in public and private facilities, which is a small percentage of significant incidents relative to the total number of procedures taking place which can be conservatively estimated at over three million exposures a year. The most common errors reported were patient identification failures, resulting in an incorrect patient receiving an exposure. These errors

OCTOBER 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

happened at various points in the patient pathway, which, while in line with previous reporting nationally and international data, highlights an area for improvement for undertakings. Further potential learnings are included within the report. When reviewing the corrective measures applied by undertakings following the occurrence of a significant event, a varied approach to patient safety was found. While a frequent corrective

measure was the re-education of staff, undertakings should consider other risk management strategies, such as simplifying or standardising procedures or the automation of processes to help prevent errors from reoccurring. It was noted that in many of the notifications submitted, there was an emphasis on the error of an individual or individuals involved in the process, rather than the evaluation of the system error that lead to such incidents.


RESPIRATORY OBESITY

ELDERLY

CARDIAC

WHEN CONTROL OF NMB REVERSAL IS WHAT MATTERS

BRIDION INDICATIONS • Reversal of rocuronium (ROC) or vecuronium (VEC) induced neuromuscular block (NMB) in adults. • For routine reversal of ROC-induced block in children and adolescents aged 2 to 17 years.1 investigated in patients receiving ROC or VEC in the ICU setting. Do not use sugammadex to reverse block induced by nonsteroidal blockers such as succinylcholine or benzylisoquinolinium compounds, or steroidal blockers other than ROC or VEC. Conditions associated with prolonged circulation time such as cardiovascular disease, old age, or oedematous state may cause longer recovery times. Be prepared for possible drug hypersensitivity reactions. This medicinal product contains up to 9.7 mg sodium per ml, equivalent to 0.5 % of the WHO recommended maximum daily intake of 2 g sodium for an adult. OVERDOSE No dose related adverse events nor serious adverse events were reported. Sugammadex can be removed using haemodialysis with a high flux filter. INTERACTIONS Toremifene and fusidic acid may displace rocuronium or vecuronium from sugammadex and delay recovery (no clinically relevant capturing interactions are expected). Interaction of sugammadex with hormonal contraceptives may lead to a decrease in progesterone exposure equivalent to one missed daily dose of oral contraceptive (no displacement interactions are expected). In general sugammadex does not interfere with laboratory tests, with the possible exception of the serum progesterone assay where interference is observed at sugammadex plasma concentrations of 100 μg/ml plasma. In a study doses of 4 mg/kg and 16 mg/kg sugammadex resulted in maximum mean prolongations of the activated partial thromboplastin time by 17 and 22% respectively and prothrombin time by 11% and 22% respectively. These were of short duration (≤ 30 minutes). In in vitro experiments pharmacodynamic interaction was noted with vitamin K antagonists, unfractionated heparin, low molecular weight heparinoids, rivaroxaban and dabigatran. PREGNANCY AND LACTATION Pregnancy and Lactation: Caution in pregnant women. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from sugammadex therapy, taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman. The effects on human fertility have not been investigated. SIDE EFFECTS Refer to SmPC for complete information on side effects. Common (≥ 1/100 to < 1/10): Anaesthetic complications including movement of limbs or body or coughing during anaesthesia, grimacing, or suckling on the endotracheal tube, airway complication of anaesthesia, procedural hypertension and procedural complication. Uncommon (≥ 1/1,000 to < 1/100): Hypersensitivity reactions, including anaphylaxis, have occurred in some patients and volunteers. Other less common and rarely reported side effects are listed in the SmPC. In clinical studies with subjects treated with rocuronium or vecuronium, where sugammadex was administered using a dose labelled for the depth of neuromuscular blockade, an incidence of 0.2% was observed for recurrence of neuromuscular blockade as based on neuromuscular monitoring or clinical evidence. The use of lower than recommended doses may lead to an increased risk of recurrence of neuromuscular blockade after initial reversal and is not recommended. HANDLING See SmPC for details of compatability with infusion solutions. Physical incompatibility has been reported with verapamil, ondansetron and ranitidine. PACKAGE QUANTITIES 10 vials of 2 ml, 10 vials of 5 ml. LEGAL CATEGORY POM. Marketing Authorisation Numbers EU/1/08/466/001-002. Marketing Authorisation Holder Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands. Date of review of prescribing information: April 2020. © Merck Sharp and Dohme B.V., 2020. All rights reserved. Further information is available on request from: MSD, Red Oak North, South County Business Park, Leopardstown, Dublin 18 or from www.medicines.ie. Date of preparation: July 2020. EMEA/H/C/000885/II/0036. Reference: 1. Bridion SPC April 2020

PREDICTABLE. COMPLETE. RAPID.

Adverse events should be reported. Reporting forms and information can be found at www.hpra.ie. Adverse events should also be reported to MSD (Tel: 01-299 8700)

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

IE-XBR-00032

BRIDION® 100 MG/ML SOLUTION FOR INJECTION (Sugammadex) ABRIDGED PRODUCT INFORMATION Refer to Summary of Product Characteristics (SmPC) before prescribing. PRESENTATION Vials of 200mg (2 ml) or 500mg (5 ml). INDICATIONS Reversal of rocuronium (ROC) or vecuronium (VEC) induced neuromuscular (NM) block in adults. For routine reversal of ROC-induced block in children and adolescents aged 2 to 17 years. DOSAGE AND ADMINISTRATION I.V. as a single bolus injection administered rapidly (within 10 seconds), into an existing I.V. line, by/under the supervision of an anaesthetist. Use appropriate technique to monitor recovery of NM block. Dose depends on the level of block to be reversed, not the anaesthetic regimen. Adults: Routine reversal following ROC- or VEC-induced block: • 4 mg/kg if recovery has reached at least 1-2 post-tetanic counts (PTC). Median recovery time (T4/T1 = 0.9) ≅ 3 minutes. • 2 mg/kg if recovery has occurred up to at least T2 following ROC- or VEC-induced block. Median recovery time (T4/T1 = 0.9) ≅ 2 minutes. Median recovery time (T4/T1= 0.9) is slightly faster with ROC- than VEC-induced block. Immediate reversal of ROC-induced block: 16 mg/kg. Median recovery time (T4/T1 = 0.9) ≅ 1.5 minutes when 16 mg/kg is given 3 minutes after a bolus dose of 1.2 mg/kg ROC. Not recommended for immediate reversal of VEC-induced block. Re-administration of sugammadex: For post-operative recurrence of block after an initial dose of 2 mg/kg or 4 mg/kg, repeat dose of 4 mg/kg is recommended. Following a second dose of sugammadex, monitor the patient closely to ascertain sustained return of neuromuscular function. Re-administration of ROC or VEC after sugammadex: Up to 4 mg/kg Sugammadex a waiting time of 5 minutes for re-use of 1.2 mg/kg ROC; 4 hours waiting time for re-use of 0.6 mg/kg ROC or 0.1 mg/kg VEC. With ROC onset of NM block may be prolonged and duration of NM block may shortened. After immediate reversal, 16 mg/kg sugammadex, a waiting time of 24 hours is recommended. See SPC for patients with mild or moderate renal impairment. Special populations: Renal impairment: For mild and moderate renal impairment use adult dose. Not recommended in severe renal impairment (including patients requiring dialysis). Elderly: Use adult dose although recovery times are slower. Obese: In obese patients, including morbidly obese patients (body mass index ≥ 40 kg/m2), adult dose based on actual body weight. Hepatic impairment: Caution in patients with severe hepatic impairment, or impairment with coagulopathy. Children and adolescents (2-17 years): 2 mg/kg for routine reversal of ROC-induced block at T2. Not recommended in other routine reversal situations. Not recommended for Immediate reversal. May be diluted for accuracy of dose. Term newborn infants and infants: Not recommended. CONTRA-INDICATIONS Hypersensitivity to sugammadex or to any excipients. PRECAUTIONS AND WARNINGS Ventilatory support is mandatory for patients until adequate spontaneous respiration is restored following reversal of block. Should block reoccur following extubation, adequate ventilation should be provided. The use of lower than recommended doses may lead to an increased risk of neuromuscular blockade after an initial reversal and is not recommended. Caution should be exercised when considering the use of sugammadex in patients receiving anticoagulation for a pre-existing or co-morbid condition. An increased risk of bleeding cannot be excluded in patients with hereditary vitamin K dependent clotting factor deficiencies; with pre-existing coagulopathies; on coumarin derivatives and at an INR above 3.5; using coagulants who receive a dose of 16mg/ kg sugammadex. If re-administration of ROC or VEC is required in patients with mild or moderate renal impairment after routine sugammadex reversal a waiting time for re-use of 0.6 mg/kg ROC or 0.1 mg/kg VEC should be 24 hours. If a shorter waiting time is required, the ROC dose for a new NM blockade should be 1.2 mg/kg within 30 minutes after Sugammadex administration. For re-administration of ROC or VEC after immediate reversal a waiting time of 24 hours is recommended. If neuromuscular block is required before the recommended waiting time has passed, a nonsteroidal neuromuscular blocking agent should be used. The use in patients with severe renal impairment is not recommended including those requiring dialysis. If neuromuscular block is reversed, while anaesthesia is continued, additional doses of anaesthetic and/or opioid should be given as clinically indicated. Marked bradycardia with cardiac arrest have been observed within minutes after administration, closely monitor patients for hemodynamic changes during and after reversal. Treat with anti-cholinergic agents such as atropine if clinically significant bradycardia observed. Sugammadex has not been


8 News Dovato as a treatment option for rapid initiation after diagnosis in adults with HIV-1 ViiV Healthcare, the global specialist HIV company majority owned by GSK, with Pfizer Inc. and Shionogi Limited as shareholders, has announced findings from the STAT study, a phase IIIb, multi-centre, open label, single arm, 48-week study in the United States presented at the American Conference for the Treatment of HIV (ACTHIV) 2020. The study evaluated Dovato (dolutegravir/ lamivudine) for rapid initiation of treatment after diagnosis in adults with HIV-1. Dovato was found to be effective and well tolerated in this setting, indicating the feasibility of its use in Test and Treat strategies. The STAT study followed a rapid Test and Treat model of care increasingly seen in clinical practice, with treatment initiated within 14 days of diagnosis before baseline HBV co-infection status, renal function and resistance test

results were available. All study participants were tested for HBV co-infection prior to receiving Dovato, with results available after initiation of treatment. In the study, 92% (n=102/111) of participants with available data at 24 weeks, achieved a viral load of <50c/mL.1 This includes participants who stayed on Dovato and those who switched to alternative ART. Eight participants switched from Dovato to an alternative antiretroviral (ART) regimen; five of the eight due to HBV co-infection and one due to baseline resistance to lamivudine.1 Data were available for five of these participants and showed that they all achieved a viral load of <50c/mL at 24 weeks, without developing HBV or HIV resistanceassociated mutations,1 indicating that rapid initiation of Dovato did not compromise outcomes for this subset of participants. 87%

(n=97/111) of participants with available data at Week 24 and still taking Dovato* achieved a viral load of <50c/mL.1 Charlotte-Paige Rolle, MD, MPH, Director of Research Operations at Orlando Immunology Center and principal investigator for the STAT study, said, “As physicians, we know the potential benefits of starting treatment as quickly as possible to reduce viral load, both to support the individual’s health as well as reduce the likelihood of HIV transmission. Data from the STAT study showed that the use of Dovato in treatment-naïve patients at the time of or soon after diagnosis, including those who were later found to have HBV co-infection or baseline resistance and underwent rapid therapy adjustment, did not adversely impact efficacy or safety outcomes.”

At the start of the study, 8% (n=10) of participants had HIV-1 RNA >1,000,000 c/mL. At week 24, 80% (n=8) of these participants had HIV-1 RNA <50 c/mL.1 At 24 weeks, 11% (n=15) of participants discontinued the study, including 9% (n=12) who were lost to follow-up or withdrew consent and 2% (n=3) due to physician decision. Data were not available at week 24 for 4% (n=5) of participants.1 The study found that Dovato was well tolerated, with low rates of grade 2-5 drugrelated AEs (2%, n=2) and serious AEs (2%, n=2).1 Reference: 1. Observed analysis, where missing patients were not included in the analysis

ICU Doctors and Nurses Charity Cycle TV celebrity Graham Norton and chief organiser Dr Patrick Seigne, Consultant Intensivist at Cork University Hospital ICU alongside other ICU Doctors and Nurses and staff from all over Ireland who recently took part in a charity cycle to Dublin

Congratulations to these ICU Doctors and Nurses and staff from all over Ireland who recently took part in a charity cycle to Dublin on September 3rd and 4th in aid of four charities supporting people specifically affected by the Covid-19 crisis. The ICU 4 U Charity Cycle aims to raise at least ¤100,000 for Alone (older people), Breakthrough Cancer Research (new cancer

treatments), Aware (mental health) and ICUsteps (ICU patient aftercare support). Several high profile ambassadors have come on board to help promote the charity initiative, including TV celebrity Graham Norton, champion Olympic rower Paul O’Donovan, and hotelier and TV personality John Brennan, who has been cocooning with non-Hodgkin’s Lymphoma.

OCTOBER 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

The concept for the charity cycle arose as many Irish doctors, nurses and ancillary staff of the Intensive Care Units across the country said that although they immensely appreciate the ongoing support of the Irish public throughout the Covid19 pandemic, they are uncomfortable being labelled ‘heroic’ and ‘frontline’ and want to turn the focus back on the patients and

the supporting charities that help the most vulnerable in society, in particular those most affected by the Covid-19 crisis. The team has already raised more than half of the ¤100k target thanks to incredible support from corporate sponsors, including lead sponsor AerCap, gold sponsors Eli Lily and BNP Paribas, silver sponsors Pfizer and Gilead, and other supporters. Commenting, chief organiser Dr. Patrick Seigne, Consultant Intensivist at Cork University Hospital ICU, said, “Many ICU staff are uncomfortable with being put up on a pedestal during the Crisis, as we are just doing our jobs albeit in challenging times. We are extremely grateful for the gifts we received from the public but we need to put the focus back where it is most needed – with the patients and charities. The impact of Covid-19 reaches far beyond the ICU, and we are only beginning to see the secondary challenges, in particular with the elderly, those in nursing homes, those experiencing anxiety and mental illness, Covid-19 ICU survivors, and cancer patients who are particularly vulnerable to the virus, have had their diagnosis delayed, and urgently need new treatments.”


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

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

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

DTG 50 mg + 3TC 300 12 mgyears used in the GEMINI studies. adolescents above weighing at least 40 kg, with no known or suspected resistance to the integrase inhibitor or lamivudine. DTG 50 mg + 3TC 300 mg used in the GEMINI studies. DOVATO is indicated for the treatment of HIV-1class, in adults and

adolescents above 12 years weighing at least 40 kg, with no known or DOVATO is indicated for the treatment of HIV-1 in adults and suspected resistance to the integrase inhibitor class, or lamivudine. adolescents above 12 years weighing at least 40 kg, with no known or suspected resistance to the integrase inhibitor class, or lamivudine. Abridged Prescribing Information Dovato (dolutegravir 50mg/lamivudine 300mg) tablets See Summary of Product Characteristics (SmPC) before prescribing.

Abridged Prescribing Information

Presentation: Film-coated tablet containing dolutegravir sodium equivalent to 50 mg about the potential risk of neural tube defects including consideration of effective Dovato (dolutegravir 50mg/lamivudine 300mg) tablets dolutegravir 300 mg lamivudine debossed with “SV-137” on one face. Indication: HIV-1 contraceptive measures. If a woman plans pregnancy, the benefits and the risks of continuing Abridgedand Prescribing Information See Summary of Product Characteristics before >40kg, prescribing. in adults & adolescents above 12 years of(SmPC) age weighing with no known or suspected treatment should be discussed with the patient. The safety and efficacy of a duel regime has Dovato (dolutegravir 50mg/lamivudine tablets resistance to theFilm-coated integrase inhibitor class, or300mg) lamivudine. Dosing: One equivalent tablet once to daily not been in pregnancy. If a pregnancy is confirmed the first trimester while on Presentation: tablet containing dolutegravir sodium 50 with mg about thestudied potential risk of neural tube defects includinginconsideration of effective See Summary of Product Characteristics (SmPC) before prescribing. or without food. 50mg tablet with of dolutegravir 12 hoursHIV-1 after contraceptive Dovato, the benefits andIfrisks of continuing Dovato versus switching another dolutegravir andUse 300an mgadditional lamivudine debossed “SV-137” onapproximately one face. Indication: measures. a woman plans pregnancy, the benefits andtothe risks ofantiretroviral continuing the dose of Dovato when co-administered with efavirenz, nevirapine, tipranavir/ritonavir, regimen should be discussed with the patient taking the gestational age and the critical time in adults & adolescents abovetablet 12 years of age weighing >40kg,sodium with noequivalent known or suspected treatment be discussed with the patient. The safety and efficacy of a duelofregime has Presentation: Film-coated containing dolutegravir to 50 mg about theshould potential risk of neural tube defects including consideration effective etravirine boosted PI), carbamazepine, oxcarbazepine, phenytoin, phenobarbital, period of studied neural tube defect development into account SmPC section 4.6). resistance(without toand the 300 integrase inhibitor class, or lamivudine. Dosing: Oneface. tablet once dailyHIV-1 with contraceptive not been in pregnancy. If aplans pregnancy is confirmed in the first whilehave on dolutegravir mg lamivudine debossed with “SV-137” on one Indication: measures. If a woman pregnancy, the (see benefits and thetrimester risks of There continuing St Wort orUse rifampicin. Elderly: Limited data 65+>40kg, yrs. Not recommended in patients been reports of mitochondrial dysfunction in HIV-negative infants exposed in antiretroviral utero and/or or John’s without an above additional 50mg of in dolutegravir approximately after treatment Dovato, theshould benefits risks ofwith continuing Dovato to another in adults & food. adolescents 12 years oftablet age weighing with no known12 orhours suspected beand discussed the patient. Theversus safetyswitching and efficacy of a duel regime has with creatinine clearance <50 mL/min. Caution in severe hepatic impairment. post-natally to nucleoside analogues. Do nottaking breast-feed. Side effects: See for full the dose oftoDovato when co-administered efavirenz, nevirapine, tipranavir/ritonavir, regimen beindiscussed withIf the patient the gestational age theSmPC critical time resistance the integrase inhibitor class, orwith lamivudine. Dosing: One tablet once daily with not beenshould studied pregnancy. a pregnancy is confirmed in the firstand trimester while on Contraindications: Hypersensitivity to any ingredient. Co-administration with substrates of Dovato, details.ofthe Headache, GIdefect disturbance, insomnia, abnormal dreams, depression, anxiety, etravirine PI), carbamazepine, phenytoin, phenobarbital, period neural tubeand into account (see SmPC section 4.6).antiretroviral There have or without(without food. Useboosted an additional 50mg tablet ofoxcarbazepine, dolutegravir approximately 12 hours after benefits risksdevelopment of continuing Dovato versus switching to another OCT-2 with therapeutic windows, suchwith as fampridine. warnings/precautions: dizziness, somnolence, rash, with pruritus, alopecia, fatigue, arthralgia, myalgia, hypersensitivity, St John’s Wort or rifampicin. Elderly: Limited data in 65+ yrs.Special Not recommended in patients regimen been reports of be mitochondrial dysfunction in taking HIV-negative infants exposed and/or the dose ofnarrow Dovato when co-administered efavirenz, nevirapine, tipranavir/ritonavir, should discussed the patient the gestational age and in theutero critical time Risk hypersensitivity reactions. Discontinue dolutegravir and other suspect agents period suicidalofideation or suicide attempt,Do hepatitis, blood(see dyscrasias, acute hepatic failure, with ofcreatinine mL/min. Caution in severe hepatic impairment. post-natally to nucleoside analogues. not Side effects: See SmPC for full etravirine (withoutclearance boosted PI),<50 carbamazepine, oxcarbazepine, phenytoin, phenobarbital, neural tube defect development intobreast-feed. account SmPC section 4.6). There have immediately. Risks of osteonecrosis, immune reactivation syndrome. Monitor LFTs in pancreatitis, angioedema, rhabdomyolysis, lactic acidosis, peripheral neuropathy. Elevations Contraindications: Hypersensitivity to any ingredient. with substrates of been details. Headache, GI disturbance, insomnia, abnormalinfants dreams, depression, St John’s Wort or rifampicin. Elderly: Limited data in 65+Co-administration yrs. Not recommended in patients reports of mitochondrial dysfunction in HIV-negative exposed in uteroanxiety, and/or Hepatitis B/C co-infection and ensure effective Hepatitis B therapy. Caution with metformin: of ALT, AST and CPK. MA Nr: EU/1/19/1370/001. MA holder: ViiV Healthcare BV, Van Asch OCT-2 with narrow therapeutic windows, such as fampridine. Special warnings/precautions: dizziness, somnolence, rash, pruritus, alopecia, fatigue, arthralgia, myalgia, hypersensitivity, with creatinine clearance <50 mL/min. Caution in severe hepatic impairment. post-natally to nucleoside analogues. Do not breast-feed. Side effects: See SmPC for full monitor renal function and consider metformin dose adjustment. Use with etravirine van Wijckstraat 3811 LPattempt, Amersfoort, Netherlands. Legal Category: POM A.anxiety, Date of Risk of hypersensitivity reactions. Discontinue dolutegravir and other suspect agents suicidal ideation55H, or GI suicide hepatitis, blood dyscrasias, acute hepatic failure, Contraindications: Hypersensitivity to any ingredient. Co-administration with substrates of details. Headache, disturbance, insomnia, abnormal dreams, depression, requires boosted PI or osteonecrosis, increased dose of dolutegravir. UseSpecial with Mg/Al-containing preparation of API: rash, July 2020. Code: PI-6305. Further information available from immediately. Risks of immune reactivation syndrome. Monitorantacids LFTs in dizziness, pancreatitis, angioedema, rhabdomyolysis, lactic acidosis, peripheral neuropathy. Elevations OCT-2 with narrow therapeutic windows, such as fampridine. warnings/precautions: somnolence, pruritus, alopecia, fatigue, arthralgia, myalgia, hypersensitivity, requires dosage separation. with calcium,Hepatitis multivitamins orand iron also requires dosage GlaxoSmithKline, 12 Citywest,hepatitis, Business Campus, Dublin Tel: 01-4955000. Hepatitis B/C co-infection andUse ensure effective B therapy. Caution with metformin: of ALT, AST and CPK. MA Nr: attempt, EU/1/19/1370/001. MA holder: ViiV24. Healthcare BV, Van Asch Risk of hypersensitivity reactions. Discontinue dolutegravir other suspect agents suicidal ideation or Riverwalk, suicide blood dyscrasias, acute hepatic failure, separation if not taken the same timeimmune with food. Use cladribine or emtricitabine monitor renal function and consider metformin dosewith adjustment. Use with etravirine Wijckstraat 55H, 3811rhabdomyolysis, LP Amersfoort, lactic Netherlands. Category: POM A. Date of immediately. Risks of at osteonecrosis, reactivation syndrome. Monitor LFTsnot in van pancreatitis, angioedema, acidosis, Legal peripheral neuropathy. Elevations Adverse events should be reported to the Health Products Regulatory Authority (HPRA) recommended. When avoid chronic co-administration sorbitol other osmotic preparation requires boosted PI orpossible, increased dose of dolutegravir. withofMg/Al-containing antacids API: July Code: PI-6305. available Hepatitis B/C co-infection and ensure effective HepatitisUse B therapy. Cautionor with metformin: of ALT, AST andofCPK. MA Nr:2020. EU/1/19/1370/001. MAFurther holder: information ViiV Healthcare BV, Van from Asch an Adverse Report FormBusiness obtainedCampus, either from the 24. HPRA electronically via acting alcohols (see SmPC section 4.5).calcium, If unavoidable, more frequent viral load GlaxoSmithKline, requires dosage separation. Use with multivitamins or iron also requires dosage 12Reaction Riverwalk, Citywest, Dublin Tel:or01-4955000. monitor renal function and consider metformin doseconsider adjustment. Use with etravirine vanusing Wijckstraat 55H, 3811 LP Amersfoort, Netherlands. Legal Category: POM A. Date of the website at www.hpra.ie. Adverse reactions can also be reported to the HPRA by calling monitoring. and lactation: fertility - no data; animal antacids fertility separation ifFertility, not taken at the same time food.Human Use Use with cladribine or emtricitabine not- preparation requires boosted PI orpregnancy increased dose ofwith dolutegravir. with Mg/Al-containing of API: July 2020. Code: PI-6305. Further information available from (01) 6764971. Adverse events should also beHealth reported to GlaxoSmithKline on 1800(HPRA) 244 255. Adverse events be reported toBusiness the Products Regulatory studies indicate no effects. Women of chronic childbearing potential (WOCBP) should be counselled recommended. possible, avoid co-administration sorbitol or other osmotic requires dosageWhen separation. Use with calcium, multivitamins orofiron also requires dosage GlaxoSmithKline, 12should Riverwalk, Citywest, Campus, Dublin 24. Tel:Authority 01-4955000. using an Adverse Reaction Report Form obtained either from the HPRA or electronically via acting alcohols SmPC section unavoidable, consider moreorfrequent viral load separation if not(see taken at the same 4.5). time Ifwith food. Use with cladribine emtricitabine not the websiteevents at www.hpra.ie. Adverse reactions can Products also be reported to the HPRA by calling Adverse should be reported to the Health Regulatory Authority (HPRA) monitoring. Fertility, and lactation: Human fertility no data;oranimal fertility recommended. WhenPpregnancy possible, avoid chronic co-administration of- sorbitol other osmotic References: 1. Cahn et al. J Acquir Immunde Defic Syndr. 2020;83(3):310-318. 2. van WYK- J et al.(01) Clin Infect Dis. 2020;ciz1243:1-10 3. DOVATO Summary ofthe Product 6764971. Adverse events should alsoobtained be reported tofrom GlaxoSmithKline 1800 244 255. using an Adverse Reaction Report Form either HPRA or on electronically via studiesalcohols indicateJune no effects. childbearing potential (WOCBP) should be counselled acting (see SmPC Women section of 4.5). If unavoidable, consider more frequent viral load Characteristics. 2020. the website at www.hpra.ie. Adverse reactions can also be reported to the HPRA by calling monitoring. Fertility, pregnancy and lactation: Human fertility - no data; animal fertility (01) 6764971. Adverse events should also be reported to GlaxoSmithKline on 1800 244 255. studies indicate no effects. childbearing (WOCBP) should be2.counselled References: 1. Cahn P et al.Women J AcquirofImmunde Deficpotential Syndr. 2020;83(3):310-318. van WYK J et al. Clin Infect Dis. 2020;ciz1243:1-10 3. DOVATO Summary of Product Characteristics. June 2020. References: 1. Cahn P et al.isJ owned Acquir Immunde Deficto Syndr. 2020;83(3):310-318. WYK J et al. Clin Infect Dis. 2020;ciz1243:1-10 3. DOVATO Summary of Product DOVATO by or licensed the ViiV Healthcare group2.ofvan companies. Characteristics. June 2020. Date of preparation: August 2020. PM-IE-DLL-ADVT-200002 ©2020 ViiV Healthcare group of companies or its licensor. DOVATO is owned by or licensed to the ViiV Healthcare group of companies. ©2020 ViiV Healthcare group of companies or its licensor. DOVATO is owned by or licensed to the ViiV Healthcare group of companies. ©2020 ViiV Healthcare group of companies or its licensor.

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


10 HIV

HIV 2020 Targets ‘won’t be met’

UNAIDS report on the global AIDS epidemic shows that 2020 targets will not be met because of deeply unequal success; COVID-19 risks blowing HIV progress way off course. Missed targets have resulted in 3.5 million more HIV infections and 820 000 more AIDS-related deaths since 2015 than if the world was on track to meet the 2020 targets. In addition, the response could be set back further, by 10 years or more, if the COVID-19 pandemic results in severe disruptions to HIV services. ‘It is estimated that globally 243 million women and girls (aged 15–49 years) have been subjected to sexual and/or physical violence perpetrated by an intimate partner in the past 12 months. Meanwhile, we know that women who experience such violence are 1.5 times more likely to acquire HIV than women who have not experienced violence. Among marginalized groups, a high prevalence of violence is also linked with higher rates of HIV infection. Female sex workers have a 30-times greater risk of acquiring HIV than the general population. ‘We know how to treat HIV and how to prevent people from becoming infected. What we desperately need is a different politics to guarantee that everyone everywhere has the right to health.

‘This must include concerted efforts to dismantle the injustices and inequalities that put young women and girls, gay men and other men who have sex with men, sex workers, transgender people, people who use drugs, prisoners and migrants at greater risk of becoming infected with HIV. ‘The HIV prevention crisis must be tackled by granting everyone everywhere the right to health, tearing down the barriers that stop people receiving essential services. In tackling COVID-19, we must learn the painful lessons from a history of unequal access in dealing with HIV. Millions died of AIDS-related illnesses while there were medicines available that could have saved their lives. We must ensure that COVID-19 treatments and an eventual vaccine against the coronavirus are made available to everyone everywhere, free at the point of use. A People’s Vaccine,’ says the report. Vulnerability to violence, exclusion and HIV, new research Meanwhile in Ireland, the law banning the purchase of sex, introduced in 2017, has had a profoundly negative impact on the health and wellbeing of sex workers, a new report has found.

OCTOBER 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

Key findings from the research highlight the extent to which sex workers manage their lives within the context of ‘structural violence’ and exacerbated by the current law. As a result, sex workers experience poorer protection from violence and abuse, increased risks from unsafe sex including HIV, and limited access to key health supports and interventions. The report, Sex worker lives under the law: A community engaged study of access to health in Ireland, was commissioned by HIV Ireland and funded by the Open Society Foundations. The research, conducted throughout Ireland with sex workers, was conducted by the authors of the report, Dr Kathryn McGarry and Dr Paul Ryan of Maynooth University, with the support of the Irish Sex Worker Research Network and the Sex Workers Alliance Ireland (SWAI). The findings from the report arise from in-depth focus groups and interviews conducted with men and women engaged in sex work (including trans men and trans women) in 2019. Sex workers interviewed for the research also included members of the LGBTI+ community, migrants and asylum seekers. Speaking ahead of the publication

of the report, lead researcher Dr Kathryn McGarry said, “The Criminal Law (Sexual Offences) Act 2017 continues to cast a shadow over the lives of sex workers working under this law. This report is important as sex workers have been so often silenced and excluded from debates about their lives. It represents their stories of life under these new laws – stories of a denial of access to health care and to justice.” Speaking at the publication of the report, HIV Ireland Executive Director Mr Stephen O’Hare said, “There can be little doubt that sex workers represent a particularly vulnerable and marginalised group in Irish society. Through this research, the law criminalising the purchase of sex has been shown to add little in the way of protection for sex workers while increasing vulnerability to negative outcomes including in relation to HIV prevention, access to justice and social exclusion.” “In her role as Chair of the Review, I urge Ms Butler to give serious consideration to adopting the recommendations contained within the report, including full decriminalisation of sex work, as a more suitable legal framework for sex work than the existing law provides”, added Mr O’Hare.


12 News

“Learn, unlearn, relearn” Written by: Barry O'Sullivan MPSI MBA Senior Pharmacist, Pharmacy Department, Mater Private Hospital, Cork

you are open to change, you are more likely to grasp the mettle and go for it. Understandably, I had concerns about what the work would be like, being a full time Hospital Pharmacist and fixating on what I didn’t know, but in reality there was much that I did know.

My classmates all took a moment to absorb what Tech leader and Irish woman Anita Sands had just said. We were sitting in a function room of a San Francisco bar at lunchtime on a May week day in 2017. We were there as part of our studies on the Corporate MBA program with the University of Limerick. Amongst other items, she was discussing the idea of having several careers, in differing roles rather than being a careerist in one segment. This was a concept which resonated strongly with me. Six weeks previously I had accepted a new position, leaving Community Pharmacy for Hospital Pharmacy. Community Pharmacy was to this point all I knew and had experienced. Summer and term holidays from university I worked in a Pharmacy in Mallow. My pre-registration year was a Community placement. All of my working career to that point was Community Pharmacy but I was eager for a new challenge.

was the relationship-building with regular patients. The Community Pharmacist has a really unique, high-contact position in the landscape of primary care. Over the years I was involved in delivery of pharmacy services to a wide number of Nursing and Residential care units. I derived great satisfaction providing these key pharmacy services, as it gave me a chance to flex my clinical skills. Detailed patient reviews with the medical and nursing teams, and tailoring medications to the patients and their needs was why I became a Pharmacist. Site visits to discuss medications with nurses and patients were very similar to what I do now in the Mater Private Hospital, Cork where I have been for over three years.

I certainly have learnt a great deal over the years working in the sector, but it was time to unlearn some of the administrative aspects of the Community Pharmacist role. It was time to commence a journey of relearning, moving my focus back to key areas of pharmacology and physiology.

The opportunity to move came about when my then employer, Sam McCauley Chemist group, asked me to provide additional Pharmacist support with the contract delivery in the Mater Private Hospital, Cork. For a number of years Sam McCauley’s Chemist group had provided the pharmacy services with on-site Pharmacist cover and off-site dispensing. In later years, with the marked success and expansion of services in the state-of-the-art facility, the contract was brought in-house and the Pharmacy Department of the Mater Private Hospital, Cork went live at the end of March 2020.

For me one of the most enjoyable aspects of Community Pharmacy

There was never going to be a perfect time to move but when

OCTOBER 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

Introspection in the time around the sectoral move threw up plenty of points for consideration such as not having a clinical diploma and no prior experience in hospital. To aid in the integration process, I did a lot of self-guided study, refreshing knowledge around absorption, distribution, metabolism and excretion of medications. I spoke to colleagues in other hospitals and leant on the support of the Pharmacy team members. Never be afraid to ask for help or direction. In both sectors of pharmacy there are commonalities and transferrable skills. Clear communication, evidence-based decision making and team playing will aid greatly in problem solving. The centre of what we do as Pharmacists is the patient, and we always strive to do our best for them. Pharmacists are expertly skilled in research skills and communication. We do it all the time, day in, day out, regardless of role or sector. We translate technical information to understandable and relatable data, appropriate to the recipient. The learning curve at times felt almost vertical but there is an exhilaration to that too. Fuel to mental fire.

COVID-19, additional complexities were added, and a greater level of infection control measures are the daily reality for the foreseeable future. For a few months, the type of patient cohort changed in the hospital in line with HSE needs and so knowledge of different types of patient care was required. A typical day for me is a mixture of chart reviews, patient counselling, clinical staff education, medication queries and aiding in discharge planning from a medication perspective. These were all the expected aspect of the job coming in the door, but additionally there is a wide number of governance committees to do policy and procedural work for. These committees are responsible for a variety of aspects of patient care such as the CPR committee, to the main medication committee: Drugs and Therapeutics. This multi-disciplinary committee has overall governance of medication use with the sole focus of optimal patient care. Private hospitals in Ireland operate to the standards of Joint Commission International. Their tri-annual routine inspection is preceded with a lot of work across the committees and wider hospital. Pharmacy has a significant part to play in all this so there is of protocol writing, auditing and training around this too. Over the years I have been lucky enough to tutor some really excellent Intern Pharmacists and I make sure I explain the logic and process I follow to the students under my tutelage. Regardless of sector, the key messages have been the same: clear communication, robust processes and keeping the patient at the centre of all your activities. Again these are commonalities for all Pharmacists. Pharmacists are a versatile and adaptive profession; with treatment guidance constantly changing, coupled with stock supply and legislative changes, we have to be.

My days in the Mater Private Hospital, Cork are busy and demanding. Working across all departments, I provide, along with my Pharmacy Department colleagues, the best care we possibly can.

With the success of the Mater Private Hospital Cork in recent years, the future holds many exciting expansion plans. The addition of new specialities and units will see the Pharmacy department challenged in a positive way to support this growth.

The pace can be quite fast and the work very varied in hospital. With

Don’t be scared of change, if change is what you seek.


14 News

Advanced predictive testing for blood cancer multiple myeloma in Ireland Dr Siobhan Glavey, Principal Investigator

By combining genomic testing and next generation sequencing technology, a new partnership led by RCSI researchers aims to advance predictive tests for multiple myeloma (MM), the second most common blood cancer in Ireland. The study will be carried out at Beaumont Hospital Dublin and run through the Blood Cancer Network Ireland with several other cancer hospitals in Ireland participating. It represents a collaboration between RCSI University of Medicine and Health Sciences and SkylineDx with funding support from Amgen; Celgene, a Bristol Myers Squibb company; and Janssen. Multiple myeloma is a cancer of plasma cells in the bone marrow that normally produce antibodies to help fight infection. Approximately 250 patients are diagnosed with this condition in Ireland every year. Globally the incidence of this disease are rising, due to population growth, an aging world population and a rise in age-specific incidence rates. Due to the complex nature of the disease, patients often require multidisciplinary

medical input and myeloma drugs are amongst the highest cost therapies worldwide. Due to improvements in new treatments for multiple myeloma, the outlook for patients has greatly improved with survival times and treatment free intervals increasing. However, in 2020 multiple myeloma is still considered an incurable disease, with the majority of patients following a relapsing course and requiring further treatment to keep the disease at bay. According to the National Cancer Registry, Ireland, the 5 year survival of multiple myeloma patients is approximately 50%, in keeping with international best standards, but greater advances in therapy and knowledge of the disease is required to improve this figure. Predicting the course of the disease and guiding treatment choice in newly diagnosed patients, is one of the major challenges in this cancer and currently available tests at diagnosis fall short of providing this information to patients and haematologists. Newly developed tests over the last number of years are helping to do this and

OCTOBER 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

one such example is Minimal residual disease (MRD). This is a test performed on the patients DNA at diagnosis by Next Generation Sequencing (NGS), which can detect if there are trace amounts of the cancer remaining in a patient after treatment, and has been shown to be highly predictive of long-term outcomes in several studies. Another test that can help to predict patients outcomes has been developed by SkylineDx, which uses a novel gene expression based test to guide prognosis called the “MMprofiler”. At Beaumont and RCSI, in collaboration with SkylineDx, scientists have implemented these novel gene based tests SkylineDx for the testing of MM patients in order to guide prognosis. This test called “MMprofiler with SKY92” establishes if patients have a high risk of relapsing and has been increasingly adopted in global clinical trials as a more predictive and robust marker than older tests like fluorescence in-situ hybridization (FISH). This study at RCSI and Beaumont aims to combine these two highly predictive modalities to provide a personalised medicine approach for patients.

“If our study can definitively determine which patients will benefit from certain treatments... it will provide clinicians with invaluable information that will lead to better outcomes" This in-depth analysis of genetic risk could enable doctors to identify which patients are at highrisk of relapse after a stem cell transplant. With this knowledge, it may in the future be possible to refine treatment for individual patients based on their specific disease molecular signature. “If our study can definitively determine which patients will benefit from certain treatments, and when, it will provide clinicians with invaluable information that will lead to better outcomes for patients with multiple myeloma.” said Dr Siobhan Glavey, Honorary Senior Lecturer at RCSI, Consultant Haematologist at Beaumont Hospital and the project’s Principal Investigator. “As we move toward personalised medicine, studies like ours will hopefully become more and more common and will help to target high cost effective therapies with greater precision. The study will initially enroll a small number of patients and follow them over time to test this theory.”


The Pelgraz® Patient App Find out how the Pelgraz® Patient App can help your patients to confidently self inject from home

One dose One less thing to worry about *

*One dose per chemo cycle

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NEW Pelgraz ® Device Patient & App

Confidence, Convenience, Compliance Abbreviated Prescribing Information Please refer to the Summary of Product Characteristics (SmPC) before prescribing Pelgraz▼(pegfilgrastim) 6 mg solution for injection in pre-filled injector. Presentation: Each pre-filled injector contains 6  mg of pegfilgrastim* in 0.6  mL solution for injection. The concentration is 10  mg/mL based on protein only**. *Produced in Escherichia coli cells by recombinant DNA technology followed by conjugation with polyethylene glycol (PEG). ** The concentration is 20 mg/mL if the PEG moiety is included. Indications: Reduction in the duration of neutropenia and the incidence of febrile neutropenia in adult patients treated with cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukaemia and myelodysplastic syndromes). Dosage and Administration: Pelgraz therapy should be initiated and supervised by physicians experienced in oncology and/or haematology. Posology: One 6  mg dose (a single pre-filled injector) of Pelgraz is recommended for each chemotherapy cycle, given at least 24 hours after cytotoxic chemotherapy. Safety and efficacy of Pelgraz in children and adolescents has not yet been established and no recommendation on a posology can be made. No dose change is recommended in patients with renal impairment, including those with end-stage renal disease. Method of administration: Pelgraz is for subcutaneous use. The injections should be given subcutaneously into the thigh, abdomen or upper arm. See SmPC for instructions on handling of the medicinal product before administration. Contraindications: Hypersensitivity to pegfilgrastim or any of the excipients in Pelgraz. Warnings and precautions: To improve the traceability of biological medicinal products, the trade name of the administered product should be clearly recorded. The long-term effects of pegfilgrastim have not been established in acute myeloid leukaemia (AML); therefore, it should be used with caution in this patient population. Granulocyte-colony stimulating factor (G-CSF) can promote growth of myeloid cells in vitro and similar effects may be seen on some non-myeloid cells in vitro. The safety and efficacy of pegfilgrastim have not been investigated in patients with myelodysplastic syndrome, chronic myelogenous leukaemia, and in patients with secondary AML; therefore, it should not be used in such patients. Particular care should be taken to distinguish the diagnosis of blast transformation of chronic myeloid leukaemia from AML. The safety and efficacy of pegfilgrastim administration in de novo AML patients aged < 55 years with cytogenetics t(15;17) have not been established. The safety and efficacy of pegfilgrastim have not been investigated in patients receiving high dose chemotherapy. This medicinal product should not be used to increase the dose of cytotoxic chemotherapy beyond established dose regimens. Pulmonary adverse reactions, in particular interstitial pneumonia, have been reported after G-CSF administration. Patients with a recent history of pulmonary infiltrates or pneumonia may be at higher risk. The onset of pulmonary signs such as cough, fever, and dyspnoea in association with radiological signs of pulmonary infiltrates, and deterioration in pulmonary function along with increased neutrophil count may be preliminary signs of Adult Respiratory Distress Syndrome (ARDS). In such circumstances pegfilgrastim should be discontinued at the discretion of the physician and the appropriate treatment given. Glomerulonephritis has been reported in patients receiving filgrastim and pegfilgrastim. Generally, glomerulonephritis resolved after dose

www.accord-healthcare.ie

reduction or withdrawal of filgrastim and pegfilgrastim. Urinalysis monitoring is recommended. Capillary leak syndrome has been reported after G-CSF administration and is characterised by hypotension, hypoalbuminaemia, oedema and haemoconcentration. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care. Generally asymptomatic cases of splenomegaly and cases of splenic rupture, including some fatal cases, have been reported following administration of pegfilgrastim. Spleen size should be carefully monitored (e.g. clinical examination, ultrasound). A diagnosis of splenic rupture should be considered in patients reporting left upper abdominal pain or shoulder tip pain. Treatment with pegfilgrastim alone does not preclude thrombocytopenia and anaemia because full dose myelosuppressive chemotherapy is maintained on the prescribed schedule. Regular monitoring of platelet count and haematocrit is recommended. Special care should be taken when administering single or combination chemotherapeutic medicinal products which are known to cause severe thrombocytopenia. Sickle cell crises have been associated with the use of pegfilgrastim in patients with sickle cell trait or sickle cell disease. Therefore, use caution when prescribing pegfilgrastim in patients with sickle cell trait or sickle cell disease, monitor appropriate clinical parameters and laboratory status and be attentive to the possible association of this medicinal product with splenic enlargement and vasoocclusive crisis. White blood cell (WBC) counts of 100 x  109 /L or greater have been observed in less than 1% of patients receiving pegfilgrastim. No adverse reactions directly attributable to this degree of leukocytosis have been reported. Such elevation in WBCs is transient, typically seen 24 to 48 hours after administration and is consistent with the pharmacodynamic effects of this medicinal product. Consistent with the clinical effects and the potential for leukocytosis, a WBC count should be performed at regular intervals during therapy. If leukocyte counts exceed 50  x  109 /L after the expected nadir, this medicinal product should be discontinued immediately. Hypersensitivity, including anaphylactic reactions, have been reported with pegfilgrastim. Permanently discontinue pegfilgrastim in patients with clinically significant hypersensitivity. Do not administer pegfilgrastim to patients with a history of hypersensitivity to pegfilgrastim or filgrastim. If a serious allergic reaction occurs, appropriate therapy should be administered, with close patient follow-up over several days. Stevens- Johnson syndrome (SJS), which can be life-threatening or fatal, has been reported rarely in association with pegfilgrastim treatment. If the patient has developed SJS with the use of pegfilgrastim, treatment must not be restarted at any time. As with all therapeutic proteins, there is a potential for immunogenicity. Rates of generation of antibodies against pegfilgrastim is generally low. Binding antibodies do occur as expected with all biologics; however, they have not been associated with neutralising activity at present. Aortitis has been reported after filgrastim or pegfilgrastim administration in healthy subjects and in cancer patients. The symptoms experienced included fever, abdominal pain, malaise, back pain and increased inflammatory markers (e.g. C-reactive protein and WBC count). In most cases aortitis was diagnosed by CT scan and generally resolved after withdrawal of filgrastim or pegfilgrastim. The safety and efficacy of Pelgraz for the mobilisation of blood progenitor

Oncology & Haematology

cells in patients or healthy donors has not been adequately evaluated. Increased haematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone-imaging findings. This should be considered when interpreting bone- imaging results. This medicinal product contains 50 mg sorbitol in each unit volume, which is equivalent to 30 mg per 6 mg dose. Pelgraz contains less than 1 mmol (23 mg) sodium per 6 mg dose, that is to say essentially ‘sodium-free’. The needle cover contains dry natural rubber (a derivative of latex), which may cause allergic reactions. Pregnancy and Lactation: Pegfilgrastim is not recommended during pregnancy and in women of childbearing potential not using contraception. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from pegfilgrastim therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman. Adverse Events include: Adverse events which could be considered serious include: Common: Thrombocytopenia. Uncommon: Sickle cell crisis, capillary leak syndrome, glomerulonephritis, hypersensitivity reactions (including angioedema, dyspnoea, anaphylaxis), splenic rupture (including some fatal cases), Sweet’s syndrome (acute febrile dermatosis), pulmonary adverse reactions including interstitial pneumonia, pulmonary oedema and pulmonary fibrosis have been reported. Uncommonly cases have resulted in respiratory failure or ARDS which may be fatal. Rare: Aortitis, pulmonary haemorrhage, Stevens-Johnson syndrome. Other Very Common adverse events: Headache, nausea, bone pain. Other Common adverse events: Leukocytosis, musculoskeletal pain (myalgia, arthralgia, pain in extremity, back pain, musculoskeletal pain, neck pain), injection site pain, non-cardiac chest pain. See SmPC for details of other adverse events. Shelf Life: 3 years. Store in a refrigerator (2°C – 8°C). Pelgraz may be exposed to room temperature (not above 25°C ± 2°C) for a maximum single period of up to 72 hours. Pelgraz left at room temperature for more than 72 hours should be discarded. Do not freeze. Accidental exposure to freezing temperatures for a single period of less than 24 hours does not adversely affect the stability of Pelgraz. Keep the container in the outer carton in order to protect from light. Pack Size: One prefilled injector with one alcohol swab, in a blistered packaging. Marketing Authorisation Number: EU/1/18/1313/002. Marketing Authorisation Holder (MAH): Accord Healthcare S.L.U, World Trade Center, Moll de Barcelona, s/n, Edifici Est, 6a planta, Barcelona, 08039 Spain. Legal Category: POM. Full prescribing information including the SmPC is available on request from Accord Healthcare Ireland Ltd, Euro House, Little Island, Co. Cork, Tel: 021-4619040 or www.accord-healthcare.ie/products. Adverse reactions can be reported to Medical Information at Accord-UK Ltd. via E-mail: medinfo@accord-healthcare.com or Tel: +44(0)1271385257. Date of Generation of API December 2019. IE-01454

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

May 2020. IE-01429


16 Lung Cancer

The evolving role of liquid biopsy in lung cancer Written by: Dr David McMahon and Dr Dearbhaile Collins Department of Medical Oncology, Cork University Hospital

Dr David McMahon is currently working as a specialist registrar in Medical Oncology department of Cork University Hospital. He graduated with an honours degree from the Royal College of Surgeons in Ireland in 2015 and has previously spent time working in hospitals throughout Ireland and spent time practising oncology at Fiona Stanley Hospital in Perth. He is a member of Cancer Trials Ireland. His subspecialty interest is in thoracic oncology. David McMahon, Department of Medical Oncology, Cork University Hospital

Lung cancer is the single biggest cause of cancer-related death in Ireland. The majority of lung cancer cases (80-85%) are Non-Small Cell Lung Cancer (NSCLC). These are divided into adenocarcinoma, squamous cell carcinoma and less common

Dr Dearbhaile Collins MBBCh MA PhD IMRCS MRCPI is an Irish trained Medical Oncologist with speciality interest in lung cancer and gynaecological malignancies but also treats a variety of other cancers. She has both a PhD in translational oncology and MA in Medical Ethics and Law. She leads the Clinical Trials Unit in Cork University Hospital.

Dearbhaile Collins, Department of Medical Oncology, Cork University Hospital

histopathological subtypes. A proportion of these cancers, predominantly adenocarcinoma, have single identifiable mutations in cancer-causing genes (oncogenes) that drive the cancer’s growth and progression. These “driver mutations” are outlined

in Figure 1 and can be found in approximately two thirds of NSCLC adenocarcinoma. Many of these mutations can now be specifically targeted with inhibitory compounds by a method fashionably called “precision” or “personalized” oncology. These

novel treatments for NSCLC with targetable driver mutations have revolutionized patient care over the past decade. For mutations in genes such as EGFR, ALK and ROS1, using targeted treatments in preference to chemotherapy has resulted in patients living longer, and with improved quality of life (QoL). Other mutations, such as KRAS, have proven more challenging to inhibit, but recently the KRAS G12C inhibitor, Sotorasib (Amgen) has been approved in this space by the FDA.

1: The breakdown of oncogenic mutations in Non-Small cell Lung Cancer (adenocarcinoma).

Although targeted therapies have had success in a variety of subtypes of NSCLC, tumours inevitably become resistant to these agents. Resistance can develop over months to years after treatment initiation. There are a wide variety of different resistance mechanisms. For instance, new secondary mutations of the same original mutation (T790M in EGFR-mutant (EGFRmut) NSCLC), development of new different mutations (cMET, HER2) and dedifferentiation into another cancer subtype such as small cell differentiation (Figure 2). These mechanisms can terminate the effectiveness of the original targeted agent and lead to cancer progression. As a result, early

Figure 1: The breakdown of oncogenic mutations in Non-Small cell Lung Cancer (adenocarcinoma)

OCTOBER 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE


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

PD-L1 1-49%

PD-L1 >50%

NONSQUAMOUS

1st line Combination** Therapy3

SQUAMOUS

1st line*** Monotherapy4

NON-SQUAMOUS AND SQUAMOUS

X

X

Line

Histology

1st line Combination* Therapy2

* KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of metastatic non-squamous NSCLC in adults whose tumours have no EGFR or ALK positive mutations. ** KEYTRUDA, in combination with carboplatin and either paclitaxel or nab-paclitaxel, is indicated for the first-line treatment of metastatic squamous NSCLC in adults. *** KEYTRUDA, as monotherapy, is indicated for the first-line treatment of metastatic non-small cell lung carcinoma (NSCLC) in adults whose tumours express PD-L1 with a≥ 50% tumour proportion score (TPS) with no EGFR or ALK positive tumour mutations. skin adverse reaction on prior treatment with other immune- stimulatory anticancer agents. Other clinically significant immune-related adverse reactions: The following additional clinically significant, immune-related adverse reactions, have been reported in clinical studies or in post-marketing experience: uveitis, arthritis, myositis, myocarditis, pancreatitis, Guillain-Barré syndrome, myasthenic syndrome, haemolytic anaemia, sarcoidosis 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


Figure 2. Common sequence of resistance mechanisms

18 Lung Cancer

Figure 2. Common sequence of resistance mechanisms

identification of these resistance mechanisms is crucial in planning changes in treatment. There are currently 10 NCCPapproved targeted agents for driver mutated NSCLC in Ireland (Table 1) and this is expected to expand in the coming years. Five in EGFRmut NSCLC, five in ALK translocated NSCLC and one in ROS1 rearranged NSCLC. The appropriate sequencing of these targeted approaches for the same mutation should maximize patient’s overall survival (OS) and QOL, at least from a bioplausibility point of view. Furthermore, detection of the specific resistance mutations that develop can help guide the choice of next compound. The best treatment option for patients with driver mutations therefore requires a deep and repeated understanding of the molecular environment. This can be difficult to achieve with traditional tissue biopsy of lung cancer. Limitations include the not insignificant risk of bleeding or pneumothorax and the phenomenon of “tumour heterogeneity”. This latter term describes the concept that the biopsied tumour itself might not be fully representative of metastatic disease elsewhere and indeed the totality of the microenvironment within the

tumour itself. Liquid biopsy is an emerging tool in oncology that has rapidly expanding clinical utility, as its cost reduces and its sensitivity and specificity improves with modern technologies. Liquid biopsies can detect circulating tumour cells (CTC) or circulating tumour DNA (ctDNA) in peripheral blood samples and assess these DNA fragments for mutations. DNA mutations circulating in the blood are more representative of the whole tumour biology and can reveal different mutations from different tumour sites, thus lessening tumour heterogeneity challenges. Liquid biopsy is also less invasive than tumour biopsy techniques and can be done repeatedly throughout the disease course with relative ease. Liquid biopsy therefore offers a convenient, fast, and precise approach of identifying targetable oncogene mutations and resistance mechanisms in addition to and at times instead of the traditional methods in NSCLC. The most common techniques for ctDNA analysis include amplification refractory mutation system (ARMS), droplet digital polymerase chain reaction (ddPCR) and next generation sequencing (NGS) based methods. Over the past decade, there have been significant improvements in detection techniques as well as a

OCTOBER 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

reduction in cost and turnaround time of these methods. ARMS is based upon qualitative PCR (qPCR) that uses specific probes to identify specific mutational variations. The commonly used cobas-ARMS to detect various EGFRmut has 100% specificity, however up to 30% false negative rate in plasma samples. Thus, tumour biopsy still remains superior in EGFRmut detection and liquid biopsy cannot yet replace tumour analysis. ALK fusions and rearrangements, KRAS variants and BRAF mutations are easily and rapidly identified through ARMS and ddPCR gene analysis methods, for example the Idylla™ platform (Biocartis Inc). In addition, actionable mutations sought out in NSCLC (Figure 1) can also be identified through NGS techniques. Whereas ddPCR and ARMS can only focus upon single-cell gene analysis or limited multi-gene panels, NGS can allow the entire tumour genome to be sequenced at once or preselected gene panels ranging from 10 to thousands of variants. Many biotechnology companies now offer NGS of blood ctDNA including FoundationOne Liquid CDx (Foundation Medicine) and Guardant360® Liquid Biopsy Assay (Guardant Health). It is expected that over the coming years many more platforms will come to market for NGS of liquid biopsy samples with reducing

expense and faster turnaround. These ctDNA NGS analyses have excellent concordance with tumour biopsy NGS and in addition, can report tumour mutational burden (TMB) and microsatellite instability (MSI). These latter two measurements aim to clinically predict cancers that may be sensitive to immunotherapy agents. TMB is a measure of the number of gene mutations per megabase of DNA, the higher the result, the more genomically unstable the cancer may be. “High-TMB” patients are thought to be more “immunogenic”. Thus, more likely to respond to reactivation of the immune system through immune checkpoint inhibitors, such as pembrolizumab (Keytruda®, MSD) and nivolumab (Opdivo®, BMS). MSI, in a similar fashion, reflects abnormalities of tumour DNA repair mechanisms and so again “MSI-high” tumours are more likely to have multiple tumour mutations that may enhance response to immunotherapy agents. In NSCLC, ctDNA gene mutation(s) levels can change over time and in response to treatments. Liquid biopsy analyses show increasing levels of EGFRmut in response to targeted therapies as tumour cells die, undergo apoptosis and are shed into the bloodstream. This is then followed by reducing


19 Gene + variant

Table 1. Irish NCCP reimbursed targeted therapies for NSCLC

Approved drugs Erlotinib (Tarceva®, Roche)

EGFR mutation (all)

Gefitinib (Iressa®, AstraZeneca) Dacomitinib (Vizimpro®, Pfizer) Afatinib (Giotrif®, Boehringer Ingelheim)

EGFR T790M only

Osimertinib (Tagrisso®, AstraZeneca) Crizotinib (Xalkori®, Pfizer) Alectinib (Alcensa®, Roche)

ALK translocation

Brigatinib (Alunbrig®, Takeda) Ceritinib (Zykadia®, Novartis) Lorlatinib (Lorbrena®, Pfizer)

ROS1 translocation

Crizotinib (Xalkori®, Pfizer)

Table 1. Irish NCCP reimbursed targeted therapies for NSCLC

levels over the following weeks.1,2 Tracking changes in ctDNA EGFR mutation levels can determine a patient’s disease state and capture dynamic changes during targeted treatment in addition to the early identification of emerging resistance mutations. All this highlights the importance of tracking EGFR mutations throughout the disease course as an adjunct to clinical decision making and treatment planning.3 A similar story can be seen in other targetable mutations. Crizotinibresistant ALK rearrangements and point mutations can be detected by ctDNA liquid biopsy methods and lead to changes in patient treatment.4,5 Ireland has only recently seen approval of osimertinib (Tagrisso®, AstraZeneca) on 1st July 2020 based on AURA trial results. This is despite Food and Drug Administration (FDA) approval five years prior, in November 2015, and European Medicines Agency (EMA) approval in February 2016 in the same indication for T790M EGFR mutations. The FDA and EMA now approve its use as a first line treatment, but this is not yet accessible for Irish patients, on account of delays with drug reimbursement. With the approval of osimertinib, the need to perform regular liquid biopsy and tumour tissue (where feasible) is

increasingly important. However, there is a growing cost to these targeted therapies. Osimertinib is the subject of confidential price negotiations with the HSE, but costs £4,722.30 monthly in the UK. With patients remaining on this agent for a year and beyond, the burgeoning individual cost, given the finite resources available in the HSE, needs to be carefully considered. Utilizing liquid biopsy in everyday practice for identification of biomarkers to predict tumour response and patient toxicity is critical to optimise the care of the individual patient. The cost of liquid biopsy is reducing all the time, and pairing these identified biomarkers with matched targeted treatments could lead to cost savings over time, by filtering out those who will not benefit from expensive anti-cancer compounds and carefully selecting those most likely to gain meaningful tumour responses to these therapies. This is likely to become increasingly important in the years to come as more and more expensive targeted agents are developed and used more frequently at earlier stages of lung cancer disease course, in the adjuvant, and even neoadjuvant, setting. The analysis of liquid biopsy for NSCLC is currently practiced in an ad hoc and infrequent

manner by most centres. In some hospitals, only the T790M mutation in sought for access to osimertinib. However, to obtain a deeper molecular understanding of oncogenic mutations identified in NSCLC and the evolution of these mutations over time, more structured assessment is key. The Thoracic Oncology team in Cork, with Dr Dearbhaile Collins as Principal Investigator, in collaboration with Professor Louise Burke and Dr Michael Bennett, is initiating a structured and regular mutational assessment protocol for NSCLC patients. All mutations and rearrangements in EGFR, ALK, KRAS, ROS1, HER2, BRAF, MET and NTRK identified will be tracked repeatedly over time. This will permit temporal evolution analysis of oncogenic driver mutations and biomarkers of NSCLC patients in serum and tumour tissue and embed this frequent assessment in standard cancer care. It is due to begin enrolling patients from the South and South West hospital group by the end of 2020. This strategy will also allow observations of mutational evolution under targeted treatment pressures, identifying resistance mutations prior to clinical and radiographic evidence of disease progression. We aim to correlate treatment modalities and changes in ctDNA with patient outcomes in real world practice. It will also

enable our patients to access expanded access anticancer drug programmes and further clinical trial opportunities that otherwise may not be available. Liquid biopsy in NSCLC needs to be integrated into patients care as standard. Lung cancers that are driven by the various detectable mutations outlined in Figure 1 evolve and change over time and in response to the treatments they are exposed to. Identifying and tracking these mutations using minimally invasive blood draws rather than challenging tumour biopsies allows a deeper understanding of the cancers evolution as well as minimizes the problem of tumour heterogeneity, both within the tumour itself and also between the different sites of disease. Liquid biopsy is becoming more cost-effective and time-efficient, making it suitable to aid real-time, individual patient treatment decisions. Using regular structured assessments of plasma for oncogene driver mutations, like that commencing in the Cork region, will allow prognostication and determination of the most appropriate treatment strategies for patients. References on Request

HOSPITALPROFESSIONALNEWS.IE | HPN • OCTOBER 2020


20 Breast Cancer

Emerging Evidence in Breast Cancer Written by: Professor Janice Walshe, Clinical Professor in Medical Oncology, St Vincentâ&#x20AC;&#x2122;s University Hospital

Breast cancer continues to represent a significant economic and clinical burden to healthcare services worldwide. In Ireland, breast cancer is the most commonly diagnosed female cancer with just over 3,000 cases annually. Of these, approximately 600 cases a year are accounted for by a subgroup of hormone sensitive, Her-2 negative breast cancer that has not spread to the axillary lymph nodes. The treatment landscape for this group of patients has underwent radical change in the last 15 years. While the vast majority of patients with this disease derive most benefit from anti-hormonal therapy, a large proportion would have received adjuvant chemotherapy to reduce the risk of disease relapse by capturing the small number of patients that derive a benefit. This has been particularly relevant in pre- and perimenopausal women. The routine introduction of the 21-gene assay also known as Oncotype Dx has challenged this approach. The 21-gene test (Oncotype DX, Genomic Health, Inc., Redwood City, CA, USA) is a gene-expression profiling assay validated to predict the estimated rate of distant recurrence of breast cancer and the likelihood of adjuvant chemotherapy benefit in patients with this type of breast cancer. The assay uses reverse transcriptase polymerase chain reaction to quantify the presence of specific mRNA for 16 cancer genes and 5 reference genes in a breast cancer tumour block. These results are then combined into a single recurrence score (RS), expressed on a continuous scale of 0 (low risk of recurrence) to 100 (high risk

"We anticipated that not only would this assay save many hundreds of women from the ill-effects of chemotherapy but it would also prove cost effective for the Irish taxpayer." of recurrence). Following the results of the TAILOR-X trial (Trial Assigning Individualized Options for Treatment), the RS which predicts chemotherapy benefit differs according to patient age. In women older than 50 years, an RS of over 25 may suggest chemotherapy benefit, while in women, aged 50 years and under, with certain high-risk tumour features, chemotherapy may need to be considered with an RS from 16. In 2005, when I worked in the National Cancer Institute, Maryland, access to the 21-gene assay was routine for this patient group. Access had permitted a sophisticated discussion regarding the likelihood of patient outcome and the need for chemotherapy. When I moved back to Ireland to start a consultant post in 2006, this was not the case. Personally, it felt like a step back as I was forced to use an educational guess as to the need for chemotherapy or not. Thankfully, in 2008, our Irish

OCTOBER 2020 â&#x20AC;˘ HPN | HOSPITALPROFESSIONALNEWS.IE

patients gained access to the 21gene assay through the TAILOR-X trial, which was achieved through the close affiliation of our National cancer research group formerly known as ICORG (All Ireland Cooperative Oncology group) with the American research group, East Co-operative Oncology Group (ECOG). Through this trial, nearly 700 Irish women gained access to this gene assay which gave us important information regarding their tumour but also aided the international fight against futile chemotherapy administration. Through participation in this trial, recognition of the importance of this assay was identified by all Irish Oncologists and under an initiative by the Irish Society of Medical Oncology (ISMO) which was led by my colleague Prof. Cathy Kelly in the Mater, access was granted to Irish patients by the National Cancer Control Program in 2011. This was an achievement on two fronts. First, we had gained access in the middle of an economic crisis and second, we were the first European country to gain reimbursement. Once access was achieved, our intention was always to assess the real-world impact of this assay. We anticipated that not only would this assay save many hundreds of women from the ill-effects of chemotherapy but it would also prove cost effective for the Irish taxpayer. In 2015, Dr Lillian Smyth and I published our primary analysis of the impact of this assay on chemotherapy administration. At that time, we noted a 59% reduction in chemotherapy administration in this patient group. Following the official publication of the TAILOR-X trial in the New England Journal of Medicine, Dr Lynda McSorley and I performed an updated analysis of these results. This was presented in Chicago at the annual American Society of Clinical Oncology meeting in June 2020. Patients with hormone receptor positive, Her-2 negative breast whose tumour samples were tested with the 21-gene assay between October 2011 and February 2019 were identified retrospectively through electronic records. Patients were identified between October 2011 and February 2013 from eight cancer centres nationally through

pathology departments in each hospital. Between February 2013 and February 2019, patients were identified from St Vincentâ&#x20AC;&#x2122;s Healthcare Group via the pathology department. In total, 963 patients who had undergone 21-gene testing with this specific breast cancer subtype were identified. Following international guidelines, 846 of these patients would have been recommended chemotherapy. Using the 21-gene assay, the number recommended chemotherapy fell to 262. This was a massive 69% reduction in chemotherapy administration within this patient group. This also resulted in a net saving to the taxpayer of 1.2 million euros. We estimate that this patient cohort represents about one quarter of the patients that would have been tested in Ireland within this period and therefore the savings could approach 5 million euros. However, this estimate is extremely conservative as it does not account for the financial impact of absenteeism from work and child care costs while undergoing treatment. Also, while we recognise the financial gain is extremely important as we continue our drive for novel and often expensive drugs for our patients, we cannot underestimate the benefits of chemotherapy avoidance both from a physical and psychological point of view. Chemotherapy avoidance will result in less menopausal symptoms, less infertility, less hair loss, more job security, less cognitive issues, less susceptibility to infection which is particularly pertinent as we navigate the current Covid pandemic. Furthermore, while the majority of patients afflicted by this disease are female, men with breast cancer also benefit from this assay. The emergence and incorporation of validated multigene diagnostic tests into international cancer management guidelines have resulted in a tailored treatment plan that avoids systemic chemotherapy in large numbers of women with early stage breast cancer. The 21-gene assay is just one example of the emerging technologies towards the goal of precision medicine, a targeted therapy for all. Clinical trial participation is key if we are going to achieve this.


For the treatment of pretreated mCRC

Make time for more moments that matter

trifluridine/tipiracil

LonsurfÂŽ is licensed to Servier by Taiho, co-developed globally and marketed in their respective territories.

This medicinal product is subject to additional monitoring. LonsurfÂŽ (trifluridine/tipiracil) Abbreviated prescribing information: Please refer to the Summary of Product Characteristics before prescribing. COMPOSITION*: Lonsurf 15 mg/6.14 mg: film-coated tablet containing 15 mg trifluridine and 6.14 mg tipiracil (as hydrochloride). Lonsurf 20 mg/8.19 mg: film-coated tablet containing 20 mg trifluridine and 8.19 mg tipiracil (as hydrochloride). INDICATION*: As monotherapy for the treatment of adult patients with metastatic colorectal cancer who have been previously treated with, or are not considered candidates for, available therapies including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF agents, and anti-EGFR agents. As monotherapy for the treatment of adult patients with metastatic gastric cancer including adenocarcinoma of the gastroesophageal junction, who have been previously treated with at least two prior systemic treatment regimens for advanced disease. DOSAGE AND ADMINISTRATION*: Recommended starting dose: 35 mg/m2/dose taken orally twice daily on Days 1 to 5 and Days 8 to 12 of each 28-day cycle, within 1 hour after completion of the morning and evening meals. Dosage calculated according to body surface area, not exceeding 80 mg/dose. Possible dosing adjustments based on individual safety and tolerability: 3 permitted dose reductions to a minimum dose of 20 mg/m2 twice daily, dose escalation not permitted after a dose reduction. CONTRAINDICATIONS*: Hypersensitivity to the active substances or to any of the excipients. WARNINGS*: Bone marrow suppression: Complete blood cell counts must be obtained prior to initiation of therapy, prior to each cycle and as needed. Treatment must not be started if absolute neutrophil count <1.5 x109/L, if platelet counts <75x109/L, or if unresolved Grade 3 or 4 non-haematological clinically relevant toxicity. Patient should be monitored closely for infections; appropriate measures should be administered as clinically indicated. Gastrointestinal toxicity: anti-emetic, anti-diarrhoeal and other measures should be administered as clinically indicated, dose modifications should be applied as necessary. Renal impairment: not recommended if severe renal impairment or end-stage renal disease. Patients with renal impairment should be monitored closely: patients with moderate renal impairment should be more frequently monitored for haematological toxicities. Hepatic impairment: not recommended if baseline moderate or severe hepatic impairment. Proteinuria: monitoring by dipstick urinalysis recommended prior to starting and during therapy. Excipients: contain lactose. INTERACTIONS*: Precautions: medicinal products that interact with nucleoside transporters CNT1, ENT1 and ENT2, inhibitors of OCT2 or MATE1, human thymidine kinase substrates (e.g. zidovudine), hormonal contraceptives. FERTILITY*.PREGNANCY AND BREASTFEEDING*: Not recommended. CONTRACEPTION*: For women and men, highly effective contraceptive measures must be used during treatment and for 6 months after stopping treatment. DRIVE & USE MACHINES*: Fatigue, dizziness or malaise may occur. UNDESIRABLE EFFECTS*: Very common: Neutropenia, leukopenia, anaemia, thrombocytopenia, decreased appetite, diarrhoea, nausea, vomiting, fatigue. Common: Lower respiratory tract infection, febrile neutropenia, lymphopenia, hypoalbuminaemia, dysgeusia, neuropathy peripheral, dyspnoea, abdominal pain, constipation, stomatitis, oral disorder, hyperbilirubinaemia, Palmar-plantar erythrodysaesthesia syndrome, rash, alopecia, pruritus, dry skin, proteinuria, pyrexia, oedema, mucosal inflammation, malaise, hepatic enzyme increased, blood alkaline phosphatase increased, weight decreased. Uncommon: Septic shock, enteritis infectious, lung infection, biliary tract infection, influenza, urinary tract infection, gingivitis, herpes zoster, tinea pedis, candida infection, bacterial infection, infection, neutropenic sepsis, upper respiratory tract infection, conjunctivitis, cancer pain, pancytopenia, granulocytopenia, monocytopenia, erythropenia, leukocytosis, monocytosis, dehydration, hyperglycaemia, hyperkalaemia, hypokalaemia, hypophosphataemia, hypernatraemia, hyponatraemia, hypocalcaemia, gout, anxiety, insomnia, neurotoxicity, dysaesthesia, hyperaesthesia, hypoaesthesia, syncope, paraesthesia, burning sensation, lethargy, dizziness, headache, visual acuity reduced, vision blurred, diplopia, cataract, dry eye, vertigo, ear discomfort, angina pectoris, arrhythmia, palpitations, embolism, hypertension, hypotension, flushing, pulmonary embolism, pleural effusion, rhinorrhoea, dysphonia, oropharyngeal pain, epistaxis, cough, enterocolitis haemorrhagic, gastrointestinal haemorrhage, pancreatitis acute, ascites, ileus, subileus, colitis, gastritis, reflux gastritis, oesophagitis, impaired gastric emptying, abdominal distension, anal inflammation, mouth ulceration, dyspepsia, gastro-oesophageal reflux disease, proctalgia, buccal polyp, gingival bleeding, glossitis, periodontal disease, tooth disorder, retching, flatulence, breath odour, hepatotoxicity, biliary dilatation, skin exfoliation, urticaria, photosensitivity reaction, erythema, acne, hyperhidrosis, blister, nail disorder, joint swelling, arthralgia, bone pain, myalgia, musculoskeletal pain, muscular weakness, muscle spasms, pain in extremity, renal failure, cystitis noninfective, micturition disorder, haematuria, leukocyturia, menstrual disorder, general physical health deterioration, pain, feeling of body temperature change, xerosis, discomfort, blood creatinine increased, electrocardiogram QT prolonged, international normalised ratio increased, activated partial thromboplastin time prolonged, blood urea increased, blood lactate dehydrogenase increased, protein total decreased, C-reactive protein increased, haematocrit decreased. Post-marketing experience: interstitial lung disease. OVERDOSE*. PROPERTIES*: Trifluridine is an antineoplastic thymidine-based nucleoside analogue and tipiracil hydrochloride is a thymidine phosphorylase (TPase) inhibitor. Following uptake into cancer cells, trifluridine, is phosphorylated by thymidine kinase, further metabolised in cells to a deoxyribonucleic acid DNA substrate, and incorporated directly into DNA, preventing cell proliferation. However, trifluridine is rapidly degraded by TPase and readily metabolised by a first-pass effect following oral administration, hence the inclusion of the TPase inhibitor, tipiracil hydrochloride. PRESENTATION*: Pack of 20 or 60 film-coated tablets. LES LABORATOIRES SERVIER, 50 rue Carnot, 92284 Suresnes cedex France. www.servier.com. Marketing Authorisation: EU/1/16/1096/001-006. Legal Category: POM. Further information available from: Servier Laboratories Ireland Ltd, Block 2, West Pier Business Campus, Old Dunleary Road, Dun Laoghaire, Co. Dublin, Tel (01) 6638110, Fax (01) 6638120, www.servier.ie. * For complete information, please refer to the Summary of Product Characteristics on www.medicines.ie Date of last revision of text: September 2019 (date of last approved SmPC: September 2019) Date of preparation of this item: February 2020 1920c1LNPress


22 Cardiovascular

Statins for primary prevention of cardiovascular disease Written by: Dr Paula Byrne, SPHeRE Scholar, National University Galway

Statins are now one of the most commonly prescribed drugs in Ireland and elsewhere,1 and it was estimated that global spend on these drugs would reach $1trillion by this year.2 While the use of statins in those with existing cardiovascular disease (CVD) has generally been uncontroversial, the same cannot be said for their use in those with no history of CVD, that is, in primary prevention.3 In this article I describe how I and my co-authors explored various aspects of statin use in primary prevention as part of a mixed methods analysis. My first paper comprised an analysis of The Irish Longitudinal Study on Ageing (TILDA) finding that about one third of over-50s in Ireland use statins and that the majority of those do so for primary prevention. Interestingly, almost three-quarters of female statin users did so for primary prevention, compared to a little over half of male statin users. A second analysis found that there has been a large increase in eligibility for statins for primary prevention supported by changes to European clinical guidelines for the prevention of CVD. In 1987 8% of a sample of over-50s could have been eligible compared to 61% of the same sample by 2016.

Having established that a large proportion of older Irish adults use statins for primary prevention, I was motivated to analyse the evidence to support this use by undertaking an overview of systematic reviews (SRs). Here I found that the evidence to support statin use in primary prevention is limited and uncertain.

in all-cause mortality for those at this baseline risk (RR 0.94 [95% CI 0.71 to 1.26]). In other words, SRs of trials reported that the relative risk (RR) of dying for those who were taking statins was 6% lower than those who were not (RR 0.94). However, trials are not the real world, and confidence intervals (CIs) are a way of estimating the range of values in which we think the real-world value lies. In this case, the CIs ranged from 0.71, (29% reduced risk of dying) to 1.26 (26% increased risk of dying) in those taking statins compared with those not taking statins. In a discussion on how to apply results of systematic reviews to patient care, Murad et al suggest that clinicians consider the upper and lower bounds of CIs. They can then consider how they would advise their patients were the upper boundary to represent the truth (in this case a 26% increase in all-cause mortality) and how they would advise their patients were the lower boundary to represent the truth (in this case a 29% decrease in all-cause mortality).4

Secondly, the evidence to support statin use in primary prevention is uncertain because many of the reductions in outcomes such as all-cause mortality, vascular deaths, major coronary events, and major vascular events were not statistically significant when stratified by baseline risk. Baseline risk is defined as a person’s risk of developing CVD over a period of time (typically five or ten years) and can be calculated by various methods (for example the online QRisk or SCORE calculators).

To further complicate matters, studies usually report relative risk reductions, that is, the difference in CVD event rates between those taking statins and those not taking statins. But the absolute risk reduction is more relevant to decision making for an individual patient. For example, a 65-yearold man who smokes, does not have heart disease, but who has high total cholesterol levels and raised blood pressure might have an estimated 38% absolute risk of having a major coronary event in the next 10 years; whereas a 45-year-old woman who does not smoke and has raised total cholesterol levels and slightly raised blood pressure woman might have a 1.4% risk. According to our review, statins would reduce the man’s relative risk by 24% and the woman’s by 41%. However, the man could expect an absolute risk reduction of about 9% (risk drops from 38% to 24%) compared with just 0.6% (risk drops from 1.4% to 0.8%) for the woman.

Take for example a person whose baseline risk is <5%. Our overview found non-significant reductions

Having considered which relative RR is most relevant to the particular individual and

Firstly, the evidence to support statin use in primary prevention is limited because most SRs of statins incorporate both primary and secondary prevention participants. Our study focused exclusively on primary prevention data.

OCTOBER 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

the associated absolute RR, the next consideration should be the potential harms from taking statins. The decision to take or prescribe any medicine involves a trade-off between the perceived benefits and harms of that medicine for the individual. Collins et al, in an analysis of trial data, have reported that treating 10,000 patients for 5 years would cause about five cases of myopathy, 50–100 new cases of diabetes and 5–10 haemorrhagic strokes.5 However, observational data suggest much higher rates of ‘musculoskeletal pain’6 Unfortunately, despite calls for the release of figures on statin harms to independent researchers,7 these data remain unavailable. Thus, doctors and patients cannot make fully informed decisions. In light of these findings, questions arise as to why so many low-risk people take statins and why doctors prescribe them. Surprisingly, given the large proportion of those taking statins for primary prevention, there is little in the literature to answer this question. Therefore, for my final study, I interviewed doctors and patients and found that rather than high cholesterol being seen as one of several risk factors that contributes to heart disease, it tended to be promoted simplistically to the status of a disease needing treatment of itself. To conclude, I found that although statins are commonly prescribed, they may be an example of low-value care particularly for low-risk people and, in some cases, represent a waste of healthcare resources. For now, I argue that the prescription, use, and reimbursement of statins in low risk individuals warrants more careful consideration and decisions made need to incorporate patient preferences. Podcasts and BMJ Analysis I discussed the significance of these three studies in a British Medical Journal analysis in two podcasts with the British Medical Journal and the New England Journal of Medicine. References available on request


NEW

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

HYPERCHOLESTEROLAEMIA

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

Rosuvastatin + Ezetimibe

Rosuvastatin + Ezetimibe

Rosuvastatin + Ezetimibe

10 mg/10 mg

20 mg/10 mg

40 mg/10 mg

NOW AVAILABLE Suvezen is indicated for substitution therapy in adult patients who are adequately controlled with rosuvastatin and ezetimibe given concurrently at the same dose level as in the fixed combination, but as separate products, as adjunct to diet for treatment of primary hypercholesterolaemia (heterozygous familial and non-familial) or homozygous familial hypercholesterolaemia1 Prescribing Information: Suvezen (rosuvastatin/ ezetimibe) film-coated tablets Please refer to the Summary of Product Characteristics (SPC) for full prescribing details. Presentations: Suvezen 10mg/10mg, 20mg/10mg and 40mg/10mg: Each film-coated tablet contains 10mg; 20mg or 40mg of rosuvastatin (as rosuvastatin calcium) respectively, and 10mg ezetimibe. Indication: Suvezen is indicated for substitution therapy in adult patients who are adequately controlled with rosuvastatin and ezetimibe given concurrently at the same dose level as in the fixed combination, but as separate products, as adjunct to diet for treatment of primary hypercholesterolaemia (heterozygous familial and nonfamilial) or homozygous familial hypercholesterolaemia. Dosage and Administration: The patient should be on and continue, an appropriate lipid-lowering diet, during treatment with Suvezen. Suvezen is not suitable for initial therapy. Treatment initiation or dose adjustment, if necessary, should only be done with the monocomponents and after setting the appropriate doses the switch to the fixed dose combination of the appropriate strength is possible. Patient should use the strength corresponding to their previous treatment. The recommended dose is one Suvezen tablet daily. To be administered at any time of the day, with or without food. The tablet should be swallowed whole with a drink of water. If co-administered with bile acid sequestrant (BAS), administration of Suvezen should occur either ≥2 hours before or ≥4 hours after administration of a BAS. Special populations: Paediatric (<18 years): Safety and efficacy has not been established. Elderly (>70 years): Starting dose of 5 mg rosuvastatin is recommended. The combination is not suitable for initial therapy. Hepatic impairment: Mild: No dosage adjustment is required. Moderate/Severe: Treatment with Suvezen is not recommended. Renal impairment: Mild: No dose adjustment is necessary. Moderate (creatinine clearance <60 ml/min): The recommended start dose is rosuvastatin 5mg. Race: The recommended start dose is rosuvastatin 5 mg for patients of Asian ancestry due to increased systemic exposure. The fixed dose combination is not suitable for initial therapy. Monocomponent preparations should be used to start the treatment or to modify the dose. Suvezen 40 mg/10 mg tablets are contraindicated in these patients. Genetic polymorphisms: In patients who are known to have specific types of genetic polymorphisms that can lead to increased rosuvastatin exposure, a lower daily dose of Suvezen is recommended. Dosage in patients with pre-disposing factors to myopathy: The recommended start dose is rosuvastatin 5mg in patients with predisposing factors to myopathy. Suvezen 40 mg/10 mg tablets are contraindicated in some of these patients. Concomitant therapy: The risk of myopathy (including rhabdomyolysis) is increased when Suvezen is administered concomitantly with certain medicinal products that may increase the plasma concentration of rosuvastatin (e.g. ciclosporin and certain protease inhibitors including combinations of ritonavir with atazanavir, lopinavir, and/or tipranavir). Whenever possible, alternative medications should be considered, and, if necessary, consider temporarily discontinuing Suvezen therapy. In situations where coadministration of these medicinal products with Suvezen is unavoidable, the benefit and the risk of concurrent treatment and rosuvastatin dosing adjustments should be carefully considered. Contraindications: Hypersensitivity to the active substances or excipients. Pregnancy, breast-feeding and in women of childbearing potential not using appropriate contraceptive measures. Active liver disease or any serum transaminase elevations which are unexplained, persistent or exceeding 3x the upper limit of normal (ULN). Severe renal impairment (creatinine clearance <30 ml/min); myopathy or receiving concomitant ciclosporin. 40mg/10mg dose contraindicated in patients with predisposing factors for myopathy/rhabdomyolysis; such factors include: Moderate renal impairment (creatinine clearance <60 ml/min), hypothyroidism, personal or family history of hereditary muscular disorders, previous history of muscular toxicity with another HMG-CoA reductase inhibitor or fibrate, alcohol abuse, situations where an increase in plasma levels of rosuvastatin may occur, Asian patients, concomitant use of fibrates. Precautions and Warnings: Skeletal muscle effects: have been reported in rosuvastatin-treated patients with all doses and in particular with doses >20 mg. As with other HMG-CoA reductase inhibitors, reporting rate for rhabdomyolysis is associated with use at doses >40mg. Post-marketing experience with ezetimibe, cases of myopathy and rhabdomyolysis have been reported. If myopathy is suspected based on muscle symptoms or is confirmed by a creatine phosphokinase (CPK) level, Suvezen and any of these other agents that the patient is taking concomitantly should be immediately discontinued. All patients starting therapy with Suvezen should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness, particularly if associated with malaise or fever. Creatine kinase (CK) measurement: CK should not be measured following strenuous exercise or in the presence of a plausible alternative cause of CK increase. If CK levels are significantly elevated at baseline (>5xULN) a confirmatory test should be carried out within 5-7 days. If the repeat test confirms a baseline CK >5xULN, treatment should not be started. Patients with pre-disposing factors for myopathy/rhabdomyolysis: Caution should be exercised in these patients. Risk: benefit of treatment should be considered and clinical monitoring is recommended. CK levels should be measured in these patients. Therapy should be discontinued if CK levels are markedly elevated (>5xULN) or if muscular symptoms are severe and cause daily discomfort. If symptoms resolve and CK levels return to normal, then consideration should be given to re-introducing treatment at the lowest dose. Immune-mediated necrotising myopathy (IMNM): Clinically characterised by proximal muscle weakness and elevated serum CK, has been reported very rarely during or after treatment with statins, including rosuvastatin, despite discontinuation of statin treatment. In clinical trials an increase in the incidence of myositis and myopathy has been seen in patients receiving other HMG-CoA reductase inhibitors together with fibric acid derivatives. Suvezen should not be used in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g. sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders; or uncontrolled seizures). Liver effects: In controlled coadministration trials in patients receiving ezetimibe with statin, consecutive transaminase elevations ≥3×ULN have been observed. It is recommended that liver function tests be carried out prior to, and 3 months following, the initiation of treatment. Rosuvastatin should be discontinued or the dose reduced if the level of serum transaminases is ≥3xULN. The reporting rate for serious events is higher at the 40mg dose. In patients with secondary hypercholesterolaemia caused by hypothyroidism or nephrotic syndrome, the underlying disease should be treated prior to initiating therapy with rosuvastatin. Liver disease and alcohol: As with other HMG-CoA reductase * Suvezen is available in 3 doses in Ireland. Suvezen 10mg/10mg, 20mg/10mg and 40mg/10mg: Each film-coated tablet contains 10mg; 20mg or 40mg of rosuvastatin (as rosuvastatin calcium) respectively, and 10mg ezetimibe. Reference: 1. Suvezen Summary of Product Characteristics LDL-C: Low-density lipoprotein Cholesterol

inhibitors, rosuvastatin should be used with caution in patients who consume excessive quantities of alcohol and/or have a history of liver disease. Renal effects: Proteinuria has been observed in patients treated with higher doses of rosuvastatin and was transient or intermittent in most cases. Proteinuria has not been shown to be predictive of acute or progressive renal disease. An assessment of renal function should be considered during routine follow-up of patients treated with a dose of 40 mg. Diabetes mellitus: Some evidence suggests that statins raise blood glucose and in some patients, at high risk of future diabetes, may produce a level of hyperglycaemia where formal diabetes care is appropriate. This risk, however, is outweighed by the reduction in vascular risk with statins and therefore should not be a reason for stopping statin treatment. Patients at risk (fasting glucose 5.6 to 6.9 mmol/l, BMI >30 kg/m2, raised triglycerides, hypertension) should be monitored both clinically and biochemically according to national guidelines. Interstitial lung disease: Exceptional cases have been reported with some statins, especially with long term therapy. Presenting features can include dyspnoea, non-productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected, statin therapy should be discontinued. Protease inhibitors: Increased systemic exposure to rosuvastatin has been observed in subjects receiving rosuvastatin concomitantly with various protease inhibitors in combination with ritonavir. Consideration should be given both to the benefit of lipid lowering by use of Suvezen in HIV patients receiving protease inhibitors and the potential for increased rosuvastatin plasma concentrations when initiating and up titrating rosuvastatin doses in patients treated with protease inhibitors. The concomitant use with certain protease inhibitors is not recommended unless the dose of rosuvastatin is adjusted. Fibrates: The safety and efficacy of ezetimibe administered with fibrates have not been established. If cholelithiasis is suspected in a patient receiving Suvezen and fenofibrate, gallbladder investigations are indicated and therapy should be discontinued. Anticoagulants: If Suvezen is added to warfarin, another coumarin anticoagulant, or fluindione, the International Normalised Ratio (INR) should be appropriately monitored. Fusidic acid: Suvezen must not be co-administered with systemic formulations of fusidic acid or within 7 days of stopping fusidic acid treatment. In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving fusidic acid and statins in combination. The patient should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness. Statin therapy may be reintroduced seven days after the last dose of fusidic acid. In exceptional circumstances, where prolonged systemic fusidic acid is needed, e.g., for the treatment of severe infections, the need for co-administration of Suvezen and fusidic acid should only be considered on a case by case basis and under close medical supervision. Suvezen contains lactose monohydrate and sodium: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine. This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’. Pregnancy, Breastfeeding and Fertility: No clinical data are available on the use of ezetimibe during pregnancy. Potential risk from inhibition of HMG-CoA reductase outweighs the advantage of treatment during pregnancy. If a patient becomes pregnant during use of Suvezen, treatment should be discontinued immediately. Animal studies have shown excretion of medicinal product through breast milk. However, there are no data in humans. No clinical trial data on the effects of fertility in humans. Interactions: Contraindicated combinations: Ciclosporin. Not-recommended combinations: Fibrates and other lipid-lowering products, protease inhibitors, transporter protein inhibitors and fusidic acid. Other possible interactions: Cytochrome P450 enzymes, antacids, colestyramine, anticoagulants, Vitamin K antagonists, erythromycin, Oral contraceptive/hormone replacement therapy. When coadministering rosuvastatin with other medicinal products known to increase exposure to rosuvastatin, doses should be adjusted (see SPC for full details). The maximum daily dose should be adjusted so that the expected rosuvastatin exposure would not likely exceed that of a 40 mg daily dose of rosuvastatin taken without interacting medicinal products. Adverse Reactions: Adverse drug reactions previously reported with one of the individual components (ezetimibe or rosuvastatin) may be potential undesirable effects with Suvezen. Common (≥1/100 to <1/10): diabetes mellitus, headache, dizziness, constipation, nausea, abdominal pain, diarrhoea, flatulence, myalgia, ALT and/or AST increased, asthenia and fatigue. Uncommon (≥1/1,000 to <1/100): decreased appetite, paraesthesia, hot flush, hypertension, cough, dyspepsia, gastroesophageal reflux disease, nausea, dry mouth, gastritis, pruritus, rash, urticaria, arthralgia, muscle spasms, neck pain, back pain, muscular weakness, pain in extremity, ALT and/or AST increased, blood CPK increased, gamma-glutamyltransferase increased, liver function test abnormal, chest pain, pain, asthenia, oedema peripheral. Rare (≥1/10,000 to <1/1,000): thrombocytopenia, hypersensitivity reactions including angioedema, pancreatitis, increased hepatic transaminases, myopathy (including myositis), rhabdomyolysis, lupuslike syndrome and muscle rupture. Very rare (<1/10,000): polyneuropathy, memory loss, jaundice, hepatitis, arthralgia, haematuria, gynaecomastia. Not known: thrombocytopenia, hypersensitivity (including rash, urticaria, anaphylaxis and angioedema), depression, peripheral neuropathy, sleep disturbances (including insomnia and nightmares), dizziness, paraesthesia, cough, dyspnoea, diarrhoea, pancreatitis, constipation, hepatitis, cholelithiasis, cholecystitis, Stevens Johnson syndrome, erythema multiforme, immune-mediated necrotising myopathy, tendon disorders (sometimes complicated by rupture), myalgia, myopathy/rhabdomyolysis, oedema, asthenia. Legal Category: POM. Marketing Authorisation Numbers: 10mg/10mg: PA0540/193/001; 20mg/10mg: PA0540/193/002; 40mg/10mg: PA0540/193/003. Marketing Authorisation Holder: Sanofi-Aventis Ireland Ltd. T/A SANOFI, Citywest Business Campus, Dublin 24, Ireland. Further information is available from: Sanofi, 18 Riverwalk, Citywest Business Campus, Dublin 24 or contact IEmedinfo@sanofi.com Tel.: (01) 4035600. Date of Preparation: December 2019. Adverse events should be reported. Reporting forms and information can be found at www.hpra.ie; email: medsafety@hpra.ie Adverse events should also be reported to Sanofi Ireland Ltd. Tel: 01 403 5600. Alternatively, send via email to IEPharmacovigilance@sanofi.com

SAIE.ZEN.19.09.0201e – December 2019


24

CPD 69: THROMBOSIS

Continuing Professional Development

CPD

AUTHORS: Comerford C1,2, Quinn J2,3, O’Sullivan JM1 1. Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons, Dublin 2. Beaumont Hospital, Dublin 3. School of Medicine, Royal College of Surgeons Ireland

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.

Cancer Associated Thrombosis; clinical challenges and therapeutic advances Introduction Cancer associated thrombosis (CAT) is a commonly encountered issue in malignancy and is a major cause of both morbidity and mortality in this population. Active malignancy accounts for approximately 20% of all cases of VTE(1,2) and is estimated to be responsible for over three million deaths per year(2). The most common cause of thrombosis in malignancy is venous thromboembolism (VTE) which has an estimated annual incidence of 0.5% in those with cancer when compared with 0.1% in the general population, though naturally this incidence varies both with type of malignancy and aggressiveness of disease(2–4). The incidence of CAT appears to be increasing(5) and unfortunately has a worse prognosis than thrombosis in the general population(2,6). It is in fact the second leading cause of death from malignancy, superseded only by progression of the disease itself(2,7). When compared to cancer patients without thrombosis, patients with CAT have been reported to have a threefold lower survival at 12 months, though this mortality rate was also strongly associated with advanced stage malignancy. There are a myriad of causative factors associated with CAT with research ongoing to understand the biological

mechanisms underpinning these links. The advent of Direct Oral Anticoagulant (DOAC) use is beginning to change the treatment landscape of CAT which can now be tailored to each individual, with treatment decisions giving weight to both the type of malignancy and disease activity to ensure the optimal therapeutic option is employed. Pathophysiology It has long been recognised that patients with cancer exhibit a hypercoagulable state which is not entirely understood. In 1856, Rudolf Virchow postulated that a triad of conditions lead to thrombosis: endothelial injury, circulatory stasis and abnormalities in blood clotting components(8) and it has been recognised for many years that specific cancers are associated with increased blood viscosity and acquired thrombophilia(2). There are particular malignancies that appear to display an increased propensity for clotting, namely haematological malignancies and lung, gastro-intestinal (GI), pancreatic and brain cancers. There appear to be an array of interdependent complex biological mechanisms that exacerbate VTE occurrence in malignancy including aberrant Tissue Factor (TF) expression, endothelial and platelet dysfunction and cancer mediated inflammation but many

OCTOBER 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

of these mechanisms remain poorly understood(9). Tissue Factor is a transmembrane protein that acts as a cofactor for Factor VII/VIIa. The TF-FVIIa complex is the primary initiator of blood coagulation and plays an essential role in haemostasis(10). In vitro- many cancer cell lines have been shown to shed TF-positive microvesicles. In patients with malignancy, particularly pancreatic, brain, colorectal and lung cancer, tumour cells appear to release TF-positive microvesicles into the circulation that may contribute to VTE(10–13). There are an array of other biological mechanisms that have been studied and appear to contribute to hypercoagulability, with most recently, a review by Patmore et al highlighting elevated Von Willebrand Factor (VWF) levels which have been found in a variety of malignancies(9,14) and how these elevated levels appear to be an independent risk factor for CAT(15). It also appears that tumour genetic characteristics have a contributory role in the causation of VTE. Recent studies in genetic profiling have focused on the link between KRAS mutation status and VTE risk. KRAS is a GTPase signalling protein that regulates cell proliferation and survival. It is found to be mutated in approximately 30-50% of colorectal tumours and has

60 Second Summary Cancer associated thrombosis (CAT) is a commonly encountered issue in malignancy and is a major cause of both morbidity and mortality in this population. The incidence of CAT appears to be increasing and unfortunately has a worse prognosis than thrombosis in the general population. It is in fact the second leading cause of death from malignancy, superseded only by progression of the disease itself. There appear to be an array of interdependent complex biological mechanisms that exacerbate VTE occurrence in malignancy including aberrant Tissue Factor (TF) expression, endothelial and platelet dysfunction and cancer mediated inflammation but many of these mechanisms remain poorly understood. Generally, those who are at higher risk from CAT are those with more advanced age, those with a previous history of thrombosis or thrombophilia or immobility. For the past number of years, following on from the CLOT trial, LMWH has been the mainstay of treatment for CAT, however, recent studies have shown the possible roles for use of DOAC medications in both treatment and prophylaxis of CAT. VTE is particularly problematic in haematological malignancies given its high rates of occurrence and the difficulties encountered when treating it due to high rates of bone marrow suppression and subsequent thrombocytopenia. CAT remains a highly significant cause of morbidity and mortality amongst patients with malignancy.


marrow suppression and subsequent thrombocytopenia. CAT remains a highly sig cause of morbidity and mortality amongst patients with malignancy.

25

Figure 1: Khorana score been found in certain studies to be associated with an almost 3-fold increased risk of VTE when compared with patients with wild-type KRAS colorectal cancer(16). Activating mutations of the KRAS oncogene appear to upregulate tissue factor (TF) expression on colorectal cancer cells and thus, given that TF is a major procoagulant associated with systemic hypercoagulability, it is perhaps no wonder that patients who harbour KRAS mutations have a higher VTE risk. This hypothesis has also been evaluated in other malignancies that are associated with the KRAS mutation, including Non-small cell lung cancer (NSCLC) where the KRAS mutation is commonly seen with small studies reporting that the KRAS mutation appears to be linked with a higher occurrence of VTE(17). Risk factors There are a multitude of additional risk factors for CAT and these are generally divided into: • Patient related factors • Tumour related factors • Treatment related factors There are a number of patient related characteristics that can predispose certain cohorts to CAT. Generally those who are at higher risk from CAT are those with more advanced age, those with a previous history of thrombosis or thrombophilia(18) or immobility. In keeping with the prevalence of thrombosis within specific ethnic groups, CAT also appears more common in black patients and less likely in Asians/ Pacific Islanders(4,19). There are innumerable treatment related factors that can predispose patients to developing CAT with the most common culprits including surgery, chemotherapeutic agents, hormonal therapy, erythropoietin stimulating agents, anti-angiogenic agents and blood transfusions(4,18). The placement and use of indwelling access devices such as central venous catheters (CVCs) is also inherently associated with an increased thrombosis risk(5). Use of chemotherapy accounts for approximately 10% of CAT in this cohort, with agents such as Tamoxifen in breast cancer and L-asparaginase treatment in acute lymphoblastic leukaemia commonly implicated(4). Very high rates of thrombosis have been reported in multiple myeloma with use of immunomodulatory agents (Lenalidomide, Pomalidomide, Thalidomide) and generally preventative measures such as use of Aspirin or low-molecular weight

Table 1: Khorana Score

Characteristic Site of Primary Cancer: Very high risk (stomach, pancreas, brain) High risk (lung, lymphoma, gynaecological, bladder, testicular) Haemoglobin <100g/L or use of red cell growth factors Prechemotherapy leucocyte count >11 x 109 Prechemotherapy platelet count >/ 350 x 109

Score 2 1 1 1 1 1

BMI >/ 35kg/m2 0= low risk, 1-2 = intermediate risk , >2= high risk heparin (LMWH) are employed to try reduce this risk. With regards to tumour type, as outlined above, there are certain malignancies that appear to have the highest risk for CAT. Generally pancreatic, brain and lung cancer, in conjunction with haematological malignancies, are widely regarded as high risk for thrombosis(19) whereas malignancies such as breast cancer and prostate cancer appear to have a lower thrombotic potential(19). It does appear however, that malignancies that present at an advanced stage or behave in a particularly biologically aggressive manner do in fact have a raised thrombogenic potential(19,20) with certain studies listing metastatic disease at diagnosis as the strongest predictor of CAT(20). Predictive scores for risk Given the multitude of risk factors for CAT as outlined above, several groups have sought to establish risk scores and strategies for identifying high and lower- risk patients for developing thrombosis. One such score is the Khorana score (Table 1) which is a risk model that was initially developed in an attempt to predict chemotherapyassociated VTE in ambulatory patients with cancer(3). This score, which is likely the most widely used score, encompasses five predicable variables: cancer site, thrombocytosis pre-chemotherapy, anaemia or use of erythropoietin stimulating agents, leucocytosis and raised BMI. After subsequent validation in further cancer patient cohorts, two laboratory markers, soluble P-selectin (sP-selectin) and D-dimer were added to increase it’s predictive value(21). However, given that sP-selectin is generally not available in routine

laboratories, clinical application of the extended tool is limited. The score is endorsed by several guideline groups(22,23) but it’s performance remains open to debate, namely in that there are queries as to the positive predictive values of some of the variables i.e. haemoglobin level, white blood cell count and body mass index(24). In light of this, other groups have sought to establish risk assessment tools for CAT in an attempt to identify high-risk patients that may be suitable for primary thromboprophylaxis. Pabinger et al established a simplified score that estimated thrombotic risk based on primary tumour site and D-dimer which did appear to improve discrimination, when compared with the Khorana score(25). Further studies are needed however to fully validate these results in a clinical setting. Moreover, improved understanding of the biological mechanisms underpinning the pathophysiology of CAT will be of significant clinical importance in the development and refinement of risk assessment tools. Routine thromboprophylaxis While prognostic scores may aid the identification of patients at high risk for CAT, the clinical implications of this are not fully clear. The PHACS (A study of Prophylaxis in High risk Ambulatory Cancer Patients) trial was carried out to evaluate the use of LMWH prophylaxis in patients deemed high risk by the Khorana score (>/3). Neither VTE rates or significant bleeding appeared to be particularly different between the prophylaxis and nonprophylaxis group, though this trial was closed prematurely due to poor accrual(26).Naturally, the daily use of LMWH subcutaneous injections also comes with

inconvenience and is associated with significant economic cost and thus is often not an enticing option for patients. Recent studies have sought to evaluate the efficacy of direct oral anticoagulants (DOACs) as primary prophylaxis in cancer patients with a high risk of thrombosis. The CASSINI trial, a randomised, double-blind, placebo-controlled trial compared the efficacy of a prophylactic dose of the DOAC Rivaroxaban 10mg vs placebo in ambulatory cancer patients who were deemed at intermediatehigh risk of thrombosis (assigned by the trial as a Khorana score >/2). The patients were screened systematically for VTE and monitored for clinically significant bleeding. Though there were fewer episodes of VTE in the group undertaking prophylaxis, there was not a statistically significant difference compared to the placebo arm. There was a 2% major bleeding rate in the prophylaxis group as opposed to a 1% rate in the placebo group and the authors ultimately concluded that Rivaroxaban prophylaxis did not significantly lower incidence of VTE or death during the trial period(27). The AVERT trial also sought to assess the efficacy of low dosage DOAC use in ambulatory cancer patients with high risk of thrombosis (Khorana score >/2) but this time the DOAC Apixaban at a dose of 2.5mg twice daily was compared to placebo. The primary efficacy endpoint was VTE over a 180-day period with the main safety outcome listed as a major bleeding episode. This study did find a significantly lower rate of VTE compared to placebo control (4.2% vs 10.2%) though higher rates of major bleeding were observed in the treatment group vs placebo (3.5% vs 1.1%). No overall difference in

HOSPITALPROFESSIONALNEWS.IE | HPN • OCTOBER 2020


associated nausea/vomiting and surgical resection of the small bowel(36).

26

General consensus is that treatment dose of LMWH or DOACs should be continued for at least six months for CAT. Strong consideration should be given to continuing the anticoagulation beyond six months if the cancer is still deemed active at this point and can be re-assessed regularly for it’s risk-benefit ratio (30,37).

CPD 69: THROMBOSIS

Hazard Ratio

Major Bleeding rates in DOAC arm

Major Bleeding rates in LMWH arm

Hazard Ratio

7.9%

0.71

11.3%

6.9%

4.0%

1.77

Rivaroxaban

4%

0.43

11%

6%

4.0%

1.83

287

Apixaban

0.7%

0.099

6.3%

0

1.4%

*

1155

Apixaban

5.6%

0.63

7.9%

3.8%

4.0%

0.82

Study Name

DOAC

HOKUSAI VTE

1046

Edoxaban

SELECT-D

406

ADAM-VTE

CARAVAGGIO

VTE recurrence rates in DOAC arm

VTE in Multiple Myeloma

VTE rates in LMWH arm

Number of Patients

Table 2; Summary of recent clinical trials using DOAC for CAT

*Hazard ratio not estimable because no bleeding in the Table 2; Summary of recent clinical trialsofusing DOAC forApixaban CAT arm

*Hazard ratio not estimable because of no bleeding in the Apixaban arm

all-cause mortality was noted(28). In light of the AVERT and CASSINI trials, international guidelines have now been updated to include consideration for primary thromboprophylaxis in high risk patients with the latest American Society of Clinical Oncologists (ASCO) guidelines stating that thromboprophylaxis with Apixaban, Rivaroxaban or LMWH may now be considered in patients at high risk for VTE. However, due consideration needs to be given to concomitant bleeding risk, possible medication interactions and ultimately patient preference and likely further studies are necessitated to extrapolate which patients will truly benefit from primary thromboprophylaxis. Treatment For the past number of years, following on from the CLOT trial(29), LMWH has been the mainstay of treatment for CAT. This pivotal trial compared LMWH in the form of dalteparin to Vitamin K antagonists and found significantly lower rates of recurrent VTE at 6 months (9% vs 17%). It also found a similar rate of clinically significant bleeding between the two groups and thus, for many years, LMWH has been the first choice for most clinicians when faced with treating CAT(29,30). With the advent of DOACs, treatment of VTE in those without malignancy has completely transformed but this has not, as of yet, fully translated into definitive change in the treatment of CAT. This is likely due to the low numbers of patients with cancer included in the initial DOAC trials which has thus necessitated further studies to examine this specific cohort(30) (Table 2). The results of two phase III trials which sought to evaluate DOAC use in CAT specifically have been published only recently. The HOKUSAI VTE trial aimed to

evaluate the safety and efficacy of Edoxaban, a direct factor Xa inhibitor, compared with treatment with LMWH. The primary outcome was a composite of recurrent VTE and bleeding events and at 12 months, this did not differ significantly between edoxaban and LMWH (12.8% vs 13.5%). However, the study did note a higher rate of gastrointestinal (GI) bleeding in the Edoxaban group, which mainly occurred in those with GI malignancies(31). A further study, the SELECT-D trial, sought to compare the use of Rivaroxaban, a direct factor Xa inhibitor with LMWH in CAT. This study found a lower rate of VTE in the Rivaroxaban group at 6 months (4% vs 11%) but did noted an increased rate of both major bleeding (6% vs 4%) and clinically relevant non-major bleeding (13% vs 4%). Similar to the HOKUSAI trial, much of this bleeding was GI bleeding and was associated with GI malignancy(32). Neither study concluded an increased risk in intracranial bleeding with use of Edoxaban or Rivaroxaban(31,32). Following on from these studies, the ADAM-VTE study was carried out to compare the use of Apixaban, another factor Xa inhibitor, with LMWH in CAT. This study did find lower recurrent VTE rates in the Apixaban group (0.7% vs 6.3%) and very low rates of major bleeding in both the Apixiban and LMWH groups (0% vs 1.4%). These rates were much lower than that seen in the HOKUSAI VTE and SELECT-D trials, which may be explained by the lower overall number of patients enrolled in the trial and also the lower numbers of patients with GI malignancy accrued(33). Most recently, the CARAVAGGIO study sought to evaluate the use of Apixaban vs LMWH in the treatment of CAT in a larger group of cancer patients. This

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study concluded that Apixaban was non-inferior to subcutaneous Dalteparin in this cohort with recurrent VTE occurring in 5.6% of the Apixaban group and 7.9% of the Dalteparin group. They did not observe an increased risk of major bleeding with use of Apixaban vs Dalteparin interestingly and rates of GI bleeding were similar. Of note, patients with brain tumours, cerebral metastasis or acute leukaemia were not included in this trial(34). In light of these findings, several guidelines now incorporate the use of DOACs in the management and treatment of CAT as an alternative to LMWH use. Current European Society of Cardiology (ESC) guidelines advise that use of Edoxaban or Rivaroxaban can be considered for use, particularly in those who do not have GI malignancy and have an anticipated low risk of bleeding(35). The International Clinical Practice guidelines for treatment and prophylaxis of venous thromboembolism in patients with cancer published in 2019 now advise consideration of Rivaroxaban or Edoxaban in patients who are not at high risk of gastrointestinal/urothelial bleeding and who do not have significant drug interactions(23). Caution is also advised with DOAC use in patients with Stage IV chronic kidney disease, active/clinically significant liver disease. Other factors that may need to be taken into account when assessing safety and efficacy of use of DOACs in malignancy include chemotherapy -associated nausea/vomiting and surgical resection of the small bowel(36). General consensus is that treatment dose of LMWH or DOACs should be continued for at least six months for CAT. Strong consideration should be given to continuing the anticoagulation beyond six months if the cancer is still deemed active at this point and can be re-assessed regularly for it’s risk-benefit ratio(30,37).

VTE is particularly problematic in haematological malignancies given it’s high rates of occurrence and the difficulties encountered when treating it due to high rates of bone marrow suppression and subsequent thrombocytopenia. In particular, patients with multiple myeloma, the second most prevalent haematological malignancy(38), have a particularly high thrombotic risk with up to 10% of patients suffering an episode of VTE(39,40). Multiple myeloma is a bone marrow malignancy that is characterised by the unregulated expansion and accumulation of monoclonal plasma cells/myeloma cells within the bone marrow. There are multitudes of factors that increase the likelihood of VTE occurrence in multiple myeloma and many appear to be as a consequence of both the disease process itself in addition to the agents that are used to treat the disease. Several groups have sought to evaluate the prothrombotic phenotype in patients with multiple myeloma, common observations include significant elevations in Factor VIII, D-dimer, fibrinogen and Von Willebrand Factor (VWF) antigen in patients with active disease(41–45). Interestingly, Factor VIII and VWF antigen also appear to be raised, but to a less extreme extent, in Monoclonal Gammopathy of Undetermined significance (MGUS) which is generally regarded as the precursor to multiple myeloma(44). Activated protein C resistance is also a known common phenomenon in multiple myeloma. Generally, Protein C is converted by thrombin into it’s active form i.e. Activated Protein C (APC) which has an anticoagulant role. The most common example of APC resistance is due to the Factor V Leiden mutation. However, in multiple myeloma, APC resistance has been found in some studies to occur in up to 10% of patients(46,47) and interestingly, many of these patients do not carry the Factor V Leiden mutation, indicating that this appears to be an acquired APC resistance, in the context of active plasma cell dyscrasia. The full thrombotic potential of the aforementioned coagulation abnormalities has not been fully evaluated as of yet. In addition to the above, many of the treatment strategies employed in multiple myeloma also increase the likelihood of CAT occurrence. High doses of Dexamethasone are generally utilised in the treatment of multiple myeloma, usually


27 in combination with additional agents. Several studies have shown that the addition of high dose steroids to a chemotherapy regimen is associated with a significantly increased thrombosis risk(39,48). The exact causative mechanism of this is unclear, though there is some in vitro evidence that Dexamethasone can stimulate the endothelium to increase expression of tissue factor, cellular adhesion modules and VWF(49). Dexamethasone is commonly used in combination with immunomodulatory agents such as Lenalidomide, Pomalidomide and Thalidomide and appears to enhance their thrombogenic potential, though these agents in themselves, are associated with an increased VTE risk(39,50,51). Indeed, the International Myeloma Working Group (IMWG) now recommends that a VTE risk assessment should be carried out in all patients receiving immunomodulatory agents and either aspirin or LMWH prophylaxis is recommended, depending on the risk factors present(52). There is no widely used multiple myeloma specific thrombotic risk score in use at present, though certain groups have validated scores e.g. the myeloma clot score, MCS(53) in an attempt to standardise this evaluation. Conclusion CAT remains a highly significant cause of morbidity and mortality amongst patients with malignancy. The era of DOAC medications has undoubtedly started to change the landscape of treatment for thrombosis in cancer. However, further studies are necessitated to fully understand the biological mechanism underpinning the pathophysiology of CAT so that appropriate thromboprophylaxis can be optimally employed in order to ultimately prevent this devastating condition in cancer patients. References 1. Heit JA, Spencer FA, White RH. The epidemiology of venous thromboembolism. J Thromb Thrombolysis. 2016;41(1):3–14. 2. Fernandes CJ, Morinaga LTK, Alves JL, Castro MA, Calderaro D, Jardim CVP, et al. Cancer-associated thrombosis: The when, how and why. Eur Respir Rev [Internet]. 2019;28(151):1–11. Available from: http:// dx.doi.org/10.1183/16000617.0119-2018 3. Elyamany G, Alzahrani AM, Bukhary E. Cancerassociated thrombosis: An overview. Clin Med Insights Oncol. 2014;8:129–37. 4. Sud R, Khorana AA. Cancer-associated thrombosis: risk factors, candidate biomarkers and a risk model. Thromb Res [Internet]. 2009;123(SUPPL. 4):S18–21. Available from: http://dx.doi.org/10.1016/S00493848(09)70137-9 5. Mukai M, Oka T. Mechanism and management of cancer-associated thrombosis. J Cardiol [Internet]. 2018;72(2):89–93. Available from: https://doi. org/10.1016/j.jjcc.2018.02.011 6. Puurunen MK, Gona PN, Larson MG, Murabito JM, Magnani JW, O’Donnell CJ. Epidemiology of venous thromboembolism in the Framingham Heart Study. Thromb Res [Internet]. 2016;145:27–33. Available from: http://dx.doi.org/10.1016/j.thromres.2016.06.033

7. Khorana A, Francis C, Culakova E, Kurderer N. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost. 2007;632–4. 8. Blann AD, Lip GYH. Clinical review Venous thromboembolism. Br Med J. 2006;332:215–9. 9. Patmore S, Dhami SPS, O’Sullivan JM. Von Willebrand Factor and Cancer; metastasis and coagulopathies. J Thromb Haemost. 2020;(May):1–13. 10. Grover SP, Mackman N. Tissue Factor: An Essential Mediator of Hemostasis and Trigger of Thrombosis. Arterioscler Thromb Vasc Biol. 2018;38(4):709–25. 11. Geddings JE, Mackman N. Tumor-derived tissue factor-positive microparticles and venous thrombosis in cancer patients. Blood. 2013;122(11):1873–80. 12. Wang JG, Geddings JE, Aleman MM, Cardenas JC, Chantrathammachart P, Williams JC, et al. Tumor-derived tissue factor activates coagulation and enhances thrombosis in a mouse xenograft model of human pancreatic cancer. Blood. 2012;119(23):5543–52. 13. Tesselaar MET, Romijn FPHTM, Van Der Linden IK, Prins FA, Bertina RM, Osanto S. Microparticleassociated tissue factor activity: A link between cancer and thrombosis? J Thromb Haemost. 2007;5(3):520–7. 14. Sorenson HT, Mellemkjaer L, Jorgen OH, Baron JA. Prognosis of Cancers Associated with Venous Thromboembolism. N Engl J Med. 2000;343(25):1846–50. 15. Pépin M, Kleinjan A, Hajage D, Büller HR, Di Nisio M, Kamphuisen PW, et al. ADAMTS-13 and von Willebrand factor predict venous thromboembolism in patients with cancer. J Thromb Haemost. 2016;14(2):306–15. 16. Ades S, Kumar S, Alam M, Goodwin A, Weckstein D, Dugan M, et al. Tumor oncogene (KRAS) status and risk of venous thrombosis in patients with metastatic colorectal cancer. J Thromb Haemost. 2015;13(6):998–1003. 17. Corrales-Rodriguez L, Soulières D, Weng X, Tehfe M, Florescu M, Blais N. Mutations in NSCLC and their link with lung cancer-associated thrombosis: A case-control study. Thromb Res [Internet]. 2014;133(1):48–51. Available from: http://dx.doi. org/10.1016/j.thromres.2013.10.042 18. Blom JW, Doggen CJM, Osanto S, Rosendaal FR. and the Risk of Venous Thrombosis. Jama. 2005;293(6):715–22. 19. Timp JF, Braekkan SK, Versteeg HH, Cannegieter SC. Epidemiology of cancer-associated venous thrombosis. Blood. 2013;122(10):1712–23. 20. Chew HK, Wun T, Harvey D, Zhou H, White RH. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med. 2006;166(4):458–64. 21. Socialista E. Ay Et Al. 2018;116(24):5377–83. 22. Key NS, Khorana AA, Kuderer NM, Bohlke K, Lee AYY, Arcelus JI, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update. J Clin Oncol. 2020;38(5):496–520. 23. Farge D, Frere C, Connors JM, Ay C, Khorana AA, Munoz A, et al. 2019 International Clinical Practice Guidelines for the Treatment and Prophylaxis of Venous Thromboembolism in Patients With Cancer. Lancet Oncol. 2019;20(10):e566–81. 24. Mulder FI, Bosch FTM, van Es N. Primary

thromboprophylaxis in ambulatory cancer patients: Where do we stand? Cancers (Basel). 2020;12(2):1–17. 25. Pabinger I, van Es N, Heinze G, Posch F, Riedl J, Reitter EM, et al. A clinical prediction model for cancerassociated venous thromboembolism: a development and validation study in two independent prospective cohorts. Lancet Haematol. 2018;5(7):e289–98. 26. Khorana AA, Francis CW, Kuderer NM, Carrier M, Ortel TL, Wun T, et al. Dalteparin thromboprophylaxis in cancer patients at high risk for venous thromboembolism: A randomized trial. Thromb Res [Internet]. 2017;151:89–95. Available from: http:// dx.doi.org/10.1016/j.thromres.2017.01.009 27. Khorana AA, Soff GA, Kakkar AK, VadhanRaj S, Riess H, Wun T, et al. Rivaroxaban for thromboprophylaxis in high-risk ambulatory patients with cancer. N Engl J Med. 2019;380(8):720–8. 28. Carrier M, Abou-Nassar K, Mallick R, Tagalakis V, Shivakumar S, Schattner A, et al. Apixaban to prevent venous thromboembolism in patients with cancer. N Engl J Med. 2019;380(8):711–9. 29. Tonnessen BH, Money SR. Low-MolecularWeight Heparin Versus Coumarin for the Prevention of Recurrent Venous Thromboembolism in Patients With Cancer. Perspect Vasc Surg Endovasc Ther. 2004;16(2):144–6. 30. Moik F, Pabinger I, Ay C. How i treat cancerassociated thrombosis. ESMO Open. 2020;5(1). 31. Raskob GE, Van Es N, Verhamme P, Carrier M, Di Nisio M, Garcia D, et al. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018;378(7):615–24. 32. Young AM, Marshall A, Thirlwall J, Chapman O, Lokare A, Hill C, et al. Comparison of an oral factor xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: Results of a randomized trial (SELECT-D). J Clin Oncol. 2018;36(20):2017–23. 33. McBane RD, Wysokinski WE, Le-Rademacher JG, Zemla T, Ashrani A, Tafur A, et al. Apixaban and dalteparin in active malignancy-associated venous thromboembolism: The ADAM VTE trial. J Thromb Haemost. 2020;18(2):411–21. 34. Agnelli G, Becattini C, Meyer G, Muñoz A, Huisman M V., Connors JM, et al. Apixaban for the treatment of venous thromboembolism associated with cancer. N Engl J Med. 2020;382(17):1599–607. 35. Konstantinides S V., Meyer G, Bueno H, Galié N, Gibbs JSR, Ageno W, et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European respiratory society (ERS). Eur Heart J. 2020;41(4):543–603. 36. Streiff MB, Holmstrom B, Angelini D, Ashrani A, Bockenstedt PL, Chesney C, et al. NCCN Guidelines® insights cancer-associated venous thromboembolic disease, version 2.2018 featured updates to the NCCN guidelines. JNCCN J Natl Compr Cancer Netw. 2018;16(11):1289–303. 37. Kraaijpoel N, Carrier M. How i treat cancerassociated venous thromboembolism. Blood. 2019;133(4):291–8. 38. Cowan AJ, Allen C, Barac A, Basaleem H, Bensenor I, Curado MP, et al. Global burden of multiple myeloma: A systematic analysis for the global burden of disease study 2016. JAMA Oncol. 2018;4(9):1221–7. 39. Swan D, Rocci A, Bradbury C, Thachil J. Venous thromboembolism in multiple myeloma – choice

of prophylaxis, role of direct oral anticoagulants and special considerations. Br J Haematol. 2018;183(4):538–56. 40. Kristinsson SY, Pfeiffer RM, Björkholm M, Goldin LR, Schulman S, Blimark C, et al. Arterial and venous thrombosis in monoclonal gammopathy of undetermined significance and multiple myeloma: A population-based study. Blood. 2010;115(24):4991–8. 41. Minnema MC, Fijnheer R, De Groot PG, Lokhorst HM. Extremely high levels of von willebrand factor antigen and of procoagulant factor VIII found in multiple myeloma patients are associated with activity status but not with thalidomide treatment. J Thromb Haemost. 2003;1(3):445–9. 42. Robak M, Treliński J, Chojnowski K. Hemostatic changes after 1 month of thalidomide and dexamethasone therapy in patients with multiple myeloma. Med Oncol. 2012;29(5):3574–80. 43. Gomperts ED, Shulman G, Lynch SR. Factor VIII and Factor-VIII-Related Antigen in Multiple Myelomatosis and Related Conditions. Br J Haematol. 1976;32(2):249–56. 44. Crowley MP, Kevane B, O’shea SI, Quinn S, Egan K, Gilligan OM, et al. Plasma Thrombin Generation and Sensitivity to Activated Protein C Among Patients With Myeloma and Monoclonal Gammopathy of Undetermined Significance. Clin Appl Thromb. 2016;22(6):554–62. 45. Auwerda JJA, Sonneveld P, De Maat MPM, Leebeek FWG. Prothrombotic coagulation abnormalities in patients with newly diagnosed multiple myeloma. Haematologica. 2007;92(2):279–80. 46. Jiménez-Zepeda VH, Domínguez-Martínez VJ. Acquired activated protein C resistance and thrombosis in multiple myeloma patients. Thromb J. 2006;4(Mm):1–6. 47. Elice F, Fink L, Tricot G, Barlogie B, Zangari M. Acquired resistance to activated protein C (aAPCR) in multiple myeloma is a transitory abnormality associated with an increased risk of venous thromboembolism. Br J Haematol. 2006;134(4): 399–405. 48. Knight R, DeLap RJ, Zeldis JB. Lenalidomide and venous thrombosis in multiple myeloma [22]. N Engl J Med. 2006;354(19):2079–80. 49. Kerachian MA, Cournoyer D, Harvey EJ, Chow TY, Neagoe PE, Sirois MG, et al. Effect of high-dose dexamethasone on endothelial haemostatic gene expression and neutrophil adhesion. J Steroid Biochem Mol Biol. 2009;116(3–5):127–33. 50. Palumbo A, Palladino C. Venous and arterial thrombotic risks with thalidomide: Evidence and practical guidance. Ther Adv Drug Saf. 2012;3(5):255–66. 51. Richardson P, Jagannath S, Hussein M, Berenson J, Singhal S, Irwin D, et al. Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma. Blood. 2009;114(4):772–8. 52. Palumbo A, Rajkumar S V., Dimopoulos MA, Richardson PG, San Miguel J, Barlogie B, et al. Prevention of thalidomide- and lenalidomideassociated thrombosis in myeloma. Leukemia. 2008;22(2):414–23. 53. Sanfilippo KM, Luo S, Wang TF, Fiala M, Schoen M, Wildes TM, et al. Predicting venous thromboembolism in multiple myeloma: development and validation of the IMPEDE VTE score. Am J Hematol. 2019;94(11):1176–84.

AUTHORS Dr. Claire Comerford is a fourth year Haematology Specialist Registrar and graduate of University College Dublin. She was recently awarded a StAR MD clinical research fellowship by Royal College of Surgeons, Ireland (RCSI) and is currently investigating the relationship between Multiple Myeloma and coagulation factors at the Irish Centre for Vascular Biology in RCSI and Beaumont Hospital.

Dr. John Quinn, MB PhD FRCPath FRCPI, Consultant Haematologist at Beaumont and Connolly Hospitals and Honorary Senior Lecturer at RCSI Dr. Jamie O’Sullivan is a principal investigator at the Irish Centre for Vascular Biology at the RCSI. She completed her PhD in Haematology at Trinity College Dublin. During her postdoctoral studies, she led an SFI-Pfizer Biotherapeutics Innovation program investigating novel therapeutics for treatment of patients with haemophilia. She also served as a visiting research fellow at KU Leuven University, Belgium, investigating coagulation protein-tumour cell interactions. Currently, she leads a growing research group investigating the bidirectional crosstalk between coagulation and cancer.

HOSPITALPROFESSIONALNEWS.IE | HPN • OCTOBER 2020


28 Educational

Understanding the often overlooked condition Thrombosis Ann Marie O'Neill, Thrombosis Ireland

Ann-Marie believed in making Thrombosis Ireland a vocal advocate and support mechanism for people suffering from health conditions surrounding Thrombosis.

Thrombosis refers to abnormal, life-threatening blood clots that form in the artery or vein. A clot in the vein (usually in the leg or pelvis) is known as a deep vein thrombosis (DVT) and a clot that breaks off and travels to the lungs is known as a pulmonary embolism (PE). Together, DVT and PE make up venous thromboembolism (VTE). One in 4 Irish people will die of causes related to thrombosis and it has now become the number one cause of preventable death in Irish hospitals. Sadly, it is the main cause of direct maternal death in Ireland’s maternity hospitals, and 1 in 5 cancer patients will get a blood clot. It is also worth noting that 60% of all blood clots happen as a direct result of a hospital stay or in the 90 days after discharge from hospital.

A mere 5 years later and Thombosis Ireland is fully voluntary, transparent, notfor-profit company limited by guarantee with charitable status and is in the enviable position with strong determined and dedicated Board of Directors. She tells Hospital Professional News, “At Thrombosis Ireland the mission has been and continues to be, to promote awareness of thrombosis among patients, medical staff and promote general public knowledge of Thrombosis nationwide. “We also provide support and advocacy for patients on anticoagulation therapy and keep their families informed about available treatments. “Primarily the group want to save lives, in particular from hospital acquired VTE through a national campaign of awareness. Foremost Thrombosis Ireland wants to see the introduction and implementation of a compulsory VTE assessment on admission to

With over 5,000 incidents of VTE in Ireland each year, it is time for a concerted preventative effort throughout the health system to save lives that might otherwise be lost. Blood clots can be very serious however there are preventative measures that can be taken, there are effective treatments to deal with them if diagnosed quickly. Establishing Representation In 2016 thrombosis patient, Ann-Marie O'Neill concerned about the lack of information surrounding thrombosis founded Thrombosis Ireland. Ann-Marie saw a need for an organisation to directly represent the views and respond to the needs of people with Thrombosis.

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hospital. It believes passionately the added distribution of the Blood Clot Alert Card to all Patients attending our Hospitals as in or out patients will save many lives.” Blood clots do not discriminate between men & women, young or old. They can strike anyone at any age and at any time. Blood clots rarely happen for one reason, therefore, in order to ascertain who is at risk and which patient needs preventative measures, health care professionals must do a VTE risk assessment on all patients who attend our hospitals. A simple questionnaire could be the difference between life and death. World Thrombosis Day Recognised on 13 October, World Thrombosis Day (WTD) focuses attention on the often overlooked and misunderstood condition of thrombosis. With thousands of educational events in countries around the world, WTD and its partners place a global spotlight on thrombosis as an urgent and growing health problem. WTD takes place every year on 13 October, the birthday of Rudolf Virchow who was a pioneer in the pathophysiology of thrombosis. A German physician, pathologist, biologist and anthropologist, Virchow developed the concept

of "thrombosis" and advanced understanding of this condition. Over a century ago, Rudolf Virchow described 3 factors that are critically important in the development of venous thrombosis: (1) venous stasis, (2) activation of blood coagulation, and (3) vein damage. These factors have come to be known as the Virchow triad. Venous stasis can occur as a result of anything that slows or obstructs the flow of venous blood. This results in an increase in viscosity and the formation of microthrombi, which are not washed away by fluid movement; the thrombus that forms may then grow and propagate. To learn more, visit the Berlin Museum of Medical History, formerly the Rudolf Virchow's Pathological Museum. For more information visit Thrombosis Ireland at www.thrombosisireland.ie How can you ascertain a Patients level of risk if you do not Risk Assess? How can your patients protect themselves if they are not informed of • Their Risk • The signs to look out for • The need to seek medical attention Fast Please talk to your patients and arm them with the information to protect themselves, particularly in the 90 days after discharge from your care when they are at home and still at increased risk of getting a blood clot. It is your professional responsibility. A Patient may be at higher risk of getting a blood clot if… • They are admitted to hospital and for 90 days when you go home • They have active cancer or receiving cancer treatment. • They are pregnant or have had a baby less than 6 weeks ago. • They are immobile (more than 3 days in bed/ travel non-stop for more than 6 hours/ in a leg cast)


Clexane Safety Syringe designed to protect against needle stick injuries

Needle completely covered by the protection shield immediately after the injection

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

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

+ m 700

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

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

an increased risk of bleeding for these patients therefore careful clinical monitoring is advised and biological monitoring by anti-Xa activity measurement might be considered. Enoxaparin sodium is not recommended for patients with end stage renal disease. In patients with severe renal impairment (creatinine clearance 15-30 mL/min) a dosage adjustment is recommended for therapeutic and prophylactic dosage ranges. Low body weight patients: are at increased risk of bleeding at prophylactic and treatment dose ranges. Obese patients: are at higher risk for thromboembolism however there is no consensus for dose adjustment; these patients should be observed carefully. Hyperkalaemia: Heparins can suppress adrenal secretion of aldosterone leading to hyperkalaemia, particularly in patients such as those with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, taking medicinal products known to increase potassium; plasma potassium should be monitored regularly especially in patients at risk. Traceability: In order to improve the LMWH traceability, it is recommended that health care professionals record the trade name and batch number of the administered product in the patient file. Sodium: For patients receiving doses >210mg/day, this medicine contains >24mg sodium, equivalent to 1.2% of the recommended maximum daily intake of sodium for an adult. Pregnancy and Lactation: Enoxaparin sodium should be used during pregnancy only if the physician has established a clear need. Pregnant women receiving enoxaparin sodium should be carefully monitored for evidence of bleeding or excessive anticoagulation and should be warned of the haemorrhagic risk. If an epidural anaesthesia is planned, it is recommended to withdraw treatment before. Enoxaparin sodium can be used during breastfeeding. Interactions: Not Recommended: Systemic salicylates, acetylsalicylic acid at anti-inflammatory doses, and NSAIDs including ketorolac. Other thrombolytics and anticoagulants. Caution: Platelet aggregation inhibitors including acetylsalicylic acid used at anti-aggregant dose (cardioprotection), clopidogrel, ticlopidine, and glycoprotein IIb/IIIa antagonists indicated in acute coronary syndrome due to the risk of bleeding, Dextran 40. Systemic glucocorticoids. Medicinal products increasing potassium levels. Adverse Reactions: Very Common: Hepatic enzyme increases (mainly transaminases >3 times the upper limit of normality). Common: Haemorrhage, haemorrhagic anaemia, thrombocytopenia, thrombocytosis, allergic reaction, headache, urticaria, pruritus, erythema, injection site haematoma / pain / other reaction (such as oedema, haemorrhage, hypersensitivity, inflammation, mass, pain, or reaction). Uncommon: Hepatocellular liver injury, bullous dermatitis, local irritation, skin necrosis at injection site. Rare: Eosinophilia, cases of immuno-allergic thrombocytopenia with thrombosis (in some cases thrombosis was complicated by organ infarction or limb ischaemia), anaphylactic/anaphylactoid reactions including shock, spinal/neuraxial haematoma resulting in varying degrees of neurologic injuries including long-term or permanent paralysis, cholestatic liver injury, alopecia, cutaneous vasculitis, skin necrosis, injection site nodules, osteoporosis following therapy >3 months, hyperkalaemia. Please refer to the SPCs for full details. Legal Category: POM. Marketing Authorisation (MA) Numbers: Clexane 2,000IU: PA540/97/4; Clexane 4,000IU: PA540/97/5; Clexane 6,000 IU: PA540/97/6; Clexane 8,000 IU: PA540/97/7; Clexane 10,000 IU: PA540/97/1; Clexane Forte 12,000 IU: PA540/97/8; Clexane Forte 15,000 IU: PA540/97/2. MA Holder and further information is available on request from: Sanofi Ireland Ltd., 18 Riverwalk, Citywest Business Campus, Dublin 24 or contact IEmedinfo@sanofi.com Tel: 01 403 5600. Date of Preparation: May 2020. Adverse events should be reported. Reporting forms and information can be found at: www.hpra.ie; E-mail: medsafety@hpra.ie Adverse events can also be reported to Sanofi Ireland Ltd. Tel: 01 403 5600. Alternatively, send via Email to IEPharmacovigilance@sanofi.com Reference: 1. Data on File – Clexane IMS Data. MAT-IE-2000431. SPC dates: June 2018 (10,000 IU (100mg)/1ml) and June 2018 (15,000 IU (150mg)/1ml). Date of preparation: June 2020.


30 Psoriasis

Celebrating World Psoriasis Day in an Era of New Treatments response at week 16 compared with 7% in the placebo group4. An extension of the phase III study (open label), showed that 76% of patients with at least a PASI75 response at week 16 and 33, maintained PASI75 after 160 weeks ofwith continuous treatment The Burden of Psoriasis Report estimated that there are 73,000 patients the skin condition (measured as last observation psoriasis in Ireland, suggesting a prevalence of 2% and at least 9,000 patients living with severe carried forward)5. Certolizumab 1 the newest TNF to disease . The treatment of psoriasis has been revolutionised by theisintroduction of inhibitor new biological be licensed for the 100% clearance (PASIthe 100). In therapies and more than any other skin condition, treatment armentarium for treatment patients with an interesting proof – of concept, of psoriasis in 2018, in patients psoriasis has expanded significantly. It therapies is not unrealistic clear skin tocertolizumab many patients these have also to ledproffer to treated with 400 who mg, increasedall understanding of the the therapeutic 74.5 % of patients achieved PASI have lived with this stigmatizing condition their lives. Across categories reduction pathogenesis of psoriasis with key 75 at week 16 and 54.6% of those in Psoriasis Area and Severity Index, a clinical ofcytokines psoriasisidentified. has increased from 75% clearance (PASI 75) pathways and treated with certolizumab 200mg6. to 100% clearance PASI 100. In an interesting proof – of concept, these therapies have led to Certolizumab is the onlyalso member Anti – TNF therapy: of this class be licensed for use increased understanding of the pathogenesis of psoriasis with key pathways and to cytokines identified. Etanercept subcutaneously during pregnancy, an important The Burden of Psoriasis Report was approved for the treatment consideration in patients of estimated that there are 73,000 of psoriasis by the FDA in childbearing age. patients with the skin condition 2004, followed by Infiximab Anti – TNF therapy: psoriasis in Ireland, suggesting Anti Il12/IL-23 inhibition: intravenously in 2006 and a prevalence of 2% and at least Adalimumab subcutaneously in Psoriasis was the first indication 9,000 patientssubcutaneously living with severewas approved Etanercept for the treatment 2008. Etanercept 50 mg twiceif psoriasis by the FDA in 2004, followed for which ustekinumab was disease1. The treatment of weekly resulted in achievement by Infiximab intravenously in 2006 and Adalimumab subcutaneously inlicensed 2008. by Etanercept mg twice the FDA in50 2009 psoriasis has been revolutionised of Psoriasis Area and Severity and paved the way for the weekly resulted in ofIndex Psoriasis Area and Severity Index PASI75 at week 12 in 47–49% of by the introduction of achievement new PASI75 at week 12 in of targetted therapies biological and with more placebo, 47–49% of patients compared patients therapies compared PASI75 response rate; at weekdevelopment 24 response was 59% (last for psoriasis. In phase III studies, than any other skin condition, with placebo, PASI75 response observation carried forward)2. Infliximab administered at 5 mg/kg at week 0, 2, ustekinumab and 6 resulted treatment with 90 in the treatment armentarium rate; at week 24 response was mg on week 0 and 4 resulted in 3. for patients with psoriasis has PASI75 responses at week 10 of59% 75.5% 80% compared with 1.9% and 3.0% with placebo (lastand observation carried 2 PASI75 responses at week 12 of expanded significantly. It is not forward) . Infliximab administered Adalimumab 80 mg week 0 followed by 40 mg at week 1 and then every other achieved a 66.4% andweek, 75.7%,71% respectively, unrealistic to proffer clear skin at 5 mg/kg at week 0, 2, and 6 4 PASI75 response athave weeklived 16 compared with 7% in the placebo group . An extension of the phase compared with 3.1% and 3.7% III to many patients who resulted in PASI75 responses 7 in the placeboat group with this(open stigmatizing at week 10 of 75.5% 80% a PASI75 study label),condition showed all that 76% of patients withand at least response week. With 16 and 33, continuous treatment, 90 mg their lives. Across the therapeutic compared with 1.9% and 3.0% maintained PASI75inafter 160 weeks of continuous treatment (measured observation carried every as 12 last weeks, similar PASI75 categories reduction Psoriasis with placebo3. Adalimumab 80 5 responses were reached in the in Area and Severity Index, a clinical forward) . Certolizumab is the newest TNF0 inhibitor to40 bemg licensed for the treatment of psoriasis mg week followed by two studies, 78.5% and 78.6%, measure of psoriasis has increased at week 1 and then every other 2018, in patients treated with certolizumab 400 mg, 74.5 % of patients achieved PASI 75 at week 16 from 75% clearance (PASI 75) to week, 71% achieved a PASI75 at week 288. 6 Written by: Prof Anne-Marie Tobin, PhD FRCPI, Consultant Dermatologist Tallaght University Hospital, Clinical Associate Professor TCD, Clinical Lead in Dermatology

and 54.6% of those treated with certolizumab 200 mg . Certolizumab is the only member of this class to be licensed for use during pregnancy, an important consideration in patients of childbearing age.

Anti IL-17 therapy: Secukinumab was the first IL17A inhibitor approved in 2015 for treatment of patients with psoriasis and in phase III studies, the proportion of patients who achieved PASI75 at week 12 was 75.9–86.7% with secukinumab 300 mg (administered once weekly for 4 weeks starting at week 0, then every 4 weeks9-11. In a subsequent head to head study of secukinumab versus ustekinumab, After 52 weeks of treatment, the proportions of patients (secukinumab versus ustekinumab) with a PASI90 response were 76% versus 61% and the proportions with a PASI100 response were 46% versus 36%12. Ixekizumab which also targets anti-IL-17A was licensed the following year in 2016 and two phase III studies of ixekizumab 160 mg as starting dose followed by 80 mg every 2 weeks were 87.3% of patients achieved PASI 75 and 89.7% at week 12. Sixty – eight percent of patients achieved PASI 90 and 37.1% PASI 10013. Brodalumab which interacts with IL-17RA is the third member of this class and was licensed in 2017 , 83 – 86 % of patients achieved PASI 7514,15. Efficacy was compared with ustekinumab was measured at the level of a PASI100 achievement at week 12, with 44% of patients treated with Brodalumab achieved PASI 10016. With this group of treatments for the first time clear or almost complete clearance of psoriasis was being discussed as an endpoint of clinical trials and an attainable goal for patients. Anti-IL-23 therapy: Guselkumab, an IL-23p19 neutralizing antibody, was approved by the FDA in July 2017 and results from phase III studies have been published, both controlled for placebo as well as for adalimumab. The largest absolute differences were seen at PASI90: Guselkumab 100 mg week 0 and 4 and then every 8 weeks, resulted in a PASI90 response at week 16 of 73.3%17.18. This has been followed by Tildrakiazumab in 2018, with efficacy at week 12, 64% and 62% of patients in the 100 mg and 200 mg groups, respectively, attained PASI-7519. Fig 1: Anti TNF therapy for Psoriasis

OCTOBER 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE


Psoriatic disease is deeper than skin1 Start early with The Complete Cosentyx Approach™*

Psoriatic disease may be progressing inside the body, even if the skin looks clear.1 With The Complete Cosentyx Approach™, you can address the underlying cause of the disease – and decrease systemic inflammation2

Look BETTER

Fast and sustained long-term efficacy in skin and persistent troublesome areas3-6

Move BETTER

Helps prevent future irreversible joint damage7

Feel

BETTER Fast and significant improvement in quality of life4,9

Joint relief for patients with PsA, including Axial symptoms8

Make Cosentyx your 1st-line treatment for psoriatic disease Indications

Plaque psoriasis: Cosentyx is indicated for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy. Psoriatic arthritis: Cosentyx, alone or in combination with methotrexate (MTX), is indicated for the treatment of active psoriatic arthritis in adult patients when the response to previous disease-modifying anti-rheumatic drug (DMARD) therapy has been inadequate. Ankylosing spondylitis: Cosentyx is indicated for the treatment of ankylosing spondylitis in adults who have responded inadequately to conventional therapy.10 ABBREVIATED PRESCRIBING INFORMATION COSENTYX (secukinumab) 150 mg solution for injection in pre-filled pen. Please refer to the Summary of Product Characteristics (SmPC) before prescribing. Presentation: Cosentyx 150 mg solution for injection in pre-filled pen. Therapeutic Indications: The treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy; the treatment of active ankylosing spondylitis in adults who have responded inadequately to conventional therapy; the treatment, alone or in combination with methotrexate (MTX), of active psoriatic arthritis in adult patients when the response to previous diseasemodifying anti-rheumatic drug (DMARD) therapy has been inadequate. Dosage & Method of Administration: Plaque Psoriasis: Recommended dose in adults is 300 mg given as two subcutaneous injections of 150 mg. Dosing at Weeks 0, 1, 2, 3 and 4, followed by monthly maintenance dosing. Ankylosing Spondylitis: The recommended dose is 150 mg by subcutaneous injection with initial dosing at Weeks 0, 1, 2, 3 and 4, followed by monthly maintenance dosing. Based on clinical response, the dose can be increased to 300 mg. Psoriatic Arthritis: For patients with concomitant moderate to severe plaque psoriasis or who are anti-TNF inadequate responders, the recommended dose is 300 mg by subcutaneous injection with initial dosing at Weeks 0, 1, 2, 3 and 4, followed by monthly maintenance dosing. Each 300 mg dose is given as two subcutaneous injections of 150 mg. For all other patients, the recommended dose is 150 mg by subcutaneous injection with initial dosing at Weeks 0, 1, 2, 3 and 4, followed by monthly maintenance dosing. Based on clinical response, the dose can be increased to 300 mg. For all of the above indications, available data suggest that a clinical response is usually achieved within 16 weeks of treatment. Consideration should be given to discontinuing treatment in patients who have shown no response up to 16 weeks of treatment. Some patients with initially partial response may subsequently improve with continued treatment beyond 16 weeks. The safety and efficacy in children below the age of 18 years have not yet been established. Contraindications: Severe hypersensitivity reactions to the active substance or to any of the excipients. Clinically important, active infection (e.g. active tuberculosis). Warnings/Precautions: Infections: Cosentyx has the potential to increase the risk of infections. Serious infections have been observed in patients receiving Cosentyx in the post-marketing setting. Infections observed in clinical studies are mainly mild or moderate upper respiratory tract infections such as nasopharyngitis not requiring treatment discontinuation. Non serious mucocutaneous candida infections more frequently reported for secukinumab than placebo in psoriasis clinical studies. Caution in patients with a chronic infection or a history of recurrent infection. Instruct patients to seek medical advice if signs or symptoms suggestive of an infection occur. If a patient develops a serious infection, close monitoring and discontinue treatment until the infection resolves. Should not be given to patients with active tuberculosis. Anti tuberculosis therapy should be considered prior to initiation in patients with latent tuberculosis. Inflammatory bowel disease: Cases of new or exacerbations of Crohn’s disease and ulcerative colitis have been reported. Caution should be exercised when prescribing to patients with inflammatory bowel disease including Crohn’s disease and ulcerative colitis. Patients should be closely monitored.

Hypersensitivity reactions: In clinical studies, rare cases of anaphylactic reactions have been observed in patients receiving Cosentyx. If an anaphylactic or other serious allergic reactions occur, administration should be discontinued immediately and appropriate therapy initiated. Latex-sensitive individuals: The removable cap of the Cosentyx pre filled pen contains a derivative of natural rubber latex. Vaccinations: Live vaccines should not be given concurrently with Cosentyx. Patients may receive concurrent inactivated or non live vaccinations. Concomitant immunosuppressive therapy: Use in combination with immunosuppressants, including biologics, or phototherapy have not been evaluated. Interactions: Live vaccines should not be given concurrently with Cosentyx. In a study in subjects with plaque psoriasis, no interaction was observed between secukinumab and midazolam (CYP 3A4 substrate. No interaction seen when administered concomitantly with methotrexate (MTX) and/or corticosteroids. Caution should be exercised when considering concomitant use of other immunosuppressants and secukinumab. Fertility, Pregnancy and Lactation: Women of childbearing potential should use an effective method of contraception during treatment and for at least 20 weeks after treatment. It is preferable to avoid the use of Cosentyx in pregnancy as there are no adequate data from the use of secukinumab in pregnant women. It is not known whether secukinumab is excreted in human milk. A decision on whether to discontinue breast feeding during treatment and up to 20 weeks after treatment or to discontinue therapy with Cosentyx must be made taking into account the benefit of breast feeding to the child and the benefit of Cosentyx therapy to the woman. The effect of secukinumab on human fertility has not been evaluated. Undesirable Effects: Very common (≥1/10); Upper respiratory tract infections. Common (≥1/100 to <1/10); Oral herpes, rhinorrhoea, diarrhoea. Uncommon (≥1/1,000 to <1/100); Oral candidiasis, tinea pedis, otitis externa, urticaria, neutropenia, conjunctivitis, lower respiratory tract infections and inflammatory bowel disease. Rare (≥1/10,000 to <1/1,000); Anaphylactic reactions, exfoliative dermatitis. Please see Summary of Product Characteristics for further information on undesirable effects. Legal Category: POM. Marketing Authorisation Holder: Novartis Europharm Ltd, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland. Marketing Authorisation Numbers: EU/1/14/980/004-005. Date of Revision of Abbreviated Prescribing Information: October 2019. Full prescribing information is available upon request from: Novartis Ireland Limited, Vista Building, Elm Park Business Park, Elm Park, Dublin 4. Tel: 01-2204100 or at www.medicines.ie. Detailed information on this product is also available on the website of the European Medicines Agency http://www.ema.europa.eu 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.

* The Complete Cosentyx Approach™ is defined as efficacy in both skin and persistent psoriasis manifestations in nails, scalp, palms,and soles, as well as psoriatic arthritis; controls irreversible structural damage (PsA) and improves quality of life. PsA = psoriatic arthritis. References: 1. Duffin KC et al. 2018 Las Vegas Dermatology Seminar. 1-3 November 2018; Las Vegas, NV, USA. Poster. 2. Krueger J et al. 24th World Congress of Dermatology. 10-15 June 2019; Milan, Italy. Poster 505. 3. Langley RG et al. N Engl J Med. 2014;371(4):326-338. 4. Bissonnette R et al. J Eur Acad Dermatol Venereol. 2018;32(9):1507-1514. 5. Reich K et al. 2017 Winter Clinical Dermatology Conference. 13-18 January 2017; Kohala Coast, HI, USA. Poster. 6. Reich K et al. 3rd Inflammatory Skin Disease Summit. 12-15 December 2018; Vienna, Austria. Poster LB 6. 7. Novartis data on file. CAIN457F2342 (FUTURE 5): Week 104 Interim Report. May 2019. 8. Baraliakos X et al. Ann Rheum Dis. 2019;78. Abstract OP0235. 9. Strober B et al. J Am Acad Dermatol. 2017;76(4):655-661. 10. Cosentyx Summary of Product Characteristics accessed January 2020.

Date of preparation: February 2020 | IE02/COS19-CNF074a


32 Psoriasis Fig 2: Anti IL-17 treatments for Psoriasis

L., Papp K., Spelman L., Toth D., Kerdel F., et al. Phase 3 studies comparing brodalumab with ustekinumab in psoriasis. N. Engl. J. Med. 2015;373:1318–1328. 15. Papp K.A., Reich K., Paul C., Blauvelt A., Baran W., Bolduc C., Toth D., Langley R.G., Cather J., Gottlieb A.B., et al. A prospective phase iii, randomized, doubleblind, placebo-controlled study of brodalumab in patients with moderate-to-severe plaque psoriasis. Br. J. Dermatol. 2016;175:273–286.

Risaknkizumab another antibody targeting the IL-23 pathway was licensed by the FDA in 2019, in Phase III trials with ustekinumab as a comparator PASI 90 was achieved by 75.3% of patients Anti-IL-23 therapy: and PASI receiving risankizumab 100 by 35.9% of patients treated20.

16. Nakagawa H., Niiro H., Ootaki K., Japanese Brodalumab Study Group Brodalumab, a human antiinterleukin-17-receptor antibody in the treatment of japanese patients with moderate-to-severe plaque psoriasis: Efficacy and safety results from a phase ii randomized controlled study. J. Dermatol. Sci. 2016;81:44–52.

4. Menter A., Tyring S.K., Gordon 9. Langley R.G., Elewski B.E., K., Kimball A.B., Leonardi C.L., Lebwohl M., Reich K., Griffiths C.E., Langley R.G., Strober B.E., Kaul M., Papp K., Puig L., Nakagawa H., Gu Y., Okun M., et al. Adalimumab Spelman L., Sigurgeirsson B., et al. therapy for moderate to severe Secukinumab in plaque psoriasispsoriasis: A randomized, controlled -results of two phase 3 trials. N. phase iii trial. J. Am. Acad. 17. Blauvelt A., Papp K.A., Griffiths Engl. J. Med. 2014;371:326–338. Dermatol. 2008;58:106–115. C.E., Randazzo B., Wasfi Y., Shen 10. . Blauvelt A., Prinz J.C., Gottlieb Y.K., Li S., Kimball A.B. Efficacy 5. Gordon K., Papp K.,was Poulinapproved Guselkumab, an IL-23p19 neutralizing antibody, by the FDA in July 2017 and results A.B., Kingo K., Sofen H., RuerNew treatments in the pipeline: and safety of guselkumab, an antiY., Gu Y.H., Rozzo S., Sasso E.H. Mulard M., Singh V., Pathan R., interleukin-23 monoclonal antibody, from phase III studies have been published, both controlled for placebo as well as for adalimumab. Long-term efficacy and safety Clinical trials are ongoing in the Papavassilis C., Cooper S., et al. compared with adalimumab for the of adalimumab in patients with development of new injectable, Secukinumab The largest absolute differencesmoderate were seen atpsoriasis PASI90: Guselkumab 100administration mg week by 0 preand 4continuous and then treatment of patients to severe oral and topical treatments for filled syringe: Efficacy, safety and with moderate to severe psoriasis: 17.18 treated continuously over 3 psoriasis, patients resulted and clinicians every 8 weeks, in a PASI90 response at week 16 ofusability 73.3%results. from Thisa randomized has been followed bythe phase iii, doubleResults from years: Results from an open-label will have a wider choice of controlled trial in psoriasis (feature) blinded, placebo- and active extension study for patients from Tildrakiazumab in 2018, with efficacy at week 12, 64% and 62% of patients in the 100 mg and 200 mg treatments. This rapid expansion Br. J. Dermatol. 2015;172:484–493. comparator-controlled voyage reveal. J.19Am. Acad. of treatments for psoriasisattained has 1 trial. J. Am. Acad. Dermatol. groups, respectively, PASI-75 , 11. Paul C., Lacour J.P., Tedremets 6. Blauvelt A, Reich K, Lebwohl as stated previously, enhanced 2017;76:405–417. L., Kreutzer K., Jazayeri S., M, Burge D, Arendt C, Peterson our understanding of the disease. Adams S., Guindon C., You R., Reich K., L, Drew J, Rollerithe R, Gottlieb Risaknkizumab another targeting IL-23 pathway was licensed by the FDA in18.2019, inArmstrong A.W., Research is also ongoing to antibody Papavassilis C., Grp J.S. Efficacy, Foley P., Song M., Wasfi Y., AB. Certolizumab pegol for the identify predictors of treatment and usability of secukinumab B., Li S., Shen Y.K., Phase III trials withpatients. ustekinumabtreatment as a comparator PASI 90 was safety achieved by 75.3% of patientsRandazzo receiving of patients with moderateresponse in psoriasis administration by autoinjector/ Gordon K.B. Efficacy and safety of to-severe chronic plaque psoriasis: 20 (PSORT) consotrium aims to100 by 35.9% of patients treated . risankizumab and PASI pen in psoriasis: A randomized, guselkumab, an anti-interleukin-23 pooled analysis of week 16 data better understand determinants of controlled trial (juncture) monoclonal antibody, compared from three randomized controlled response to biologic therapies and J. Eur. Acad. Dermatol. with adalimumab for the treatment trials.J Eur Acad Dermatol Venereol. stratify patients accordingly. 2015;29:1082–1090. of patients with moderate to 2019 Mar;33(3):546-552. severe psoriasis with randomized Referelences: 12. Blauvelt A., Reich K., Tsai T.F., 7. Leonardi C.L., Kimball A.B., Papp withdrawal and retreatment: Results New treatments in the pipeline:K.A., Yeilding N., Guzzo C., Wang Tyring S., Vanaclocha F., Kingo K., from the phase iii, double-blind, 1. The Burden of Psoriasis Y.H., Li S., Dooley L.T., Gordon Ziv M., Pinter A., Vender R., Hugot placebo- and active comparatorIrish Skin Foundation https:// K.B.,development Investigators P.S. of Efficacy S., et al. Secukinumab is superiortreatments for Clinical trials are ongoing in the newandinjectable, oral and topical controlled voyage 2 trial. J. Am. irishskin.ie/wp-content/ safety of ustekinumab, a human to ustekinumab in clearing skin of Acad. Dermatol. uploads/2016/.../Burden_of_ psoriasis, patients and clinicians will have amonoclonal wider choice ofsubjects treatments. This rapid expansion of 2017;76:418–431. interleukin-12/23 with moderate-to-severe Psoriasis_Report_final.pdf 19. Reich K, Papp KA, Blauvelt Aet antibody, in patients with plaque psoriasis up to 1 year: treatments for Powers psoriasis stated76-week previously, our understanding of theal. disease. 2. Leonardi C.L., J.L., has as Tildrakizumab versus placebo psoriasis: results fromenhanced a Results from the clear study. J. Am. Matheson R.T., Goffe B.S., Zitnik R., or etanercept for chronic plaque randomised, double-blind, placebo- response Acad. Dermatol. 2017;76:60–69. Psoriasis Research is also ongoing to identify predictors of treatment in psoriasis patients. Wang A., Gottlieb A.B., Etanercept psoriasis (reSURFACE 1 and controlled trial (phoenix 1) Lancet. 13. Griffiths C.E., Reich aims. K., Lebwohl Psoriasis Study to Group Etanercept reSURFACE 2): results from two consortium Stratification Optimise Relevant Therapy (PSORT) The PSORT 2008;371:1665–1674. M., van de Kerkhof P., Paul C., as monotherapy in patients randomised controlled, phase 3 8. Papp K.A., Langley R.G., Menter A., Cameron G.S., Erickson with psoriasis. N. Engl. J. Med. trials. Lancet 2017; 390: 276–288. Lebwohl M., Krueger G.G., Szapary J., Zhang L., Secrest R.J., et al. 2003;349:2014–2022. 20. Gordon KB, Strober B, Lebwohl P., Yeilding N., Guzzo C., Hsu M.C., Comparison of ixekizumab with 3. Reich K., Nestle F.O., Papp M, et al. Efficacy and safety of Wang Y.H., Li S., et al. Efficacy and etanercept or placebo in moderateK., Ortonne J.P., Evans R., Guzzo risankizumab in moderate-tosafety of ustekinumab, a human to-severe psoriasis (uncover-2 C., Li S., Dooley L.T., Griffiths severe plaque psoriasis (UltIMMa-1 interleukin-12/23 monoclonal and uncover-3): Results from two C.E.M., Investigators E.S. Infliximab and UltIMMa-2): results from two antibody, in patients with phase 3 randomised trials. Lancet. induction and maintenance therapy double-blind, randomised, placebopsoriasis: 52-week results from a 2015;386:541–551. controlled and ustekinumabfor moderate-to-severe psoriasis: A randomised, double-blind, placebo14. Lebwohl M., Strober B., Menter controlled phase 3 trials. Lancet. phase iii, multicentre, double-blind controlled trial (phoenix 2) Lancet. 2018;392(10148):650–66. A., Gordon K., Weglowska J., Puig trial. Lancet. 2005;366:1367–1374. 2008;371:1675–1684.

OCTOBER 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE


has Crohn's disease

""II was was prescribed prescribed idacio idacio

and Fresenius Fresenius Kabi Kabi and supported me me all all the way"

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Amy, 41, 41, Amy, has Plaque Plaque psoriasis psoriasis

® is an adalimumab ® is an adalimumab biosimilar, which is approved approved for the same indications asthe the IDACIO biosimilar, which is approved for use use inthe thesame sameindications conditionsas IDACIO is an adalimumab biosimilar, which is for IDACIOIDACIO is an adalimumab biosimilar, which is approved for in the same conditions as thetreatment treatmentof ofmoderately moderateto to severe chronic biologic reference product, including the treatment of moderately tosevere severely activeCrohn’s Crohn’s asthe thebiologic biologic reference product, including the treatment of moderate chronic biologicreference referenceproduct, product, including including the to severely active 1,1,22 1, 2 plaque prescribed IDACIO can access access KabiCare, web-based resource 1, 2 Patients disease ulcerative colitis patients. prescribed IDACIOcan can access Patients prescribed IDACIO can KabiCare, aaweb-based resource plaquepsoriasis. psoriasis. disease and andPatients ulcerative colitis in in adult adult patients. Patients prescribed IDACIO access developed with approach to support. KabiCare, aholistic resource developed with aa holistic holistic approach approachto topatient patientsupport. support. developed with aa holistic approach to patient patient support. KabiCare, a web-based web-based resource developed with

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The moderate to to severe severe chronic chronic plaque plaquepsoriasis psoriasisin inadult adultpatients patients Theindications indicationsfor for IDACIO IDACIO include include the the treatment treatment of of moderate 11 The for include the ofIDACIO moderately toconsult severely active Crohn’s diseaseand and Theindications indications for IDACIO IDACIO include the treatment treatment moderately to severely active Crohn’s disease Before prescribing please the Summary ofProduct Product who for therapy. Before prescribingofIDACIO please consult the Summary of whoare arecandidates candidates for systemic systemic therapy. ulcerative colitis in have had inadequate response tocard. conventional therapies orwho who areintolerant intolerant ulcerative colitisprescribed in adults adults who response to conventional therapies or are Characteristics. Patients IDACIO should receive aa patient patient alert card. Formore more information about Characteristics. Patients prescribed receive alert For information about 11 Before prescribing IDACIO please consult the Summary of to or have contraindications to such therapies. Before prescribing IDACIO please consult the Summary of to or have contraindications IDACIO and KabiCare, please contact your local Fresenius Kabi representative. IDACIO and KabiCare, please contact representative. Product should receive receive aa patient patientalert alertcard. card.For Formore moreinformation information Product Characteristics. Characteristics. Patients Patients prescribed IDACIO should about Fresenius Kabi Kabi representative. representative. about IDACIO IDACIO and and KabiCare, KabiCare, please contact your local Fresenius References: References: 1.1.IDACIO solution Summary of ofProduct ProductCharacteristics. Characteristics.Fresenius FreseniusKabi KabiDeutschland DeutschlandGmbH. GmbH. References: IDACIO40mg 40mg solutionfor forinjection injectionin inpre-filled pre-filled syringe syringe and pre-filled pen. Summary References: 1.1.IDACIO Summary of Characteristics. Fresenius Ltd. of 2.2.Humira solution for in syringe Summary ofProduct ProductCharacteristics. Characteristics.AbbVie AbbVieDeutschland DeutschlandGmbH GmbH&&Co. Co.KG. KG. IDACIO Summary of Product Product Characteristics. Kabi Ltd. Humira40mg 40mg solution forinjection injection inpre-filled pre-filled syringe and pre-filled pen. Summary 2.2.Humira HumiraSummary Summary of of Product Product Characteristics. Characteristics. Abbvie Ltd. KabiCare KabiCareisisfunded fundedand anddeveloped developed by by Fresenius Fresenius Kabi. KabiCare KabiCareisisfunded funded and and developed developed by Fresenius Kabi. IDACIO IDACIOand andKabiCare KabiCareare areregistered registered trademarks trademarks of Fresenius Kabi. IDACIO Kabi. IDACIOand andKabiCare KabiCare are are registered registered trademarks of Fresenius Kabi.

Abbreviated PrescribingInformation. Information.Consult ConsultthetheSummary SummaryofofProduct ProductCharacteristics Characteristics Abbreviated Prescribing information.Additional Additionalinformation informationis isavailable availableononrequest. request. forfor fullfull information. Idacio(adalimumab) (adalimumab)4040mgmg Idacio medicinalproduct productis issubject subjectto toadditional additionalmonitoring. monitoring.This Thiswillwillallow allowquick quick ThisThismedicinal askedtotoreport reportany any identificationof ofnewnewsafety safetyinformation. information.Healthcare Healthcareprofessionals professionalsareareasked identification suspected adversereactions. reactions.SeeSeebelow belowforforhow howtotoreport reportadverse adversereactions. reactions. suspected adverse Idacio solutionforforinjection injectionin inpre-filled pre-filledsyringe syringe Idacio 4040 mgmg solution Idacio solutionforforinjection injectionin inpre-filled pre-filledpenpen Idacio 4040 mgmg solution Idacio solutionforforinjection injectionin invialvialforforpaediatric paediatricuseuse Idacio 4040 mgmg solution Presentation methodof ofadministration: administration:Each Eachsingle singledose dose0.80.8mlmlpre-filled pre-filledsyringe, syringe,0.80.8mlml Presentation andand method pre-filledpenpenor or0.80.8mlmlvialvialcontains contains4040mgmgofofadalimumab adalimumabforforsubcutaneous subcutaneousinjection. injection. pre-filled Indications and Dosage: Please refer to SmPC for full information. Idacio treatment shouldbebe Indications and Dosage: Please refer to SmPC for full information. Idacio treatment should initiated supervisedbybyspecialist specialistphysicians physiciansexperienced experiencedininthethediagnosis diagnosisand andtreatment treatment initiated andand supervised of conditionsforforwhich whichIdacio Idaciois isindicated. indicated.Ophthalmologists Ophthalmologistsareareadvised advisedtotoconsult consultwith withanan of conditions appropriate specialistbefore beforeinitiation initiationof oftreatment treatmentwith withIdacio. Idacio.Patients Patientstreated treatedwith withIdacio Idacio appropriate specialist should be given a patient alert card. After proper training in injection technique, patients may should be given a patient alert card. After proper training in injection technique, patients may self-injectwithwithIdacio Idacioif their if theirphysician physiciandetermines determinesthat thatit itis isappropriate appropriateand andwith withmedical medical self-inject follow-upas asnecessary. necessary.During Duringtreatment treatmentwith withIdacio, Idacio,other otherconcomitant concomitanttherapies therapies(e.g., (e.g., follow-up corticosteroids and/or immunomodulatoryagents) agents)should shouldbebeoptimised. optimised.Rheumatoid Rheumatoidarthritis arthritis corticosteroids and/or immunomodulatory (RA), adults: In combination with methotrexate (MTX) for moderate to severe, active RA with (RA), adults: In combination with methotrexate (MTX) for moderate to severe, active RA with inadequate responseto todisease-modifying disease-modifyinganti-rheumatic anti-rheumaticdrugs drugs(DMARDs) (DMARDs)including includingMTX. MTX.InIn inadequate response combination severe,active activeandandprogressive progressiveRARAwhen whennotnotpreviously previouslytreated treatedwith with combination withwith MTXMTXforforsevere, given monotherapyif intolerance if intolerancetotoororwhen whencontinued continuedtreatment treatmentwith withMTX MTXisis MTX.MTX. CanCan be be given as asmonotherapy inappropriate. Reduces rate of progression of joint damage on X-ray and improves physical inappropriate. Reduces rate of progression of joint damage on X-ray and improves physical function,in incombination combinationwithwithMTX. MTX.Dosage:40 Dosage:40mgmgsingle singledose doseevery everyother otherweek week(EOW). (EOW). function, ConcomitantMTXMTXshould shouldbebecontinued. continued.In Inmonotherapy, monotherapy,patients patientsmay mayrequire require4040mgmgevery every Concomitant week or 80 mg EOW if they experience a decrease in clinical response. Treatment beyond week or 80 mg EOW if they experience a decrease in clinical response. Treatment beyond 1212 weeks should be reconsidered if no clinical response in that time. Consider need for dose weeks should be reconsidered if no clinical response in that time. Consider need for dose interruption, e.g. before surgery or if serious infection occurs. Reintroduction after 70 days or interruption, e.g. before surgery or if serious infection occurs. Reintroduction after 70 days or longer of discontinuation gave same magnitudes of clinical response and similar safety longer of discontinuation gave same magnitudes of clinical response and similar safety profile as before dose interruption. Polyarticular juvenile idiopathic arthritis (pJIA), profile as before dose interruption. Polyarticular juvenile idiopathic arthritis (pJIA), paediatrics 2 years and above: In combination with MTX for active pJIA with inadequate paediatrics 2 years and above: In combination with MTX for active pJIA with inadequate response to one or more DMARDs. Can be given as monotherapy if intolerance to or when response to one or more DMARDs. Can be given as monotherapy if intolerance to or when continued treatment with MTX is inappropriate. Dosage: 10 kg to < 30 kg 20 mg single dose continued treatment with MTX is inappropriate. Dosage: 10 kg to < 30 kg 20 mg single dose EOW. If ≥ 30 kg: 40 mg single dose EOW. Treatment beyond 12 weeks should be reconsidered EOW. If ≥ 30 kg: 40 mg single dose EOW. Treatment beyond 12 weeks should be reconsidered if no clinical response in that time. Enthesitis-related arthritis (ERA), paediatrics 6 years and if no clinical response in that time. Enthesitis-related arthritis (ERA), paediatrics 6 years and above: For active ERA with inadequate response to or intolerance to conventional therapy. above: For 15active response to conventional therapy. Dosage: kg to ERA < 30 with kg: 20inadequate mg single dose EOW. Ifto≥or30intolerance kg: 40 mg single dose EOW. Ankylosing Dosage: 15 kg to(AS), < 30 kg: 20 mgForsingle doseactive EOW. IfAS≥with 30 kg:inadequate 40 mg single dose EOW. Ankylosing spondylitis adults: severe response to conventional spondylitis (AS), adults: activedose AS EOW. with inadequate response12 toweeks conventional therapy. Dosage: adults:For40severe mg single Treatment beyond should be therapy. Dosage: ifadults: 40 mg response single dosein EOW. 12 weeks should be reconsidered no clinical that Treatment time. Axialbeyond spondyloarthritis without reconsidered if no clinical response in that time. Axial spondyloarthritis radiographic evidence of AS (nr-axSpA), adults: For severe nr-axSpA with objectivewithout signs of radiographic evidence of AS (nr-axSpA), adults: For severe nr-axSpA with objective signs inflammation (elevated CRP and/or MRI), and an inadequate response to or intoleranceofto inflammation CRP and/ordrugs. MRI),Dosage: and an 40inadequate or intolerance nonsteroidal(elevated anti-inflammatory mg singleresponse dose EOW.toTreatment beyondto12 nonsteroidal anti-inflammatory Dosage:response 40 mg single Treatment beyond 12 weeks should be reconsidereddrugs. if no clinical in thatdose time.EOW. Psoriatic arthritis (PsA), weeks should be reconsidered if no clinical response in that time. Psoriatic arthritis adults: For active and progressive PsA with inadequate response to DMARDs. Reduces(PsA), rate of adults: For active and progressive PsA with inadequate response to DMARDs. Reduces rate of progression of peripheral joint damage on X-ray in polyarticular symmetrical subtypes of the progression of improves peripheralphysical joint damage on Dosage: X-ray in 40 polyarticular symmetrical subtypesbeyond of the12 disease and function. mg single dose EOW. Treatment disease improves physical function. mg single dosetime. EOW. Psoriasis, Treatment beyond weeksandshould be reconsidered if no Dosage: clinical 40 response in that adults: 12For weeks should be reconsidered if no clinical response in that time. Psoriasis, adults: moderate to severe chronic plaque psoriasis in candidates for systemic therapy. Dosage:For80 moderate to severe psoriasis in candidates for systemic therapy. Dosage: 80 mg initial dose atchronic Week 0,plaque followed by 40 mg EOW from Week 1. Treatment beyond 16 weeks mgshould initial be dose at Week 0,iffollowed by response 40 mg EOW fromtime Week(refer 1. Treatment 16 weeks reconsidered no clinical in that to SmPC).beyond Paediatric Plaque should be reconsidered no clinical in thatplaque time (refer to SmPC). Paediatricresponse Plaque Psoriasis, 4 years andif above: For response severe chronic psoriasis with inadequate Psoriasis, 4 yearstherapy and above: For severe chronic plaque psoriasis with inadequate to or if topical and phototherapies are inappropriate. Dosage: 15 kg to < 30response kg: 20 mg to or if topical therapy and phototherapies are inappropriate. Dosage: 15 kg to < 30 kg: dose initially followed by 20 mg EOW starting one week after initial dose. If ≥ 30 kg:2040mgmg dosedose initially If ≥ 30 kg:beyond 40 mg16 initiallyfollowed followedbyby2040mgmgEOW EOWstarting startingone oneweek week after initial dose. Treatment dose initially followed by 40 mg EOW starting one week after initial dose. Treatment beyond 16

weeksshould shouldbebereconsidered reconsideredififnonoclinical clinicalresponse responseinin that that time. time. Hidradenitis Hidradenitis suppurativa weeks (HS),adults adultsand andadolescents adolescentsfrom from1212years yearsand and above: above: For For active active moderate to severe HS (HS), (acneinversa) inversa)with withinadequate inadequateresponse responsetotoconventional conventional systemic systemic HS therapy. Dosage: HS, (acne adults:160 160mgmgdose doseinitially initiallyatatDay Day1,1,followed followedbyby8080mg mgtwo twoweeks weeks later later at Day 15. Two weeks adults: later(Day (Day29)29)continue continuewith withaadose doseofof4040mg mgevery every week week oror 80 80 mg mg EOW.HS, adolescents 12 later yearsand andabove above≥≥3030kg:kg:8080mg mginitial initialdose doseatatWeek Week0,0,followed followedbyby 40 40 mg EOW from Week 1. If years thereisisinadequate inadequateresponse responsetoto4040mg mgEOW, EOW,ananincrease increaseinindosage dosage toto 40 mg every week or 80 there EOWmay maybebeconsidered. considered.Antibiotics Antibioticsmay maybebecontinued continued ifif necessary. necessary. Concomitant topical mgmgEOW antisepticwash washononHSHSlesions lesionsisisrecommended recommendedtotobebeused usedon onaadaily daily basis. Treatment beyond antiseptic weeksshould shouldbebereconsidered reconsideredififnonoimprovement improvementininthat thattime. time.Reintroduction Reintroduction of Idacio after 1212weeks treatmentinterruption interruptionasasappropriate. appropriate.Evaluate Evaluateperiodically periodicallythe thebenefit benefit and and risk risk ofof continued continued treatment long-term treatment. Crohn’s disease (CD), adults: For moderately severely active active CD CD with with long-term treatment. Crohn’s disease (CD), adults: For moderately toto severely responsedespite despiteaafull fulland andadequate adequatecourse courseof,of, intolerance intolerance toto oror contraindication contraindication for for aa nonoresponse corticosteroidand/or and/orananimmunosuppressant immunosuppressanttherapy. therapy.Dosage: Dosage:Induction: Induction: 80 80 mg mg dose dose atat Week Week corticosteroid followedbyby4040mg mgatatWeek Week2.2.For Foraamore morerapid rapidresponse: response:160 160 mg mg atat Week Week 0,0, followed followed by by 80 80 0,0,followed mg at Week 2; risk of adverse events higher during rapid induction. Maintenance: 40 mg dose mg at Week 2; risk of adverse events higher during rapid induction. Maintenance: 40 mg dose EOW.During During maintenance, maintenance, corticosteroids corticosteroids may may bebe tapered tapered inin accordance accordance with with clinical clinical EOW. guidelines.IfIfdecrease decreaseininclinical clinicalresponse, response,can canincrease increase dosage dosage toto 40 40 mg mg every every week week or or 80 80 guidelines. EOW.Patients Patientswith withnonoresponse response byby Week Week 44 may may benefit benefit from from continued continued maintenance maintenance mgmgEOW. therapy to Week 12. Treatment beyond 12 weeks should be reconsidered if no clinical response therapy to Week 12. Treatment beyond 12 weeks should be reconsidered if no clinical response thattime. time.Paediatric PaediatricCrohn’s Crohn’sdisease disease(CD), (CD),66years yearsand andabove: above: For For moderately moderately toto severely severely ininthat activeCDCDwith withinadequate inadequateresponse responseto,to,intolerance intolerance toto oror contraindication contraindication for for conventional conventional active therapy including primary nutrition therapy and a corticosteroid and/or an immunomodulator. therapy including primary nutrition therapy and a corticosteroid and/or an immunomodulator. Dosage:< <4040kg:kg:Induction: Induction:4040mg mgdose doseatatWeek Week0,0,followed followed byby 20 20 mg mg atat Week Week 2.2. For For aa more more Dosage: rapidresponse: response:8080mg mgatatWeek Week0,0,followed followedbyby4040mg mgatatWeek Week2;2; risk risk ofof adverse adverse events events higher higher rapid duringrapid rapidinduction. induction.Maintenance: Maintenance:2020mg mgdose doseEOW EOW from from week week 4.4. IfIf insufficient insufficient response, response, during considerananincrease increaseinindosing dosingfrequency frequencytoto2020mg mgevery everyweek. week. IfIf ≥≥ 40 40 kg: kg: Induction: Induction: 80 80 mg mg consider dose at Week 0, followed by 40 mg at Week 2. For a more rapid response: 160 mg dose at Week dose at Week 0, followed by 40 mg at Week 2. For a more rapid response: 160 mg dose at Week 0, followed by 80 mg at Week 2; risk of adverse events higher during rapid induction. 0, followed by 80 mg at Week 2; risk of adverse events higher during rapid induction. Maintenance: 40 mg dose EOW from week 4. If insufficient response, consider an increase in Maintenance: 40 mg dose EOW from week 4. If insufficient response, consider an increase in dosage to 40 mg every week or 80 mg EOW. Treatment beyond 12 weeks should be dosage to 40 mg every week or 80 mg EOW. Treatment beyond 12 weeks should be reconsidered if no clinical response in that time. Ulcerative colitis (UC), adults: For reconsidered if no clinical response in that time. Ulcerative colitis (UC), adults: For moderately to severely active UC with inadequate response to, intolerance to or moderately to severely active UC with inadequate response to, intolerance to or contraindication for conventional therapy including corticosteroids and 6-mercaptopurine contraindication for conventional therapy including corticosteroids and 6-mercaptopurine (6-MP) or azathioprine (AZA). Dosage: Induction: 160 mg dose at Week 0, followed by 80 mg at (6-MP) or azathioprine (AZA). Dosage: Induction: 160 mg dose at Week 0, followed by 80 mg at Week 2. Maintenance: 40 mg dose EOW. During maintenance, corticosteroids may be tapered Week 2. Maintenance: 40 mg dose EOW. During maintenance, corticosteroids may be tapered in accordance with clinical guidelines. If insufficient response, consider an increase in dosage intoaccordance clinical If insufficient response, an increase in dosage 40 mg everywithweek or 80guidelines. mg EOW. Treatment beyond 8 weeksconsider should not be continued if no toclinical 40 mgresponse every week or 80time. mg EOW. Treatment 8 weeks should not be continued no in that Uveitis, adults: beyond For non-infectious intermediate, posteriorifand clinical response in that time. Uveitis, adults: For non-infectious intermediate, posterior and panuveitis with inadequate response to corticosteroids, in patients in need of corticosteroidpanuveitis inadequate responsetreatment to corticosteroids, in patients in need sparing, orwith in whom corticosteroid is inappropriate. Dosage: 80 of mgcorticosteroidinitial dose at sparing, in whombycorticosteroid treatment inappropriate. initial dosewith at Week 0,orfollowed 40 mg EOW from Week 1. isTreatment can beDosage: initiated80inmg combination Week 0, followed by 40 mg EOW from Week 1. Treatment can be initiated in combination with corticosteroids and/or with other non-biologic immunomodulatory agents. Concomitant corticosteroids and/or with other non-biologic immunomodulatory agents. Concomitant corticosteroids may be tapered in accordance with clinical practice starting two weeks after corticosteroids may bewithtapered accordance starting twoofweeks after initiating treatment Idacio.inEvaluate on awith yearlyclinical basispractice the benefit and risk continued initiating withPaediatric Idacio. Evaluate yearlyand basisabove: the benefit and risknon-infectious of continued long-termtreatment treatment. Uveitis,on2a years For chronic long-term treatment. Paediatric Uveitis, 2 years and above: For chronic non-infectious anterior uveitis with inadequate response to or intolerance to conventional therapy, or in anterior uveitis with therapy inadequate response toDosage: or intolerance to mg conventional or in whom conventional is inappropriate. < 30 kg: 20 dose EOW intherapy, combination whom conventional is inappropriate. Dosage: 30 kg: mg dose combination with MTX. Optional therapy 40 mg (for patients < 30 kg) or 80<mg (for20patients ≥ EOW 30 kg)in loading dose with mg of(formaintenance patients < 30therapy. kg) or 80 (for patients ≥ 30of kg) loading oneMTX. weekOptional prior to40start No mg clinical data in use loading dosedose <6 one week prior to start of maintenance therapy. No clinical data in use of loading dose years of age (see SmPC). If ≥ 30 kg: 40 mg dose EOW in combination with MTX. Evaluate on< 6a years age (see SmPC). and If ≥risk 30 kg: 40 mg dose EOW in combination with may MTX.beEvaluate onina yearlyofbasis the benefit of continued long-term treatment. Idacio available yearly the benefit andpresentations risk of continued long-termontreatment. Idacio may be available otherbasis strengths and/or depending the individual treatment needs.in other strengths and/or presentations on theor individual treatment needs. Contraindications: Hypersensitivity to thedepending active substance to any excipients (see SmPC); Contraindications: Hypersensitivity to the active substance or to any excipients (see SmPC); Active tuberculosis (TB) or other severe infections such as sepsis and opportunistic Active tuberculosis or other sepsis and infections; Moderate(TB) to severe heartsevere failure infections (NYHA classsuch III/IV).as Warnings andopportunistic precautions: infections; Moderate to severe heart failure (NYHA class III/IV). Warnings and precautions:

Clearly record the name and andbatch batchnumber numberofofadministered administeredproduct producttotoimprove improvetraceability traceabilityofof biological products. Infections: Infections: Patients Patients taking taking TNF-antagonists TNF-antagonistsare aremore moresusceptible susceptibletoto serious infections. Impaired Impaired lung lung function function may mayincrease increasethe therisk riskforfordeveloping developinginfections. infections. Monitor for infections, including includingTB, TB,before, before,during duringand andfor foratatleast least44months monthsafter aftertreatment. treatment. Treatment with Idacio should not be initiated in patients with active infections including should not be initiated in patients with active infections including chronic or localised infections infections until until infections infections are are controlled. controlled.InInpatients patientswho whohave havebeen been exposed to tuberculosis and and patients patientswho whohave havetravelled travelledininareas areasofofhigh highrisk riskofoftuberculosis tuberculosis or endemic mycoses, such such asas histoplasmosis, histoplasmosis,coccidioidomycosis, coccidioidomycosis,ororblastomycosis, blastomycosis,thetherisk risk and benefits of treatment treatment with with Idacio Idacio should should bebe considered considered prior priortotoinitiating initiatingtherapy. therapy. Evaluate new infections during during treatment treatmentand andmonitor monitorclosely. closely.Stop Stoptreatment treatmentififnew newserious serious infection infection oror sepsis sepsis and and treat treat appropriately. appropriately. Exercise Exercise caution cautionininpatients patientswith withaahistory historyofof recurring recurring infections infections oror who who are are predisposed predisposedtotoinfections, infections,including includingthe theuse useofofconcomitant concomitant immunosuppressive medications. Serious infections: Serious infections, including immunosuppressive medications. Serious infections: Serious infections, includingthose those associated associated with with hospitalisation hospitalisation oror death, death,were werereported reportedininpatients patientsreceiving receivingtreatment. treatment.TB:TB: Consult Consult SmPC SmPC for for details. details. Reactivation Reactivation and and new new onset onset TB, TB, both both pulmonary pulmonaryand andextraextrapulmonary pulmonary (disseminated), (disseminated), were were reported. reported. Screen Screen allallpatients patientsbefore beforetherapy therapyinitiation initiationforfor active active or or inactive inactive (latent) (latent) TB. TB. Appropriate Appropriatescreening screeningtests tests(i.e. (i.e.tuberculin tuberculinskin skintest testand andchest chest X-ray) X-ray) should should be be performed performed inin allall patients. patients.IfIflatent latentTBTBisissuspected, suspected,consult consultphysician physicianwith with appropriate appropriate expertise expertise and and follow follow local local treatment treatmentrecommendations recommendationsforforprophylaxis prophylaxisprior priortoto initiation of Idacio. Despite prophylaxis, TB reactivation has occurred on adalimumab. If active initiation of Idacio. Despite prophylaxis, TB reactivation has occurred on adalimumab. If active TB TB isis diagnosed, diagnosed, do do not not initiate initiate Idacio Idacio treatment. treatment. Other Other opportunistic opportunistic infections: infections: Opportunistic Opportunistic infections infections were were observed observedininpatients patientsreceiving receivingadalimumab. adalimumab.Stop Stoptreatment treatmentinin patients with signs and symptoms of such infections. Consult with physician patients with signs and symptoms of such infections. Consult with physicianwith withappropriate appropriate expertise expertise for for diagnosis diagnosis and and administration administration ofofempiric empiricantifungal antifungaltherapy therapyininthese thesepatients. patients. Hepatitis Hepatitis BB reactivation: reactivation: Reactivation Reactivation ofof HBV HBV has has occurred occurred ininchronic chroniccarriers carriers(surface (surface antigen antigen positive). positive). Patients Patientsshould shouldbebetested testedfor forHBV HBVinfection infectionbefore beforeinitiating initiatingtreatment. treatment.HBV HBV carriers carriers should should consult consultaaspecialist specialistphysician physicianand andbebeclosely closelymonitored monitoredforforreactivation reactivationofofHBV HBV infection throughout therapy and for several months following termination of treatment. If infection throughout therapy and for several months following termination of treatment. If reactivation occurs, stop treatment and initiate appropriate antiviral and supportive reactivation occurs, stop treatment and initiate appropriate antiviral and supportive treatment. Neurological events: Caution in patients with pre-existing or recent-onset central treatment. Neurological events: Caution in patients with pre-existing or recent-onset central or peripheral nervous system demyelinating disorders. Discontinuation of treatment should or peripheral nervous system demyelinating disorders. Discontinuation of treatment should be considered if any of these disorders develop. Neurologic evaluation should be performed be considered if any of these disorders develop. Neurologic evaluation should be performed in patients with non-infectious intermediate uveitis prior to initiation of treatment and in patients with non-infectious intermediate uveitis prior to initiation of treatment and regularly during treatment, to assess for pre-existing or developing central demyelinating regularly during treatment, to assess for pre-existing or developing central demyelinating disorders. Allergic reactions: Reports of serious allergic reactions including anaphylaxis disorders. Allergic reactions: Reports of serious allergic reactions including anaphylaxis received. For serious allergic or anaphylactic reaction, stop Idacio immediately and initiate received. For serious allergic or anaphylactic reaction, stop Idacio immediately and initiate appropriate therapy. Malignancies and lymphoproliferative disorders: A possible risk has appropriate Malignancies andlymphomas lymphoproliferative disorders: A possibleincluding risk has been reportedtherapy. of malignancy, including and leukaemia, in all patients, been reported of malignancy, including in all patients, including paediatric patients, treated with Tumourlymphomas Necrosis and Factorleukaemia, (TNF) antagonists. Examine all paediatric patients, treated with Tumour Necrosis Factor (TNF) antagonists. Examine patients, especially those with a medical history of extensive immunosuppressant or PUVAall patients, especially those withskin a medical extensive PUVA treatment, for non-melanoma cancer history prior toofand during immunosuppressant treatment; caution inorCOPD treatment,andforinnon-melanoma skin cancer to and during cautionConsider in COPD patients, patients with increased risk prior for malignancy due totreatment; heavy smoking. patients, andrisk in patients increasedofrisk for malignancy due to heavy smoking. Consider the potential with thewith combination azathioprine or 6-mercaptopurine and adalimumab the potential risk with the combination of azathioprine or 6-mercaptopurine and adalimumab (hepatosplenic T-cell lymphoma has occurred). Risk of hepatosplenic T-cell lymphoma cannot (hepatosplenic T-cell inlymphoma has occurred). of hepatosplenic T-cell lymphoma cannot be excluded. Caution patients with a history ofRisk malignancy. Risk of developing dysplasia or be excluded. in patients of malignancy. of developing dysplasia or colon cancer isCaution unknown. Patientswith withaUChistory with increased risk ofRisk dysplasia or colon carcinoma, colon cancer is unknown. Patients with UC with increased risk of dysplasia or colon carcinoma, or history of dysplasia or colon carcinoma, to be screened for dysplasia before treatment and or history ofdisease dysplasia or colon carcinoma, toreactions: be screened for dysplasia treatment and throughout course. Haematological Adverse events ofbefore the haematological throughout disease Haematological reactions: events of the haematological system reported withcourse. adalimumab. Patients should seek Adverse immediate medical attention if signs system reportedofwith immediate medical attention signs and symptoms bloodadalimumab. dyscrasias Patients develop should while onseek treatment. Vaccinations: Patientsif may and symptoms of blood dyscrasias develop while on treatment. Vaccinations: Patients may receive concurrent vaccinations, except for live vaccines. Bring paediatric patients up to date receive vaccinations, except forIdacio live vaccines. BringCongestive paediatricheart patients up toSee date with all concurrent immunisations prior to initiating treatment. failure: with all immunisations to initiating Idacioheart treatment. Congestive failure: See contraindications. Cautionprior is advised with mild failure (NYHA class heart I/II). Discontinue contraindications. is symptoms advised with mild heartheart failurefailure. (NYHAAutoimmune class I/II). processes: Discontinue treatment if new orCaution worsening of congestive treatment if new or worsening symptoms of congestive heart failure. Autoimmune processes: Autoimmune antibodies may form with Idacio. Stop treatment if development of a lupus-like Autoimmune may form against with Idacio. Stop treatment development of a lupus-like syndrome withantibodies positive antibodies double-stranded DNA.if Surgery: Consider the long syndrome with positive antibodies against double-stranded DNA. Surgery: Consider the long

FreseniusKabi Kabi Ireland Fresenius Kabi Ireland Fresenius Ireland Fresenius Kabi Ireland Unit3B 3B Fingal Bay Business Park, Unit 3B Fingal Bay Business Park, Unit Fingal Bay Business Park, Unit 3B Fingal Bay Business Park, Balbriggan,Co.Dublin, Co.Dublin, Ireland Balbriggan, Ireland Balbriggan, Co.Dublin, Ireland Balbriggan, Co.Dublin, Ireland T:+353 +353(0)1 (0)1 8413030 T:T: +353 8413030 +353 (0)1 8413030 T: (0)1 8413030 F:+353 +353(0)1 (0)1 8496949 F:F: 8496949 +353 (0)1 8496949 F: +353 (0)1 8496949 www.fresenius-kabi.ie www.fresenius-kabi.ie www.fresenius-kabi.ie www.fresenius-kabi.ie Dateofofpreparation: preparation: July 2020 Date July 2020 Date of preparation: July 2020 Date of preparation: July 2020 Jobcode: code:BIO/IDACIO/011.20 BIO/IDACIO/011.20 Job Job code: BIO/IDACIO/012.20 Job code: BIO/IDACIO/012.20 Additional information available request Additional information is is available onon request Additionalinformation information available request Additional is is available onon request

half-life half-lifeofofIdacio Idacioforforplanned plannedsurgical surgicalprocedures. procedures.Monitor Monitorclosely closelyforforinfections. infections.Elderly Elderly patients: some of which hadhad a a patients:Serious Seriousinfections infectionswere werehigher higherin inpatients patientsover over6565years yearsof ofage,age, some of which fatal Antibody formation fataloutcome. outcome.Consider Considerriskriskofofinfections infectionsin inthese thesepatients. patients.Interactions: Interactions: Antibody formation was waslower lowerwhen whenadalimumab adalimumabwaswasgiven giventogether togetherwithwithMTXMTXin incomparison comparisonwithwithuseuseas as monotherapy. anakinra andand abatacept) monotherapy.Combination CombinationofofIdacio Idaciowith withother otherbiologic biologicDMARDs DMARDs(e.g.(e.g. anakinra abatacept) ororother otherTNF-antagonists TNF-antagonistsis isnotnotrecommended. recommended.Fertility, Fertility,pregnancy pregnancyandandlactation: lactation:Idacio Idacio should should shouldonly onlybebeused usedduring duringpregnancy pregnancyif ifclearly clearlyneeded. needed.Women Womenof ofchildbearing childbearingageage should consider after considerthetheuseuseofofadequate adequatecontraception contraceptionandandcontinue continueitsitsuseuseforforat atleast least5 months 5 months after thethelast to Idacio lasttreatment. treatment.NoNoadministration administrationofoflivelivevaccines vaccines(e.g.(e.g.BCG) BCG)to toinfants infantsexposed exposed to Idacio ininutero s last Idacio cancan uteroforfor5 5months monthsfollowing followingmother’ mother’ s lastIdacio Idaciotreatment treatmentduring duringpregnancy. pregnancy. Idacio bebeused usedduring duringbreast-feeding. breast-feeding.Adverse AdverseReactions: Reactions:Very Verycommon common≥ ≥1/10:1/10:Respiratory Respiratorytracttract infections infections(including (includinglower lowerandandupper upperrespiratory respiratorytract tractinfection, infection,pneumonia, pneumonia,sinusitis, sinusitis, pharyngitis, nasopharyngitis and pneumonia herpes viral), leukopenia (including neutropenia pharyngitis, nasopharyngitis and pneumonia herpes viral), leukopenia (including neutropenia and andagranulocytosis), agranulocytosis),anaemia, anaemia,lipids lipidsincreased, increased,headache, headache,abdominal abdominalpain, pain,nausea nauseaandand vomiting, vomiting,elevated elevatedliver liverenzymes, enzymes,rash rash(including (includingexfoliative exfoliativerash), rash),musculoskeletal musculoskeletalpain,pain, injection 1/100 to <to1/10: Systemic injectionsite sitereaction reaction(including (includinginjection injectionsitesiteerythema). erythema).Common Common≥ ≥ 1/100 < 1/10: Systemic infections (including sepsis, candidiasis and influenza), intestinal infections infections (including sepsis, candidiasis and influenza), intestinal infections(including (including gastroenteritis gastroenteritisviral), viral),skin skinandandsoftsofttissue tissueinfections infections(including (includingparonychia, paronychia,cellulitis, cellulitis, impetigo, impetigo,necrotising necrotisingfasciitis fasciitisandandherpes herpeszoster), zoster),earearinfections, infections,oraloralinfections infections(including (including herpes herpessimplex, simplex,oral oralherpes herpesandandtooth toothinfections), infections),reproductive reproductivetract tractinfections infections(including (including vulvovaginal mycotic infection), urinary tract infections (including pyelonephritis), vulvovaginal mycotic infection), urinary tract infections (including pyelonephritis),fungal fungal infections, infections,joint jointinfections, infections,skin skincancer cancerexcluding excludingmelanoma melanoma(including (includingbasal basalcellcellcarcinoma carcinoma and and squamous squamous cellcell carcinoma), carcinoma),benign benignneoplasm, neoplasm,leucocytosis, leucocytosis,thrombocytopenia, thrombocytopenia, hypersensitivity, hypersensitivity,allergies allergies(including (includingseasonal seasonalallergy), allergy),hypokalaemia, hypokalaemia,uricuricacidacidincreased, increased, blood bloodsodium sodiumabnormal, abnormal,hypocalcaemia, hypocalcaemia,hyperglycaemia, hyperglycaemia,hypophosphatemia, hypophosphatemia,dehydration, dehydration, mood mood alterations alterations(including (includingdepression), depression),anxiety, anxiety,insomnia, insomnia,paraesthesias paraesthesias(including (including hypoesthesia), hypoesthesia), migraine, migraine,nerve nerveroot rootcompression, compression,visual visualimpairment, impairment,conjunctivitis, conjunctivitis, blepharitis, eye swelling, vertigo, tachycardia, hypertension, flushing, haematoma, asthma, blepharitis, eye swelling, vertigo, tachycardia, hypertension, flushing, haematoma, asthma, dyspnoea, cough, GI haemorrhage, dyspepsia, gastroesophageal reflux disease, sicca dyspnoea, cough, GI haemorrhage, dyspepsia, gastroesophageal reflux disease, sicca syndrome, worsening or new onset of psoriasis (including palmoplantar pustular psoriasis), syndrome, worsening or new onset of psoriasis (including palmoplantar pustular psoriasis), urticaria, bruising (including purpura), dermatitis (including eczema), onychoclasis, urticaria, bruising (including purpura), dermatitis (including eczema), onychoclasis, hyperhidrosis, alopecia, pruritus, muscle spasms (including blood creatine phosphokinase hyperhidrosis, alopecia, pruritus, muscle spasms (including blood creatine phosphokinase increased), renal impairment, haematuria, chest pain, oedema, pyrexia, coagulation and increased), renal impairment, haematuria, chest pain, oedema, pyrexia, coagulation and bleeding disorders (including activated partial thromboplastin time prolonged), autoantibody bleeding disorders (including activated partial thromboplastin time prolonged), autoantibody test positive (including double stranded DNA antibody), blood lactate dehydrogenase test positive (including double stranded DNA antibody), blood lactate dehydrogenase increased, impaired healing. Serious, including fatal, adverse reactions have been reported increased, impaired healing. Serious, including fatal, adverse reactions have been reported including infections/sepsis, TB, opportunistic infections, allergic reactions (including including infections/sepsis, (including anaphylaxis), HBV reactivationTB,andopportunistic malignancies infections, (including allergic leukaemia,reactions lymphoma and anaphylaxis), T-cell HBV reactivation and malignancies (including leukaemia, hepatosplenic lymphoma). Serious haematological, neurological and lymphoma autoimmuneand hepatosplenic T-cell lymphoma). Serious haematological, neurological and autoimmune reactions have also been reported. These include rare reports of pancytopenia, aplastic reactionscentral have and also peripheral been reported. These include aplastic anaemia, demyelinating eventsrare and reports reports ofof pancytopenia, lupus, lupus-related anaemia, and central and peripheralsyndrome. demyelinating events and reports of lupus, lupus-related conditions Stevens-Johnson Other less common and rarely reported adverse conditions and Stevens-Johnson syndrome. Other less common and rarely reported adverse reactions are listed in the SmPC. Legal Category: POM. Marketing Authorisation Holder: reactionsKabi are listed in the SmPC. Category: POM.1, 61352 Marketing Holder: Fresenius Deutschland GmbH, Legal Else-Kröner-Straße Bad Authorisation Homburg v.d.Höhe, Fresenius Marketing Kabi Deutschland GmbH, Else-Kröner-Straße 1, 61352 Bad EU/1/19/1356/002, Homburg v.d.Höhe, Germany. authorisation numbers: EU/1/19/1356/001, Germany. Marketing authorisation EU/1/19/1356/001, EU/1/19/1356/003 Package size and cost: UKnumbers: / ROI - Idacio 40mg/0.8ml vial EU/1/19/1356/002, x 1: £316.93 / EU/1/19/1356/003 Package pre-filled size and syringe cost: UKx 2:/ £633.86 ROI - Idacio 40mg/0.8ml vial x 1: £316.93 €309.31, Idacio 40mg/0.8ml / €618.63, Idacio 40mg/0.8ml pre- / €309.31, Idacio 40mg/0.8ml pre-filled syringe x 2: £633.86 / €618.63, Idacio 40mg/0.8ml filled pen x 2: £633.86 / €618.63 Further information: available from Fresenius Kabi Ltd.,prefilled pen x 2:Eastgate £633.86Way, / €618.63 Further information: Kabi533Ltd., Cestrian Court, Manor Park, Runcorn, Cheshire,available WA7 1NT. from Tel +44Fresenius (0)1928 533 Cestrian Court, Eastgate Park, Runcorn, Cheshire, WA7 1NT. Tel +44 (0)1928 533 533 Date of preparation of PI: Way, AprilManor 2020 001/API/IDACIO/FKUK-IRL Date of preparation of PI: April 2020 001/API/IDACIO/FKUK-IRL Adverse events should be reported. Adverse events reported. Reporting forms and information can should be foundbeat: yellowcard.mhra.gov.uk Reporting www.hpra.ie/homepage/about-us/report-an-issue forms and information can be found at: yellowcard.mhra.gov.uk Adverse www.hpra.ie/homepage/about-us/report-an-issue events should also be reported to Fresenius Kabi Ltd. Adverse should be Park, reported to Fresenius Kabi Cestrian Court,events Eastgate Way,also Manor Runcorn, Cheshire, WA7Ltd.1NT Cestrian Court, Eastgate Way,(0)1928 Manor 533 Park,533 Runcorn, Cheshire, WA7 1NT Tel +44 Tel +44 (0)1928 533 533


36 Arthritis Tofacitinib inhibits monocyte-derived dendritic cells differentiation in rheumatoid and psoriatic arthritis: a novel mechanism of action Written by: Dr Viviana Marzaioli, Molecular Rheumatology, Trinity Biomedical Sciences Institute, TCD and Centre for Arthritis and Rheumatic Diseases, St Vincent’s University Hospital, UCD

Inflammatory arthritis (IA), including Rheumatoid arthritis (RA) and Psoriatic arthritis (PsA) are chronic autoimmune diseases characterised by neo-angiogenesis, immune cell infiltration of the synovium and fibroblast-like synoviocyte expansion, leading to joint destruction. While the two diseases have many common clinical manifestations, there are significant pathogenic differences at a clinical, anatomical, cellular and molecular level, which may explain differential disease outcomes and prognoses. Strategies examining the specificity of novel therapeutics for RA or PsA are in progress; for example, while TNF inhibitors are used in both RA and PsA patients, anti-IL-17A therapies have a greater response in PsA patients, whereas IL-6 inhibition appears to be more effective in RA. The pathogenesis of IA is very complex, and it is promoted and perpetuated by cytokine production from different cells of both the innate and adaptive immunity. Cytokines are primarily involved in driving pro-inflammatory mechanisms maintained in chronic synovitis, leading to bone erosion and functional disability. The intricate cytokine network activates different molecular signalling pathways, one of which is the Janus Kinase (JAK) family of receptor-associated tyrosine kinase. Activation of JAKs induces signal transducer and activator of transcriptions (STATs), leading to the activation of multiple genes that drive joint inflammation. In this context a new class of drugs have emerged, which specifically block the JAK/STAT pathway, thus decreasing the inflammation within the IA joint Among the different class of JAK inhibitors, Tofacitinib (Xeljanz®) belongs to the first generation of JAK inhibitors and it shows

selectivity for JAK1 and JAK3, with functional specificity over JAK2. Tofacitinib is a reversible, competitive inhibitor that binds to the adenosine triphosphate (ATP) binding of the kinase domain of JAK, inhibiting the phosphorylation and activation of JAK, thereby preventing the phosphorylation and activation of STATs, and thus the activation of gene transcription. This leads to decreased cytokine production and modulation of the immune response. Studies to date have demonstrated that Tofacitinib inhibits pro-inflammatory cytokine secretion, cellular invasion and metabolic pathways in RA/PsA explants and fibroblasts. A comparison of synovial tissue from RA patients at baseline and 4 weeks post-treatment with Tofacitinib, showed no difference in the cellular composition, but significantly decreased expression of destructive enzymes matrix metalloproteinases 1 and 3, and of downstream target genes of the interferon pathway. These patients demonstrated both sustained clinical and molecular improvements following tofacitinib treatment at 4 months. In addition, our group has shown that tofacitinib inhibits mitochondrial function and promotes a switch in cellular metabolism in primary synovial fibroblasts. The effect of this was paralleled by a decrease in the migratory and invasive capacity of synovial cells, in addition to inhibition in the spontaneous secretion of pro-inflammatory mediator from PsA explant. In addition, Tofacitinib has been shown to reduce the T cell stimulatory capacity of human monocyte-derived dendritic cells (Mo-DC) in healthy subjects; however, its mechanism of action is unknown. Dendritic cells (DC) are a specific population of immune cells that have a key role in the

OCTOBER 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

pathogenesis of inflammatory arthritis. They are abundant in the synovium of RA and PsA patients when compared to osteoarthritis and are associated with disease activity and progression. There are different subsets of DC, classified by their location and function. A specific subset of DCs derived from monocytes (Mo-DC), termed “inflammatory Mo-DC” have also been identified in autoimmune diseases including IA. Although their precise function is still unclear, due to limited studies and lack of definitive markers, it is widely accepted that inflammatory Mo-DC plays a complementary role to that of conventional DC, and possibly synergise with them in the potentiation of the inflammatory response. While conventional DCs are critical for self-tolerance and activation of specific immune responses, inflammatory DCs are implicated in innate defence and T-cell activation, however little is know about their role in IA. Therefore to further understand their contribution to pathogenic mechanisms in IA, we developed in-vitro/ex vivo assays, to examine the presence and function of these cells in patients with IA. The differentiation of monocyte into dendritic cells can be replicated in vitro by isolating monocytes from blood, that specifically express on their surface CD14 marker, and stimulating them with a cocktail of cytokines (GM-CSF and IL-4) for 7 days, this will lead to an immature Mo-DC phenotype, responsible for antigen uptake and processing. These cells can be further stimulated (with LPS), leading to a mature Mo-DC profile, responsible for antigen presentation and T-cell activation. In our study we observed that freshly isolated monocytes from RA patients displayed a different morphology to those of PsA and healthy subjects (HC), displaying dendritic-like protrusions, indicative or a more mature phenotype. Their morphological features were further enhanced one day after Mo-DC differentiation stimuli, with longer dendrite formation demonstrated for RA compared to PsA and HC. This was paralleled by a significant increase in the expression of a specific DC cell surface marker CD209, in addition to activation markers (CD40 and CD86), further supporting the concept of a more mature phenotype, and suggesting that RA monocytes are primed compared to their PsA and HC counterparts. The main function of dendritic cells in their immature stage is the uptake and processing of antigens, which are subsequently presented to T cells; placing DC at the interface of innate and adaptive immunity, thus highlighting their importance in inflammatory diseases. Interestingly, we demonstrate that antigen uptake was impaired in RA, compared to PsA and HC, where antigen uptake remained functional. This observation, along with the increased rate of differentiation observed for


fluticasone furoate

Allergic rhinitis relief

Relieving the symptoms of allergic rhinitis in patients over 6 years1

The incidence of epistaxis during long term treatment was higher than 10% but was generally mild to moderate in intensity1

www.avamys.ie

Prescribing Information (Please refer to the full Summary of Product Characteristics before prescribing) Avamys Nasal Spray Suspension (fluticasone furoate 27.5 micrograms/metered spray) Uses: Treatment of symptoms of allergic rhinitis in adults and children aged 6 years and over. Dosage and Administration: For intranasal use only. Adults and adolescents (12 years and older): Two sprays per nostril once daily (total daily dose, 110 micrograms). Once symptoms controlled, use maintenance dose of one spray per nostril once daily (total daily dose, 55 micrograms). Reduce to lowest dose at which effective control of symptoms is maintained. Children aged 6 to 11 years: One spray per nostril once daily (total daily dose, 55 micrograms). If patient is not adequately responding, increase daily dose to 110 micrograms (two sprays per nostril, once daily) and reduce back down to 55 micrograms daily dose once control is achieved. Contraindication: Hypersensitivity to active substance or excipients. Special warnings and precautions: Systemic effects of nasal corticosteroids may occur, particularly when prescribed at high doses for prolonged periods. These effects are much less likely to occur than with oral corticosteroids and may vary in individual patients and between different corticosteroid preparations. Potential systemic effects may include Cushing’s syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, cataract, glaucoma and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children). Treatment with higher than recommended doses of nasal corticosteroids may result in clinically significant adrenal suppression. Consider additional systemic corticosteroid cover during periods of stress or elective surgery. Caution when prescribing concurrently with other corticosteroids. A reduction in

growth velocity has been observed in children treated with fluticasone furoate 110 micrograms daily for one year. Therefore, children should be maintained on the lowest possible efficacious dose which delivers adequate symptom control. It is recommended that growth of children receiving prolonged treatment with nasal corticosteroids is regularly monitored. Consider referring to a paediatric specialist. May cause irritation of the nasal mucosa. If a patient presents with visual disturbance they should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma, central serous chorioretinopathy. Drug interactions: Caution is recommended when co-administering fluticasone furoate with potent CYP3A inhibitors including cobicistat-containing products as an increase in the risk of systemic side effects is expected. Co-administration should be avoided unless the benefit outweighs the increased risk. Co-administration with ritonavir is not recommended because of the risk of increased systemic exposure of fluticasone furoate. Pregnancy and Lactation: No adequate data available. Recommended nasal doses result in minimal systemic exposure. It is unknown if fluticasone furoate nasal spray is excreted in breast milk. Only use if the expected benefits to the mother outweigh the possible risks to the foetus or child. Side effects: Very common (≥1/10): epistaxis. Epistaxis was generally mild to moderate, with incidences in adults and adolescents higher in longer-term use (more than 6 weeks). Common (≥1/100 and <1/10): headache, dyspnoea, nasal ulceration. Uncommon (≥1/1000 and <1/100): rhinalgia, nasal discomfort (including nasal burning, nasal irritation, and nasal soreness), nasal dryness. Rare (≥1/10,000 and <1/1000): hypersensitivity reactions including anaphylaxis, angioedema, rash, and urticaria. Very rare (<1/10,000): Nasal septum perforation. Not known: transient ocular changes, vision blurred, bronchospasm, growth retardation.

Marketing Authorisation (MA) Holder: GlaxoSmithKline (Ireland) Limited, 12 Riverwalk, Citywest Business Campus, Dublin 24, Ireland. MA Number: EU/1/07/434/003. Legal category: POM B. Last date of revision: April 2020. Job Ref: PI-5555. Further information available on request from GlaxoSmithKline, 12 Riverwalk, Citywest Business Camp, Dublin 24. Tel: 01-4955000.

Adverse events should be reported to the Health Products Regulatory Authority (HPRA) using an Adverse Reaction Report Form obtained either from the HPRA or electronically via the website at www.hpra.ie. Adverse reactions can also be reported to the HPRA by calling (01) 6764971. Adverse events should also be reported to GlaxoSmithKline on 1800 244 255.



+285 ())(&7

Reference: 1. Avamys Summary of Product Characteristics, available on www.medicines.ie, accessed January 2020 PM-IE-FLF-ADVT-190007 Date of preparation: January 2020

Not actual size


38 Arthritis Figure 1. Freshly isolated monocytes from RA patients, but not PsA, exhibits an activated morphology, with small dendrites which are further enhanced 1-day post-differentiation. At day 7 post differentiation both RA and PsA express similar DC-features. (B) Proposed mechanism of action of Tofacitinib on Mo-DC differentiation. Tofacitinib, by inhibiting the JAK pathway, leads to a decrease of NOX5 and a subsequent decrease of Mo-DC differentiation (adapted from1)

early/2017/08/22/blood-201610-746347?sso-checked=true. doi:10.1182/blood-2016-10 RA monocytes, suggests earlier activation of RA Mo-DC, which could partially explain the higher state of inflammation observed in these patients when compared to PsA. Several studies have addressed the signalling pathway required for the differentiation of monocytes into dendritic cells. It has been shown that multiple stimuli and an intricate signalling network are required for the Mo-DC differentiation, which includes, among others, the JAK-STAT pathway. Therefore, we sought to investigate whether the JAK/ STAT inhibition by Tofacitinib could modulate Mo-DC differentiation. We observed, in fact, that JAK inhibition by Tofacitinib significantly reduced the differentiation of monocytes into DC in both RA and PsA patients, with cells remaining in a monocytic stage, with lower CD209 DC marker and higher CD14 monocytic marker. Tofacitinib reduced Mo-DC differentiation, as early as one day post-differentiation, an effect that led to a reduction in the activation state of DC from both RA and PsA patients, evident by the observed decrease in both CD40 and CD86. Interestingly, Tofacitinib inhibition of Mo-DC differentiation also translated into a functional impairment of DC function, through inhibition of antigen uptake in both HC and PsA, and to a lesser extent in RA Thus tofacitinib appears to have direct involvement the regulation of innate immune function. Reactive oxygen species (ROS), have been associated with autoimmune diseases, including

RA and PsA. Although studies are controversial, describing both a protective and a pathogenic role of ROS in rheumatic disease, it is widely accepted that a normal oxidative burst is necessary to maintain the homeostasis of the joint. Several studies, including ours, have highlighted the importance of NADPH oxidases (NOX) expression in Mo-DC differentiation and antigen presentation. In particular, our study identified a significant induction of NOX5, mirrored by a decrease in NOX2 expression during Mo-DC differentiation. In addition, we also showed that JAK/STAT mediated the effect of NOX5 on Mo-DC function. Therefore we postulated that alteration of Mo-DC differentiation by Tofacitinib was associated with an imbalance in NOX expression and ROS production. Indeed, we demonstrated that Tofacitinib altered the NOX2/NOX5 balance during Mo-DC differentiation, leading to an increase in NOX2 expression and a decrease of NOX5 expression in both RA and PsA patients. This imbalance was associated with impaired NOX5dependent ROS production in PsA Mo-DC treated with Tofacitinib. In line with the more active state of Mo-DC from RA patients, a lack of NOX5-dependent ROS production was observed in RA patients, leading to a limited effect of Tofacitinib. The direct involvement of NOX5 as a downstream effector of Tofacitinib was confirmed by pharmacological inhibition of NOX5 and NOX2. Indeed, we observed a loss of effect of Tofacitinib in the presence of the

OCTOBER 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

NOX5 inhibitor, but not in presence of NOX2 inhibitor, suggesting that NOX5 is a downstream target for Tofacitinib’s mechanism of action. Conclusion: In conclusion (Figure 1), we observed different morphological and functional profiles between monocytes obtained from RA and PsA patients, with RA monocytes primed to differentiate into DC and exhibiting differentiation and activation markers at earlier time point compared to that of PsA. We further demonstrated a novel mechanism of action for Tofacitinib in RA and PsA patients, which inhibits Mo-DC differentiation via the regulation of NOX5 expression and ROS production, giving us further insight into the use of the drug as a successful treatment strategy for IA. References 1. Marzaioli V, Canavan M, Floudas A, Wade SC, Low C, Veale DJ, Fearon U. Monocyte-Derived Dendritic Cell Differentiation in Inflammatory Arthritis Is Regulated by the JAK/STAT Axis via NADPH Oxidase Regulation. Frontiers in Immunology. 2020 [accessed 2020 Sep 11];11:1406. https://www. frontiersin.org/article/10.3389/ fimmu.2020.01406/full. doi:10.3389/fimmu.2020.01406 2. Marzaioli V, Hurtado-Nedelec M, Pintard C, Tlili A, Marie J-C, Monteiro RC, Gougerot-Pocidalo M-A, My-Chan Dang P, El-Benna J. NOX5 and p22phox are 2 novel regulators of human monocytic differentiation into dendritic cells. Blood. 2017 [accessed 2017 Aug 23];130(15):1734–1745. http:// www.bloodjournal.org/content/

3. Veale DJ, Fearon U. What makes psoriatic and rheumatoid arthritis so different? RMD open. 2015 [accessed 2018 Oct 3];1(1):e000025. http:// www.ncbi.nlm.nih.gov/ pubmed/26509055. doi:10.1136/ rmdopen-2014-000025 4. Hodge JA, Kawabata TT, Krishnaswami S, Clark JD, Telliez JB, Dowty ME, Menon S, Lamba M, Zwillich S. The mechanism of action of tofacitinib - an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. Clinical and Experimental Rheumatology. 2016;34(2):318–328. 5. Mirshafiey A, Mohsenzadegan M. The Role of Reactive Oxygen Species in Immunopathogenesis of Rheumatoid Arthritis. 2008. https:// ijaai.tums.ac.ir/index.php/ijaai/ article/view/219 6. Gao W, McGarry T, Orr C, McCormick J, Veale DJ, Fearon U. Tofacitinib regulates synovial inflammation in psoriatic arthritis, inhibiting STAT activation and induction of negative feedback inhibitors. Annals of the rheumatic diseases. 2015:1–5. http://www.ncbi.nlm.nih.gov/ pubmed/26353790. doi:10.1136/ annrheumdis-2014-207201 7. McGarry T, Orr C, Wade S, Biniecka M, Wade S, Gallagher L, Low C, Veale DJ, Fearon U. JAK / STAT Blockade Alters Synovial Bioenergetics, Mitochondrial Function, and Proinflammatory Mediators in Rheumatoid Arthritis. Arthritis & Rheumatology. 2018 [accessed 2019 May 30];70(12):1959–1970. https://onlinelibrary.wiley.com/ doi/abs/10.1002/art.40569. doi:10.1002/art.40569


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

MOVYMIA®: THE NEW TERIPARATIDE BIOSIMILAR FROM CLONMEL HEALTHCARE

RELIABLE: Movymia®’s quality, safety and efficacy is highly similar to its reference product1,2,* EFFECTIVE: Anabolic MoA effectively rebuilds bone through the stimulation of osteoblasts1,3 AFFORDABLE: Allows more eligible patients to benefit due to its cost advantage4,5 RE-USABLE: One high quality reuseable pen for the entire treatment period1 MOVYMIA 20 MICROGRAMS/80 MICROLITERS SOLUTION FOR INJECTION Each dose of 80 microliters contains 20 micrograms of teriparatide. One cartridge of 2.4 ml of solution contains 600 micrograms of teriparatide (corresponding to 250 micrograms per ml). Presentation: Glass cartridge. Indications: Movymia is indicated in adults. Treatment of osteoporosis in postmenopausal women and men at increased risk of fracture. In postmenopausal women, a significant reduction in the incidence of vertebral and non-vertebral fractures but not hip fractures has been demonstrated. Treatment of osteoporosis associated with sustained systemic glucocorticoid therapy in women and men at increased risk for fracture. Dosage: The recommended dose is 20 micrograms administered once daily. Patients should receive calcium and vitamin D supplements if dietary intake is inadequate. The maximum total duration of treatment is 24 months. The 24 month course should not be repeated over a patient’s lifetime. Following cessation of teriparatide therapy, patients may be continued on other osteoporosis therapies. Teriparatide must not be used in severe renal impairment. Use with caution in moderate renal impairment and impaired hepatic function. Teriparatide should not be used in paediatric patients (less than 18 years), or young adults with open epiphyses. Method of administration: Movymia should be administered once daily by subcutaneous injection in the thigh or abdomen. It should be administered exclusively with the Movymia Pen reusable, multidose medicine delivery system and the injection needles which are listed as compatible in the instructions provided with the pen. The pen and injection needles are not included with Movymia. However, for treatment initiation a cartridge and pen pack should be used. Movymia must not be used with any other pen. Patients must be trained to use the proper injection techniques. Contraindications: Hypersensitivity to the active substance or excipients. Pregnancy and Breast-feeding. Pre-existing hypercalcaemia, severe renal impairment, metabolic bone diseases other than primary osteoporosis or glucocorticoid-induced osteoporosis, unexplained elevations of alkaline phosphatase, prior external beam or implant radiation therapy to the skeleton, patients with skeletal malignancies or bone metastases. Warnings and precautions: In normocalcaemic patients, slight and transient elevations of serum calcium concentrations have been observed following teriparatide injection. Serum calcium concentrations reach a maximum between 4 and 6 hours and return to baseline by 16 to 24 hours after each dose of teriparatide. Therefore, if blood samples for serum calcium measurements are taken, this should be done at least 16 hours after the most recent teriparatide injection. Routine calcium monitoring during therapy is not required. Teriparatide may cause small increases in urinary calcium excretion, but the incidence of hypercalciuria did not differ from that in the placebo-treated patients in clinical trials. Teriparatide should be used with caution in patients with active or recent urolithiasis because of the potential to exacerbate this condition. In short-term clinical studies with teriparatide, isolated episodes of transient orthostatic hypotension were observed. Typically, an event began within 4 hours of dosing and spontaneously resolved within a few minutes to a few hours. When transient orthostatic hypotension occurred, it happened within the first several doses, was relieved by placing subjects in a reclining position, and did not preclude continued treatment. Caution should be exercised in patients with moderate renal impairment. Experience in the younger adult population, including premenopausal women, is limited. Treatment should only be initiated if the benefit clearly outweighs risks in this population. Women of childbearing potential should use effective methods of contraception during use of teriparatide. If pregnancy occurs, teriparatide should be discontinued. The recommended treatment time of 24 months should not be exceeded. Contains sodium. Interactions: Digoxin, digitalis. Fertility, pregnancy and lactation: Women of childbearing potential should use effective methods of contraception during use of teriparatide. If pregnancy occurs, Movymia should be discontinued. Movymia is contraindicated for use during pregnancy and breast-feeding. The effect of teriparatide on human foetal development has not been studied. The potential risk for humans is unknown. Driving and operation of machinery: Teriparatide has no or negligible influence on the ability to drive and use machines. Transient, orthostatic hypotension or dizziness was observed in some patients. These patients should refrain from driving or the use of machines until symptoms have subsided. Undesirable effects: Nausea, pain in limb, headache, dizziness. Refer to Summary of Product Characteristics for other adverse effects. Pack size: 1. Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie. Marketing authorisation holder: STADA Arzneimittel AG, Stadastrasse 2-18, 61118 Bad Vilbel, German. Marketing authorisation number: EU/1/16/1161/001-003. Medicinal product subject to medical prescription. Date last revised: July 2019. 1. Movymia® SmPC. 2. Movymia® EPAR – public assessment report, available at: https://www.ema.europa.eu/documents/assessment-report/movymia-epar-public-assessment-report_en.pdf 3. Brixen KT et al. Basic Clin Pharmacol Toxicol. 200494(6):260–70. 4. Lyman GH et al. N Engl J Med. 2018378(21):2036–2044. 5. Janjigian YY et al. Future Oncol. 201814(23):2403–2414.* Forsteo®

October 2019. 2019/ADV/TER/122H


40 News

Marking World Osteoporosis Day Paul Neill, Director Generics Products Teva Ireland

World Osteoporosis Day (WOD) takes place this month, occuring on October 20 each year and marking a year-long campaign dedicated to raising global awareness of the prevention, diagnosis and treatment of osteoporosis. WOD aims to make osteoporosis and fracture prevention a global health priority by reaching out to health-care professionals, the media, policy makers, patients, and the public at large. The campaign will feature “THAT’S OSTEOPOROSIS” as a headline, highlighting emotionally impactful visuals and stories of real people living with osteoporosis in all regions of the world. The campaign will emphasise the direct link between osteoporosis (the silent, underlying disease) and broken bones, which have a serious, life-changing impact in terms of pain, disability and lost independence. It will also focus on osteoporosis as a ‘family affair’, with family caregivers often carrying the burden of care, and the disease affecting multiple generations of the family. At present it is estimated that 300,000 people in Ireland have Osteoporosis. One in 4 men and 1 in 2 women over 50 will develop a fracture due to Osteoporosis in their lifetime. The disease can also affect children. 20% of people aged 60+ who break their hip will die within 6 to 12 months, due to the secondary complications of breaking a bone. 50% of people aged 60+ who break a hip will lose their independence. They will be unable to wash or dress

themselves or walk across a room unaided. These statistics are why it is so important that people take responsibility for their bone health and check to see if they are at risk. Only 15% of people in Ireland are actually diagnosed with bone loss, leaving 280,000 undiagnosed and facing losing their independence. New Treatment Teva has announced the launch of Tetridar® (teriparatide), the 20 microgram/ 80 microlitres Solution for injection in a pre-filled pen for treating patients living with osteoporosis. The treatment simulates osteoblastic activity and new bone tissue formation, reducing the risk of fracture in those with osteoporosis. The new treatment is bioequivalent and functionally comparable to the original, Forsteo®.i It is estimated that there are currently 300,000 people in Ireland living with osteoporosis with only 15% of people diagnosed.ii Teriparatide is a self-injecting device which can be administered at home with a recommended dose of 20 micrograms, to be administered once daily by subcutaneous injection in the thigh or abdomen. Each dose of 80 microlitres contains 20 micrograms of teriparatide and one pre-filled pen of 2.4ml contains 600 micrograms of teriparatide (corresponding to 250 micrograms per ml). Alongside treatment with teriparatide, supplemental calcium and vitamin D should also be taken by patients if dietary intake is inadequate.iii Patients must be trained to use the proper injection technique

OCTOBER 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

and on the correct use of the pen. The maximum treatment duration should be no more than 24 months and treatment should not be repeated over a patient’s lifetime. Following cessation of teriparatide therapy, patients should be continued on other osteoporosis therapies. Of those living with the osteoporosis in Ireland, one in four men and one in two women over 50 will develop a fracture due to the condition during their lifetime.ii Teriparatide is indicated for the treatment of osteoporosis in postmenopausal women, men at increased risk of fracture and those in glucocorticoid-induced osteoporosis. It is generally considered a second line therapy for the treatment of osteoporosis however may be considered first line therapy in specific cases such as postmenopausal women at very high risk of fracture or patients with glucocorticoidinduced osteoporosis and multiple prior vertebral fractures. Paul Neill, Director Generics Products Teva Ireland said, “Tetridar® will help with the prevention of osteoporotic fractures and aid the overall management of osteoporosis. It is worrying to see that an estimated 85% of people living with osteoporosis in Ireland are going undiagnosed. A fracture, or worry of one, can have a huge impact on a person’s quality of life, both mentally and physically”. The most commonly observed adverse events in osteoporosis patients treated with teriparatide are nausea, pain in limb, headaches and dizziness. Teriparatide has been shown to reduce the risk of vertebral and non-vertebral fractures and

increase lumbar spine and hip BMD in postmenopausal women, increase lumbar spine and femoral neck BMD in male patients with osteoporosis and have greater anti-fracture efficacy and greater increase in lumbar spine and hip BMD in those with glucocorticoidinduced osteoporosis.iii Osteoporosis is progressive, systemic skeletal disorder characterised by low bone mass and micro-architectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture.iv Worldwide, osteoporosis causes more than 8.9 million fractures annually, resulting in an osteoporotic fracture every three seconds.v Teva employs around 800 people in Ireland and has three sites in the Republic of Ireland and one site in Northern Ireland. Teva Ireland supply medicines to treat a wide range of diseases and conditions – from multiple sclerosis, asthma, cancer and Chronic Obstructive Pulmonary Disease, to pain relief, cholesterol reducers and antibiotics. Dosage forms include extended and immediate release tablets and capsules, injectables, creams, ointments, solutions, suspensions and inhalers. Date of preparation July 2020. IE/ GEN/20/0001d. i Data on File: Bioequivalence Teriparatide Teva 20 mcg/0.08 mL Solution for Injection (PL 00289/2005) and Tetridar® (teriparatide) 20 mcg/0.08 mL Solution for Injection (PA 1986/053/001). Teva UK Limited Medical Information Department, July 2020 ii https://www.irishosteoporosis. ie/about-osteoporosis/, last accessed 28 May 2020 iii Teriparatide Teva SmPC 2018 iv Kanis JA, Cooper C, Rizzoli R, Reginster JY; Scientific Advisory Board of the European Society for Clinical and Economic Aspects of Osteoporosis (ESCEO) and the Committees of Scientific Advisors and National Societies of the International Osteoporosis Foundation (IOF). European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int. 2019;30(1):3-44. v https://www.iofbonehealth. org/references-facts-andstatistics#ref_214, last accessed 10 June 2020


42 News European Society of Radiology Online Congress – ‘Outstanding Success’ Quality, Safety and Standards Committee Chairperson Dr Adrian Brady and ESR President, Professor Boris Brkljacic

Boris Brkljačić, play host as he awarded exemplary members of the radiology community with Honorary Membership and Gold Medallist awards.

The European Society of Radiology (ESR) 2020 Congress proved to be an outstanding success in overcoming Covid-19, attracting a record 15,265 professional delegates to its online sessions, an increase of 5% on the previous year.

available for participants, this year’s ECR was a unique experience that sought to overcome the challenges posed by the pandemic and succeeded.

The online meeting saw viewers tuning in from over 130 countries across the world to participate in the society’s first ever online congress. With a vast mix of educational, scientific, interactive and industry-related content

The congress featured many special highlights throughout the week. A phenomenal Opening Ceremony saw Chairman of the ESR Board of Directors and ECR 2020 Congress President, Professor

A congress packed with highlights

Over the course of the week, attendees were treated to over 50 live sessions. From exciting plenary lectures and special focus sessions to state-of-the-art talks on Covid-19 and a special live stream dedicated to radiographers, there was educational content for all, with 28 CME credits available for participants. Over 2,000 people tuned in on Thursday morning to take part in a long-standing ECR tradition, the Imaging Interpretation Quiz, which was broadcasted live from Australia and hosted by former President of the ESR, Professor Paul M. Parizel. Attendees experienced a charming and fitting end to the congress in the form of the Closing Ceremony with more delightful talks and music from the Vienna Boys’ Choir.

Insights from the congress president Professor Boris Brkljačić shared his thoughts on the online congress. “When we decided to convert ECR 2020 into an onlineonly congress, there was a lot of uncertainty about how this would look and whether it would still be possible to capture the magic of ECR in a digital format. After an incredible congress week, I am extremely pleased to say, there are no longer any doubts. ECR 2020 has been an outstanding event with so much interactivity and inclusivity from our attendees that truly kept the magic alive. “The educational content at this year’s congress has been of an extremely high standard and, although I hope that we can all meet together in Vienna again soon, I think this congress has proved that online conference formats are possible and that the ESR has successfully set an industry standard with last week’s meeting. “I would like to thank everyone who has contributed to this incredible meeting, from our programme planning committee and ESR staff to all congress speakers and, of course, all our attendees.”

Poor awareness of co-morbidities in Irish Psoriasis Patients Dr Cathal O'Connor, Dermatology Specialist Registrar and PhD Fellow with the Irish Clinical and Academic Training (ICAT) programme The study, carried out at University Hospital Waterford, examined patient awareness of co-morbidities associated with psoriasis. Psoriasis is a skin condition that causes red, dry, flaky or scaly skin and can appear anywhere on the body. It can profoundly impair quality of life. People with psoriasis are at risk of several other diseases, especially people with severe psoriasis.

Fewer than one in five people with psoriasis are aware of their increased risk of heart and bowel disease, according to a new study.

Author of the study was Dr Cathal O’Connor, Dermatology Specialist Registrar and PhD Fellow with the Irish Clinical and Academic Training (ICAT) programme. He told Hospital Professional News, “Psoriasis is associated with several other important medical conditions such as heart

OCTOBER 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

disease and inflammatory bowel disease. People with psoriasis die four years earlier than people without psoriasis, mostly due to the increased risk of major cardiovascular events.

was good. However, only 16% of patients knew about the increased risk of heart disease and only 12% knew about the increased risk of inflammatory bowel disease,” Dr O’Connor continues.

“We performed a study in University Hospital Waterford assessing the knowledge of our patients with psoriasis regarding the causes, exacerbating factors, and associated conditions of psoriasis.”

“On the other hand, patients were well informed on the association with arthritis and depression, with 87% of our patients correctly identifying these as risks.”

In total, 214 patients attending Dermatology clinics completed the surveys. Participants between the age of 17-85 completed the survey with the mean age being 50.1 years old. 94% of those taking the survey were Irish and 59% had finished education at secondary level. 90% of patients had moderate to severe psoriasis and were on systemic or biologic treatments. “Knowledge of the causes and exacerbating factors of psoriasis

Emphasising the importance of knowledge regarding risks, he adds, “It is vital that patients are aware, so that other modifiable risk factors can be optimally managed in conjunction with our colleagues in primary care. We have launched an education campaign in the department and plan to reassess patient knowledge in 12 months.” The study was a single-centre cross-sectional study conducted in the dermatology department at University Hospital Waterford between January 2019 and June 2020.


Dexamethasone Dexamethasone Phosphate Krka Krka

solution for for 4 mg/ml solution injection/infusion injection/infusion dexamethasone dexamethasone phosphate phosphate

• Dexamethasone Dexamethasone Phosphate PhosphateKrka Krka4 mg/ml 4 mg/ml solution for injection/infusion: for injection/infusion: avaiable as as 22 ml ml ampule, ampule,which whichcontains contains88mg mg of dexamethasone dexamethasone phosphate phosphate (as dexamethasone dexamethasonesodium sodiumphosphate) phosphate)(1) (1) • Krka has decades decades of of experiences experienceswith with dexamethasone (2) dexamethasone (2)

Composition:Each Eachampoule ampoule 2 ml contains 8 mg dexamethasone phosphate dexamethasone sodium phosphate). Composition: of of 2 ml contains 8 mg of of dexamethasone phosphate (as (as dexamethasone sodium phosphate). Therapeutic indications, posology and method of administration: intravenous, intramuscular, intraarticular, intralesional Therapeutic indications, posology and method of administration: ForFor intravenous, intramuscular, intraarticular, intralesional or or subconjunctival use. Treatment duration depends indication. Systemic Swelling of the brain: Initially, in acute states, subconjunctival use. Treatment duration depends on on thethe indication. Systemic use:use: Swelling of the brain: Initially, in acute states, depending on the cause and severity 8–10 mg (up to 80 mg) into a vein (i.v.), then 16–24 mg (up to 48 mg) daily, divided depending on the cause and severity 8–10 mg (up to 80 mg) into a vein (i.v.), then 16–24 mg (up to 48 mg) daily, divided intointo 3–4(up(upto to6) 6) individual doses days. Swelling of the brain to bacterial meningitis: mg/kg body weight every 3–4 individual doses forfor 4–84–8 days. Swelling of the brain duedue to bacterial meningitis: 0.150.15 mg/kg body weight every 6 hours 4 days, children: mg/kg body weight every hours 2 days, starting before antibiotics. Severe cases 6 hours forfor 4 days, children: 0.40.4 mg/kg body weight every 12 12 hours for for 2 days, starting before thethe firstfirst antibiotics. Severe cases withwith intoxication-like conditions: 4–20 daily, a few days, in conjunction adequate anti-infectious therapy; in single intoxication-like conditions: 4–20 mgmg i.v.i.v. daily, forfor a few days, onlyonly in conjunction withwith adequate anti-infectious therapy; in single cases (e.g. typhoid) initial doses then gradually reduced. Shock states after severe injury: Initially 40–100 cases (e.g. typhoid) initial doses upup to to 200200 mgmg i.v.,i.v., then gradually reduced. Shock states after severe injury: Initially 40–100 mg mg (children4040mg) mg)i.v.,i.v., a repeated dose after hours 16–40 every 6 hours days. Severe acute asthma attack: (children a repeated dose after 12 12 hours or or 16–40 mgmg every 6 hours for for 2–32–3 days. Severe acute asthma attack: Adults: 8–20 soon possible, if necessary repeated dose based individual response clinical need. Children: Adults: 8–20 mgmg i.v.i.v. as as soon as as possible, if necessary repeated dose based on on thethe individual response andand clinical need. Children: 0.15–0.3 mg/kg body weight. Doses should repeated if necessary, based individual response clinical need. Acute 0.15–0.3 mg/kg body weight. Doses should be be repeated if necessary, based on on thethe individual response andand clinical need. Acute skindiseases: diseases: Depending nature extent of the disease, daily doses of 8–40 in single cases up100 to 100 skin Depending onon thethe nature andand extent of the disease, daily doses of 8–40 mgmg i.v., i.v., in single cases up to mg.mg. Followedbybytreatment treatment with tablets decreasing doses. Systemic lupus erythematosus: 6–16 Severely progressive Followed with tablets at at decreasing doses. Systemic lupus erythematosus: 6–16 mg.mg. Severely progressive formform rheumatoid arthritis, forms that quickly lead to joint destruction: 12–16 when tissue outside joints is affected: ofof rheumatoid arthritis, e.g.e.g. forms that quickly lead to joint destruction: 12–16 mg,mg, when tissue outside the the joints is affected: 6–12mg. mg.Supportive Supportivetreatment treatment malignant tumours: Initially 8–16 mg/day, during longer lasting treatment 6–12 in in malignant tumours: Initially 8–16 mg/day, during longer lasting treatment 4–124–12 mg.mg. Prophylaxis and treatment cytostatic-induced vomiting in anti-emetic regimens: 8–20 i.v. before starting chemotherapy, Prophylaxis and treatment of of cytostatic-induced vomiting in anti-emetic regimens: 8–20 mgmg i.v. before starting chemotherapy, then 4–8 one twotimes times daily days as necessary (moderately emetogenic chemotherapy) or to up3–4 to 3–4 (highly then 4–8 mgmg one to to two daily forfor 2–32–3 days as necessary (moderately emetogenic chemotherapy) or up daysdays (highly emetogenic chemotherapy). Prophylaxis treatment of post-operative vomiting: A single of 4–8 i.v. before emetogenic chemotherapy). Prophylaxis andand treatment of post-operative vomiting: A single dosedose of 4–8 mg mg i.v. before the the startstart surgery; children over 2 years age: 0.15 mg/kg body weight (max. 8 mg). Local Local infiltration injection ofof surgery; in in children over 2 years of of age: 0.15 mg/kg body weight (max. up up to 8tomg). Local use:use: Local infiltration andand injection therapy is usually carried with 2 mg of dexamethasone sodium phosphate is sufficient if injected small joints therapy is usually carried outout with 4–84–8 mg;mg; 2 mg of dexamethasone sodium phosphate is sufficient if injected intointo small joints or or administered subconjunctival injection. Contraindications: Allergic to dexamethasone to any of the excipients, administered byby subconjunctival injection. Contraindications: Allergic to dexamethasone andand to any of the excipients, havehave an an infection(bacterial, (bacterial, viral, fungal), joint calcification tendon rupture. Special information about some of the ingredients: infection viral, fungal), joint calcification andand tendon rupture. Special information about some of the ingredients: Containssodium sodium(6 (6mgmgforfor8mg/2ml). 8mg/2ml). Special precautions warnings: If treated gastrointestinal ulcers; Contains Special precautions andand warnings: If treated for: for: gastrointestinal ulcers; bonebone loss loss (osteoporosis); heart failure; mental (psychological) disorders including suicidal tendencies; (osteoporosis);high highblood bloodpressure; pressure;diabetes; diabetes; heart failure; mental (psychological) disorders including suicidal tendencies; increased intraocular pressure (narrowandand wide-angle glaucoma; injuries andand ulcers of the cornea of the eye.eye. Interactions withwith increased intraocular pressure (narrowwide-angle glaucoma; injuries ulcers of the cornea of the Interactions other medicinal products and other form of of medicines: If taking: barbiturates; seizures medicines (phenytoin, carbamazepine, other medicinal products and other form medicines: If taking: barbiturates; seizures medicines (phenytoin, carbamazepine, primidone) and certain tuberculosis medicines (rifampicin); antifungal medicines (ketoconazole, itraconazole); certain female sex sex primidone) and certain tuberculosis medicines (rifampicin); antifungal medicines (ketoconazole, itraconazole); certain female hormones (e.g. contraceptive pill); Ephedrine (e.g. medicines for hypotension, chronic bronchitis, asthma attacks); medicines for for hormones (e.g. contraceptive pill); Ephedrine (e.g. medicines for hypotension, chronic bronchitis, asthma attacks); medicines rhinitis swelling and appetite suppressants cancan contain ephedrine); Antidiabetics medicines; Antimalarial drugs (e.g.(e.g. chloroquine), rhinitis swelling and appetite suppressants contain ephedrine); Antidiabetics medicines; Antimalarial drugs chloroquine), etc.etc.Dexamethasone Krka may have an an effect on on these drugs. andand adolescents: NotNot recommended routine use use in in Dexamethasone Krka may have effect these drugs.Children Children adolescents: recommended routine premature infants with lung problems. May slow down thethe growth in children (given onlyonly if necessary). Pregnancy andand breastpremature infants with lung problems. May slow down growth in children (given if necessary). Pregnancy breastfeeding: During pregnancy, especially firstfirst three months, thethe medicine should onlyonly be used afterafter careful benefit-risk assessment. feeding: During pregnancy, especially three months, medicine should be used careful benefit-risk assessment. Long-term treatment during pregnancy, growth disorders in the unborn child cannot be excluded. Towards the the endend of pregnancy, Long-term treatment during pregnancy, growth disorders in the unborn child cannot be excluded. Towards of pregnancy, there of of underactive adrenal cortex in the newborn, which maymay necessitate replacement therapy thatthat has has to be thereis isa risk a risk underactive adrenal cortex in the newborn, which necessitate replacement therapy to slowly be slowly reduced. Dexamethasone excreted in breast milk. Harm to the infant is not yetyet known. Nevertheless, the the need for treatment during reduced. Dexamethasone excreted in breast milk. Harm to the infant is not known. Nevertheless, need for treatment during lactation should bebe closely examined. If the disease requires higher doses, breast-feeding should be discontinued. Possible sideside lactation should closely examined. If the disease requires higher doses, breast-feeding should be discontinued. Possible effects: During short-term treatment: RiskRisk of undesirable effects is low, withwith thethe exception of parenteral high-dose therapy where effects: During short-term treatment: of undesirable effects is low, exception of parenteral high-dose therapy where changes electrolytes, occurrence of of swelling, possible increase in blood pressure, heart arrest, heart rhythm disturbances or or changesin in electrolytes, occurrence swelling, possible increase in blood pressure, heart arrest, heart rhythm disturbances seizures cancan occur. During long-term treatment: Especially of high doses sideside effects of varying degrees cancan be expected regularly seizures occur. During long-term treatment: Especially of high doses effects of varying degrees be expected regularly (frequency cannot be estimated from the available data). Contents in the pack: Ampoule 2 ml contains 8 mg of dexamethasone (frequency cannot be estimated from the available data). Contents in the pack: Ampoule 2 ml contains 8 mg of dexamethasone sodium Legal category: Prescription only medicine. Revised date: MayMay 2020. Marketing authorisation holder: sodiumphosphate. phosphate. Legal category: Prescription only medicine. Revised date: 2020. Marketing authorisation holder: KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia. Market authorisation number: PA1347/091/001. Further KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia. Market authorisation number: PA1347/091/001. Further information is available on request. information is available on request. References: 1. SmPC Dexamethasone Phosphate Krka, 2. First registration 1968. Data on file Krka 09.2020 References: 1. SmPC Dexamethasone Phosphate Krka, 2. First registration 1968. Data on file Krka 09.2020

09/2020, Ireland, 96302-2020, RB/KS.

Dexamethasone Dexamethasone Phosphate Krka Krka

dexamethasone dexamethasone

09/2020, Ireland, 96302-2020, RB/KS.

Solution for for injection/infusion4 mg/ml injection/infusion4 mg/ml Solution


44 News Breakthrough trial for Motor Neuron Disease Professor Orla Hardiman, Principal Investigator, Trinity College Dublin

expansion of the MND-associated gene C90rf72 using a novel gene therapy that is designed to switch off the abnormal part of the gene. Up to 10% of all people diagnosed in Ireland with MND carry the abnormal C9orf72 gene, which can cause both MND and dementia. Researchers at Trinity College Dublin are to participate in an early phase gene-based clinical trial for motor neuron disease (MND). The research team represents one of only four centres in Europe to take part in such an exciting clinical trial for this devastating disease. The first Irish patient entered the study at the Clinical Research Facility at St James’s Hospital Dublin last month (September).

MND is a devastating condition, which causes progressive paralysis, increasing physical disability and ultimately death within an average of two to three years. There are over 350 people in Ireland with MND, and one person is diagnosed every 3 days with the condition. There is currently no effective treatment. The clinical trial, sponsored by the US Pharmaceutical Company Biogen, targets an abnormal

The Phase 1 trial which has been divided into five sections involving 75 patients worldwide, was recently approved by the HPRA (Health Products Regulatory Authority). Only 24 patients in the world will be enrolled in the fifth section, including the first Irish patient to enter the study. Professor Orla Hardiman, Principal Investigator in the Irish part of the study and a leading world authority on MND says, “Up to

10% of people in Ireland with MND carry an abnormal expansion of the C9orf72 gene. Gene therapy is an exciting new approach and considerable progress has already been made in turning off another MND associated gene (SOD1), as the results of early clinical trials have shown. We are very hopeful that the same approach will work for those with the C9orf72 gene.” Earlier this summer, Professor Hardiman provided an invited editorial for the New England Journal of Medicine commenting on these early trials using gene therapy for SOD1. “While we do not have any patients with SOD1 mutations in Ireland, we have many people carrying the abnormal C9orf72 gene, and for these people, the current trial could be a true gamechanger. “And the pharmaceutical industry is also looking at other modifier genes that we could target, which could help many other people with MND who do not carry the C9orf72 mutation. While these are early days, there is now genuine hope that MND will become a treatable disease in the near future.”

Voices of Pharma Event Following on from the Pharmaceutical Managers Institute (PMI) first event in the Voices of Pharma series on September 10th featuring Professor Martin Curley – HSE, Professor Derek O’Keeffe – UHG & NUI Galway and Dr Frank O’Donnell – Microsoft – the series continues on October 15th. The event will take place from 12-2pm. This event will focus on Healthcare Professionals – their experience through Covid-19: How they are continuing to provide care, how the landscape has changed, and how they are now engaging with industry. The Voice of Pharma Series is sponsored by United Drug.

Insulin pump therapy uptake low in Ireland New research has identified that insufficient structure of the health service, lack of awareness and individual preferences are among barriers for adults with type 1 diabetes in getting insulin pump therapy. The study was led by researchers from RCSI University of Medicine and Health Sciences. This research builds on previous studies by RCSI researchers, which showed that people with type 1 diabetes in Ireland use insulin pump therapy at lowered rates compared internationally and there is an unequal availability of insulin pump therapy in Irish adult diabetes clinics. Even though insulin pump therapy is recommended as a first-choice

therapy for pre-schoolers and is beneficial for people with type 1 diabetes of all ages, only 10.5% of people with type 1 diabetes in Ireland is using a pump to administer their insulin.

is lower in Ireland, the researchers conducted 21 interviews and four focus groups among people with type 1 diabetes, healthcare professionals and other key stakeholders.

This compares significantly lower to the average uptake in Nordic, Central and Western countries, which was 15–20% in 2010.

The same topics were discussed in all groups and aligned with four main themes: awareness, structure, capacity and impact of an individual (a person with diabetes or healthcare professional). The main finding was that if the structure of the health service is insufficient, the quality of care is not standardised and capacity is poor, the uptake of insulin pump therapy is more reliant on the individual’s interest, leadership skills, willingness and motivation.

Regional disparities in insulin pump use were found, with uptake as low as 2% among adults in Roscommon compared to 9.6% in Kildare. One-third of Irish adult clinics, usually in rural areas, do not offer any type of insulin pump therapy support, and less than a half provides training to commence the therapy. To identify the reasons why uptake

OCTOBER 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

“These factors may make the regional differences in accessing diabetes related technology and the quality of care more evident,” said Dr Katarzyna Gajewska, the study’s lead author and HRB PhD scholar in population health and health service research at RCSI. “The results of this study may inform healthcare professionals and policy makers regarding gaps in the delivery of diabetes care. Solutions are needed to reduce the disparities in health service provision in the countries where reimbursement of diabetes technology is offered. Such steps may include the development of national guidelines, models of care, and structured approaches to provide equal access to insulin pump therapy across the country.”


Clinical R&D 45 MERCK ANNOUNCES ¤59 MILLION ANTIBODY-DRUG CONJUGATE MANUFACTURING EXPANSION Merck, a leading science and technology company, has announced a ¤59 million expansion of its HPAPI and ADC manufacturing capabilities and capacity at its facility near Madison, Wisconsin, USA. This investment will allow large-scale manufacturing of increasingly potent compounds for therapies that have the potential to treat cancer. Completion is expected by mid-2022 and should add approximately 50 full-time jobs starting in 2021. "ADCs have posted incredible growth over the last decade, and regulatory agencies' approvals in recent years demonstrate their promise as a targeted therapy," said Andrew Bulpin, head of Process Solutions, Life Science, at Merck. "With more than 35 years of experience in this space, we have been a frontrunner in the development and manufacturing of biologics, conjugation processes and small molecules. This investment underscores our commitment to working with innovators to bring new treatments to patients quickly and more efficiently." Merck's new 6,500-square meter commercial building will be one of the largest dedicated HPAPI manufacturing facilities specifically designed to handle single-digit nanogram occupational exposure limit materials. The project is in addition to the company's Madison campus, which was the first commercial ADC facility in North America designed to handle highly active materials. The new building will join Merck's established campus in St. Louis, Missouri, USA, which specializes in ADC bioconjugation, active pharmaceutical ingredients, excipient and adjuvants manufacturing. While ADCs can provide many benefits compared with other therapeutic options, they also present a unique set of challenges. Their development is complex, necessitating stringent containment infrastructure, and their structural exceptionality requires expertise in a number of different technologies for small and large molecules, as well as analytical capabilities. Due to these challenges, more than 70 percent of ADC projects are outsourced to contract development and manufacturing organizations. With more than 35 years of experience in the development and manufacturing of small molecules, biologics and ADC technologies, Merck offers extensive experience in both clinical and commercial manufacturing. The company's

comprehensive service portfolio combines the steps of drug development and production — from pre-clinical to commercial — from a single source. This consolidation helps reduce risk and streamlines the process of getting therapies to patients faster.

turnaround time and allowing earlier patient management decisions, following diagnosis."

LARGE PROSPECTIVE LUNG CANCER STUDY TO BE PRESENTED AT ESMO CONGRESS

Prothena Corporation plc (NASDAQ:PRTA), announced that results from the Phase 2 PASADENA study of prasinezumab have been highlighted at the International Parkinson and Movement Disorder Society's MDS Virtual Congress 2020 (MDS Congress). Prasinezumab is the first potentially disease-modifying, anti-alpha-synuclein antibody to demonstrate signals of efficacy on multiple pre-specified secondary and exploratory clinical endpoints in patients with early Parkinson's disease. As previously reported, the study did not meet the primary objective, but signals of efficacy showing a reduction in disease progression were observed in both of the prasinezumab arms when compared to placebo. In the study, prasinezumab significantly reduced decline in motor function by 35% (pooled dose levels) vs. placebo after one year of treatment on the centrally rated assessment of Movement Disorder SocietyUnified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III, a clinical examination of motor function. Motor symptoms associated with Parkinson's disease include slowness of movement (bradykinesia), tremor, rigidity, and gait. Prasinezumabtreated patients also demonstrated a significant delay in time to clinically meaningful worsening of motor progression on the site rated assessment of time to at least a 5-point progression on MDSUPDRS Part III vs. placebo over one year, with a hazard ratio of 0.82 (pooled dose levels). There are currently no treatments available that target the underlying cause of Parkinson's disease and can slow its progression.

Biocartis Group NV (the 'Company' or 'Biocartis'), an innovative molecular diagnostics company (Euronext Brussels: BCART), has announced that a large prospective lung cancer study, co-supported by AstraZeneca, a global scienceled biopharmaceutical company (LON: AZN), has been selected to be presented at the renowned European Society for Medical Oncology ('ESMO') Virtual Congress taking place between 19-21 September 2020. Rapid and accurate EGFR mutation testing is essential to make informed treatment decisions for patients with advanced non-small cell lung cancer (NSCLC), and the study concluded that Idylla™ reduced turnaround time by more than a week versus reference methods, allowing earlier patient management decisions. The FACILITATE study is a large, prospective, real-world data set study across 16 European sites3 that was launched as part of the agreement between Biocartis and AstraZeneca4, aimed at obtaining faster lung cancer molecular diagnostic biomarker results in Europe. Between January 2019 and July 2020 a large set of 1,370 advanced non-small cell lung cancer (NSCLC) patient samples were tested using the Idylla™ EGFR Mutation Test5 (CE-IVD) and local reference methods6 including targeted next-generation sequencing (NGS). Results showed a 97.6%7 overall percentage agreement between Idylla™ and reference methods. Ninety percent of all samples were tested in less than 7 days using the Idylla™ technology, versus less than 21 days using the reference methods. This demonstrates that Idylla™ improves turnaround time, allowing for fast-track testing when required, complementary to slower existing laboratory processes and systems. Herman Verrelst, Chief Executive Officer of Biocartis, commented, "A large study with a broad data set such as this one with our partner AstraZeneca, who is at the forefront of lung cancer treatment, shows once again how Idylla™ can make a significant improvement for patients. With Idylla™, a fully automated rapid EGFR mutation diagnostic workflow8 becomes possible, decreasing testing

PRASINEZUMAB SLOWS PROGRESSION ON MEASURES OF PARKINSON'S DISEASE IN PHASE 2 STUDY

The clinical results have been posted online on the MDS Virtual Congress website as an ePoster in the Virtual Poster Hall and were also presented by Roche on Tuesday, September 15, as a Top Abstract oral presentation. Prothena conducted an investor webcast on Tuesday, September 15 at 1:30PM ET. Prasinezumab is being developed through a worldwide collaboration between Prothena and Roche. "Our expectation that both dose levels tested would saturate aggregated alpha-synuclein in the brain was confirmed by the similar outcomes across multiple endpoints in both prasinezumab arms of the study after a single year of treatment, including a significant 35% reduction in motor

function decline in patients with early Parkinson's disease versus placebo, a significant delay in time to clinically meaningful worsening of motor progression, and other clinical endpoints such as bradykinesia, that assess activities impacted in patients with Parkinson's disease," stated Gene Kinney, PhD, president and chief executive officer of Prothena. "We are further encouraged to see consistent signals favoring prasinezumab across other secondary and exploratory endpoints. In totality, these clinical results support further clinical development of prasinezumab to assess its potential as a first-inclass disease-modifying therapy to slow progression of Parkinson's disease, and add to the growing body of clinical evidence that selective and specific targeting of pathogenic proteins implicated in a wide variety of central and peripheral disorders has the potential to fundamentally change the course of these devastating diseases." DATA FROM PRECLINICAL STUDIES OF MRNA-BASED VACCINE CANDIDATE AGAINST COVID-19 Pfizer Inc. (NYSE: PFE) and BioNTech SE (Nasdaq: BNTX, "BioNTech") has announced preliminary preclinical data in mouse and non-human primate models from their BNT162b2 mRNA-based vaccine program against SARS-CoV-2, the virus that causes COVID-19 disease. In a non-human primate preclinical study, immunization with BNT162b2, a nucleosidemodified messenger RNA (modRNA) candidate, protected rhesus macaques against SARSCoV-2 infection. The manuscript describing these preclinical data is available on the preprint server bioRxiv and is concurrently undergoing scientific peer-review for potential publication. In the preclinical study, BNT162b2 demonstrated protective anti-viral effects in rhesus macaques, with concomitant high neutralizing antibody titers and a TH1-biased cellular response in rhesus macaques and mice. In a viral infection model, macaques that received two injections with 100 µg BNT162b2 and macaques that received saline control injections were challenged 55 days after the second immunization with a very high viral inoculum of approximately 1 million plaqueforming units of SARS-CoV-2, via both intranasal (nose) and intratracheal (lung) routes. Immunization with BNT162b2 reduced viral infection with no viral RNA detected in the lower respiratory tract of the immunized animals, while in most non-

HOSPITALPROFESSIONALNEWS.IE | HPN • OCTOBER 2020


46 Clinical R&D immunized (saline) animals, there was evidence of viral RNA. Importantly, BNT162b2 induced potent SARS-CoV-2 neutralizing antibodies in vaccinatedmacaques, and viral antigenspecific CD4+ and CD8+ T cells. Rhesus macaques (2- to 4-yearold males) were immunized by intramuscular (IM) immunization with 30 µg or 100 µg of BNT162b2 or saline control on Days 0 and 21 (2 doses). After two immunizations, neutralization titers were detectable in rhesus sera with geometric mean titers of 962 (on Day 35 for the 30 µg group) or 1,689 (on Day 28 for the 100 µg group). Neutralizing antibody titers persisted to at least day 56, with higher geometric mean titers (GMTs) than those in a panel of human convalescent sera. BNT162b2 vaccination elicited a high frequency of CD4+ T cells that produced IFN-ɣ, IL-2, and TNF-α, and almost no IL-4 producing CD4+ cells were detectable, indicating a TH1-biased response, which is an immune profile thought to promote vaccine safety. BNT162b2 also elicited spikespecific IFN-ɣ-producing CD8+ T cell responses, which is thought to promote an anti-viral effect. In a preclinical murine model, a single IM immunization of BNT162b2 (0.2, 1, or 5 µg) generated B- cell and T- cell immune responses in BALB/c mice, and SARS-CoV-2 pseudovirus neutralizing activity increased steadily to Day 28, the last day for which titers are reported. CD4+ and CD8+ T- cells from splenocytes isolated from BNT162b2-immunized mice were strongly positive for IFN-ɣ and IL-2, producing high levels of the TH1 cytokines but minute amounts of TH2 cytokines, suggesting a robust, TH1-biased T cell adaptive immune response. Many of these preclinical data and the Phase 1 clinical results contributed to the decision by Pfizer and BioNTech to commence the global (except for China) Phase 2/3 safety and efficacy portion of clinical study C4591001 to evaluate potential prevention of COVID-19 disease by BNT162b2. The Phase 2/3 study has enrolled over 25,000 participants 18 to 85 years of age in the U.S., Argentina, and Brazil. Additional enrollment is planned in Germany, Turkey and South Africa. The study is an event-driven trial. Pfizer and BioNTech are committed to decreasing health disparities in underrepresented populations through the clinical trial process. To that end, many investigator sites are in diverse communities that have been disproportionately affected by COVID-19 so that individuals who have been most impacted have the opportunity to participate. The companies

are also working together with investigator sites and advocacy partners to raise awareness about the importance of participation in this trial. BNT162b2 remains under clinical study and is not currently approved for distribution anywhere in the world. Assuming clinical success, Pfizer and BioNTech are on track to seek regulatory review for BNT162b2 as early as October 2020 and, if regulatory authorization or approval is obtained, currently plan to supply up to 100 million doses worldwide by the end of 2020 and approximately 1.3 billion doses by the end of 2021. FDA GRANTS DUPIXENT® (DUPILUMAB) BREAKTHROUGH THERAPY DESIGNATION FOR EOSINOPHILIC ESOPHAGITIS The U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to Dupixent® (dupilumab) for the treatment of patients 12 years and older with eosinophilic esophagitis (EoE). The designation for this investigational use is based on positive results from Part A of a Phase 3 trial in patients with EoE. There are currently no FDAapproved medicines for EoE, a chronic and progressive type 2 inflammatory disease that damages the esophagus and prevents it from working properly. Over time, excessive type 2 inflammation causes scarring and narrowing of the esophagus, making it difficult to swallow. If left untreated, EoE can affect a patient's ability to eat and cause food to become stuck after being swallowed (food impaction), which can lead to a medical emergency. In the U.S. alone, there are approximately 160,000 patients with EoE who are currently being treated with various unapproved therapies or diet modification. Of these patients, approximately 50,000 have failed multiple treatments.

profile of Dupixent in its approved indications. The EoE trial is ongoing, with additional patients enrolling in Part B as well as patients continuing in a 28-week extended active treatment period (Part C) after completing either Part A or Part B. Breakthrough Therapy designation is designed to expedite the development and review of drugs in the U.S. that target serious or life-threatening conditions. Drugs qualifying for this designation must show preliminary clinical evidence that the drug may demonstrate a substantial improvement on clinically significant endpoints over available therapies, or over placebo if there are no available therapies. In 2017, Dupixent also was granted Orphan Drug designation for the potential treatment of EoE. This is given to investigational medicines intended for the treatment of rare diseases that affect fewer than 200,000 people in the U.S. The potential use of Dupixent in eosinophilic esophagitis is currently under clinical development, and its safety and efficacy for this indication have not been evaluated by any regulatory authority. INTRODUCING ALTAVITA D3 50,000 IU SOFT CAPSULES Consilient Health Ltd. is pleased to announce the launch of Altavita D3 50,000 iu (Colecalciferol) capsules for the treatment of vitamin D deficiency. The recommended dose is one Altavita D3 50,000 iu weekly for 6 to 8 weeks for your patients with vitamin D deficiency (plasma 25(OH)D < 25 nmol/l). Consilient Health continue to supply all presentations of Altavita D3 designed for your patient’s routine. These presentations include the 1,000 iu (daily prevention), 7,000 iu (weekly prevention) and 25,000 iu (monthly prevention). The Altavita range is reimbursed under the General Medical and Drug Community Scheme.

Sanofi and Regeneron previously reported positive results from Part A of the pivotal Phase 3 trial evaluating Dupixent in patients 12 years and older with EoE. Part A of the randomized, doubleblind, placebo-controlled trial of 81 patients met both of its co-primary endpoints, as well as all key secondary endpoints. Patients treated weekly with Dupixent 300 mg over a 24-week treatment period experienced a reduction in symptoms, esophageal inflammation and abnormal endoscopic findings in the esophagus.

Following on from the successful launch of its patient-activated, pre-filled injector (PFI) to deliver pegfilgrastim (Pelgraz® ), Accord Healthcare are delivering another first, with the launch of their Pelgraz® support app in Ireland.

Part A of the trial also demonstrated safety results consistent with the known safety

The app is designed specifically for patients who have been prescribed Pelgraz® PFI. “We appreciate that

OCTOBER 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

For further information please visit altavita.ie or medicines.ie. Alternatively contact your local sales representative. ACCORD HEALTHCARE LAUNCH INNOVATIVE PATIENT FOCUSED APP

patients undergoing treatment for cancer can feel like they have very little control over their illness and we believe it is important to give patients back some sense of control. We have therefore developed our app to help give patients the confidence to self-administer their treatment from the convenience of their own home, while offering them the peace of mind that they are complying with their prescribed treatment regimen”, says Mr Tony Hynds, Managing Director, Accord Healthcare Ireland Ltd. The app supports patients to administer their medication at the correct time and in the correct way. It also provides relevant educational content and the ability to track side-effects along with highlighting how to report any sideeffects. The app allows a patient to set a reminder to administer their treatment, based on when their last chemotherapy session took place and when the clinician indicated to use the product. Once the reminder is opened, the app automatically presents the administration instructions, which includes an animated video and step-by-step instructions. The symptom tracker allows patients to log their side-effects and symptoms post-chemotherapy and track them over a given period, providing the patient with the tools and information to have an in-depth conversation at their subsequent meeting with their healthcare professional should they wish. The ethos behind Accord’s Pelgraz® PFI launch is to give patients the confidence to administer pegfilgrastim from the comfort of their own home. With pegfilgrastim administered at least 24 hours after cytotoxic chemotherapy, patients will often have to return to hospital or await a visit from a home care nurse to administer pegfilgrastim. “Evidence shows that travelling to and attending hospital visits are one of the major contributing factors that negatively impact the quality of life for people living with cancer. Reducing the number of times that a patient must visit the clinic or hospital, at a time when they are living with the side-effects of chemotherapy and when their immune systems are compromised, must be a priority for patients and their healthcare team. Being able to offer the option of spending more time at home during chemotherapy treatment is something I know patients genuinely welcome,” said Professor Hartmut Link, Professor of Medicine, external faculty at University Medical Centre, Hannover, Germany.


Skin clearance should stand the test of time For superior skin clearance vs secukinumab and adalimumab TREMFYA® achieved PASI 90 in: • 84.5% of patients at week 48, compared with 70% on secukinumab (P<0.001)1 • 73.3% of patients at week 16, compared with 49.7% on adalimumab (P<0.001) sustained out to week 482

For long-lasting skin clearance that stands the test of time TREMFYA® maintained PASI 90 out to 4 years in 82.2% of patients3

For skin clearance with a generally well-tolerated safety profile* TREMFYA® has no specific class effect warnings for candidiasis, Crohn’s disease, demyelinating diseases or congestive heart failure†4

Stand for lasting skin clearance with TREMFYA®3 PASI = Psoriasis Area and Severity Index * The most common adverse drug reaction was upper respiratory infection † Special warning and precautions for TREMFYA®: infections, tuberculosis, serious hypersensitivity reaction and immunisations (please refer to Summary of Product Characteristics for further details).

Tremfya▼ 100 mg solution for injection in pre-filled pen PRESCRIBING INFORMATION. ACTIVE INGREDIENT(S): Guselkumab. Please refer to Summary of Product Characteristics (SmPC) before prescribing. INDICATION(S): Treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy. DOSAGE & ADMINISTRATION: For use under guidance/supervision of physician experienced in diagnosis and treatment of plaque psoriasis. Subcutaneous injection. Avoid areas showing psoriasis. Adults: 100 mg at weeks 0 and 4, followed by maintenance dose every 8 weeks. Consider discontinuation if no response after 16 weeks of treatment. Children: No data available in children/adolescents <18 years. Elderly: No dose adjustment required, limited information in subjects aged ≥ 65 years. Renal & Hepatic impairment: Not studied. CONTRAINDICATIONS: Serious hypersensitivity to active substance or excipients; clinically important, active infection. SPECIAL WARNINGS & PRECAUTIONS: Infections: Potential to increase risk. If signs/symptoms of clinically important chronic/acute infection occur, monitor closely and discontinue Tremfya until resolved. Tuberculosis: Evaluate patients for TB pre-treatment; monitor for signs/symptoms of active TB during and after treatment. Consider anti-TB therapy prior to Tremfya if past history of latent/active TB and adequate treatment course not confirmed. Serious hypersensitivity reaction: Includes anaphylaxis. Some serious hypersensitivity reactions occurred several days after treatment and included urticaria and dyspnoea. If occurs, discontinue Tremfya immediately and initiate appropriate therapy. Immunisations: Consider completing all appropriate immunisations prior to Tremfya. Do not use live vaccines concurrently with Tremfya; no data available; before live vaccination, withhold Tremfya for at least 12 weeks and resume at least 2 weeks after vaccination. SIDE EFFECTS: Very common: Upper respiratory infection. Common: Gastroenteritis, herpes simplex infections, tinea infections, headache, diarrhoea, urticaria, arthralgia, injection site reactions. Other side effects: hypersensitivity, anaphylaxis, rash. Refer to SmPC for other side effects. LEGAL CATEGORY: Prescription Only Medicine (POM). PRESENTATIONS, PACK SIZES, MARKETING AUTHORISATION NUMBER(S): Pre-filled pen, x1, EU/1/17/1234/002. MARKETING AUTHORISATION HOLDER: Janssen-Cilag International NV, Turnhoutseweg 30, B-2340 Beerse, Belgium. FURTHER INFORMATION IS AVAILABLE FROM: Janssen Sciences Ireland UC, Barnahely, Ringaskiddy, IRL - Co. Cork, P43 FA46. Prescribing information last revised: May 2020 (CHMP opinion).

Adverse events should be reported. ▼ This medicinal product is subject to additional monitoring and it is therefore important to report any suspected adverse events related to this medicinal product. Healthcare professionals are asked to report any suspected adverse events via: HPRA Pharmacovigilance Website: www.hpra.ie Adverse events should also be reported to Janssen Sciences Ireland UC on 1800 709 122 or at dsafety@its.jnj.com. © Janssen-Cilag Limited 2020 References: 1. Reich K et al. Guselkumab versus secukinumab for the treatment of moderate-to-severe psoriasis (ECLIPSE). The Lancet Available Online August 08, 2019. 2. Blauvelt A et al. J Am Acad Dermatol 2017; 76(3); 405–417. 3. Griffiths C.E.M. et al. Fall Clinical Dermatology Conference; October 17-20, 2019; Las Vegas, NV. 4. TREMFYA® Summary of Product Characteristics. Available at www.medicines.ie. CP-164192 | Date of Preparation: July 2020 Janssen Sciences Ireland UC 2020


For COPD patients on treatment with ICS/LABA and at risk of exacerbation*1 *A worsening of symptoms or a history of exacerbation treated with antibiotics or oral corticosteroids in the past 12 months

It’s the things you do today that make a big difference 1-3 to their tomorrows TRELEGY Ellipta provides your patients with statistically superior improvements in lung function and health-related quality of life, and reduction in annualised rate of moderate/ severe exacerbations** vs. budesonide/formoterol***1–3 Fictional patient, for illustrative purposes only

Start your patients on TRELEGY Ellipta today, expect more from tomorrow 1,2

**Moderate exacerbation is a worsening of symptoms or a history of exacerbation treated with antibiotics or oral corticosteroids. A severe exacerbation is a worsening in symptoms that required hospitalisation.

TRELEGY Ellipta (FF/UMEC/VI) 92/55/22 mcg OD is indicated for maintenance treatment in adult patients with moderate to severe COPD who are not adequately treated by a combination of an ICS and a LABA or a combination of a LAMA and a LABA1

Today. Tomorrow. TRELEGY. 2-3

▼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. ***Co-primary endpoints were change from baseline in trough FEV1 and SGRQ at week 24 (n=1810). A subset of patients (n=430) remained on blinded study treatment for 52 weeks. Trelegy showed an improvement in trough FEV1 of 171mL versus budesonide/formoterol (p < 0.001, 95% CI 148,194) at week 24. Trelegy showed an improvement in health-related quality of life (SGRQ) of 2.2 units (p <0.001, 95% CI 3.5, 1.0) at week 24. At week 52 in a subset of patients Trelegy showed a 44% reduction in annualised rate of moderate/severe exacerbations versus budesonide/formoterol (95% CI 15,63, p=0.006, Absolute difference 0.16). TRELEGY Ellipta is generally well tolerated. Common adverse reactions include: pneumonia, upper respiratory tract infection, bronchitis, pharyngitis, rhinitis, sinusitis, influenza, nasopharyngitis, candidiasis of mouth and throat, urinary tract infection, headache, cough, oropharyngeal pain, constipation, arthralgia, back pain1 FF, fluticasone furoate; ICS, inhaled corticosteroid; LABA, long-acting ß2-agonist; LAMA, long-acting muscarinic antagonist; OD, once-daily; UMEC, umeclidinium, VI, vilanterol References: 1. TRELEGY Ellipta SmPC 2019. 2. Lipson DA et al. Am J Respir Crit Care Med 2017; 196:438–446. 3. Lipson DA et al.N Engl J Med 2018; 378:1671–1680. Trelegy▼ Ellipta (fluticasone furoate/umeclidinium/vilanterol [as trifenatate]) Prescribing information. Please consult the full Summary of Product Characteristics (SmPC) before prescribing. Trelegy Ellipta (fluticasone furoate/umeclidinium/vilanterol [as trifenatate]) inhalation powder. Each single inhalation of fluticasone furoate (FF) 100 micrograms (mcg), umeclidinium bromide (UMEC) 62.5 micrograms and vilanterol as trifenatate (VI) 25 mcg provides a delivered dose of 92 mcg FF, 55 mcg UMEC and 22 mcg VI. Indications: Maintenance treatment in adult patients with moderate to severe COPD who are not adequately treated by a combination of an inhaled corticosteroid (ICS) and a long-acting ß2-agonist (LABA) or a combination of a LABA and a long acting muscarinic antagonist. Dosage and administration: One inhalation once daily at the same time each day. Contraindications: Hypersensitivity to the active substances or to any of the excipients (lactose monohydrate & magnesium stearate). Precautions: Paradoxical bronchospasm, unstable or life-threatening cardiovascular disease or heart rhythm abnormalities, convulsive disorders or thyrotoxicosis, pulmonary tuberculosis or patients with chronic or untreated infections, narrow-angle glaucoma, urinary retention, hypokalaemia, patients predisposed to low levels of serum potassium, diabetes mellitus. In patients with moderate to severe hepatic impairment patients should be monitored for systemic corticosteroid-related adverse reactions. Eye symptoms such as blurred vision may be due to underlying serious conditions such as cataract, glaucoma or central serous chorioretinopathy (CSCR); consider referral to ophthalmologist. Increased incidence of pneumonia has been observed in patients with COPD receiving inhaled corticosteroids. Risk factors for pneumonia include: current smokers, old age, patients with a history of prior pneumonia, patients with a low body mass index and severe COPD. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Trelegy. Acute symptoms: Not for acute symptoms, use short-acting inhaled bronchodilator. Warn patients to seek medical advice if short-acting inhaled bronchodilator use increases. Therapy should not be abruptly stopped without physician supervision due to risk of symptom recurrence. Systemic effects: Systemic effects of ICSs may occur, particularly at high doses for long periods, but much less likely than with oral corticosteroids. Interactions with other medicinal products: Caution should be exercised with concurrent use of ß-blockers. Caution is advised when co-administering with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir, cobicistat-containing products), hypokalaemic treatments or non-potassium-sparing diuretics. Co-administration with other long-acting muscarinic antagonists or long acting ß2-adrenergic agonists is not recommended. Pregnancy and breast-feeding: Experience limited. Balance risks against benefits. Side effects: Common (≥1/100 to <1/10): pneumonia, upper respiratory tract infection, bronchitis, pharyngitis, rhinitis, sinusitis, influenza, nasopharyngitis, candidiasis of mouth and throat, urinary tract infection, headache, cough, oropharyngeal pain, arthralgia, back pain. Uncommon (≥1/1,000 to

Find out more here:

www.trelegy.ie or request a visit from a GSK representative

<1/100): viral respiratory tract infection, supraventricular tachyarrhythmia, tachycardia, atrial fibrillation, dysphonia, dry mouth, fractures; Not known (cannot be estimated from the available data): vision blurred. Marketing Authorisation (MA) Holder: GlaxoSmithKline Trading Services Limited, Curabinny, Co. Cork, Ireland. MA No. [EU/1/17/1236/002]. Legal category: POM B. Last date of revision: June 2019. Code: PI-2093. Further information available on request from GlaxoSmithKline, 12 Riverwalk, Citywest Business Campus, Dublin 24. Tel: 01-4955000.

A full list of adverse reactions for TRELEGY Ellipta can be found in the Summary of Product Characteristics. Adverse events should be reported to the Health Products Regulatory Authority (HPRA) using an Adverse Reaction Report Form obtained either from the HPRA or electronically via the website at www.hpra.ie. Adverse reactions can also be reported to the HPRA by calling: (01) 6764971. Adverse events should also be reported to GlaxoSmithKline on 1800 244 255. TRELEGY Ellipta was developed in collaboration with ©2020 GSK Group of Companies or its licensor Trademarks are owned by or licensed to the GSK Group of Companies PM-IE-FVU-ADVT-200002 | February 2020

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