HOSPITAL PROFESSIONAL NEWS IRELAND
HPN August 2021 Issue 87 HOSPITALPROFESSIONALNEWS.IE
Ireland’s Dedicated Hospital Professional Publication
IN THIS ISSUE: NEWS: Cardiac Rehab in Crisis Page 4 2021 NOMINATIONS NOW OPEN
PHARMACY REVIEW: Gene Based Therapeutics Page 12
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PHARMACY REVIEW: Antiretroviral Therapy Page 17 PHARMACY REVIEW: Depression Page 22
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HOSPITAL REVIEW: Asthma Diagnosis Approaches Page 30 HOSPITAL REVIEW: Sexual Health during a Pandemic Page 63
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HOSPITAL REVIEW: Disorders of Sex Development Page 88
Sustained clearance when and where it matters…1-11
Kyntheum® (brodalumab) is indicated for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy1
Prescribing Information for Kyntheum® (brodalumab) 210 mg solution for injection in pre-filled syringe Please refer to the full Summary of Product Characteristics (SmPC) (www.medicines.ie) before prescribing. 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. Indication: Treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy. Active ingredient: Each pre-filled syringe contains 210 mg brodalumab in 1.5 ml solution. 1 ml solution contains 140 mg brodalumab. Dosage and administration: Posology: Adults: The recommended dose is 210 mg administered by subcutaneous injection at weeks 0, 1, and 2 followed by 210 mg every 2 weeks. Consideration should be given to discontinuing treatment in patients who have shown no response after 12-16 weeks of treatment. Some patients with initial partial response may subsequently improve with continued treatment beyond 16 weeks. Administer by subcutaneous (SC) injection. Each pre-filled syringe is for single use only. Elderly: No dose adjustment recommended. Hepatic and renal impairment: No dose recommendations can be made. Children and adolescents below the age of 18 years: Safety and efficacy of Kyntheum have not been established. Method of administration: Kyntheum should not be injected into areas where the skin is tender, bruised, red, hard, thick, scaly, or affected by psoriasis. The pre-filled syringe must not be shaken. After proper training in SC injection technique, patients may self-inject Kyntheum when deemed appropriate by a physician. Patients should be instructed to inject the full amount of Kyntheum according to the instructions provided in the package leaflet. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Active Crohn’s disease. Clinically important active infections (e.g. active tuberculosis). Precautions and warnings: Inflammatory bowel disease (including Crohn’s disease and ulcerative colitis): Cases of new or exacerbations of inflammatory bowel disease have been reported with IL-17 inhibitors. Therefore Kyntheum is not recommended in patients with inflammatory bowel disease. If a patient develops signs and symptoms of inflammatory bowel disease, or experiences an exacerbation of pre-existing inflammatory bowel
disease, Kyntheum should be discontinued and appropriate medical management should be initiated. Suicidal ideation and behaviour: A causal association between treatment with Kyntheum and increased risk of suicidal ideation and behaviour has not been established. Carefully weigh the risk and benefit of treatment with Kyntheum for patients with a history of depression and/or suicidal ideation or behaviour, or patients who develop such symptoms. Patients, caregivers and families should be advised of the need to be alert for the emergence or worsening of depression, suicidal ideation, anxiety, or other mood changes, and they should contact their healthcare provider if such events occur. If a patient suffers from new or worsening symptoms of depression and/or suicidal ideation or behaviour is identified, it is recommended to discontinue treatment with Kyntheum. Hypersensitivity reactions: In the event of an anaphylactic reaction, or any other serious allergic reaction, administration of Kyntheum should be discontinued and appropriate therapy initiated. Infections: Kyntheum may increase the risk of infections. Caution should be exercised when considering the use of Kyntheum in patients with a chronic infection or a history of recurrent infection. Patients should be instructed to seek medical advice if signs or symptoms suggestive of an infection occur. If a patient develops a serious infection, they should be closely monitored and Kyntheum should not be administered until the infection resolves. Kyntheum should not be given to patients with active tuberculosis. Anti-tuberculosis therapy should be considered prior to initiation of Kyntheum in patients with latent tuberculosis. Reduced absolute neutrophil count: A decrease in absolute neutrophil count, generally transient and reversible, has been observed in 5.6% of patients receiving Kyntheum. Vaccinations: It is recommended that patients be brought up-to-date with all immunisations in accordance with local immunisation guidelines prior to initiation of treatment with Kyntheum. Live vaccines should not be given concurrently with Kyntheum. The safety and efficacy of Kyntheum in combination with immunosuppressants, including biologics, or phototherapy have not been evaluated. Drug interactions: Live vaccines should not be given concurrently with Kyntheum. Fertility, pregnancy and lactation: Women of childbearing potential: Use an effective method of contraception during treatment and for at least 12 weeks after treatment. Pregnancy:
A welcome break for patients with moderate to severe plaque psoriasis. With Kyntheum®, 25% of patients (n=1,236) reached PASI 75 at 2.1 weeks (vs. 4.8 weeks for ustekinumab (n=613; p<0.001).2 Clearance rates were also sustained through to 2 years, in an observed data analysis of PASI 75, 90 and 100 (n=90 at 120 weeks, no p values calculated).3
There are no or limited amount of data from the use of brodalumab in pregnant women. As a precautionary measure, it is preferable to avoid the use of Kyntheum in pregnancy. Benefit risk for exposure of the infant to live vaccines following third trimester exposure to Kyntheum should be discussed with a physician. Breast-feeding: It is unknown whether brodalumab is excreted in human milk. A risk to the newborns/infants cannot be excluded. Whether to discontinue breastfeeding or discontinue Kyntheum therapy should be decided, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility: No data are available on the effect of brodalumab on human fertility. Side effects: Common (≥1/100 to <1/10): Influenza, tinea infections (including tinea pedis, tinea versicolor, tinea cruris), neutropenia, headache, oropharyngeal pain, diarrhoea, nausea, arthralgia, myalgia, fatigue, injection site reactions (including injection site erythema, pain, pruritus, bruising, haemorrhage). Uncommon (≥1/1,000 to <1/100): Candida infections (including oral, genital and oesophageal infections), conjunctivitis. Precautions for storage: Store in a refrigerator (2°C-8°C). Do not freeze. Keep the pre-filled syringe in the outer carton in order to protect from light. Kyntheum may be stored at room temperature (up to 25°C) once, in the outer carton, for a maximum single period of 14 days. Once Kyntheum has been removed from the refrigerator and has reached room temperature (up to 25°C) it must either be used within 14 days or discarded. Legal category: POM. Marketing authorisation number and holder: EU/1/16/1155/001, LEO Pharma A/S, Ballerup, Denmark. Last revised: July 2020. Reporting of Suspected Adverse Reactions Adverse events should be reported. Reporting forms and information can be obtained from: HPRA Pharmacovigilance, Earlsfort Terrace, Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517, Website: www.hpra.ie, e-mail: firstname.lastname@example.org. Adverse events should also be reported to Drug Safety at LEO Pharma by calling +353 1 4908924 or e-mail: email@example.com
References: 1. Kyntheum® SPC, UK: www.medicines.org.uk / IE: www.medicines.ie. Last accessed: March 2021. 2. Blauvelt A, et al. J Am Acad Dermatol 2017;77:372–74. 3. Puig L, et al. J Am Acad Dermatol 2020;82(2):352–9. 4. Baker KF and Isaacs JD. Ann Rheum Dis 2018;77:175–87. 5. Lebwohl M, et al. N Engl J Med 2015;373:1318–28. 6. Papp KA, et al. Br J Dermatol 2018;179(2):320–328. 7. Segaert S, et al. Poster P0457. Presented at 27th EADV Congress, 12−16 September 2018, Paris, France. 8. Philipp S, et al. Abstract ID: 3440. Presented at 27th EADV Congress, 12−16 September 2018, Paris, France. 9. Lebwohl M, et al. Poster 5296. Presented at Annual Meeting of the American Academy of Dermatology, Orlando, FL, March 3-7, 2017. 10. Elewski B, et al. J Dermatolog Treat 2020;DOI: 10.1080/09546634.2020.1749546. 11. Hsu S, et al. Br J Dermatol 2020;182:880–888. Further information can be found in the Summary of Product Characteristics or from: LEO Pharma, Cashel Road, Dublin 12, Ireland. E-mail: firstname.lastname@example.org ® Registered trademark
Date of preparation: March 2021 IE/MAT-43349 V1
August Issue Issue 87
Cardiac Rehab services in Ireland at Crisis Point P4
Editor In lead news this issue, Medicines for Ireland (MFI) have welcomed the opportunity to participate in negotiations to agree a new Framework Agreement on the Supply of Medicines to the Health Services.
New drug discovery at RCSI P9 Pharmacy Peer Review: Antiretroviral Therapy P17
Over recent decades, the parameters of pricing mechanisms and supply arrangements for medicines in Ireland have been determined by the terms of successive agreements between the State and the respective representative bodies of the pharmaceutical industry in Ireland. The most recent agreement was the Framework Agreement on the Supply of Medicines to the Health Services 2016-2020 (FASPM).
Pharmacy Peer Review: Trends in Opioid Prescribing P20
Detailed proposals from Medicines for Ireland have been submitted, which if implemented can help increase patient access to medicines in a sustainable way and improve affordability for the HSE.You can read about this on page 5.
Pharmacy Peer Review: Ketamine for Treatment-Resistant Depression P22 Hospital Peer Review: Revolution in Genetic Disorders P46
The analysis is authored by James O’Connell and Professor Derek O’Keeffe from the College of Medicine, Nursing and Health Sciences. In their work, James O’Connell and Professor O’Keeffe discuss how South Korea learned important lessons from their MERS (Middle East Respiratory Syndrome) epidemic in 2015 and put in place a political, legal and technological foundation that enabled an agile digital health response to the first wave of Covid-19.
Hospital Peer Review: A Focus On Advances In Breast Surgery P54 REGULARS
Peer Review: Non-Small Cell Lung Cancer P37
In other news on page 8, researchers at NUI Galway have highlighted how different approaches to digital contact tracing were taken during the Covid-19 pandemic by jurisdictions with and without prior recent experience of epidemics.
Meanwhile, on page 9, we detail how additional places for medicine and pharmacy students in universities will be included in a plan by Minister for Further and Higher Education Simon Harris to create 4,500 extra third-level places.
Peer Review: Rheumatoid Arthritis P50
Of course August brings with it Hospital Professional News’ Peer Review annual bumper issue. We have a fantastic series of authorcontributed articles covering a wide range of therapeutic areas to bring you for 2021. In addition, we have expanded this to include a special section focused on hospital pharmacy developments.
Peer Review: Stromal Cells in Colorectal Cancer P57 Clinical R&D: P95
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.
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On page 22, Ciara Ni Dhubhlaing examines Ketamine for Treatment-Resistant Depression and asks the question, “Can you teach an old dog new tricks?” On page 26 Richard Nuttall gives readers an overview of Dose Banding Systemic Anti-Cancer Therapy. Our Hospital Peer Review covers areas ranging from lung cancer, cardiology and mental health to sexual health, genetic disorders and urology. I hope you have a lovely summer and enjoy the issue.
CONTRIBUTORS Katie McCormick | Dr Sarinj Fattah | Professor Sally Ann Cryan | Conor Moran Bridget Norris | Dr Amelia Smith | Ciara Ni Dhubhlaing | Richard Nuttall | Dr Shona Meagher Dr Breda Cushen | Rory Johnson | Michela Coan | Professor Robert A Byrne Himanshu Rai | Laurna McGovern | Theresa Lowry-Lehnen | Professor Julian Gillmore Professor Malcolm Kell | Aoife Sartini-Bhreathnach | Professor Brendan Kelly Galway Academic Intestinal cancer Network (GAIN) | Conor Prendergast | Dr Orlaith B Kelly Dr Gareth Fitzpatrick | Dr Rosa McNamara | Dr Shane O’Hanlon | Sali Salgaonkar Andrew Crowe | D Gorman | Dominic Rowley | Dr Oisin O’Connell | Dr Dervla Devine Dr Michael Killian | Dr Michael Hanly | Dr Dominic A. Hegarty | Dr Daniel Galvin Professor Barry O’Reilly | Mr Fardod O’Kelly
BUSINESS & SALES EXECUTIVE Natasha Lynch - Natasha@hospitalprofessionalnews.ie DIGITAL MARKETING AND EDITORIAL EXECUTIVE Sarah Sweeney - firstname.lastname@example.org HOSPITALPROFESSIONALNEWS.IE CPD Lead Sibongile Swan Mude - email@example.com @HospitalProNews DESIGN DIRECTOR Ian Stoddart Design
HOSPITAL PROFESSIONAL NEWS IRELAND Ireland’s Dedicated Hospital Professional Publication
HOSPITALPROFESSIONALNEWS.IE | HPN • AUGUST - 2021
New President for Hospital Pharmacists Delegates from the 35 member countries of the European Association of Hospital Pharmacists (EAHP) came together on the 11th and the 12th of June for their 51st General Assembly. Due to the Covid-19 Pandemic, the event was organised to take place virtually. During the General Assembly, delegates received updates on EAHP’s educational activities, the core projects of the Association and current policy developments. Discussions centred around the implementation of the 44 European Statements of Hospital Pharmacy, the Common Training Framework for hospital pharmacy specialisation, access to medicines and the growing problem of medicines shortages, in particular those linked to immunoglobulins that are increasingly impacting patient care. At the end of the General Assembly, András Süle was welcomed as EAHP’s new President. For the next three years, he will be steering the Association.
Dr András Süle is currently the Chief Pharmacist at Péterfy Hospital and Trauma Center as well as the Chief Pharmacy Advisor at Duna Medical Center, both located in Hungary. He is a guest lecturer and lead developer of the Hospital Pharmacy Specialisation programme at Semmelweis University in Budapest. In 2008, he obtained a PhD from Semmelweis University and has since gone on to complete a PharmD Specialisation in Pharmaceutical Technology and a PharmD Specialisation in Clinical Pharmacy. Reflecting on the goals for this 3-year presidency, Dr András Süle outlined the following, “I feel very honoured to take over EAHP’s primary leadership role from Petr Horák and his predecessors who have done a great job in improving patient care and advancing the hospital pharmacy profession in the almost 50 years that our Association now exists. I will have some very big shoes to fill, especially since I am taking over as EAHP’s President during
a global pandemic. However, knowing our profession has gone above and beyond during this unprecedented time, I also feel confident that I will be able to build on this experience and to use the momentum created by the Covid-19 pandemic to improve patient safety through the delivery of pharmacy services. “In the coming years, I plan to foster partnerships with other fellow pharmacy organisations at European level, to support our members in the endeavour of capitalising on opportunities linked to their changing roles in a changing world and to continue to drive forward EAHP’s flagship projects linked to the creation of a Common Training Framework for the profession and the Europeanwide implementation of the Statements of Hospital Pharmacy. I thank again all of EAHP’s member associations for placing their confidence in me and I look forward to delivering our shared vision together with my colleagues on the Board.”
EAHP President András Süle and Director of Professional Development Tjalling van der Schors were joined by 8 newly appointed Board members, several of them re-elected. Together with Aida Batista (Portugal) as Vice President, Nenad Miljković (Serbia) as Director of Finance and the 6 Directors of Professional Development Louis Bertin (France), Darija Kuruc Poje (Croatia), Ana Lozano (Spain), Despoina Makridaki (Greece), Claudia Plesan (Romania) and Piera Polidori (Italy) they will be shaping the work of EAHP. Petr Horák will continue to advise his colleagues until June 2022 as Immediate Past President. To further boost EAHP’s policy activity, the General Assembly adopted two new position papers touching on the enabler and barriers linked to the access of medicines for patients and the hospital pharmacy specialisation. In line with the new Statutes approved in 2020, EAHP also welcomed its first Associate Member the Egyptian Foundation of Clinical Pharmacy (EFCP).
Cardiac Rehab ‘in Crisis’ Dr Angie Brown, Medical Director, Irish Heart Foundation
statistics in joint research with the Irish Association of Cardiac Rehabilitation (IACR). “This service was considered world class in 2005, but it's now in absolute crisis,” said Dr Angie Brown, the Irish Heart Foundation’s Medical Director. “HSE recruitment embargoes and chronic under-investment have stripped it bare. Nurses are being transferred to other work and not being replaced and even though it’s an essential service, none of our hospitals have all the expertise in place to deliver high quality cardiac rehabilitation.”
Lifesaving rehabilitation for heart patients is in ‘absolute crisis’ and no hospital in Ireland has a full team in place to help them recover, the Irish Heart Foundation has warned.
The cardiac rehab waiting list for heart attack, stroke and heart failure patients has exceeded 2,800 – a 54% increase since 2013 – while staffing levels have plummeted by 40%. The vital service is now being treated as an ‘optional add on’ in hospitals, according to the charity, which uncovered the grim
AUGUST - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE
The research also showed that 77% of centres closed during the pandemic – most of them for over 12 weeks, despite the fact that CR reduces heart disease deaths by around 20%. Properlyresourced CR is delivered through a dozen different disciplines, ranging from specialist nursing staff to pharmacists, physiotherapists, occupational
therapists, smoking cessation specialists and cardiologists. A core element is monitored exercise training which helps patients get physically active again.Psychological support also drives the improvements achieved by CR, but the data shows that only seven of the 35 cardiac rehabilitation centres surveyed have access to a psychologist. Twelve centres surveyed did not have a physiotherapist. Since 2010, the number of medical directors in the programme has fallen from 38 to 21, CR co-ordinators from 38 to 31 and dietitians from 36 to 24. Thirty-three cardiac rehabilitation centres are missing four or more key staff and since 2013, cardiac specialist nurses from 11 centres were transferred to other duties. In addition, 40% of patients are waiting at least three months for CR, when they should be starting courses weeks after hospital discharge.
Supply of Medicines Framework Medicines for Ireland (MFI) have welcomed the opportunity to participate in negotiations to agree a new Framework Agreement on the Supply of Medicines to the Health Services. Over recent decades, the parameters of pricing mechanisms and supply arrangements for medicines in Ireland have been determined by the terms of successive agreements between the State and the respective representative bodies of the pharmaceutical industry in Ireland. The most recent agreement was the Framework Agreement on the
Supply of Medicines to the Health Services 2016-2020 (FASPM). It has been confirmed that Medicines for Ireland, as the representatives of the suppliers of the majority of medicines to the HSE and to patients directly in Ireland, will be participating in the negotiations to agree a new Framework Agreement on the Supply of Medicines to the Health Services.
Expenditure on medicines represents one of the largest areas of expenditure across the health service and will continue to grow in the years ahead and as an organisation Medicines for Ireland (MFI) share the objective of Government and the HSE in helping to secure affordable access to existing and new medicines in a timely manner.
Detailed proposals from Medicines for Ireland have been submitted, which if implemented can help increase patient access to medicines in a sustainable way and improve affordability for the HSE.
The current Framework Agreement on the Supply of Medicines to the Health Services was due to end in July 2020, however, due to COVID-19 it was necessary to implement an extension until 31
July 2021 to facilitate preparatory work on the successor agreement within the context of the ongoing COVID-19 challenges. The HSE has statutory responsibility for medicine pricing and reimbursement decisions, in accordance with The Health (Pricing and Supply of Medical Goods) Act 2013. The Act specifies the criteria for decisions on the reimbursement of medicines, including provision for the existence of any framework agreements in place.
IMVO Corporate Strategy The Irish Medicines Verification Organisation (IMVO) Board has recently signed off IMVO’s first Corporate Strategy covering the period 2021-2023. Since 2017, IMVO has prioritised meeting our obligations to set up the Irish Medicines Verification System (IMVS) and connecting over 2000 pharmacies, hospitals and wholesalers, as well as onboarding over 300 marketing authorisation holders whose pack data is hosted in the IMVS. Our focus from now until 2023 is operational excellence and developing a culture that consistently delivers value to our members, employees, and users of the IMVS through excellence in everything we do. This will be important as we support IMVS users in moving out of ‘use and learn’ and meeting their FMD obligations in full. Activity to achieve operational excellence will be built around four strategic pillars: • Strong governance • System stability and usability • Patient safety and alert management • Partnerships and collaboration The strategy envisions the IMVO of the future as a collaborative, trusted partner supporting the Irish healthcare system in protecting Irish patients from falsified prescription medicines and working seamlessly with EMVO and other NMVOs to deliver an integrated pan-European verification system. Visit www.imvo.ie for the full document.
Emotional Visit for Covid-19 Survivor Covid-19 survivor Mike Moloney had an emotional reunion with staff at University Hospitals Limerick last month, when he and his family completed a symbolic 1km walk to the hospital to show their gratitude to the healthcare workers who cared for him during his time in hospital. Mike, family and close friends were met with cheers from healthcare staff on arrival to the CERC at UHL. A surprise visit from Shane Dowling @LimerickGAA & the Liam MacCarthy Cup added to a joyous occasion.
HOSPITALPROFESSIONALNEWS.IE | HPN • AUGUST - 2021
6 News New Initiative Ahead of New Agreement Talks and Budget three times as long to make new medicines available to patients in Ireland compared to Denmark. For cancer medicines, Ireland is in 21st place for time to availability, with an average of 606 days to reimbursement. We are in 24th place for time to availability for orphan medicines which treat rare conditions, with an average of 756 days to reimbursement.
The Irish Pharmaceutical Healthcare Association (IPHA) has launched #InvestInOurFutures, a campaign aimed at supporting negotiations on a new medicines supply Agreement and advocating for enough funding for new medicines in the Budget. The campaign features five video assets – one hero film and four motion graphics. The hero film makes the case for medicines, treating them as an investment and not just as a cost. The motion graphics break out the economic and clinical impact of medicines innovation, as well as illustrating the access to medicines problem and how it can be fixed. The campaign comes as the industry prepares to start negotiations with the State on a new supply Agreement. New
figures show Ireland lagging European peers on speed of access to new medicines. Data, gathered by data analysts IQVIA for EFPIA, the European industry body, place Ireland in 18th place for time to availability for 152 medicines, with an average of 477 days to reimbursement. Among western European countries, only France and Portugal are slower than Ireland. Other countries, including Austria, Belgium, Denmark, Finland, Norway, Sweden, Germany, Greece, Italy, Spain, the Netherlands, England and Scotland, are faster. Germany is four times faster than Ireland to make new medicines available to patients through public reimbursement. It takes almost
A new supply Agreement, and a Budget funding announcement, can begin to address Ireland’s problem with introducing innovative new medicines in the health services. Oliver O’Connor, Chief Executive at IPHA, said: “This Government, especially the Taoiseach, Micheál Martin, the Minister for Public Expenditure, Michael McGrath, and the Minister for Health, Stephen Donnelly, deserve credit for providing ¤50 million for new medicines this year. The allocation is releasing a backlog of medicines that had gathered due to a funding freeze imposed in 2019. “But data shows Ireland still has a major problem with speed of access to new medicines, compared with peer countries in western Europe. It is not because all these countries’ assessment processes are somehow less stringent than ours. Our processes are not organised to deliver fast
access for patients. A funding shortfall in previous years has meant medicines were left unfunded, even when they were deemed cost-effective after price negotiations. We need to fix these problems, together, through a new supply Agreement and in Budget 2022. “Innovative medicines have significantly improved survival, delivering treatments to patients with chronic diseases, tackling previously untreatable cancers and genetic conditions, eliminating some infectious diseases and addressing unmet medical needs. “In recent years, innovation in medicines has been fast. The industry’s pipeline is strong. The true value of innovation is realised when patients have access to it. So, we need to design a reimbursement process that works better and to build a funding framework that is sustainable for the health system and delivers faster access to innovation for patients. These should be urgent priorities for both industry and the State. “Investing in medicines is investing in our futures.” The campaign, #InvestInOurFutures, is live across Twitter, Facebook and LinkedIn and on ipha.ie.
Launch of HIPPOCRATES International team of research partners, pharmaceutical companies, SMEs and patient organisations have joined forces to develop innovative personalised treatment options for people affected by psoriatic arthritis. By looking into the disease mechanisms of psoriatic arthritis an International teams of 26 research partners, pharmaceutical companies, SMEs and patient organisations, led by University College Dublin (UCD), are collaborating in HIPPOCRATES a new ¤21 million research project which aims to improve diagnostic and therapeutic options for patients living with psoriatic arthritis. By gaining a better understanding of the complex interplay between clinical and environmental factors, genotype and molecular pathways, the HIPPOCRATES team aims to enable earlier diagnosis and a more accurate prediction of
disease progression. This will revolutionise treatment and deliver profound patient benefits. The 5-year project has been funded by the Innovative Medicines Initiative (IMI 2), a Joint Undertaking (JU) of the European Union (EU) and the European Federation of Pharmaceutical Industries and Associations (EFPIA). Of the total budget, 50% is being contributed by the EFPIA partners (Novartis [EFPIA lead], UCB [EFPIA Co-lead], Pfizer and BMS) and 50% by the EU. Psoriatic arthritis (PsA) is a chronic immune-mediated inflammatory disease that affects joints and other components of the musculoskeletal system, together with skin involvement, in an estimated 5-10 million individuals in the EU. Future treatments will need to focus on earlier disease stages and be selected on the basis of detailed patient molecular profiling so as to limit poor long-term
AUGUST - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE
outcomes and possibly prevent the development of PsA altogether.
sustainable infrastructure for future PsA research.”
“We anticipate that the advances provided by HIPPOCRATES will result in significant new developments that improve patients’ quality of life,” said Professor Oliver FitzGerald, Newman Clinical Research Professor, UCD School of Medicine and the UCD Conway Institute of Biomedical and Biomolecular Research, and co-ordinator of the HIPPOCRATES consortium.
In order to achieve its goals, the HIPPOCRATES project will set up a single integrated database combining the cohorts and datasets of the most important European PsA studies and establish a Europe-wide library of relevant clinical biosamples.
Joint co-coordinator, Professor Stephen Pennington, Professor of Proteomics at the UCD School of Medicine and the UCD Conway Institute of Biomedical and Biomolecular Research and founder, Atturos said, “The advances will include the identification of sub-populations and endotypes, the validation of existing and identification of new biomarkers, improved imaging options and the development of a
HIPPOCRATES will also establish a large, prospective, observational study of 25,000 patients with psoriasis who will be recruited and followed on-line for development of PsA, with patient-centric blood sampling at defined intervals. Furthermore, the team of experts will evaluate and validate newly discovered biomarker signatures for the early diagnosis of PsA, for the identification of psoriasis patients at risk of developing PsA, for the identification of PsA patients at highest risk of damage progression and for personalised or stratified treatment strategies so as to maximise treatment response.
TAFINLAR + MEKINIST DURABLE 5-YEAR SURVIVAL1 TAFINLAR + MEKINIST is the first targeted therapy to show a 5-year survival benefit in patients with BRAF V600 unresectable or metastatic melanoma1 1.0
34% of patients alive at 5 years in a pooled analysis of COMBI-v and COMBI-d ITT populations1
TAFINLAR + MEKINIST (n=216)
at 2 years
at 4 years
at 2 years
at 4 years
at 5 years
No. at risk: 563 499
at 5 years
at 3 years
at 3 years
TAFINLAR + MEKINIST (n=563)
Month since randomisation
55% of patients with low tumour burden* alive at 5 years1
No. at risk: 216 208
Month since randomisation
Predictable and manageable safety profile with no new signals at 5 years2 ABBREVIATED PRESCRIBING INFORMATION Non-fixed dose combination of MEKINIST® and TAFINLAR® Before prescribing Mekinist and Tafinlar in combination, please refer to the Summary of Product Characteristics (SmPC) of both products. Presentation of each product: MEKINIST (trametinib) 0.5 mg and 2.0 mg film-coated tablets. Each film-coated tablet contains trametinib dimethyl sulfoxide equivalent to 0.5 mg and 2.0 mg of trametinib respectively. TAFINLAR (dabrafenib) 50 mg and 75 mg hard capsules. Each capsule contains dabrafenib mesilate, equivalent to 50 mg and 75 mg of dabrafenib respectively. Indications: Combination of Mekinist and Tafinlar: • for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation • for the adjuvant treatment of adult patients with stage III melanoma with a BRAF V600 mutation following complete resection • for the treatment of adult patients with advanced non-small cell lung cancer (NSCLC) with a BRAF V600 mutation. Dosage and Administration: Adults: recommended dose of Mekinist is 2mg once daily in combination with Tafinlar 150mg twice daily. Dose modification: Management of ADRs may require treatment interruption, dose reduction, or discontinuation. Elderly: No initial dose adjustment required in patients >65 years. Paediatrics: Safety and efficacy not established in patients <18 years. Renal impairment: No dose adjustment required in mild or moderate impairment. Caution advised in severe renal impairment. Hepatic impairment: No dose adjustment required in mild hepatic impairment. Caution advised in moderate and severe hepatic impairment. In the adjuvant melanoma setting, patients should be treated for a period of 12 months unless there is disease recurrence or unacceptable toxicity. Contraindications: Hypersensitivity to active substance or excipients. Warnings/Precautions for Mekinist (used as a monotherapy or in combination with Tafinlar): Left ventricular ejection fraction (LVEF) reduction/Left ventricular dysfunction: Cases of LVEF decrease have been reported. Should be used with caution when conditions could impair left ventricular fraction. All patients should be evaluated for LVEF prior to initiation of treatment with continued evaluation during treatment. Consider dose modification guidelines. In patients receiving Mekinist in combination with Tafinlar, there have been occasional reports of acute, severe LVEF due to myocarditis. Full recovery was observed when stopping treatment. Physicians should be alert to the possibility of myocarditis in patients who develop new or worsening cardiac signs or symptoms. Haemorrhage: Haemorrhagic events including major and fatal haemorrhagic events occurred in patients taking Mekinist as monotherapy and in combination with Tafinlar. Hypertension: Blood pressure should be measured at baseline and monitored during treatment with Mekinist, with control of hypertension by standard therapy as appropriate. Interstitial lung disease (ILD)/Pneumonitis: Mekinist should be withheld in patients with suspected ILD or pneumonitis, including patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnoea, hypoxia, pleural effusion,
Novartis Ireland Ltd., Vista Building, Elm Park Business Campus, Merrion Road, Dublin 4, Ireland, D04A9N6
or infiltrates, pending clinical investigations. Mekinist should be permanently discontinued for patients diagnosed with treatmentrelated ILD or pneumonitis. If Mekinist is being used in combination with Tafinlar then therapy with Tafinlar may be continued at the same dose. Rhabdomyolysis: Signs or symptoms of rhabdomyolysis should warrant an appropriate clinical evaluation and treatment as indicated. Visual impairment: visual disturbances, including chorioretinopathy or retinal pigment epithelial detachment (RPED) and retinal vein occlusion (RVO) have been observed. Not recommended for patients with history of RVO. Ophthalmological evaluation should be performed at baseline and during treatment if clinically warranted. If retinal abnormality is observed, treatment should be interrupted immediately and referral to specialist should be considered. Permanently discontinue treatment if RVO is noticed. Rash: observed in 60% of patients in monotherapy and 24% of patients in combination with Tafinlar. Severe cutaneous adverse reactions (SCARs): SCARs, including Stevens-Johnson syndrome, and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported with Mekinist in combination with Tafinlar. Before initiating treatment, patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of SCARs appear, Mekinist and Tafinlar should be withdrawn. Deep vein thrombosis (DVT)/pulmonary embolism (PE): can occur when used as a monotherapy or in combination with Tafinlar. Seek immediate medical care if patients develop symptoms of DVT or PE. Colitis and gastrointestinal perforation: Colitis and gastrointestinal perforation, including fatal outcome, have been reported. Treatment with Mekinist monotherapy or in combination with Tafinlar should be used with caution in patients with risk factors for gastrointestinal perforation, including a history of diverticulitis, metastases to the gastrointestinal tract and concomitant use of medications with a recognized risk of gastrointestinal perforation. If patients develop symptoms of colitis and gastrointestinal perforation they should immediately seek medical care. Sarcoidosis: Cases of sarcoidosis have been reported in patients treated with trametinib in combination with dabrafenib, mostly involving the skin, lung, eye and lymph nodes. In the majority of the cases, treatment with trametinib and dabrafenib was maintained. In case of a diagnosis of sarcoidosis, relevant treatment should be considered. It is important not to misinterpret sarcoidosis as disease progression Warnings/Precautions for Tafinlar (used as a monotherapy or in combination with Mekinist): Pyrexia including severe rigors, dehydration and hypotension (including acute renal insufficiency) reported. Incidence and severity increased when used in combination with Mekinist. During and following severe pyrexia events, serum creatinine and other evidence of renal function should be monitored. Serious non-infections febrile events have been observed. For management of pyrexia, dose modification guidelines should be followed. Cutaneous squamous cell carcinoma (cuSCC) and new primary melanoma: skin examination prior, during and for 6 months after discontinuation of treatment or until initiation of another anti-neoplastic therapy. Non-cutaneous secondary/ recurrent malignancy: monitoring as clinically appropriate for up to 6 months after discontinuation of Tafinlar or until initiation of another anti-neoplastic therapy. Pancreatitis: unexplained
abdominal pain should be promptly investigated to include measurement of serum amylase & lipase. Close monitoring when re-starting Tafinlar. Uveitis: monitoring patients for visual signs and symptoms during therapy. Colitis and gastrointestinal perforation: Colitis and gastrointestinal perforation, including fatal outcome, have been reported in patients taking dabrafenib in combination with trametinib. Sarcoidosis: Cases of sarcoidosis have been reported in patients treated with dabrafenib in combination with trametinib, mostly involving the skin, lung, eye and lymph nodes. In the majority of the cases, treatment with dabrafenib and trametinib was maintained. In case of a diagnosis of sarcoidosis, relevant treatment should be considered. It is important not to misinterpret sarcoidosis as disease progression. Interactions: Mekinist: None known. Tafinlar: Effect of other medicinal products on dabrafenib: Caution with co-administration of strong inhibitors (e.g. ketoconazole, gemfibrozil, nefazodone, clarithromycin, ritonavir, saquinavir, telithromycin, itraconazole, voriconazole, posaconazole, atazanavir) of CYP2C8 or CYP3A4. Avoid co-administration with strong inducers (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital, or St John’s wort (Hypericum perforatum) of CYP2C8 and CYP3A4. Avoid agents that increase gastric pH, when possible. Effect of dabrafenib on other medicinal products: Avoid concomitant use with medicinal products that are sensitive substrates of certain metabolising enzymes or transporters, if monitoring for efficacy and dose adjustment is not possible. Please refer to Section 4.5 of SPC for groups of medicinal products that can be affected. A drug utilisation review (DUR) is essential on initiating dabrafenib treatment. Exercise caution when co-administering with warfarin and consider additional INR (lnternational Normalised Ratio) monitoring. Exercise caution when co-administering with digoxin and additional monitoring is recommended. Effects of dabrafenib on substance transport systems: Tafinlar inhibits OATP1B1 and OATP1B3. Monitoring recommended of drugs that are sensitive substrates of OATP1B1 and OATP1B3 and known to have a narrow therapeutic index with regards to high peak concentrations (Cmax). Fertility, Pregnancy & Lactation: Women of child-bearing potential: When Mekinist and Tafinlar are use in combination, use effective methods of contraception during therapy and for at least 16 weeks after stopping treatment. Tafinlar may decrease the efficacy of oral or any systemic hormonal contraceptives; use an effective alternative method of contraception. Pregnancy: Caution should be exercised by considering the expected benefit to the mother against possible risk to the foetus. Breast-feeding: Caution should be exercised by considering the benefit of breastfeeding for the child and the benefit of therapy for the woman. Fertility: Mekinist may impair human fertility. Tafinlar represents a potential risk for impaired spermatogenesis, which may be irreversible. Ability to Drive and Use Machines: Trametinib and Dabrafenib have minor influence. Patients should be made aware of the potential for fatigue, dizziness and eye problems. Adverse reactions with Mekinist monotherapy in metastatic melanoma: Very common (≥ 1/10): hypertension, haemorrhage, cough; dyspnoea, diarrhoea, nausea, vomiting, constipation, abdominal pain, dry mouth, rash, dermatitis acneiform, dry skin, pruritus, alopecia, fatigue, oedema peripheral, pyrexia,
asparate aminotransferase increased. common (≥ 1/100, < 1/10): folliculitis; paronychia; cellulitis; rash pustular; anaemia; hypersensitivity; dehydration; vision blurred; periorbital oedema; visual impairment; left ventricular dysfunction; ejection fraction decreased; bradycardia; lymphoedema; pneumonitis; stomatitis; erythema; palmar-plantar erythrodysaesthesia syndrome; skin fissures; skin chapped; face oedema; mucosal inflammation; asthenia; alanine aminotransferase increased; blood alkaline phosphatase increased; blood creatine phosphokinase increased. Adverse reactions with Tafinlar monotherapy: Very common (≥ 1/10): papilloma; decreased appetite; headache; cough; nausea, vomiting, diarrhoea; hyperkeratosis, alopecia, rash, PPE, arthralgia, myalgia, pain in extremity, pyrexia, fatigue, chills, asthenia. common (≥ 1/100, < 1/10): cuSCC; seborrhoeic keratosis; skin tags; basal cell carcinoma; hypophosphataemia; hyperglycaemia; constipation; dry skin; pruritus; actinic keratosis; skin lesion; erythema; photosensitivity reaction; influenza-like illness. Adverse reactions observed when Mekinist and Tafinlar are used in combination: Very common (≥ 1/10):, nasopharyngitis, decreased appetite, headache, dizziness, hypertension, haemorrhage, cough; abdominal pain, constipation, diarrhoea, nausea, vomiting, alanine aminotransferase increased, aspartate aminotransferase increased, dry skin, pruritus, rash, erythema, arthralgia, myalgia, pain in extremity, muscle spasms, fatigue, oedema peripheral, pyrexia, chills, asthenia, influenza-like illness. common (≥ 1/100, < 1/10): urinary tract infection, cellulitis; folliculitis; paronychia; rash pustular; cuSCC; papilloma; seborrhoeic keratosis; neutropenia,; anaemia; thrombocytopenia; leukopenia; dehydration; hyponatraemia; hypophosphataemia; hyperglycaemia; vision blurred; visual impairment; uveitis; ejection fraction decreased; hypotension; lymphoedema; dyspnoea; dry mouth; stomatitis; dermatitis acneiform; actinic keratosis; night sweats; hyperkeratosis; alopecia; palmar-plantar erythrodysaesthesia syndrome; skin lesion; hyperhidrosis; panniculitis; skin fissures; photosensitivity; mucosal inflammation; face oedema; blood alkaline; phosphatase increased; gamma-glutamyltransferase increased; blood creatine phosphokinase increased. For more details on adverse reactions, please see SmPC. Pack Size: Mekinist is supplied in bottles of 30 tablets. Tafinlar is supplied in packs of 120 hard capsules. Legal category: POM. Marketing Authorisation Numbers: Mekinist: EU/1/14/931/002 (0.5mg), EU/1/14/931/006 (2.0mg). Tafinlar: EU/1/13/865/002 (50 mg), EU/1/13/865/004 (75 mg). Marketing Authorisation Holder: Novartis Europharm Ltd, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland. Date of revision of text: January 2021 Full prescribing information is available upon request from: Novartis Ireland Limited, Vista Building, Elm Park Business Park, Elm Park, Dublin 4. Tel: 01-2601255 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.
*Low tumour burden is defined as normal LDH and <3 metastatic sites. BRAF, gene encoding the protein B-Raf; ITT, intent-to-treat; LDH, lactate dehydrogenase. References: 1. Robert C, et al. N Engl J Med 2019; June 4: doi: 10.1056/NEJMoa1904059 [Epub ahead of print]; 2. Robert C, et al. N Engl J Med 2019; June 4: doi: 10.1056/NEJMoa1904059 [Epub ahead of print] Supplement.
106002 Preparation date: January 2021
Digital Health Lessons Learned Pictured from L-R Professor Derek O’Keeffe, HIVE Lab and James O’Connell, NUI Galway. Photo: HIVE Lab, NUI Galway
who are not able to access such technology (such as the digital divide ) and also in non-native language speakers (such as migrant communities). The NUI Galway authors also discuss the apparent idiosyncrasy that many people freely share significant amounts of personal data with large multinational corporations for no health benefit and yet had significant ideological issues in sharing similar data with governments during an emergency health scenario.
Researchers at NUI Galway have highlighted how different approaches to digital contact tracing were taken during the Covid-19 pandemic by jurisdictions with and without prior recent experience of epidemics. The analysis, authored by James O’Connell and Professor Derek O’Keeffe from the College of Medicine, Nursing and Health Sciences, has been published by the prestigious New England Journal of Medicine. In their work, James O’Connell and Professor O’Keeffe discuss how South Korea learned important lessons from their MERS (Middle East Respiratory Syndrome) epidemic in 2015 and put in place a political, legal and technological foundation that enabled an agile digital health response to the first wave of Covid-19. By comparison, Western countries struggled with both the societal and technical requirements needed to implement a digital solution to augment traditional manual contact tracing, which is a critical tool in managing infectious disease outbreak. Automation using geolocation tracking allowed teams of epidemiologic investigators in South Korea to trace not only contacts but also the setting in which contact occurred up to 14 days before symptom onset or diagnosis. This information allowed them to gain a greater understanding of the settings in which SARS-CoV-2 transmission was occurring and to implement more targeted health protection measures in response. In contrast, traditional contacttracing systems in most Western
countries had the capacity to identify and notify only people who had come into contact with an infected person within 48 hours before symptom onset or diagnosis. This digital limitation perhaps contributed to the first wave of Covid-19 in Western countries that outpaced the epidemic in South Korea. By the end of their first epidemic wave in April 2020, South Korea had reported 10,423 infections and only 204 deaths — a remarkable achievement given the population size of just over 50 million. In contrast, European countries saw more than 2.1 million cases and 180,000 deaths by the end of their first wave in June. James O’Connell, author and HIVE lab postgraduate researcher at NUI Galway, says, “This analysis highlights important learnings from this pandemic that will enable a better response to the next. We have all seen how important proportionate, effective, efficient and timely contact tracing is during this pandemic. Digital technologies can enhance the capacity of contact tracing systems to perform in this way, aiding efforts to achieve and maintain epidemic control.”
Table graphic of a Selection of Digital Contact Tracing Systems in the United States and Europe. Photo: HIVE Lab, NUI Galway
AUGUST - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE
Professor Derek O’Keeffe, Consultant Physician, Professor of Medical Device Technology and Director of the HIVE lab at NUI Galway, adds, “This research highlights the importance of learning from critical events and then creating the necessary technological tools and political and legal frameworks, so that when it occurs again, we are ready to respond quickly.” The work also highlights the importance of realising the limitations of using digital contact tracing solutions in populations
As the first epidemic wave came to an end and the imminent threat of further loss of life eased, geolocation-based digital contact-tracing systems and their interference with personal privacy and data protection rights became less palatable. They became the subject of intense scrutiny in countries that used them, including South Korea and also Norway and Israel. In a pandemic that had the potential to last several years, many Western countries recognised the need for trustworthy, transparent, privacypreserving digital contact-tracing technologies that were acceptable to Western populations. To read the full study entitled 'Contact Tracing for Covid-19 — A Digital Inoculation against Future Pandemics' in the New England Journal of Medicine, visit: https:// www.nejm.org/doi/10.1056/ NEJMp2102256.
Third Level Places for Pharmacy Additional places for medicine and pharmacy students in universities will be included in a plan by Minister for Further and Higher Education Simon Harris to create 4,500 extra third-level places, it has emerged. A spokesperson for Mr Harris has been unable to confirm as yet, how many extra places will be created. The Irish Pharmacy Union (IPU) has welcomed a proposed increase in the number of third level places for pharmacy students. Reports have indicated that the Minister for Higher Education Simon Harris TD is
seeking approval to fund 4,600 new third level places, with pharmacy being among the areas set to benefit.
because of Brexit. Any increase in the provision of third level pharmacy education would be extremely welcome.
Welcoming the proposal Secretary General of the Irish Pharmacy Union Darragh O’Loughlin said, “Pharmacy is an exciting and diverse career that offers practitioners the opportunity to play an active role on the frontline of healthcare in their communities. There has always been a high demand for the limited number of third level places in Ireland. Many students have been required to study in the UK, which is now more complicated
“As evidenced by our efforts in the COVID-19 vaccination rollout the role of the pharmacist has expanded and should expand more in the years ahead. As Sláintecare is implemented it will place care in the community at its core, the very essence of community pharmacies. All of this indicates there will be a sharp increase in the demand for pharmacists and it is appropriate that the education system prepares for this.
“Throughout the pandemic, when GPs and other healthcare providers were unavailable, many people sought advice from their community pharmacy. The dispensing of medicines is of vital importance to the wider health system and requires significant expertise when managing medicines for patients with complex needs. Our universities currently offer an excellent level of training and graduates are in high demand due to their knowledge and expertise. With an increase in pharmacy places the Irish population will benefit from this expertise in their local communities.”
HSE Approval for Patisiran (Onpattro) The Minister for Health, Stephen Donnelly TD has announced that the drug Patisiran (Onpattro) has been approved by the HSE for reimbursement in the treatment of hereditary transthyretin-mediated (hATTR) amyloidosis. hATTR amyloidosis is an inherited, rare, life-limiting, multi-systemic disease where there are limited treatment options currently available. In order for the HSE to recommend in favour of reimbursement of Patisiran (Onpattro), the HSE has undertaken considerable engagement and negotiation with the manufacturer Alnylam over a protracted period. Minister Donnelly said, “The reimbursement of Patisiran by the HSE is a welcome decision for hereditary transthyretin-mediated amyloidosis patients, their families and friends. "Our country continues to make new and innovative treatment available to patients and the allocation of ¤50m in Budget 2021 for new medicines ensures that this continues. However, securing access to treatments for patients at an affordable price remains the key priority. I wish to take the opportunity to thank the HSE for the dedication it has put into the Patisiran negotiations over a long period, which required significant work and deserves recognition.” The HSE now advise that they will develop and implement the required managed access programme, as required for reimbursement, in order for all eligible patients with hATTR amyloidosis with stage 1 or stage 2 polyneuropathy to access treatment with Patisiran in the near future.
New Drug Breakthrough at RCSI Scientists have identified a drug that can prevent the virus that causes Covid-19 from binding to human cells, potentially preventing damage to the lung, clot formation and the development of sepsis. The study, led by researchers from RCSI University of Medicine and Health Sciences, is published in PLOS ONE. The researchers identified that a mutation, present in all the variants of the virus to date, creates an additional binding site in the virus’ spike protein. This additional binding site increases viral impact in the body, including damage to the lung tissue that causes breathing problems in Covid-19 patients. The significant damage to the lung tissue allows the virus to spread from the lungs to the bloodstream, where it can cause clots and vascular damage. In pre-clinical testing, a drug called cilengitide successfully prevented
Professor Steve Kerrigan, study’s senior author, Deputy Head, RCSI School of Pharmacy and Biomolecular Sciences the virus from causing the tissue damage associated with Covid-19 by stopping the virus from sticking to the cell types that line the lungs and blood vessels. “More pre-clinical and clinical testing is needed before this treatment can be used on patients, but the results are very promising,” said Professor Steve Kerrigan, the study’s senior author and Deputy Head of the RCSI School of Pharmacy and Biomolecular Sciences.
potential to significantly reduce the deaths associated with Covid-19.”
“It is imperative that we continue to develop treatments for Covid-19 for the many people who will not have access to vaccines and for patients with breakthrough infections. Our research in the lab has shown that cilengitide has the
RCSI spin-out company Inthelia Therapeutics has recently been formed to commercialise this and other findings relating to the treatment of sepsis from Professor Kerrigan’s research group.
Ms Danielle Nader, PhD candidate in Professor Kerrigan’s group, carried out the work. The research was funded by an Enterprise Ireland Commercialisation Fund, an EMBARK fund award from Enterprise Ireland and Knowledge Transfer Ireland as well as a philanthropic donation from the 3M Foundation and GlobalGiving.
HOSPITALPROFESSIONALNEWS.IE | HPN • AUGUST - 2021
Study of Referral Source and Final Diagnosis. The Journal of Cardiovascular Nursing: 3/4 2017 Volume 32 - Issue 2 - p E1-E8 Knuuti J, Wijns W, Saraste A et al; 2019 ESC Guidelines for the diagnosis and management of chronic CARDIOLOGY 10 PHARMACY REVIEW: coronary syndromes: The Task Force for the diagnosis and management of chronic coronary syndromes of the European Society of Cardiology (ESC) European Heart Journal, Volume 41, Issue 3, 14 January 2020, Pages 407–477
Rathod K, Ward H , Farooqi F. 2014 BMJ Qual Improv Rep. Oct 21;3(1):u203864.w1691. doi:10.1136/bmjquality.u203864.w1691. eCollection 2014
Tallaght University Hospital Integrated Community TUH: Caring for the Future —A Clinical Services Strategy 2016-2018 . https://www.tuh.ie/AboutChest Pain Clinic: Right Care, Right Place, Right Time us/Caring-for-the-Future-Clinical-Services-Strategy-2016-2018.pdf Written by Shirley Ingram MSc, Advanced Nurse Practitioner, Registered Nurse Prescriber, Cardiology Figure 1 Tallaght Hospital has the busiest Emergency Department (ED) in the Dublin Midlands hospital group, with 50,000+ adult attendances per year. The highlevel of ED use by residents in the direct catchment; with 40% of household’s surveyed indicating use of the adult ED is a key driver of sustained emergency access pressures and growing trolley numbers (TUH 2016-18). Chest pain is a principal presenting symptom of coronary heart disease, and places a significant burden on the ED and primary care. Patient presentations with chest pain to TUH ED rose from 5% of all ED presentations in 2009 to 9% in 2019 (Figure 1.), 31% (n-1446) of which were referred after an initial visit to the General Practitioner (GP). Of these GP referrals, 0.8% were acute coronary syndrome (ACS), 78% were low risk and 70% were subsequently discharged. These growth levels have continued as expected with an ageing demographic in a socially deprived area. In the primary care setting chest pain is a common presenting complaint with an over diagnosis/ suspicion of stable angina (Rathod et al, 2014), however GPs lack access to a cardiac specialist in a timely fashion, hence the referral to ED. As 78% of these GP referrals are low risk, this leads to prolonged patient experience time (PET) in ED and adds to the overcrowded nature of the department. The Slaintecare integrated community chest pain clinic (ICCPC) commenced in September 2020 as a pilot project awarded by the Slaintecare integration fund. The ICCPC is a natural expansion of the innovative advanced nurse led chest pain service in Tallaght University Hospital (Ingram et al, 2017), to the community for nonacute chest pain patients. The clinic is led by an advanced nurse practitioner (ANP). Integrated Community Chest Pain Clinic This ANP led clinic aims to provide an alternative avenue to
which local GPs can directly refer patients with non-acute chest pain, thereby shifting the focus of care and providing hospital avoidance as per the Slaintecare vision. This project sits within the ‘Innovations in shifting care to the community or providing hospital avoidance measures’, in that successful projects will be delivered in partnership between hospitals and CHOs, highlighting the emphasis on integrated care (Slaintecare Annual report 2020). The clinic is based in a local primary care centre adjacent to the main hospital campus. The referral process was set up in collaboration with the Tallaght Clondalkin local integrated care committee (TCLInCC) which includes both hospital representative (medical, nursing, and managerial) and local GPs. Suitable patients are those who present to the GP with nonacute chest pain which may be indicative of coronary heart disease > 25 years of age. The clinic is run by an advanced nurse practitioner (ANP) who has 10 years of advanced chest pain assessment experience, with 0.5 cardiology physiologist and 0.5 clerical admin support.
AUGUST - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE
Aims & Objectives This project aims to provide an alternative avenue for non-acute chest pain assessment referral instead of a busy ED, providing a nurse led chest pain clinic in the community setting that can be accessed by all GPs in the TUH area that is NOT linked to a particular GP practice. This clinic enables a shift in care from the ED to the community, whilst
maintaining integration with TUH chest pain service, cardiology diagnostics and Consultant Cardiologists. The ANP has the autonomy to assess, devise a care plan, prescribe medications and refer for diagnostic testing if required. The ANP can complete an episode of care and discharge the patient to the GP. ICCPC Process The ANP patient assessments are carried out either face to face (F2F) or by telephone. At each F2F the ANP undertakes a focused health history, advanced
ICCPC Objectives: 1. Accept direct referral from GPs as per specific criteria 2. Expert patient assessment leading to accurate diagnosis 3. Reduce chest pain presentation to ED 4. Reduce OPD clinic waiting times for cardiology clinics 5. Assess patients in the community setting 6. Make ‘Every contact count’ re health promotion and heart disease prevention 7. Influence heart disease management with early diagnosis, prevention and prescribing
Patient feedback “I think the location of the clinic outside, and away from the hospital is such a good idea. Hope it can continue. My visit to the clinic was a pleasure and I give it top marks” “I could not believe the service I received and how quickly I was seen and tested it felt like a very personal service. Why do we not have this type of outreach clinic for other expertise in our hospitals I think it's the future” “The treatment I received was excellent and within a few days the problem I presented with was sorted out for me. I am extremely grateful for the care and kindness I received from the team and I feel this is a wonderful service and I thank all involved for setting this service up which was very much needed” “I have to say the quick response and care I received from the team was exceptional. Having the Chest Pain Clinic ……is so relieving when you're not feeling too good. I think this is an excellent way forward for the HSE” “The integrated chest clinic is quite literally a life saver in many cases and the work they do is unbelievable. I was dealt with in a professional and friendly manner” GP Feedback “It is an excellent service with very good waiting times for patients with potential cardiac symptoms to be seen and further investigated, treated and reassured” “My experience is that the patients are seen promptly, which during this time with the pandemic and restrictions is excellent given that other hospital services have reduced face to face appointments with patients. You provide a thorough work up of potential cardiac symptoms and illness which means that patients that do require further specialist input are cared for and not left on lengthy outpatient waiting lists.” “As we work in an area of deprivation with resultant accelerated and premature CHD…..our patients have benefitted enormously from timely assessment and access to investigations in the community”
physical assessment, and ECG/ Vital signs. After the assessment, a differential diagnosis is formulated utilising the ESC pretest probability score for coronary heart disease (CHD) (Knuuti et al, 2019) and an exercise stress test (EST) scheduled if required. The EST takes place in the hospital by the designated physiologist. Forty-two percent of all referrals underwent EST. ANP autonomy is further enabled by medicinal prescribing and referral for chest x-ray in the community if required. Health promotion regarding cardiovascular risk modification is offered, ‘Making every contact count’ (HSE 2021). If a diagnostic test or symptom review is required, the patient receives a telephone appointment explaining the results and plan of care. If the EST is abnormal the case may be managed in collaboration with the Consultant cardiologist and the patient may be referred for further diagnostic testing such as coronary angiogram. The clinic
has remained open for F2F visits during the pandemic. The First 9 Months To date the ANP has completed 566 episodes of F2F and telephone care. The majority of patients have been discharged to the referring GP with non-anginal symptoms, however 33 coronary angiograms have been completed with CHD diagnosed in 88%, including 6 CABGs and 4 PCIs. Over 60% of all cases have been managed autonomously by the ANP. As per the clinic targets, GP referrals are 17% above target and chest pain referrals to ED by GPs have reduced by 16%; success in the midst of a pandemic. Patient and GP feedback has been truly positive (Figure 2), and formal research is underway to capture this. Conclusion This new way of working presented a timely response to the management of the patient with chest pain especially during the COVID-19 pandemic.
The clinic is enabled by ANP autonomy, clinical experience, and clinical governance provided by the consultant cardiologist. Integrated care is demonstrated with a funded physiologist enabling cardiology diagnostics and consultant collaboration when needed. Local GP support allows true integrated care ‘bringing care closer to home and putting the patient at the centre of service design and delivery’ (Slaintecare Annual report 2020). References Government of Ireland (2020) Slaintecare Integration Fund Projects 2020. Department of Health. https://www.gov.ie/en/ publication/ca8a1d-slaintecarein-action/ HSE https://www.hse.ie/eng/ about/who/healthwellbeing/ making-every-contact-count/ accessed April 2021 Ingram, S., McKee, G., Quirke, M B., Discharge of Non–Acute Coronary Syndrome Chest Pain Patients from Emergency Care to
an Advanced Nurse Practitioner–Led Chest Pain Clinic: A Cross-Sectional Study of Referral Source and Final Diagnosis. The Journal of Cardiovascular Nursing: 3/4 2017 - Volume 32 - Issue 2 - p E1-E8 Knuuti J, Wijns W, Saraste A et al; 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes: The Task Force for the diagnosis and management of chronic coronary syndromes of the European Society of Cardiology (ESC) European Heart Journal, Volume 41, Issue 3, 14 January 2020, Pages 407–477 Rathod K, Ward H , Farooqi F. 2014 BMJ Qual Improv Rep. Oct 21;3(1):u203864.w1691. doi:10.1136/bmjquality.u203864. w1691. eCollection 2014 TUH: Caring for the Future —A Clinical Services Strategy 20162018 . https://www.tuh.ie/Aboutus/Caring-for-the-Future-ClinicalServices-Strategy-2016-2018.pdf
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12 PHARMACY REVIEW: GENE THERAPY
Gene-based Therapeutics Written by Katie McCormick, Dr Sarinj Fattah and Professor Sally Ann Cryan School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences
Katie McCormick, School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences
Dr Sarinj Fattah, School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences
Professor Sally Ann Cryan, School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences
Over the past three decades, the field of gene therapy has seen extraordinary scientific advances and has captured the attention of academics, industry and clinicians alike as a potential solution to previously unmet clinical needs. Gene therapy medicinal products are defined by the European Medicines Agency (EMA) as recombinant nucleic acids that are administered to humans with the aim of regulating, repairing, replacing, adding or deleting a genetic sequence. Initially, gene therapy research focused on monogenetic disorders, that is to say diseases caused by one single genetic mutation. However, in recent years, due to advances in science and the increasing number of successful clinical trials, the applicability of gene therapeutics has expanded to many other areas including cancer, infectious disease, cardiovascular disease and regenerative medicine (Figure 1). In the past year the world’s focus has been on methods to treat and prevent SARS-CoV-2 infection (COVID-19) and resulted in the licensing of four vaccines that involve gene-based technology: Comirnaty® (Pfizer-BioNTech), Moderna COVID-19 (Moderna), Vaxzevria® (Oxford-AstraZeneca) and Janssen COVID-19 vaccine (Janssen Pharmaceutica). Both the Moderna and Comirnaty® vaccines are based on mRNA
technology whereas the Janssen and Vaxzevria® vaccines are based on recombinant viral vector technology. The speed with which these vaccines were developed and their ongoing success worldwide highlights the tremendous potential of genebased healthcare technologies and will almost certainly pave the way for scale-up and clinical translation of other gene-based therapeutics in the very near future.
To date, there are nine gene therapy medicinal products which have been approved and are currently available for use within the EU (Table 1). The majority of these medicines are licenced for the treatment of orphan diseases but even over the short to medium term, we are likely to see an increasing number of similar products being developed for more prevalent diseases. The regulation of gene therapy in Europe is evolving and although only nine therapies are, at present, regulated as a “gene therapy medicinal product (GTMP)” (Table 1), there are many more licensed medicines that utilise gene-based therapeutic technology to exert their effects, with the COVID-19 vaccines being prime examples. Throughout this article we will explore the various kinds of gene-based therapeutics that are emerging, their clinical implications and the barriers and challenges that the field still faces.
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Depending on the final objective, a diverse range of nucleic acid cargoes may be used to achieve either gene augmentation, gene silencing or gene editing. Being able to target a disease at a genetic level opens up a whole new therapeutic approach for the treatment of disease and is likely to lead to a new generation of medicines. Some of the most common therapeutic cargoes, used both in research and clinically, are detailed below and depicted in Figure 2: • Plasmid DNA (pDNA) represents one of the simplest methods of introducing new genes into cells. Plasmids are circular pieces of DNA found in nearly all bacterial species where, typically, they encode proteins for antibiotic
resistance. Using recombinant DNA technology, plasmids can be genetically engineered to carry therapeutic genes for delivery to human cells. With the ability to code for virtually any protein, pDNA is an extremely versatile molecule which has been widely investigated for a range of clinical applications including DNA vaccination, cancer, immunotherapy and tissue engineering applications. Furthermore, it has excellent stability, its manufacturing process is, by now, well established and it is also relatively cheap to produce. The main limitation with pDNA gene therapy is achieving successful delivery to its intended site of action. In order to exert its effects, pDNA must first enter the cell nucleus where it uses endogenous transcription and translation machinery to produce the protein of interest (Figure 2). Crossing of the nuclear membrane has long been established as a significant barrier to successful DNA delivery. However, advancements in the design and manufacture of suitable delivery vectors are now at last beginning to overcome these issues.
Figure 1: Indications Targeted by Gene Therapy Clinical Trials. Adapted with permission from Ginn et al., Gene therapy clinical trials worldwide to 2017: An update. J Gene Med. 20185
13 Table 1: Gene Therapy Medicinal Products (GTMP) and other gene-based licensedMedicinal for use in EU Table therapeutics 1: Gene Therapy Products (GTMP) and other gene-based therapeutics licensed for use in EU.
Gene therapy Medicinal Products Imlygic (talimogene laherparepve)
Hepes simplex virus-1 (HSV-1)
Lentiviral vector (LVV)
Diffuse large B-cell lymphoma (DLBCL)
Yescarta (axicabtagene ciloleucel)
Primary mediastinal large B-cell lymphoma (PMBCL) B-cell acute lymphoblastic leukaemia (ALL) Diffuse large B-cell lymphoma (DLBCL)
Inherited retinal dystrophy
Adenoassociated virus (AAV2)
Transfusiondependent βthalassaemia (TDT)
Lentiviral vector (LVV)
Spinal muscular atrophy
Adenoassociated virus (AAV9)
Mantle Cell Lymphoma (MCL)
Metachromatic leukodystrophy (MLD)
Lentiviral vector (LVV)
(voretigene neparvovec) Zynteglo (betibeglogene autotemcel) Zolgensma
Recombinant vector vaccines Vaxzevria
Prevention of COVIDNo 19
COVID-19 Vaccine Janssen
Prevention of COVIDNo 19
Comirnaty COVID-19 vaccine
Prevention of COVIDNo 19
COVID-19 Vaccine Moderna
Prevention of COVIDNo 19
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PHARMACY REVIEW: GENE THERAPY
Figure 2: Site of action for nucleic acid cargoes. Figure created with BioRender.com
Within our own Tissue Engineering Research Group (TERG) in RCSI, pDNA is commonly employed to supplement natural tissue regeneration by encoding for proteins such as growth factors. For example, in the case of bone regeneration, pDNA nanoparticles are embedded in collagen sponges which serve to mimic natural bone and act as a depot for controlled release of the nucleic acid cargoes. This ‘gene-activated’ scaffold can then be implanted into a defect site where cells infiltrate and the pDNA nanoparticles are released, producing growth factors that support new bone growth. • Messenger RNA (mRNA) has recently attracted much interest as an alternative to DNA-based therapeutics for gene replacement, gene augmentation and vaccination strategies. Messenger RNA is a single stranded molecule that can be produced synthetically from a DNA template. Unlike pDNA, which requires entry into the cell nucleus to be functional, mRNA is translated directly in the cytoplasm of cells and significantly, this direct translation leads to faster and higher levels of protein expression (Figure 2). Furthermore, mRNA does not integrate into the host genome resulting in transient expression of the encoding protein and notably reducing the risk of mutagenesis that can be associated with DNA therapies. This increased safety profile confers a huge advantage over its DNA counterparts in terms of patient safety and regulatory concerns. The concept of mRNA delivery has been explored since the early 1990s but issues with stability and immunogenicity limited its clinical translation. Over the past two decades, huge efforts have been made in
understanding the structure of mRNA and developing chemical modification techniques to increase its stability and translation efficiency and thereby produce a clinically viable drug molecule. The licensing of two mRNA-based vaccines this year is testament to the tremendous effort that has been invested by researchers and the pharmaceutical industry in developing this innovative and exciting technology. With companies like Moderna and BioNTech having now firmly developed and established scale up processes for these technologies, we are likely to see a range of mRNA-based medicines in the years to come. As boldly stated on the Moderna website, “if an mRNA medicine works for one disease, it should work for many diseases”. • siRNA/miRNA where both pDNA and mRNA are used to introduce new genes encoding for proteins into cells, short interfering RNAs (siRNAs) and microRNAs (miRNAs) can be used to create a gene silencing effect. siRNAs and miRNA are short, double stranded RNA molecules that play an important role in the natural cellular process that regulate gene expression. Discovered just over two decades ago, both types of RNA molecule exert their effects at the post-transcriptional level by targeting mRNAs and causing a downregulation or silencing of genes. Onpattro® was the first siRNAbased medicine to be licensed by the EMA in August 2018. Onpattro® is indicated for the treatment of polyneuropathy in patients with hereditary transthyretin-mediated amyloidosis (hATTR). In this rare disease, transthyretin protein is defective and breaks easily, leading to amyloid
deposits building up in organs and tissues including nerves. The siRNA technology used in Onpattro® is designed to specifically target the mRNA within cells that codes for transthyretin and blocks its translation. This reduces production of transthyretin, thereby reducing the formation of amyloids and relieving the symptoms for the patient. In 2020 alone, three new medicinal products based on siRNA technologies were licensed by the EMA (Givlaari®, Oxlumo® and Leqvio®) and it is likely that we will continue to see an exponential growth in this new generation of medicines. • Gene editing is another option that is being actively explored in gene therapy research. There are currently three techniques used in research for targeted gene editing – Zinc Finger Nucleases (ZFNs), Transcription-Activator Like Effector Nucleases (TALENs) and CRISPR-Cas9, the last-mentioned of which is the fastest, cheapest and currently the most reliable technique for achieving gene knock-out in a cell. Indeed, the Nobel Prize in Chemistry was awarded to Emmanuelle Charpentier and Jennifer Douda in 2020 for their contribution to the discovery of this ground-breaking technology. CRISPR technology was adapted from a naturally occurring genome editing system found in bacteria that are used to respond to invading pathogens. CRISPR/Cas9 acts as a genetic scissors allowing DNA molecules to be cut or edited at predetermined sites. While only recently developed this technology is likely to take research and medicine into a new and potentially revolutionary era of drug discovery and development.
In the EU, GTMPs are classified as an Advanced Therapeutics Medicinal Product (ATMP) and as such they are subject to the same regulatory framework as other medicinal therapeutic products (Directive 2001/83/EC) with approval of new GTMPs falling under the remit of The Committee of Advanced Therapies (CAT). Successful translation of gene medicine from bench to bedside requires deep knowledge of the targeted disease, welldesigned preclinical/clinical investigation including immune response, toxicity studies and access to suitable scale-up manufacturing that complies with good manufacturing process (GMP). Despite the immense possibilities presented by nucleic acid-based therapeutics, they all face significant challenges in terms of clinical and commercial translation including the need for effective and safe delivery vehicles. As therapeutics, nucleic acids are large, negatively charged molecules and are rapidly cleared by circulating nucleases in the body. Many of the existing excipient materials used for delivery of small molecule therapeutics are not suitable for nucleic acid delivery. The safety of both the delivery mechanism and the gene therapy itself is the key for successful translation. Gene therapies are divided into two broad classes: in vivo e.g. mRNA vaccines and ex vivo e.g. Strimvelis (Figure 3). Briefly, in vivo is direct insertion of genetic materials to the cells within the human body while ex vivo involves the delivery to the patient of cells which have been genetically manipulated in vitro. Various viral and non-viral vectors have been developed for delivery of GTMPs. In the following section, a brief description of these vectors, as well as their clinical application, is outlined. • Viral vectors are repurposed mammalian viruses that are genetically engineered to deliver the GTMP. Viral vectors are considered “as per definition of nanotechnology” as natural nanomaterials since the viruses are on nanoscale length. The most common viral vectors are retroviruses and adenoviruses. Retroviruses (RV) such as lentiviruses (LV) are small
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16 PHARMACY REVIEW: GENE THERAPY Figure 3: In vivo vs. ex vivo gene therapy. Figure created with BioRender.com
types including macrophages, stem cells and respiratory cells. This patented technology is being commercialised with support from Enterprise Ireland.
RNA-based viruses while adenoviruses (AV) are larger DNA-based viruses which are replicated by integration into the host’s genome. Despite the large amounts of resources spent on developing RV and AV as gene delivery vectors their clinical application is limited due to issues with immunogenicity, genotoxicity and other safety issues. GTMPs based on RV and LV viral vectors, however, are approved by the EMA for inherited disorders such as sickle cell disease and β-thalassemia (Table 1). The learning outcomes from these trials has led scientists to develop the recombinant adenoassociated virus (AAV). AAV requires the presence of a helper virus as well as an AAV gene to enable vector replication. Compared with RV and AV, AAV has been shown to be safer and more effective. Glybera® is the first EMA-approved (2018) AAV based GTMP for treating lipoprotein lipase deficiency. More recent approval of GTMPs based on viral vectors will act as a source of inspiration for many scientists and encourage them to even greater efforts to develop safer-to-use next generation viral vectors. The more recent Janssen COVID-19 and Vaxzevria® vaccines are also AAV based. Despite all of these positives, viral vectors embody crucial drawbacks associated with the risk of immunogenicity, prolonged expensive manufacturing and the requirement for complex
specialist facilities thus, these issues have driven the development of non-viral vector alternatives. • Non-viral vectors a range of nanotechnology platforms such as lipid-based nanoparticles, polymeric-based nanoparticles and combinations of both in a hybrid system have been developed to overcome the immunogenicity and slow and expensive manufacturing of viral vectors. Lipid-based nanoparticles are among the most clinically advanced non-viral vectors for gene delivery. There are several forms of lipid-based nanosystems such as liposomes, solid lipid and semi-solid lipid nanoparticles. The nature of these nano-systems depends on the particular types of lipids and processing used in their formulation. Ionizable lipids and lipid-like materials have recently been introduced as an alternative for cationic lipids. Conventional cationic lipids, are highly positively-charged lipids which pose safety issues. The lipid-based nano-systems are designed to aid in cellular uptake and endosomal escape thus leading to the release of gene materials intracellularly. The first approved lipid-based gene delivery system, Onpattro®, was designed to mediate siRNA for the treatment of hereditary ATTR amyloidosis in 2018. Additionally, both mRNA-based vaccines, BioNTech/Pfizer and
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Moderna COVID-19 vaccines are delivered using solid-lipid nanoparticle technology. The vaccines consist of ionizable lipids, which are positively charged at low pH aiding mRNA complexation and reducing potential toxicity. Moreover, the formulations also contain a helper phospholipid to permit cell binding, cholesterol to fill the gaps between the lipids and lipid-anchored polyethylene glycol (PEG) to reduce fast clearance by the endogenous phagocytic system. Some of the challenges associated with using lipid-based delivery systems include instability and the transfer to large scale, rapid manufacturing processes. Polymeric nanoparticles offer an alternative non-viral vector approach with greater flexibility in design, improved stability and easier scale-up of production. A wide range of polymers are being developed as gene delivery vectors including polyamines, dendrimers and biodegradable polymers. Our group within RCSI work with a number of clinical research groups in Ireland on the development of gene delivery strategies for novel gene therapy approaches targeting unmet clinical needs for a range of diseases. Our new gene delivery technology “StarMAT technology” is based on starshaped polypeptides that can be tailored to deliver gene therapeutics to a range of cell
A combination of lipid and polymer materials in a so-called hybrid system is currently gaining more attention as a next generation gene delivery platform especially as delivery vehicles for chemotherapeutic agents. Finally, it is worth mentioning the gene delivery potential of biological nanoparticles such as exosomes. Exosomes are a natural-nanoparticles released by neurons, astrocytes and neural cells. Bioengineered exosomes, have been shown to deliver antiinflammatory drugs to the brain when administered intranasally. Conclusion and future direction The emergence of gene-based therapeutics is built on many decades of work both on the genetic cargoes themselves and the delivery systems with which they can be delivered to patients. In addition, there have been significant learnings in terms of clinical trial design and regulation based on past failures and successes during development. A range of scientific, pharmaceutical and clinical researchers in Ireland, including our own team in RCSI, have been working in the field of gene therapy for many years and are well placed to support new initiatives in the area. Even pre-pandemic the field was growing very significantly but the momentum gained over the last year particularly in the rapid development and scale-up of production for the COVID-19 vaccines has no doubt accelerated the emergence of these type of therapeutics for other diseases both as treatments and vaccines. References: 1. European Medicines Agency website. Available from: https:// www.ema.europa.eu/en 2. Walsh et al. (2021). Biomaterials Science. 3. Alhakamy et al. (2021). Drug Discovery Today. 4. Kim et al. (2021). Advance Drug Delivery Review. 5. Ginn et al. (2018). The Journal of Gene Medicine.
PHARMACY REVIEW: ANTIRETROVIRALS
Antiretroviral Therapy – Is 3 a Crowd? There have been huge advances in the pharmacologic treatments of Human Immunodeficiency Virus (HIV) in recent years. It has evolved from a once fatal diagnosis to become a manageable, chronic condition where people living with HIV have a life expectancy that is comparable to those without HIV1. Current antiretroviral (ARV) medication is now more readily available and provides maximal virologic efficacy, yields high genetic barriers to resistance, has more tolerable side effect profiles and a reduced pill burden in comparison to older agents. HIV treatment is instigated to achieve the following goals:
Written by Conor Moran, Infectious Diseases Pharmacist, Mater Misericordiae University Hospital
• HIV RNA suppression • To restore and preserve immunologic function • To reduce HIV-associated morbidity and mortality • To prevent onward transmission2 In 1987, the first drug to treat HIV, Zidovudine (AZT), a nucleoside reverse transcriptase inhibitor (NRTI), was approved to be used as monotherapy. However, it was quickly established that AZT did not maintain viral RNA suppression and therefore lead to the emergence of drug resistance, failure of therapy and patient deterioration3. In the early 1990s research progressed to the idea of treating HIV with three drug regimens, known as “triple therapy”. By targeting different stages of the HIV replication life cycle, “triple therapy” was shown to rapidly
reduce HIV RNA levels, sustain an undetectable viral load and improve patients’ immune function, assessed by means of CD4 lymphocyte count monitoring. Over the past 30 years, antiretroviral therapy has mainly consisted of a two-drug NRTI backbone plus a drug from one other class such as Protease Inhibitors (PI), NonNucleotide Reverse Transcriptase Inhibitors (NNRTI) or Integrase Inhibitors (INI). In the past decade attempts have been made to reduce from three active antiretroviral drugs to two
drug maintenance therapy. The emergence of new antiviral agents with increased viral potency combined with the desire to reduce drug exposure has driven the exploration of dual therapy HIV regimes in recent years. People living with HIV (PLWH) are living longer since the introduction of highly effective three drug antiretroviral therapy. In 2018, 51% of HIV positive Americans were over the age of 504. The Pharmacokinetic and Clinical Observations in People Over Fifty (POPPY) Study highlighted
the increasing burden of comorbidities in older people living with HIV (PLWH) in the UK and Ireland5. Lifelong treatment with antiretroviral therapy poses challenges such as polypharmacy and long-term toxicities of ARVs. Drug-drug interactions pose a risk to an ARV regimen by decreasing ARV concentrations by methods such as induction or inhibition of the metabolic pathway, chelation of drug and polyvalent cations or by reduction of stomach acidity. This can lead to loss of treatment efficacy and cause subsequent viral breakthrough. Similarly,
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Darunavir in 2007; generic versions of each are available on the Irish market. Dual therapy single tablet antiretroviral regimes are likely to be covered by patents for the foreseeable future; therefore prescribing individual medicines including a generic should be considered.
18 PHARMACY REVIEW: ANTIRETROVIRALS
Table 1: studies comparing dual agents with three drug regimens
Trial Name NEAT001/ANRS1438
FLAIR12 Table 1: studies comparing dual agents with three drug regimens
the ARV regimen can have a detrimental effect on concomitant medication a patient may be taking therefore dual ARV therapy may help to avoid unwanted drug-drug interactions in the future. Adverse effects have been reported with most ARVs and to achieve and sustain HIV RNA suppression over a lifetime, both short-term and long-term toxicities must be anticipated and managed. Long-term complications of ARVs can be underestimated and may take years of real world prescribing experience to uncover because of the selective inclusion criteria of clinical trials and the relatively short follow up time. ARVs have been associated with long term adverse effects such as renal disease, decreased bone mineral density, CNS toxicity, fat distribution and weight gain. Not only can such complications lead to poor health status and a diminished quality of life but ARV related adverse effects that ultimately result in increased morbidity and mortality may contribute to the burden on healthcare resources and costs associated with HIV. Reducing HIV treatment from three to two antiretroviral drugs will lower the exposure of patients to long term toxicities; specifically if one or both NRTIs are removed from the regime. NRTIs are linked to an increase risk of renal impairment, reduction in bone mineral density and an increase in cardiovascular risk. Development of resistance to ARVs is a major impediment to optimum treatment of HIV. Resistance mutations develop when viral suppression is not maintained due to suboptimal drug concentrations. Resistance mutations can affect more than one drug in the class (and often
Treatment arms studied Darunavir/r & Raltegravir v Darunavir/r & Tenofovir DF/Emtricitabine Dolutegravir & Rilpivirine v Current 3 Drug Antiretrovial Regimen (2 NNRTIs & a third agent) Dolutegravir & Lamivudine v Dolutegravir & Tenofovir DF/Emtricitabine Dolutegravir & Lamivudine v Current Tenofovir AF Based 3 Drug Antiretroviral Regimen Cabotegravir & Rilpivirine (Long Acting Injectable) v Abacavir/Lamivudine/Dolutegravir
Conclusion • Non-inferiority between study arms at Week 48 • Dual therapy arm was less efficacious if starting with CD4 cell count <200/mm3 • Non-inferiority between study arms at Week 148 • Non-inferiority between study arms at Week 48 • Similar tolerability profile supports the role of DTG/3TC in treatment naïve patients at Week 48 • Non-inferiority Vs a TAF based regimen supporting it as a simplification strategy for patients who are virally suppressed at Week 48 • No breakthrough resistance seen in either arm • Non-inferiority between study arms at Week 48 • Long acting injectable CAB & RPV well tolerated
These clinical trial results were reassuring and supported the use of dual therapy in certain
render the entire ARV class Guidelines provided patients have CAB/RPV LA injectable has circumstances and supported their introduction to<500,000 guidelines. Dolutegravir and Lamivudine obsolete); this is known as cross a baseline viral load been approved by the European resistance. Protectionas of a ARV copies/ml option and are in HBsAg is recommended first line treatment the European AIDS Clinical Society Medicines Agency but (EACS) has not 13 classes for future treatment negative . Raltegravir/Darunavir/r been incorporated in the options by avoiding prescribing is listed as an alternative regimen, EACS guidelines. them is a commonly used strategy while Dolutegravir/Rilpivirine is and in practice this would be listed as an option for suppressed Dual antiretroviral therapy has easier to achieve with a dual switch - that is switching a patient been incorporated into HIV ARV regimen6. who has already achieved HIV guidelines around the world for RNA suppression. The introduction both treatment initiation and switch Lower pill burden is also an of dual therapy treatment options therapy; however, it is important advantage of dual therapy and is is mirrored in worldwide HIV associated with higher rates of to note it’s place in prescribing in guidelines such as the US Center adherence to HIV treatment and HIV. Patients should be carefully for Disease Control and Prevention better virologic outcomes7. The selected and each clinical scenario (CDC) Guidelines, Australasian research also showed that onceassessed on an individual basis. Society for HIV, Viral Hepatitis and daily regimes had better adherence At present, those with a history Sexual Health Medicine (ASHM) than twice-daily regimes, however of poor adherence, documented and British HIV Association they did not have advantages in resistance, Hepatitis B, (BHIVA) Guidelines. terms of virologic suppression. tuberculosis or who are pregnant Many first-world countries have In January 2021 the US Food should not be treated with dual access to several combination and Drug Authority (FDA) antiviral therapy. The potential single tablet antiretroviral regimens approved the first long-acting (LA) however this is not equitable benefits of reduced renal and bone injectable antiretroviral regimen around the world. In this scenario toxicity, adherence and tolerability Cabotegravir (CAB)/Rilpivirine dual therapy as two tablets may and reduced cost are predicted. (RPV) and in February 2021 this still prove preferable and beneficial At present more real world data was incorporated into the US to patients. Dual therapy provides is required to assess benefits of HIV treatment guidelines14. The an opportunity for cost-effective panel recommends the CAB/RPV dual therapy long term. Studies of prescribing as several ARVs monthly intramuscular injection two-drug combinations are also used in clinical practice have can be used as an optimisation necessary to evaluate the debated expired patents, allowing for the strategy for patients currently on existence of low viral replication in production of generic versions. antiretroviral therapy who fit the Lamivudine was first licenced in tissues and on immune activation following criteria: Europe in 1996, Ritonavir in 1997 and onward transmission15. and Darunavir in 2007; generic • Suppressed HIV RNA for at least Dual antiretroviral therapy versions of each are available 3 months represents a suitable long-term on the Irish market. Dual therapy • No baseline resistance to either single tablet antiretroviral regimes option for people living with HIV medication are likely to be covered by in clinical practice. While there is patents for the foreseeable future; no need to urgently switch • Do not have active Hepatitis B therefore prescribing individual patients on stable three drug (unless on HBV treatment) medicines including a generic antiretroviral regimes; dual therapy should be considered. • Are not pregnant or planning is worth considering in future pregnancy These clinical trial results were treatment decisions. reassuring and supported the • Are not receiving medication References available on request use of dual therapy in certain that may interact with oral or circumstances and supported injectable CAB or RPV their introduction to guidelines. • Tolerate a four week lead in of Dolutegravir and Lamivudine oral therapy with CAB and RPV is recommended as a first line before initiation of the longtreatment option in the European AIDS Clinical Society (EACS) acting IM injectable
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Launching Launchingour our powder powder for forconcentrate concentrate for for solution forinfusion infusion for Anidulafungin 100mg 100mg Anidulafungin
PRESCRIBING INFORMATION: Consult the Summary of Product Characteristics for further information. Additional information is available upon request. Anidulafungin Fresenius Kabi 100mg powder for concentrate for solution for infusion. Active ingredients: Each vial contains 100mg anidulafungin. Indications: Treatment of invasive candidiasis in adults. Posology and method of administration: Treatment should be initiated by a physician PRESCRIBING INFORMATION: Consult the Summary of Product Characteristics forfungal further information. Additional information available upon request. Anidulafungin Fresenius KabiSingle 100mg200mg powder for concentrate experienced in management of invasive fungal infections. Obtain specimens for culture prior to therapy; treatment can beisstarted before results are known and adjusted accordingly. loading dose on day 1 for solution for infusion. ingredients: Each vialduration containsbased 100mg Indications: of invasivetherapy candidiasis adults. Posology method administration: Treatment should by a physician followed by 100mgActive daily thereafter. Treatment onanidulafungin. patient’s clinical response. InTreatment general, antifungal shouldincontinue for at leastand 14 days afteroflast positive culture. Insufficient databe toinitiated support 100mg dose for longer than 35 days of No dosing adjustments for for adults withculture renal insufficiency (including those can on dialysis) or hepatic or for weight, gender,accordingly. ethnicity, HIV positivity or loading elderly. Safety experienced in management of treatment. invasive fungal infections. Obtainrequired specimens fungal prior to therapy; treatment be started before impairment, results are known and adjusted Single 200mg dose onand day 1 efficacy have not established in children and adolescents below 18 clinical years ofresponse. age. Method of administration: intravenous only. Reconstitute waterafter for injections to aculture. concentration of 3.33mg/ml and subsequently followed by 100mg dailybeen thereafter. Treatment duration based on patient’s In general, antifungalFortherapy shoulduse continue for at leastwith 14 days last positive Insufficient data to support 100mg dose dilutethan to 0.77mg/ml (see SmPC). Rate of infusion should notrequired exceed 1.1mg/min 1.4ml/min when reconstituted and diluted or perhepatic instructions). Must not be given as gender, bolus injection. Contraindications: for longer 35 days of treatment. No dosing adjustments for adults(equivalent with renal to insufficiency (including those on dialysis) impairment, or for weight, ethnicity, HIV positivity or Hypersensitivity elderly. Safety and to the substance, any ofinthe excipients or other medicinal the echinocandin class. SpecialFor warnings and precautions for use: Haswith notwater been for studied in patients with Candida endocarditis, or efficacy haveactive not been established children and adolescents below products 18 years ofofage. Method of administration: intravenous use only. Reconstitute injections to a concentration of 3.33mg/mlosteomyelitis and subsequently Efficacy has onlyRate beenofevaluated in a limited number1.1mg/min of neutropenic patients. Monitor patients with increased hepatic enzymes during treatment forbe evidence of bolus worsening hepatic function and evaluate for risk/ dilutemeningitis. to 0.77mg/ml (see SmPC). infusion should not exceed (equivalent to 1.4ml/min when reconstituted and diluted per instructions). Must not given as injection. Contraindications: Hypersensitivity continuedany therapy. reactions (includingproducts shock) have been reported; if these occur discontinue anidulafungin and Has administer appropriate Infusion-related adverse events reported or to thebenefit active ofsubstance, of theAnaphylactic excipients or other medicinal of the echinocandin class.reactions Special warnings and precautions for use: not been studied intreatment. patients with Candida endocarditis, osteomyelitis (infrequent when rateevaluated does not exceed 1.1mg/min). when co-administering anidulafungin andwith anaesthetic – may be exacerbation of infusion-related Patients with function rare hereditary problems meningitis. Efficacy hasinfusion only been in a limited numberCare of neutropenic patients. Monitor patients increasedagents hepatic enzymes during treatment for evidencereactions. of worsening hepatic and evaluate for of risk/ fructose intolerance should not take unless strictly necessary. Not recommended during pregnancy unless maternal benefit clearly outweighs and potential foetal risk. Unknowntreatment. whether anidulafungin is excreted humanreported milk. benefit of continued therapy. Anaphylactic reactions (including shock) have been reported; if these reactions occur discontinue anidulafungin administer appropriate Infusion-related adverseinevents Undesirable allexceed cause adverse reactions from 840 subjects receiving 100mg anidulafungin - Very common Hypokalaemia, nausea. Common (≥1/100 to <1/10): Hyperglycaemia, (infrequent when effects: infusionFrequency rate doesofnot 1.1mg/min). Care when co-administering anidulafungin and anaesthetic agents –(≥1/10): may be exacerbationdiarrhoea, of infusion-related reactions. Patients with rare hereditaryconvulsion, problems of headache, hypotension, hypertension, dyspnoea, vomiting, increased alanine aminotransferase, increased blood alkaline phosphatase, increased aminotransferase, increased blood bilirubin, cholestafructose intolerance should not take unlessbronchospasm, strictly necessary. Not recommended during pregnancy unless maternal benefit clearly outweighs potential foetal aspartate risk. Unknown whether anidulafungin is excreted in human milk. sis, rash, pruritis, increased blood creatinine. Uncommon (≥1/1000 to <1/100): Coagulopathy, flushing, hot flush, upper abdominal pain, gamma-glutamyltransferase increased, urticaria, infusion site pain. Frequency not known: Undesirable effects: Frequency of all cause adverse reactions from 840 subjects receiving 100mg anidulafungin - Very common (≥1/10): Hypokalaemia, diarrhoea, nausea. Common (≥1/100 to <1/10): Hyperglycaemia, convulsion, Anaphylactic shock or anaphylactic reaction. Legal Category: POM Marketing Authorisation Number: PA2059/071/001. Marketing Authorisation Holder: Fresenius Kabi Deutschland GmbH, Else-Kroener Strasse 1, Bad Homburg headache, hypotension, hypertension, bronchospasm, dyspnoea, vomiting, increased alanine aminotransferase, increased blood alkaline phosphatase, increased aspartate aminotransferase, increased blood bilirubin, cholestav.d.H 61352, Germany Further Information: See the SmPC for further details. Adverse events should be reported. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, sis, rash, pruritis, increased blood creatinine. Uncommon (≥1/1000 to <1/100): Coagulopathy, flushing, hot flush, upper abdominal pain, gamma-glutamyltransferase increased, urticaria, infusion site pain. Frequency not known: Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517. Website: www.hpra.ie, E-mail: firstname.lastname@example.org. Adverse events should also be reported to Fresenius Kabi Limited via email Pharmacovigilance.GB@ Anaphylactic shock or anaphylactic reaction. Legal Category: POM Marketing Authorisation Number: PA2059/071/001. Marketing Authorisation Holder: Fresenius Kabi Deutschland GmbH, Else-Kroener Strasse 1, Bad Homburg Fresenius-Kabi.com. Date of Preparation: March 2021 API/Anidulafungin/01 v.d.H 61352, Germany Further Information: See the SmPC for further details. Adverse events should be reported. 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: email@example.com. Adverse events should also be reported to Fresenius Kabi Limited via email Pharmacovigilance.GB@ Fresenius-Kabi.com. Date of Preparation: March 2021 API/Anidulafungin/01
Fresenius Kabi Limited Fresenius Kabi Ireland Unit 3BKabi Fingal Bay Fresenius Limited Balbriggan, Dublin Fresenius Kabi Co. Ireland Ireland Unit 3B Fingal Bay
Balbriggan, Co. Dublin Ireland
Website: www.fresenius-kabi.com/ie/ Email: FKfirstname.lastname@example.org Phone: +353 (0)1 841 3030 Website: www.fresenius-kabi.com/ie/
Email: FKemail@example.com Phone: +353 (0)1 841 3030
Date of Prep: April 2021 Job Code: IV/ANI/01/21
Date of Prep: April 2021 Job Code: IV/ANI/01/21
20 PHARMACY REVIEW: OPIOIDS
Trends in Strong Opioid Prescribing in Ireland Written by Bridget Norris & Dr Amelia Smith, School of Medicine, Trinity College Dublin gender. The number of GMS eligible patients aged 16 years and over during each year of the study period ranged from 1,219,749 to 1,421,795. Key Findings • The prescribing prevalence of strong opioids increased over the study period from 14.43% in 2010 to 16.28% in 2019, with the greatest increase in the ≥65 years age group. • Overall, the prescribing prevalence of strong opioids in the GMS population aged ≥65 years was twice that in the population aged 16-64 years; it increased from 20.3% in 2010 to 23.48% in 2019.
Bridget Norris, School of Medicine, Trinity College Dublin
Dr Amelia Smith, School of Medicine, Trinity College Dublin
Opioid analgesics are commonly used to effectively manage acute, terminal and cancer pain. However, there is limited evidence to support their long-term use in chronic non-cancer pain. Opioids are associated with harms such as misuse, addiction and fatal overdose. In addition, the use of opioid analgesics in the elderly can be problematic, due to an increased risk of cognitive issues, falls and fractures. Furthermore, there are concerns that increases in opioid prescribing may lead to increases in the abuse and diversion of opioids.
published in the journal Pharmacoepidemiology and Drug Safety (doi:10.1002/pds.5247), has examined recent trends in strong opioid prescribing in Ireland.4 The researchers carried out a repeated cross-sectional analysis of the Health Service Executive-Primary Care & Reimbursement Service (HSE-PCRS) pharmacy claims database between 2010 and 2019 to identify adults, aged 16 years and over that were prescribed a strong opioid, under the General Medical Services (GMS) scheme.
Despite these issues, there has been a well-documented increase in prescription opioid use in many developed countries over the past twenty years, most notably in the United States. Studies in European countries have demonstrated increasing trends in opioid prescribing for chronic non-cancer pain.1,2 A 2019 report by the Organisation for Economic Co-operation and Development (OECD) highlighted that opioidrelated deaths in Ireland are higher than the OECD average, with an increasing trend evident from 2011 to 2016.3 There is a paucity of research on strong opioid prescribing in Ireland. A new study by a team of researchers in Trinity College Dublin and the Health Service Executive’s Medicines Management Programme,
The researchers categorised opioids as ‘strong’ in accordance with the British National Formulary classification.5 The following strong opioids were included in the study: morphine, morphine combinations, hydromorphone, buprenorphine, fentanyl, oxycodone, oxycodone and naloxone, pethidine, tapentadol, tramadol, tramadol and paracetamol and tramadol and dexketoprofen. The analysis was conducted in terms of prescribing prevalence (number of individuals receiving a strong opioid prescription in the year x 100/number of GMS eligible individuals for that year). In addition, defined daily dose (DDD) per 1,000 population per day was calculated for each study year, as this metric takes dose and treatment duration into account. The data was stratified by route of administration, age (16-64 years and ≥65 years) and
AUGUST - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE
• The prescribing prevalence of strong opioids in the female GMS population was 1.3 times that of the male GMS population. • Non-combination oxycodone demonstrated a 2.1-fold increase in prescribing prevalence over the study period, while oxycodone and naloxone increased 5.2-fold between 2011 and 2019. • The prescribing prevalence and DDD per 1,000 population per day of tapentadol increased 8.8fold and 9.9-fold, respectively between 2012 and 2019. • Tramadol was the most commonly prescribed, accounting for 63.9% of total strong opioid prescribing. There was a decrease in the prescribing prevalence of tramadol over the ten-year period, from 10.80% to 8.47%. • The use of transdermal strong opioid formulations increased markedly over the ten-year period. The Medicines Management Programme aims to provide sustained national leadership relating to safe, effective, and cost-effective prescribing in Ireland, in collaboration with the National Medicines Information Centre (NMIC), the National Centre for Pharmacoeconomics (NCPE), and the HSE-Primary Care Reimbursement Service (HSEPCRS).The researchers noted that it is possible that the increase in opioid prescribing observed was in part associated with inappropriate prescribing. Further
studies to investigate potentially inappropriate prescribing should be conducted, given the harms associated with opioid analgesics and the uncertainly regarding their benefits in chronic noncancer pain. It is important that strong opioids are initially trialled for a short duration of time, at low doses and treatment ceased if not found to be beneficial. In addition, consideration should be given to the addition of nonpharmacological pain relief options and/or non-opioid analgesics, to reduce the overall opioid burden. The researchers concluded that there was an overall increase in the prescribing of strong opioids in Ireland between 2010 and 2019, particularly in older adults. Tramadol was the most frequently prescribed strong opioid to GMS patients over the study period, while oxycodone and tapentadol prescribing increased markedly in all demographic groups. Continued surveillance of oxycodone, tapendatol and tramadol prescribing in Ireland is warranted. References 1. Zin CS, Chen LC, Knaggs RD. Changes in trends and pattern of strong opioid prescribing in primary care. Eur J Pain. 2014;18(9):1343-1351. 2. Chenaf C, Kabore JL, Delorme J, et al. Prescription opioid analgesic use in France: Trends and impact on morbidity-mortality. Eur J Pain. 2019;23(1):124-134. 3. Organisation for Economic Co-operation and Development. Urgent action needed to address growing opioid crisis. https://www. oecd.org/health/urgent-actionneeded-to-address-growingopioid-crisis.htm. Published 2019. 4. Norris BA, Smith A, Doran S, Barry M. Trends in strong opioid prescribing in Ireland: A repeated cross-sectional analysis of a national pharmacy claims database between 2010 and 2019. Pharmacoepidemiol Drug Saf. doi:10.1002/pds.5247 5. Joint Formulary Committee. British national formulary 78. London: British Medical Association and Royal Pharmaceutical Society of Great Britain; 2020.
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22 PHARMACY REVIEW: MENTAL HEALTH
Ketamine for Treatment-Resistant Depression: Can you teach an old dog new tricks? Written by Ciara Ni Dhubhlaing MPharm, MSc, MPSI, MCMHP Chief Pharmacist, St. Patrick's University Hospital, Dublin and President of the College of Mental Health Pharmacy (CMHP)
Treatment resistant depression (TRD) is most often defined as a minimum of two antidepressant treatment failures despite adequate dose and duration.1 Rates of TRD have been estimated at up to one third of the total population diagnosed with depression.2 Compared to treatment-responsive depression, this represents significant additional healthcare and productivity costs (2013 US figures estimate $5,481 and $4,048 higher per annum, respectively).3 A more recent European review noted “TRD patients had significantly lower quality of life, greater work productivity and activity impairment, and increased healthcare resource utilization as compared with non-TRD and general population.”4
the use of older treatment strategies. These include ECT; use of older medications such as tricyclic antidepressants (TCAs) or monoamine oxidase inhibitors (MAOIs); or the less ideal practice of polypharmacy which may involve more than one antidepressant, addition of lithium, or addition of an antipsychotic. The options are therefore limited, carry a greater side effect burden, and are often more costly for health services. It is perhaps reasonable, then, that researchers have looked backwards as well as forwards for innovation and sought to review seemingly redundant medication choices as treatment options in TRD. One such old drug that may have some new tricks is ketamine, a drug familiar as an anaesthetic and with an increasing evidence base suggesting it may be useful in TRD. Ketamine’s antidepressant potential was first reported
The World Health Organisation acknowledged the significant burden of disease & costs associated with depression in 2004 by identifying unipolar depression as the leading global cause of years lost to disease, in high, middle, and low-income countries; in both men and women.5 This does not include the direct impact of suicide, the risk of which is 2 to 4 times higher in patients suffering from affective disorders, and higher again in TRD.6 Given that TRD responds poorly to newer antidepressants, and that patients may be too unwell to engage in psychological interventions, management of this illness often involves
AUGUST - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE
by Berman et al.7 over twenty years ago though its proposed use in psychiatry goes back much further to 1973.8 Berman et al. considered the potential role of glutamate systems in depression and proposed that the N-methyl-D-aspartate (NMDA) receptor antagonist might have an antidepressant effect by disinhibiting glutamate transmission in the brain setting off a cascade of events affecting synaptic plasticity and potentially reversing some effects of chronic stress on the brain. Interestingly, ketamine may be more effective in patients exposed to childhood adversity and trauma.9 It is likely there are several mechanisms of action involved, including some yet to be determined, however the initial successful treatment of seven patients with IV ketamine indicated that the hypothesis had merit. Subsequent and ongoing trials have focused on determining ketamine’s effectiveness versus current TRD treatment options (such as ECT)10 and on refining the dose, duration11, and treatment routes8 to improve acceptability and feasibility of ketamine as a treatment for TRD. This includes a current clinical trial sponsored by Trinity College Dublin with St Patrick’s Mental Health Services
investigating Ketamine as an Adjunctive Therapy for Major Depression [KARMA-Dep-2]. There is also some emerging evidence for ketamine’s efficacy in acute treatment of patients who carry an immediate risk to themselves due to suicidality.12 Currently this risk is managed on inpatient units using sedative benzodiazepines and antipsychotics as so-called ‘major tranquilisers’ in anticipation of other treatments taking effect over time. Though necessary and often life-saving, this can be distressing and traumatic for patients. There is a need for faster-acting targeted treatments in this population. NICE are currently reviewing the place of esketamine nasal spray for TRD in the UK.13 In Ireland, the National Centre for Pharmacoeconomics (NCPE) recommends that esketamine not be considered for reimbursement unless costeffectiveness can be improved relative to existing treatments.14 In the interim, research continues into the novel use of this 40-year old drug to address the unmet needs of a significant proportion of the world’s population. References available on request
Enabling people with depression to feel, think and do better1
Brintellix is indicated for the treatment of major depressive episodes in adults1 Brintellix® (vortioxetine) film-coated tablets Prescribing information: Please refer to the full Summary of Product Characteristics (SPC) before prescribing, particularly in relation to side effects, precautions and contraindications. Presentation: Tablets containing 5, 10, 15 or 20mg vortioxetine. Indication: Treatment of major depressive episodes in adults. Dosage: 10mg once daily. May be increased to a maximum 20mg daily or reduced to 5mg if necessary. After symptoms resolve, treatment recommended for at least 6 months. Can be taken with or without food. Elderly (≥65 years): Initial dosage is 5mg once daily. Caution advised if using doses above 10mg daily. Children (7-11 years): Not recommended. Adolescents (12-17 years): Not recommended in major depressive disorder; efficacy not established. Cytochrome P450 inhibitors and inducers: Consider a dose reduction of vortioxetine if a strong CYP2D6 inhibitor is added. Consider a dose adjustment if a broad CYP450 inducer is added to treatment. Renal or hepatic impairment: No dose adjustment; subpopulations are vulnerable and data on the use of Brintellix are limited. Contraindications: Hypersensitivity to the active substance or excipients. Concomitant use with non-selective, monoamine oxidase inhibitors (MAOIs) or selective MAO-A inhibitors (e.g. moclobemide). Fertility, pregnancy and lactation: Limited data; should only be administered to pregnant women if the expected benefits outweigh the potential risk to the foetus. Animal studies showed reproductive toxicity. Use of SSRIs in pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). Potential risk of postpartum haemorrhage following exposure to an SSRI or SNRI within the month prior to birth. Excreted into human milk, risk to the breastfeeding child cannot be excluded. Animal data showed no effect on fertility, sperm quality or mating performance. Human case reports with some SSRIs have shown that an effect on sperm quality is reversible. Impact on human fertility has not been observed. Please refer to SPC for more detail. Warnings & Precautions: Closely supervise patients, especially those at high risk for suicide-related behaviours during first few weeks of treatment and during dose changes. Use with caution in patients: at risk of hyponatraemia; with a history of mania/hypomania; aggression/agitation; undergoing ECT; with unstable epilepsy (discontinue if seizures begin for the first time or increase in frequency); with bleeding tendencies/disorders, taking anticoagulants or medicines affecting platelet function; in patients on lithium or tryptophan; with increased intraocular pressure, or those at risk of acute narrow angle glaucoma. Monitor patients for appearance of serotonin syndrome or neuroleptic malignant syndrome and discontinue if occurs. Patients may experience feelings of aggression, anger, agitation and irritability. Patients/caregivers should seek medical advice if such behaviour emerges or aggravates. SSRIs/SNRIs may increase the risk of postpartum haemorrhage. Brintellix tablets contain sodium (<1mmol/tablet). Drug interactions: Alcoholic drinks not advisable. Vortioxetine is extensively metabolised in the liver. Potential for interactions with: MAOIs, MAO-A and MAO-B inhibitors; serotonergic medicines; St John’s wort; products which may lower the seizure threshold, e.g. antidepressants, neuroleptics, mefloquine or bupropion. Lower dose may be considered if strong CYP2D6 inhibitor is added to treatment depending on patient response, these effects may be greater in patients who are poor metabolisers of CYP2D6. Dose adjustment may be considered if a broad cytochrome P450 inducer is added to treatment. Reports of false positive results in urine enzyme immunoassays for methadone in patients taking vortioxetine.
Exercise caution in interpreting positive drug screen results. Effects on ability to drive and operate machines: No or negligible influence, dizziness has been reported; use caution at the start of treatment or when the dose is changed. Adverse events: Most common adverse reaction is nausea, usually mild or moderate, transient and occurs within first two weeks of treatment. The following have been reported in clinical trials and during post-marketing use: Very common (≥1/10 patients): nausea. Common (≥1/100 to <1/10): abnormal dreams, dizziness, diarrhoea, constipation, vomiting, pruritus, including generalised pruritus. Uncommon (≥1/1,000 to <1/100): flushing, night sweats. Rare (≥1/10,000 to <1/1,000): mydriasis (which may lead to acute narrow- angle glaucoma). Not known: anaphylactic reaction, hyponatraemia, insomnia, agitation, aggression, serotonin syndrome, haemorrhage (including contusion, ecchymosis, epistaxis, gastrointestinal or vaginal bleeding), angioedema, urticaria, rash. Sexual dysfunction: 20mg dose was associated with increase in sexual dysfunction. Class effect: Studies in patients ≥50 years of age, show an increased risk of bone fractures in patients receiving SSRIs and TCAs. Not known if relevant to vortioxetine. Paediatrics: Higher incidences reported in adolescents for abdominal pain-related events and suicidal ideation. Prescribers should consult the full SPC in relation to other side effects. Overdose: Management consisting of treating clinical symptoms and relevant monitoring. Legal category: POM, for non-renewable supply. Brintellix Tablets, blisters of: 5mg (EU/1/13/891/002) 28 tablets. 10mg (EU/1/13/891/010) 28 tablets. 15mg (EU/1/13/891/019) 28 tablets. 20mg (EU/1/13/891/028) 28 tablets. Further information available from: Lundbeck Ireland Ltd, 4045 Kingswood Road, Citywest Business Park, Co. Dublin. Tel: 01 468 9800. Date of last revision of PI: November 2020. Reference: IE-BRIN-0254. Brintellix® is a Registered Trade Mark. Job number: IE-BRIN-0261 Date of preparation: March 2021
Reference: 1. Brintellix Summary of Product Characteristics. Available at https://www.medicines.ie/medicines/brintellix-10-mg-film-coated-tablets-34817/smpc Adverse events should be reported. Reporting forms and information can be found at www.hpra.ie. Adverse events should also be reported to Lundbeck on: 01 468 9800 Email: SafetyLuIreland@lundbeck.com
Discover Strength of Balance Introducing JYSELECA (filgotinib)– a preferential JAK1 inhibitor for moderate to severe RA1
Indicated for the treatment of moderate to severe active rheumatoid arthritis in adults who have responded inadequately to, or are intolerant to one or more disease modifying anti-rheumatic drugs.1 May be used as monotherapy or in combination with methotrexate.1 Refer to Summary of Product Characteristics (SmPC) before prescribing, and for full prescribing information. JYSELECA®
filgotinib 100 mg or 200 mg film-coated tablets.
Indication: Jyseleca is indicated for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more disease modifying anti-rheumatic drugs (DMARDs). Jyseleca may be used as monotherapy or in combination with methotrexate (MTX). Dosage: Adults: 200 mg once daily. Taken orally with/without food. It is recommended that tablets are swallowed whole. Laboratory Monitoring: Refer to the SmPC for information regarding laboratory monitoring and dose initiation or interruption. Elderly: A starting dose of 100 mg once daily is recommended for patients aged 75 years and older as clinical experience is limited. Renal impairment: No dose adjustment required in patients with estimated creatinine clearance (CrCl) ≥ 60 mL/min. A dose of 100 mg of filgotinib once daily is recommended for patients with moderate or severe renal impairment (CrCl 15 to < 60 mL/min). Not recommended in patients with CrCl < 15 mL/min. Hepatic impairment: Mild moderate hepatic impairment: no dose adjustment required. Severe hepatic impairment: not recommended. Children (< 18 years): Safety and efficacy not yet established. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Active tuberculosis (TB) or active serious infections. Pregnancy. Warnings/ Precautions: See SmPC for full information. Immunosuppression: Combination use, with immunosuppressants e.g. azathioprine, ciclosporin, tacrolimus, or biologic DMARDs (bDMARDs) or other Janus kinase (JAK) inhibitors is not recommended as
a risk of additive immunosuppression cannot be excluded. Infections: Infections, including serious infections such as; pneumonia and opportunistic infections e.g. tuberculosis (TB), oesophageal candidiasis, and cryptococcosis have been reported. In some cases, treatment should be temporarily interrupted. There is a higher incidence of serious infections in the elderly aged 75 years and older, caution should be used when treating this population. Treatment should be interrupted if a patient develops a serious infection until the infection is controlled. Patients should be closely monitored for the development of signs and symptoms of infections during and after filgotinib treatment. Tuberculosis: Patients should be screened for TB before initiating filgotinib, and filgotinib should not be administered to patients with active TB. Viral reactivation: Cases of herpes virus reactivation (e.g., herpes zoster), were reported in clinical studies (see SmPC). If a patient develops herpes zoster, filgotinib treatment should be temporarily interrupted until the episode resolves. Screening for viral hepatitis and monitoring for reactivation should be performed. Malignancy: Immunomodulatory medicinal products may increase the risk of malignancies. Malignancies were observed in clinical studies (see SmPC). Fertility: In animal studies, decreased fertility, impaired spermatogenesis, and histopathological effects on male reproductive organs were observed (see SmPC). The potential effect of filgotinib on sperm production and male fertility in humans is currently unknown. Haematological abnormalities: Do not start therapy, or temporarily stop, if Absolute Neutrophil Count (ANC) <1 × 109 cells/L, ALC <0.5 × 109 cells/L or haemoglobin <8 g/dL Temporarily stop therapy if these values are observed during routine patient management. Vaccinations: Use of live vaccines during, or immediately prior to, filgotinib treatment is not recommended. Lipids: Treatment
JYSELECA, GILEAD and the JYSELECA and GILEAD logos are registered trademarks of Gilead Sciences, Inc. or one of its related companies. © 2021 Gilead Sciences, Inc. All rights reserved.
JYSELECA is now reimbursed and will be dispensed under the High Tech Arrangement effective March 1st 2021
JYSELECA 200 mg offers a balance of sustained efficacy from Week 2 to Week 52,2 with acceptable tolerability and low rates* of JAK inhibitor-associated adverse events1,3† ACR20 response seen by Week 2 in 37% of JYSELECA patients (n=475) vs. 15% of those in the placebo group (n=475; p<0.001)2 By Week 52, 44% of JYSELECA patients had achieved ACR70 response (n=475)2 Similar observed rates of serious infections and herpes zoster vs. adalimumab2,3 * Based on AE rates observed as ‘Uncommon’ (<1% and >0.1%) or of lower frequency in the JYSELECA clinical trials.1,3 ACR, American College of Rheumatology; MTX, methotrexate. † JAK-associated adverse events defined as VTEs, Herpes Zoster Reactivation and Serious Infections.4
Visit strengthofbalance.co.uk to learn more with filgotinib was associated with dose dependent increases in lipid parameters, including total cholesterol, and high-density lipoprotein (HDL) levels, while low density lipoprotein (LDL) levels were slightly increased (see SmPC). Cardiovascular risk: Rheumatoid arthritis patients have an increased risk for cardiovascular disorders. Patients should have risk factors (e.g., hypertension, hyperlipidaemia) managed as part of usual standard of care. Venous thromboembolism: Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving JAK inhibitors including filgotinib. Caution should be used in patients with risk factors for DVT/PE, such as older age, obesity, a medical history of DVT/ PE, or patients undergoing surgery, and prolonged immobilisation. Lactose content: Contains lactose; patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take filgotinib. Interactions: Co-administration with sensitive OATP1B1 or OATP1B3 substrates (e.g., valsartan, statins) is not recommended. See SmPC for full list. Pregnancy/Lactation: Filgotinib is contraindicated in pregnancy. Filgotinib should not be used during breast-feeding. Women of childbearing potential must use effective contraception during and for at least 1 week after cessation of treatment. Driving/Using machinery: No or negligible influence, however dizziness has been reported. Side effects: See SmPC for full information. Common (≥1/100 to <1/10): nausea, upper respiratory tract infection, urinary tract infection and dizziness. Uncommon (≥1/1000 to <1/100): herpes zoster, pneumonia, neutropenia and blood creatine phosphokinase increase. Serious side effects: See SmPC for full information Legal category: POM Pack: 30 filmcoated tablets/ bottle Price: UK Basic NHS cost: £863.10 Ireland: POA Marketing
authorisation number(s): Great Britain: PLGB 11972/0033, PLGB 11982/0034. Ireland & United Kingdom (Northern Ireland): EU/1/20/1480/001, EU/1/20/1480/003 Further information: Gilead Sciences Ltd, 280 High Holborn, London, WC1V 7EE, Great Britain & Northern Ireland: +44 (0) 8000 113700; Ireland: +353 214825999. email@example.com. Jyseleca® is a trade mark. Date of Preparation: February 2021 UK-INF-2021-01-0032 Additional monitoring required Adverse events should be reported. For Great Britain & Northern Ireland, reporting forms and information can be found at www.mhra.gov.uk/yellowcard or via the Yellow Card app (download from the Apple App Store or Google Play Store). Adverse events should also be reported to Gilead to safety_FC@gilead.com or +44 (0) 1223 897500.
Adverse events should be reported. For Ireland, reporting forms and information can be found at www.hpra.ie and can be reported to HPRA on +353 1 6764971. Adverse events should also be reported to Gilead to safety_FC@gilead.com or +44 (0) 1223 897500.
References: 1. JYSELECA SPC. Available at: www.medicines.ie. Last accessed: March 2021. 2. Combe B, et al. Ann Rheum Dis 2021;doi:10.1136/annrheumdis-2020-219214. 3. Genovese MC, et al. Poster presented virtually at the European League Against Rheumatism (EULAR) 2020 E-Congress, June 3–6, 2020. 4. Angelini J, et al. Biomolecules 2020;10(7):E1002. doi: 10.3390/biom10071002. Date of preparation: March 2021 Job code: UK-INF-2021-03-0036
26 PHARMACY REVIEW: DOSE BANDING
Dose Banding Systemic Anti-Cancer Therapy in England Written by Richard Nuttall Richard is an electronic prescribing pharmacist who has been working at the Royal Marsden NHS Foundation Trust since 2008. He has a background in paediatric and haemato-oncology from work at Great Ormond Street Hospital and has helped develop electronic chemotherapy prescribing at the Royal Marsden. His work on the national dose banding project won an HSJ Award in 2017.
Doses of cytotoxic drugs are traditionally calculated using patient body surface area, on the assumption that there is a rough correlation between this and metabolic rate. A reasonable number of the mainly newer agents are also dosed by weight (mg/ kg), with carboplatin standing out as the only one dosed according to renal function. This has resulted in a situation where the majority of systemic anti-cancer treatments (SACTs) are supplied as individualised patient doses. Add to this the requirement to check and possibly adjust doses each cycle, and we add a significant burden on the system to prescribe and supply in time.
• Convert one series of dose bands to a series of volumes instead. From that the dose bands for any drug could be derived simply by multiplying out the volume by the raw material strength of the drug. Core Principles We had a working group in Manchester to agree the master volume set from which all inexpensive chemotherapy drugs could then be banded. To ensure the bands are measurable in the aseptic unit we used the markings on the relevant syringe sizes: 0.01 mL on 1 mL syringes, 0.2 mL on 3 mL, 5 mL and 10 mL syringes, and 1 mL for anything larger. All doses up to 50 mL must be able to be drawn up in a single syringe. Combining smaller and larger syringes to improve the accuracy of larger doses must be avoided for introducing unnecessary steps in aseptic manipulation and is not mathematically required.
from going down. 6% is also applied to antibody-conjugates (e.g. polatuzumab vedotin) as the conjugate is often related to traditional SACT. This variance was increased again in biological agents which do not have a narrow therapeutic index (e.g. monoclonal antibodies). A 20% dose reduction can usually be achieved by dropping two dose bands. An inventory of five dose bands will cover more than 70% of patient doses for a given surface area-based dose. And finally, because the tables are roughly logarithmic in scale, the ‘step points’ between bands are not exactly halfway but fall slightly lower, using the square root of the upper and lower band squared. Implementation
The nationwide implementation of dose banding has been a huge success. The first wave of tables were published by NHS England in April 2016. Hospital Trusts were encouraged to adopt the new Other core principles followed (see bands using a financial incentive Figure 1). More expensive drugs scheme which rewarded them require the bands adjusted to land with payment based on meeting on vial sizes where possible. If and automate the methodology percentage targets on the listed fractions of a vial were needed, we of dose banding such that new drugs. This success is highlighted ensured these were either perfectly drugs could be banded quickly with bortezomb which started and accurately. In around 2015 two equal, or rounded down to the off already matching 60% of the nearest measurable dose. (This core principles evolved. national dose bands but quickly means that 2.4 mL is used for half • Dose band ranges of doses rose to over 95%. This also a 5 mL vial for example). (as opposed ranges of is often related to traditional SACT. This variance illustrates many of the dose vedotin) as thetoconjugate wasthat increased again in We agreed the maximum variance patient weight, surface area bands that were calculated were biological agents which do not have a narrow therapeutic index (e.g. monoclonal antibodies). a calculated dose could be from or creatinine clearance). This sensible and were already in use. means it doesn’t matter how the standard dose of a band. We See figure 2. the dose calculated,can andusually be pushed this toby6% to allow two for dose bands. An inventory of five A 20% doseisreduction achieved dropping the bands could be used Paediatrics were not included. quirks that logarithmic scales dose will cover more than 70% of patient doses for a given surface area-based dose. And for bands drugs which have similar produce when percentages Evidence is emerging that there is concentrations or doses. finally, because the tables are roughly logarithmic in scale, the ‘step points’ between not going up are slightly different no clinical reason bands to avoidare banding
exactly halfway but fall slightly lower, using the square root of the upper and lower band squared. Figure 1: The nine core principles of dose banding adopted by NHS England
One approach to reducing this burden is to introduce of dose banding. This is a system where doses are grouped into predefined ranges (or bands) and for each band a ‘standard dose’ that lies at the mid-point is supplied for any dose calculated to be within the band. Given the flexibility in choosing the size of your bands, and which dose becomes standard, many different versions evolved across the UK. Whilst working at the Royal Mardsen Hospital, a tertiary oncology centre in London, I was attempting to standardise
Figure 1: The nine core principles of dose banding adopted by NHS England.
AUGUST - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE
Figure 2: Data showing the impact of the incentive scheme on the increase in the percentage of bortezomib doses that matched the national dose bands. The incentive scheme commenced in April 2016.
provides within NHS England.
provide the full product definitions for SACT. This will include recommendations for stability, fluid type and volume, and volume range cut-offs for concentrationdependent drugs (e.g. paclitaxel). All of this complements the banding tables to provide a complete and robust product definition.
The next steps are well underway. We now include dose banding as part of the submission to
A centralised evidence-based web service is currently in the final stages of development which will
The first licenced banded products have reached the UK market now with gemcitabine, and irinotecan.
Figure 2: Data showing the impact of the incentive scheme on the increase in the percentage of in children, and most centres will inventory ranges are much larger NICE for all relevant new SACT bortezomib doses that matched theand national dose bands. The incentive scheme commenced in April round doses up to 5% already. submissions. This is a service stockholdings per dose lower. It would probably be easier to a working group I participate in 2016.
continue the same system for adults and paediatrics in electronic prescribing systems. Some of the benefits seen in adults will not materialise however as the Future Directions
The next steps are well underway. We now include dose banding as part of the submission to NICE for all relevant new SACT submissions. This is a service a working group I participate in provides within NHS England.
Review Pharmacy News
A centralised evidence-based web service is currently in the final stages of development which will provide the full product definitions for SACT. This will include recommendations for stability, fluid type and volume, and volume range cut-offs for concentration-dependent drugs (e.g. paclitaxel). All of this complements the banding tables to provide a complete and robust product definition.
European Association of Hospital Pharmacists: Congress 2022 The 2022 European Association of Hospital Pharmacists (EAHP)
diversity, I firmly believe that all of us will gather to celebrate the
therapeutic modalities have brought about many challenges
touch of pharmaceutical care are paving the way towards the future of our profession.
EAHP President says, “While these unprecedented times have turned our world upside down, our profession has prevailed and hospital pharmacists have never ceased to proactively adapt to a changing world in order to continuously serve our patients best interests.
the loss the pandemic made us endure. This new beginning will also bring about a vast of novel scientific and practical knowledge upon which we can further develop and strengthen our services for our patients in Europe and beyond. Therapeutic possibilities are growing rapidly in several disease groups, including those for which treatment options have been seriously limited for many decades. These emerging
services are delivered. Hospital pharmacists have to acquire more knowledge related to immunology, infection control, the human genome, cell regulation and much more. Besides these novel therapeutic areas, our emerging competencies of frontline patient care in the clinical setting call for new and changing roles of our profession. These "high tech" modalities, going hand-in-hand with the irreplaceable personal
“Besides the professional and methodological challenges, healthcare systems all over the world have to find a way to employ these new possibilities with the limited resources that are available. That rather complex issue calls for a deep involvement and input from hospital pharmacists as well. I am sure that the scientific programme at the Congress will help all of us to face these challenges and find valid answers.”
The firstCongress licencedwill banded have reached the up UKinmarket with gemcitabine, andand they hospital pharmacists to meet person now for Annual be heldproducts opportunity keep changing the way pharmacy again and to commemorate all in March 2022. Dr Andras Sule, irinotecan.
“Fortunately, EAHP has proved resilient during this period and continued to work hard for the upcoming EAHP 2022 Congress undaunted by the challenges our Association has to face. We are very much looking forward to welcoming you in Vienna, on March 23rd, 2022 when spring will, hopefully, be already shining its heart-warming light on the Danube Valley. “Spring, being the season of awakening, a period when nature applauds life with colourful
HOSPITALPROFESSIONALNEWS.IE | HPN • AUGUST - 2021
28 HOSPITAL REVIEW: FRAILTY
Frailty Identification: Positively Impacting Ireland’s Future Health and Social Care Policy A new study from ageing experts at The Irish Longitudinal Study on Ageing (TILDA) at Trinity College, highlights the potential benefit of using the Clinical Frailty Scale (CFS) in community-based healthcare assessments, to better inform patterns of health and social care utilisation and help improve allocation of care resources for older adults. The study contains pertinent information for healthcare providers and planners to help prepare and improve the future of overall care for Ireland’s growing ageing population, using targeted interventions. By 2030, one in five adults in Ireland will be 65 years or older. This research is particularly relevant following increased policy interest to consider frailty measures (rather than chronological age alone) to inform fair and equitable distribution of health and social care resources. What does the study show? The Clinical Frailty Scale (CFS) has attracted interest for its simplicity and consideration of multiple health concerns that affect older people such as multimorbidity, impaired mobility, low levels of physical activity, dependency on others, and memory problems. Using data from Wave 5 of TILDA, researchers applied the Clinical Frailty Scale tree to divide older adults aged 65 and over into sub-groups to assess acute medical service needs, community-based healthcare needs, and formal and informal social care supports. The CFS does not assess other important geriatric domains (Figure 1), but the assessed dimensions are reasonably comprehensive and can not only be scored by doctors but a wide range of healthcare and allied health professionals19. In addition, even though the CFS does not directly assess some important dimensions, it can do so indirectly, since geriatric syndromes tend to overlap (Figure 1). Frailty and its impact on Ireland’s growing ageing population In older adults, frailty occurs when several systems in the body gradually lose their inbuilt reserves. This can have a negative influence on health, as older people living with frailty face more adverse impacts when exposed to infection, illness or injury compared to those with more robust health reserves.
Frailty is not a medical diagnosis, and the good news is that it is not an inevitable part of ageing. In many cases, it can be delayed and even reversed. As society gradually re-emerges from the COVID-19 crisis, this has led to a greater need for rehabilitative and social care supports for older adults, following not only COVID-19 related illnesses, but a rise in cases of de-conditioning in those who had to ‘cocoon’. There is also an increased policy emphasis on the enhancement of community-based supports to ensure that the right care is available in the right place at the right time (and as close to home as possible), so that everyone will have equitable access to services based on need. In this context, the proactive identification of those in greater need, and the provision of timely inter-ventions to prevent or delay frailty in older adults is more important than ever. KEY FINDINGS • According to the CFS classification, only a minority (about 30%) of adults aged 65 or more in the community were living with some degree of frailty (CFS 4 or more). • Increasing CFS categories were associated with a sharp rise in the use of hospital and community health services, and hours of formal and informal social care provision. • The benefit of TILDA being a long-term longitudinal study is that over the course of 8 years, it was clear that the CFS status of older individuals is dynamic over time, with improvements evident.
• Given how dynamic frailty is, the study recommends that if used in the community, the CFS status of individuals is reviewed at least every 2 years. The findings from this study serve as an important resource for policymakers and planners to aid Ireland’s future health policy, addressing priorities identified in the recent Sláintecare Implementation Strategy and Action Plan 2021 — 2023 to reduce avoidable hospital admissions and support ageing in place. The study also signifies the importance of implementing and appropriately resourcing community-based ‘hubs’ and integrated care programmes for older people. Implementation of the national falls prevention programme, and increased capacity in reablement, frailty and enhanced intermediate short stay care will bolster prevention and healthy living programmes and improve healthcare delivery.
healthier lives. This is particularly important for older people. This latest piece of TILDA research provides vital insight for healthcare planners and policymakers to consider the proactive identification of frailty in the community, as part of a strategy that enhances community-based integrated care to reduce avoidable hospitalisations and help our older people stay well at home for as long as possible.” Senior Research Fellow, TILDA Biobank Manager and first author of the study, Dr Aisling O’Halloran said, “Ageing in place is a key goal of the Irish National Positive Ageing Strategy, which explicitly outlines the Government’s policy of supporting older people to live in dignity and live independently in their own homes or communities as long as is feasible. Previous research has shown the utility of the CFS, rather than chronological age, to predict mortality, negative health outcomes and healthcare utilisation in older people across clinical settings in Canada. Our research highlights how this model can be replicated in the Irish context to show the average levels of health and social care utilisation that can be expected for our ageing population. This evidence is of vital importance for health and social care service planning and delivery into the future which will benefit healthcare access, health outcomes and quality of life for Ireland’s older people.”
Associate Professor, Consultant in Medical Gerontology in Trinity, and member of the TILDA Leadership team, Professor Roman RomeroOrtuno said, “Sláintecare presents a pathway to reform and strengthen Ireland’s health system and policy to meet the needs of our growing population. Elements of the recent Sláintecare Implementation Plan focus on prevention and successful interventions to reduce the prevalence of unhealthy behaviours Figure 1. Geriatric dimensions assessed byFigure the Clinical Frailtydimensions Scale (in red). 1. Geriatric assessed that contribute to chronic disease, by the Clinical Frailty Scale (in red) to help people live longer and Figure 1. Geriatric dimensions assessed by the Clinical Frailty Scale (in red).
• For example, older people who were classified as ‘Vulnerable’ at one wave, had a 22% probability of being classified as “Fit” 2 years later. • Findings suggest the CFS classification was able to segment the TILDA population aged 65 years and over into subgroups with increasing health and social care needs; and suggests CFS could be used (as part as an integrated assessment) to aid the allocation of health and social care O'Halloran AM, Hartley P, Moloney al. Informing patternsofofhealth health and and social O'Halloran AM, Hartley P, Moloney D etDal.etInforming patterns socialcare care resources in older people in utilisation Irish people older people according to the Clinical FrailtyScale Scale[version [version 1]. utilisation in Irishinolder according to the Clinical Frailty 1]. HRB HRBOpen OpenRes Res 2021, 4:54 (doi: 10.12688/hrbopenres.13301.1) 2021, 4:54 (doi: 10.12688/hrbopenres.13301.1) Ireland.
AUGUST - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE
DIFFERENT QUESTIONS SAME ANSWER. EPCLUSA offers a simplified pathway to HCV cure1,2 EASL defines cure as SVR i.e. undetectable HCV RNA after treatment completion.1
Pan-genotypic1 and pan-fibrotic1,a
1 tablet, once a day3,b Except when coadministered with ribavirin3
No food requirement3 Except when coadministered with ribavirin or PPIs3 Coadministration with PPIs is not recommended3
Suitable despite unknowns in liver fibrosis stage2
Suitable as a test-and-treat option1,2,4,c EPCLUSA renders genotyping unnecessary1,2,4
94% SVR for PWID with varied adherence5
Not actual patients.
Please click here to access EPCLUSA Prescribing Information
EPCLUSA is indicated for the treatment of chronic hepatitis C virus (HCV) infection in patients aged 6 years and older and weighing at least 17 kg.3 See the SmPC or UKPI for complete dosing information. Adverse events should be reported. For the UK, reporting forms and information can be found at https://yellowcard.mhra.gov.uk or via the Yellow Card app (download from the Apple App Store or Google Play Store). For Ireland, Reporting forms and information can be found at www.hpra.ie and can be reported to HPRA on +353 1 6764971. Adverse events should also be reported to Gilead safety_FC@gilead.com or +44 (0) 1223 897500.
Abbreviations: AE = adverse event; CPT = Child-Pugh-Turcotte; DAA = direct-acting antiviral; EASL = European Association for the Study of the Liver; GT = genotype; HBV = hepatitis B virus; HCV = hepatitis C virus; IFN = interferon; LTFU = lost to follow-up; NS5A = nonstructural protein 5A; PPI = proton-pump inhibitor; PWID = people who inject drugs; RBV = ribavirin; RNA = ribonucleic acid; SmPC = Summary of Product Characteristics; STR = single-tablet regimen; SVR = sustained virological response. Footnotes: a Assessment of liver disease severity is recommended prior to initiating treatment with EPCLUSA and is recommended by EASL guidelines.1,3 b EPCLUSA offers an RBV-free STR option for the majority of HCV patients, excluding those with decompensated cirrhosis. For further information on restrictions, please refer to the SmPC. RBV is recommended for the treatment of patients with decompensated cirrhosis and may be considered for the treatment of HCV GT3 patients with compensated cirrhosis. 3 c Cases of HBV reactivation, some of them fatal, have been reported during or after treatment with DAA agents. HBV screening should be performed in all patients before initiation of treatment. HBV/HCV coinfected patients are at risk of HBV reactivation, and should therefore be monitored and managed according to current clinical guidelines. 3 References: 1. European Association for the Study of the Liver (EASL). J Hepatol 2020;73(5):1170–1218. 2. Mangia A et al. Liver Int 2020;40:1841–1852. 3. EPCLUSA Summary of Product Characteristics, January 2021. 4. World Health Organization. WHO Model List of Essential Medicines 21st List (August 2019). Available from: www.who.int/medicines/ publications/essentialmedicines/en/. Accessed March 2021. 5. Grebely J et al. Lancet Gastroenterol Hepatol 2018;3(3):153–161.
Date of preparation: June 2021 Job code: UK-HCV-2021-01-0006
30 HOSPITAL REVIEW: ASTHMA
An Approach to Asthma Diagnosis Written by Dr Shona Meagher and Dr Breda Cushen
Dr Shona Meagher, MB BCH BAO, is a graduate of University College Cork and a Specialist Registrar in Respiratory Medicine
Dr Breda Cushen, MB BCh BAO, MRCPI, PhD, is a consultant respiratory physician at Beaumont Hospital. She completed respiratory specialist training in Ireland, following which she worked as a consultant physician with expertise in severe asthma at the Royal Brompton Hospital in London, UK. Her specialist interests include the management of chronic airway diseases
non-steroidal anti-inflammatory medications, viral infections or other irritants.
Asthma is a common chronic respiratory disease which affects approximately 10% of the Irish adult population. The term asthma describes a clinical syndrome of breathlessness, chest tightness, wheeze and/or cough. These symptoms result from an exaggerated physiological response to airway irritants which trigger airway inflammation and bronchial hyper-responsiveness. Repeated episodes of airway inflammation lead to hypertrophy of bronchial smooth muscle and mucous glands, increased vascularity and deposition of subepithelial collagen. These structural changes in the bronchial wall are collectively referred to as airway remodelling. A common misconception is that asthma is a disease which always starts in childhood however asthma can develop at any age. Several asthma phenotypes are now recognised including allergy-predominant childhood onset disease, adult onset eosinophilic asthma, aspirin-exacerbated asthma and exercise-induced asthma. Asthma symptoms can range in severity from mild and infrequent, to life-threatening asthma exacerbations. Many patients with asthma will describe periods of relative clinical stability interspersed with episodes of extremely poor symptom control. Often, but not always, patients will be able to identify specific symptom triggers, e.g. exercise, allergens, cigarette smoke,
This characteristic variability in symptom onset, intensity and frequency, means that, despite being such a common condition, asthma can be difficult to diagnose. A Canadian review of self-reported asthma diagnoses found that in one-third of patients asthma was misdiagnosed. Symptoms suggestive of asthma are non-specific and are common to many other acute and chronic disease pathologies. The absence of a single goldstandard diagnostic test adds to the challenge of confirming a diagnosis of asthma however there are several investigations that can support a clinical diagnosis. These focus largely on detecting airflow obstruction or bronchial hyper-responsiveness, and airway inflammation. The identification of specific biomarker profiles characteristic of recognised asthma phenotypes can also aid diagnosis and management. In this review, we discuss investigations currently available to support a diagnosis of asthma, and discuss important pitfalls in their performance and interpretation. Variable Airflow Obstruction Spirometry and serial peak expiratory flow rate measurement are the most commonly employed methods to detect airflow obstruction. Spirometry Spirometry is the gold standard test to confirm airflow obstruction in patients with chronic airways disease and asthma is no exception. An FEV1/FVC ratio of <0.70 is indicative of obstruction. Typically there will be an improvement in FEV1 and/ or FVC values by more than 200 ml and 12% post inhalation
AUGUST - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE
of short-acting beta-2-agonist or muscarinic antagonist. This reversibility of airflow obstruction is a classic feature of asthma but may be absent during severe exacerbations, in patients with long-standing disease who have significant airway remodelling, or in co-existent COPD. Conversely, due to the variable nature of asthma, spirometry may be entirely normal. A diagnosis of asthma cannot therefore be excluded based on a finding of normal spirometry and this finding should prompt further investigation. Asthma demonstrates strong diurnal variation. Airflow obstruction and thus asthma symptoms are typically worse in the early hours of the morning. The timing of spirometry measurement can therefore influence results, e.g. spirometry performed in the late afternoon may be less likely to detect airflow obstruction than early morning measurements. Peak Expiratory Flow Rate (PEFR) Serial measurement of PEFR is a simple tool to detect diurnal variation with average daily fluctuations of >10% indicative of excessive variability. The likelihood of capturing PEFR variability increases with frequent recordings over a prolonged period of time. International guidelines recommend a minimum of twice daily PEFR measurement performed over two weeks. Adherence to PEFR measurements can be problematic
but it can yield highly valuable data at little cost and without a requirement for specialised testing. As well as being diagnostic, PEFR measurement is a useful prognostic tool. Greater fluctuations in PEFR are associated with an increased risk of death. The presence of nocturnal dips in PEFR and nocturnal asthma symptoms is an important warning sign; 80% of fatal asthma attacks in hospitalised patients were found to have commenced in the early hours of the morning. Bronchial Hyperresponsiveness Bronchial Provocation Tests Bronchial provocation tests should be considered in patients with no objective evidence of airflow obstruction on spirometry or PEFR measurements. Commonly used challenge agents include methacholine and histamine (direct challenge agents) and exercise, eucapnic voluntary hyperventilation or mannitol (indirect challenge agents). Methacholine is the most commonly used agent. Methacholine acts directly on muscarinic receptors inducing airway smooth muscle contraction and airway narrowing. During bronchial provocation testing, nebulised methacholine is delivered at incremental doses from 0.16 – 16mg/ml with FEV1 measurement at 30 and 90 seconds after each dose. The provocation concentration which causes a 20% fall in FEV1 (PC20) from baseline is determined. A test is positive when the PC20 is less than 8mg/ml and negative if PC20 is 16 mg/ml or above. Bronchial provocation tests should only be performed in patients with normal or
ONCE DAILY ENERZAIR® BREEZHALER® + SENSOR*
The 1st LABA/LAMA/ICS combination for asthma1 Now available to prescribe as a co-pack with a Sensor* and App2, which provides: INHALATION CONFIRMATION3
REAL DATA** TO SUPPORT THERAPEUTIC DECISIONS3
* The Propeller® Sensor for the BREEZHALER® device (referred to here as “Sensor”) and the Propeller® mobile app are property of Propeller Health®. ** When patients opt in to data collection & sharing, real data includes information on the patient’s rescue medication use and maintenance medication adherence collected via the sensor and app, as well as information on the patient’s asthma control status (as measured by Asthma Control Test, ACT).
ENERZAIR® BREEZHALER® is indicated as a maintenance treatment of asthma in adult patients not adequately controlled with a maintenance combination of a long-acting beta2-agonist and a high dose of an inhaled corticosteroid who experienced one or more asthma exacerbations in the previous year.2 Abbreviated Prescribing Information Please refer to Summary of Product Characteristics (SmPC) before prescribing. Enerzair® Breezhaler® (indacaterol (as acetate), glycopyrronium bromide, mometasone furoate) inhalation powder, hard capsules. Presentation: Hard capsules for inhalation each containing 150 mcg of indacaterol (as acetate), 63 mcg of glycopyrronium bromide equivalent to 50 mcg of glycopyrronium and 160 mcg of mometasone furoate. Each delivered dose contains 114 mcg of indacaterol acetate, 46 mcg of glycopyrronium and 136 mcg of mometasone furoate. Indications: Maintenance treatment of asthma in adult patients not adequately controlled with a maintenance combination of a long-acting beta2-agonist and a high dose of an inhaled corticosteroid who experienced one or more asthma exacerbations in the previous year. Dosage and Administration: One capsule once daily, administered at the same time of the day each day, using the Enerzair Breezhaler inhaler. No dose adjustment is required in elderly patients, in patients with mild to moderate renal impairment, or in patients with mild or moderate hepatic impairment. Caution should be observed in patients with severe renal impairment or end-stage renal disease requiring dialysis. No data available for patients with severe hepatic impairment, only use in these patients if the expected benefit outweighs the potential risk. The safety and efficacy in paediatric patients below 18 years of age have not been established. Contraindications: Hypersensitivity to the active substances, lactose monohydrate or magnesium stearate. Warnings/Precautions: Deterioration of disease: Should not be used to treat acute asthma symptoms, including acute episodes of bronchospasm. Treatment should not be stopped abruptly. Hypersensitivity: Immediate hypersensitivity reactions have been observed after administration. If signs suggesting allergic reactions occur, in particular angioedema, urticaria or skin rash, treatment should be discontinued immediately and alternative therapy instituted. Paradoxical bronchospasm: If paradoxical bronchospasm occurs, treatment should be discontinued immediately and alternative therapy instituted. Cardiovascular effects: Like other medicinal products containing beta2-adrenergic agonists, may produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, blood pressure, and/or symptoms. Use with caution in patients with cardiovascular disorders (coronary artery disease, acute myocardial infarction, cardiac arrhythmias, hypertension), convulsive disorders, thyrotoxicosis, and in patients who are unusually responsive to beta2-adrenergic agonists. Long acting beta2-adrenergic agonists (LABA) or LABA containing combination products such as Enerzair Breezhaler should be used with caution in patients with known or suspected prolongation of the QT interval or who are being treated with medicinal products affecting the QT interval. Hypokalaemia: Beta2-adrenergic agonists may produce significant hypokalaemia in some patients, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. In patients with severe asthma hypokalaemia may be potentiated by hypoxia and concomitant treatment, which may increase the susceptibility to cardiac arrhythmias. Hyperglycaemia: Inhalation of high dose of beta2-adrenergic agonists and corticosteroids may produce increases in plasma glucose. Upon initiation of treatment, plasma glucose should be monitored more closely in diabetic patients. Anticholinergic effect related to glycopyrronium: use with caution in patients with narrow-angle glaucoma or urinary retention. Prevention of oropharyngeal infections: In order to reduce the risk of oropharyngeal candida infection, patients should be advised to rinse their mouth or gargle with water without swallowing it or brush their teeth after inhaling the prescribed dose. Systemic effects of corticosteroids: Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged periods. Should be administered with caution in patients with pulmonary tuberculosis or in patients with chronic or untreated infections. Excipients: Contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose galactose malabsorption should not take this medicinal product. Interactions: No specific interaction studies
December 2020 | 103207
Indacaterol acetate / glycopyrronium bromide / mometasone furoate inhalation powder
were conducted with indacaterol/glycopyrronium/mometasone furoate. Information on the potential for interactions is based on the potential for each of the monotherapy components. Medicinal products that prolong QTc interval: Should be administered with caution in patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or medicinal products known to prolong the QT-interval. Hypokalaemic treatment: Concomitant treatment with methylxanthine derivatives, steroids, or nonpotassium sparing diuretics may potentiate the possible hypokalaemic effect of beta2-adrenergic agonists. Beta-adrenergic blockers: Should not be given together with beta-adrenergic blockers unless there are compelling reasons for their use. Where required, cardioselective beta-adrenergic blockers should be preferred, although they should be administered with caution. CYP3A4 and P-glycoprotein inhibitors: Inhibition of CYP3A4 and P-gp has no impact on the safety of therapeutic doses of Enerzair Breezhaler. Cimetidine and inhibitors of organic cation transport: No clinically relevant drug interaction is expected when glycopyrronium is co-administered with cimetidine or other inhibitors of the organic cation transport. Other long-acting antimuscarinics and LABAs: Co-administration with other medicinal products containing long-acting antimuscarinics or LABAs is not recommended. Fertility, Pregnancy and Lactation: Should only be used during pregnancy if the expected benefit to the patient justifies the potential risk to the foetus. No information available on the presence of indacaterol, glycopyrronium or mometasone furoate in human milk, on the effects on a breast-fed infant, or on the effects on milk production. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Studies do not indicate a concern regarding fertility in either males or females. Undesirable Effects: Very common (≥1/10): nasopharyngitis, asthma (exacerbation). Common (≥1/100 to <1/10): upper respiratory tract infection, candidiasis, urinary tract infection, hypersensitivity, headache, tachycardia, oropharyngeal pain, cough, dysphonia, gastroenteritis, musculoskeletal pain, muscle spasms, pyrexia. Uncommon (≥1/1,000 to <1/100): hyperglycaemia, cataract, dry mouth, rash, pruritus, dysuria. Please consult the Summary of Product Characteristics for a detailed listing of all adverse events before prescribing. Pack Size(s): Single pack containing 30 x 1 hard capsules, together with one inhaler. Pack containing 30 x 1 hard capsules, together with 1 inhaler and 1 sensor. The sensor and App are not required for administration to the patient. The sensor and App do not control or interfere with delivery of the medicinal product using the inhaler. Legal Category: POM. Product (Marketing) Authorisation Number(s): EU/1/20/1438/002 & 003. Product (Marketing) Authorisation Holder: Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland. Full prescribing information is available upon request from: Novartis Ireland Limited, Vista Building, Elm Park Business Park, Elm Park, Dublin 4. Tel: 01-2601255 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 Prescribing Information last revised: July 2020. Reporting suspected adverse reactions of the medicinal product is important to Novartis and the HPRA. It allows continued monitoring of the benefit/risk profile of the medicinal product. All suspected adverse reactions should be reported via HPRA Pharmacovigilance, website www.hpra.ie. Adverse events could also be reported to Novartis preferably via www.report.novartis.com or by email: firstname.lastname@example.org or by calling 01 2080 612. References: 1. European Medicines Agency CHMP Press Release. Available at: https://www.ema. europa.eu/en/news/meeting-highlights-committee-medicinal-products-human-use-chmp-28-30-april-2020 Date accessed: January 2021. 2. ENERZAIR® BREEZHALER®. Summary of Product Characteristics. Available at www.medicines.ie Date accessed: January 2021. 3. Propeller® Sensor for Enerzair® Breezhaler® Instructions for Use. Available in each pack of Enerzair® Breezhaler® plus Sensor.
32 HOSPITAL REVIEW: ASTHMA
near-normal spirometry and those able to perform good quality spirometry. In addition to standard spirometry contraindications, a methacholine challenge should not be performed in pregnant or lactating women or in those taking anti-cholinesterase medication. Oral theophyllines and all beta2-agonist and anti-muscarinic therapies should be withheld prior to testing. The degree of airway hyperresponsiveness may increase during exacerbations and may be decreased or absent during treatment with inhaled corticosteroids or when asymptomatic. A negative methacholine challenge test is useful to exclude asthma however a positive test may occur in other conditions e.g. allergic rhinitis, cystic fibrosis and COPD. Results should therefore be interpreted in the context of the individual clinical presentation.
phenotypes. The detection of raised Th2 biomarkers provides an important indicator of future risk of asthma exacerbations and predicts response to treatment with inhaled corticosteroids (ICS). Additionally, there are now several effective monoclonal antibody (“biologic”) treatments which specifically target Th2-high inflammatory pathways and are indicated for use in patients with severe refractory disease.
presence of atopy does not mean that the allergen is causing symptoms and the relevance of the result should be confirmed by patient history. Fractional Exhaled Nitric Oxide
and eosinophilic pneumonias. The timing of measurement is important; eosinophil counts will be suppressed by oral corticosteroids and may be elevated during acute asthma exacerbations. Asthma patients with eosinophilic airway inflammation will usually respond to treatment with inhaled corticosteroids. As with FeNO, elevated eosinophil counts are suggestive of uncontrolled airway inflammation and are associated with increased exacerbation risk.
Nitric oxide is produced in the airway and exhaled in the breath of patients with Th2 high asthma as a result of IL-13 mediated airway inflammation. FeNO is a simple, short and reproducible measure of exhaled nitric oxide An increase in asthma therapy levels. Several FeNO cut-offs should be considered in those have been described; levels with uncontrolled asthma Allergic Sensitisation Tests above >40 parts per billion are symptoms and persistent elevated whereas levels <25 Elevated serum IgE level and eosinophilia or raised FeNO. On parts per billion are within normal positive allergen RAST or the other hand, patients with limits. FeNO is usually highest skin prick test are important both low FeNO and low blood when measured in the morning. biomarkers of allergy mediated eosinophil counts respond poorly Airway infection and high levels inflammation in asthma. Allergic to inhaled corticosteroids. In of atopy may increase FeNO asthma is classically associated such instances, these biomarkers readings whilst active smoking with childhood onset disease and can be used to guide reductions and exercise reduce them. FeNO patients will describe worsening in ICS. Persistent symptoms in is highly responsive to treatment symptoms on exposure to patients with low biomarkers with ICS and thus is useful to allergens. Skin prick testing and normal lung function should identify Th2 inflammation and to common aeroallergens is a prompt an investigation for to monitor the response (and simple and inexpensive test adherence) to treatment. Ongoing alternate pathologies which to perform. During the skin raised FeNO is associated with commonly mimic or co-exist prick tests, allergen extract an increased risk of asthma with asthma such as laryngeal Airway Inflammation applied to the skin andas a laryngeal dysfunction, breathing pattern disorder commonly mimic or co-exist iswith asthma such exacerbation and, in those dysfunction, breathing pattern lancet used to penetrate the adherent to prescribed ICS, disorder or deconditioning. The identification of biomarker skin surface. The development should prompt an increase in profiles specific to asthma or deconditioning. of a wheal 3mm or greater in Conclusion ICS dose. phenotypes can support a diameter than a saline control diagnosis of asthma. Biomarkers Asthma is commonly indicates an immediate reaction Blood eosinophil count of type 2 airway inflammation misdiagnosed due to the to the allergen. False negatives (Th2) in particular have been The eosinophil is a potent absence of a gold standard will arise in patients taking Conclusion identified and include serum mediator of Th2 airway diagnostic test. A diagnosis of antihistamine medications, H2Immunoglobulin E (IgE), allergen inflammation in asthma. Peripheral asthma should be supported receptor antagonists and tricyclic Asthma is commonly misdiagnosed due to the absence ofeosinophil a gold standard diagnostic test. A evidence of airflow radioallergosorbent test (RAST) counts of greater than by objective antidepressant medications. 3 or skin prick tests, Fractional can or equal to 300 cells/mm obstruction or bronchial Measurement of serum specific Exhaled Nitricof Oxide (FeNO)should be supported by objective evidence support a of diagnosis of asthma in diagnosis asthma airflow obstruction or bronchial hyper-responsiveness. The IgE to aeroallergens (RAST) is as and peripheral blood eosinophil those in whom clinical suspicion additional measurement of effective as skin prick tests but count. These biomarkers are is high. Elevated blood eosinophil novel biomarkers significantly more expensive. hyper-responsiveness. The additional measurement of novel biomarkers such as FeNO and blood such as easy to measure, and repeat counts are also detected in FeNO and blood eosinophil measurements should be taken Whilst useful in supporting several other disease pathologies count can be useful to support eosinophil to support an atopy asthma diagnosis to guide management. over time in allcount patients.can Typebe 2 useful an asthma diagnosis, includingand hypereosinophilic an asthma diagnosis and to airway inflammation is a driving is not specific to asthma and syndromes, eosinophilic guide management. factor in both allergic and nonis prevalent in the general granulomatosis with polyangiitis References on request allergic eosinophilic asthma (EGPA), helminth infection, population. Furthermore the References available on request
Investigations which support a diagnosis of Asthma* Variable Airflow Obstruction Bronchial Hyperresponsiveness Spirometry with reversibility Bronchial Provocation Test Serial Peak Expiratory Flow Rate Direct tests - Methacholine - Histamine Indirect tests - Mannitol - Exercise - Eucapnic Voluntary Hypercapnia *Always interpret results in the context of clinical history
AUGUST - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE
Airway Inflammation Serum Immunoglobulin E (IgE) Allergen RAST or skin prick test Fractional Exhaled Nitric Oxide Peripheral blood eosinophil count
Genuair -has it ‘clicked’ yet? ®
The ONLY prefilled inhaler with visual and audible feedback for confirmed dose delivery 1-4
Genuair - a simple to use inhaler for patients with COPD 4
LAMA + LABA
LAMA Abbreviated Prescribing Information Eklira® Genuair® 322 micrograms inhalation powder. Please consult the Summary of Product Characteristics (SPC) for the full prescribing information. Presentation: Inhalation powder in a white inhaler with an integral dose indicator and a green dosage button. Each delivered dose contains 375 µg aclidinium bromide equivalent to 322 µg of aclidinium. Also, contains lactose. Use: Maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). Dosage: For inhalation use. Recommended dose is one inhalation of 322 micrograms aclidinium twice daily. Patients should be instructed on how to administer the product correctly as the Genuair inhaler may work differently from inhalers used previously. It is important to instruct the patients to read the Instructions for Use in the pack. No dose adjustments are required for elderly patients, or those with renal or hepatic impairment. No relevant use in children and adolescents. Contraindications: Hypersensitivity to aclidinium bromide or to any of the excipients. Warnings and Precautions: Stop use if paradoxical bronchospasm occurs and consider other treatments. Do not use for the relief of acute episodes of bronchospasm. Use with caution in patients with myocardial infarction in the previous 6 months, unstable angina, newly diagnosed arrhythmia within the previous 3 months, or hospitalisation within the previous 12 months for heart failure functional classes III and IV. Dry mouth, observed with anticholinergic treatment, may be associated with dental caries in the long term. Use with caution in patients with symptomatic prostatic hyperplasia or bladder-neck obstruction or with narrow-angle glaucoma. Do not use in patients with rare hereditary problems of galactose intolerance, total lactose deficiency or glucose-galactose malabsorption. Interactions: Do not administer with other anticholinergic-containing medicinal products. No other interactions expected. Please consult the SPC for more details. Fertility, pregnancy and lactation: No data on use in pregnancy. Risk to newborns/infants cannot be excluded. Consider risk-benefit before using during lactation. Unlikely to affect fertility at the recommended dose. Side-effects: Common (1-10%): Sinusitis, nasopharyngitis, headache, cough, diarrhoea, nausea. Uncommon (0.1-1%): Dizziness, blurred vision, tachycardia, palpitations, dysphonia, dry mouth, stomatitis, rash, pruritus, urinary retention. Rare (0.01-0.1%): hypersensitivity. Not known: angioedema, anaphylactic reaction. Pack sizes: Carton containing 1 inhaler with 60 unit doses. Legal category: POM Marketing Authorisation Number: EU/1/12/778/002 Marketing Authorisation holder: AstraZeneca AB, SE151 85 Södertälje, Sweden. Marketed by: A. Menarini Pharmaceuticals Ireland Ltd., Castlecourt, Monkstown Farm, Monkstown, Glenageary, Co. Dublin A96 T924. Further information is available on request to A. Menarini Pharmaceuticals Ireland Ltd. or may be found in the SPC. Last updated: February 2020
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 to: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517, Website: www.hpra.ie, e-mail: medsafety@ hpra.ie. Adverse events should also be reported to A. Menarini Pharmaceuticals Ireland Ltd. Phone no: 01 284 6744. Date of item: November 2020. IR-BRI-10-2020
1. MIMS Ireland November 2020 2. Eklira® Genuair® Summary of Product Characteristics, last updated November 2019 3. Brimica® Genuair® Summary of Product Characteristics, last updated August 2019 4. Magnussen, H et al. COPD. 2019 Apr;16(2):196-205
Abbreviated Prescribing Information Brimica® Genuair® 340 micrograms/12 micrograms inhalation powder. Please consult the Summary of Product Characteristics (SPC) for the full prescribing information. Presentation: Inhalation powder in a white inhaler with an integral dose indicator and an orange dosage button. Each delivered dose contains 396 µg aclidinium bromide (equivalent to 340 µg of aclidinium) and 11.8 micrograms of formoterol fumarate dihydrate. Also, contains lactose. Use: Maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). Dosage: For inhalation use. Recommended dose is one inhalation of 340 µg/12 µg twice daily. Patients should be instructed on how to administer the product correctly as the Genuair inhaler may work differently from inhalers used previously. It is important to instruct the patients to read the Instructions for Use in the pack. No dose adjustments are required for elderly patients, or those with renal or hepatic impairment. No relevant use in children and adolescents. Contraindications: Hypersensitivity to the active substances or to any of the excipients. Warnings and Precautions: Do not use in asthma. Stop use if paradoxical bronchospasm occurs and consider other treatments. Do not use for the relief of acute episodes of bronchospasm. Use with caution in patients with myocardial infarction in the previous 6 months, unstable angina, newly diagnosed arrhythmia within the previous 3 months, or hospitalisation within the previous 12 months for heart failure functional classes III and IV. Discontinue if increases in pulse rate, blood pressure or changes in ECG occur. Use with caution in patients with a history of or known prolongation of the QTc interval or treated with products affecting the QTc interval. Use with caution in patients with severe cardiovascular disorders, convulsive disorders, thyrotoxicosis and phaeochromocytoma. Hypokalaemia may occur, is usually transient and supplementation not needed. In patients with severe COPD, hypokalaemia may be potentiated by hypoxia and concomitant treatment. Use with caution in patients with symptomatic prostatic hyperplasia, urinary retention or with narrow-angle glaucoma. Dry mouth, observed with anticholinergic treatment, may be associated with dental caries in the long term. Do not use in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption. Interactions: Do not administer with other anticholinergic and/or long-acting β2-adrenergic agonist containing medicinal products. Caution in use with methylxanthine derivatives, steroids, non-potassium-sparing diuretics, β-adrenergic blockers or medicinal products known to prolong the QTc interval. Please consult the SPC for more details. Fertility, pregnancy and lactation: No data on use in pregnancy. Consider risk-benefit before using during lactation. Unlikely to affect fertility at the recommended dose. Sideeffects: Common (1-10%): Nasopharyngitis, urinary tract infection, sinusitis tooth abscess, insomnia, anxiety, headache, dizziness, tremor, cough, diarrhoea, nausea, dry mouth, myalgia, muscle spasms, peripheral oedema, increased blood creatine phosphokinase. Uncommon (0.1- 1%): Hypokalaemia, hyperglycaemia, agitation, dysgeusia, blurred vision, tachycardia, electrocardiogram QTc prolonged, palpitations, angina pectoris, dysphonia, throat irritation, stomatitis, rash, pruritus, urinary retention, increased blood pressure. Rare (0.01-0.1%): Hypersensitivity, bronchospasm, including paradoxical. Not known: anaphylactic reaction, angioedema. Pack sizes: Carton containing 1 inhaler with 60 unit doses. Legal category: POM Marketing Authorisation Number: EU/1/14/963/001 Marketing Authorisation holder: AstraZeneca AB, SE-151 85 Södertälje, Sweden. Marketed by: A. Menarini Pharmaceuticals Ireland Ltd., Castlecourt, Monkstown Farm, Monkstown, Glenageary, Co. Dublin A96 T924. Further information is available on request to A. Menarini Pharmaceuticals Ireland Ltd. or may be found in the SPC. Last updated: October 2019 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@ hpra.ie. Adverse events should also be reported to A. Menarini Pharmaceuticals Ireland Ltd. Phone no: 01 284 6744.
patients alive at 5 years 1,2
62.5% overall survival (0S) at 5 years with ALECENSA vs 45.5% with crizotinib * 1,2
Difference (95% CI): -17.0% (-33.5 to -2.5) Clinically meaningful improvement in OS ALEX Phase III trial: Global, multicentre, randomised, open-label trial comparing efficacy and safety between ALECTINIB and crizotinib in treatment-naïve patients with stage IIIB/IV ALK+ NSCLC (n=303)1-3
ALECENSA first line in ALK+ non-small cell lung cancer Indication: ALECENSA as monotherapy is indicated for the first-line treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC).4 Data cut-off: 29 November 2019.1,2 *OS data remain immature.1,2 ALK: anaplastic lymphoma kinase. NSCLC: non-small cell lung cancer. OS: overall survival. References: 1. Mok T et al. Annals of Oncology 2020. DOI: https://doi.org/10.1016/j.annonc.2020.04.478. 2. Peters S et al. Poster 9518. Presented at ASCO Annual Meeting 29-31 May 2020. 3. Peters S et al. Alectinib versus Crizotinib in Untreated ALK-Positive Non–Small-Cell Lung Cancer. N Engl J Med 2017; 377:829-38. 4. ALECENSA SmPC 03 April 2020, available at www.medicines.ie. Date of item: November 2020. M-IE-00000403 ABRIDGED PRESCRIBING INFORMATION (API) For full prescribing information refer to the Summary of Product Characteristics [SmPC].
▼ (alectinib) 150 mg hard capsules (Each hard capsule contains alectinib hydrochloride equivalent to 150 mg alectinib).
▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report
any suspected adverse reactions. See box below for details on how to report. Indications: As monotherapy for the first line treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC). As monotherapy for the treatment of adult patients with ALK-positive NSCLC previously treated with crizotinib. Dosage and Administration: Treatment initiated and supervised by a physician experienced in the use of anticancer medicinal products. Validated ALK assay is necessary for the selection of ALK-positive NSCLC patients. Establish ALK-positive NSCLC status prior to initiation of Alecensa therapy. Recommended dose of Alecensa is 600 mg (four 150mg capsules) taken twice daily with food (total daily dose of 1200 mg). Patients with underlying severe hepatic impairment (Child-Pugh C) should receive a starting dose of 450 mg taken twice daily with food (total daily dose of 900 mg). Hard capsules to be swallowed whole, not to be opened or dissolved. Continue treatment until disease progression or unacceptable toxicity. If a planned dose is missed, make up that dose unless the next dose is due within 6 hours. Do not take 2 doses at the same time. If vomiting occurs after taking a dose, take the next dose at the scheduled time. When dose adjustment is necessary, reduce in steps of 150 mg twice daily based on tolerability. Refer to SmPC for dose modification advice. For all patients with hepatic impairment, appropriate monitoring is advised. No available data on patients over 80 years. No available data on children and adolescents <18 years or on patients with body weight above 130 kg. Contraindications: Hypersensitivity to alectinib or to any of the excipients. Special Warnings and Precautions: Interstitial lung disease (ILD)/pneumonitis: Cases of ILD/pneumonitis have been reported in Alecensa clinical trials. Monitor for pulmonary symptoms indicative of pneumonitis. Immediately interrupt in patients diagnosed with ILD/pneumonitis and permanently discontinue if no other potential causes of ILD/pneumonitis have been identified, refer to SmPC. Hepatotoxicity: AST, ALT (>5 x ULN) and bilirubin elevations (>3 x ULN) occurred in Alecensa pivotal clinical trials. The majority of these occurred during the first 3 months of treatment. Monitor AST, ALT and bilirubin at baseline, and then every 2 weeks during the first 3 months of treatment. Thereafter monitoring should be performed periodically, with more frequent monitoring in patients who develop aminotransferase and bilirubin elevations. Treatment should be withheld and resumed at a reduced dose, or permanently discontinued, refer to SmPC. Severe myalgia and creatine phosphokinase (CPK) elevation: Myalgia and musculoskeletal pain was reported in patients in pivotal trials, including Grade 3 events. Patients should be advised to report any unexplained muscle pain, tenderness, or weakness. CPK levels should be assessed every two weeks for the first month of treatment and as clinically indicated in patients reporting symptoms. Based on the severity of the CPK elevation, Alecensa should be withheld, then resumed at the same dose or dose reduced, refer to SmPC. Bradycardia: Symptomatic bradycardia can occur. Monitor heart rate and blood pressure as clinically indicated. Evaluate concomitant medicinal products known to cause bradycardia, as well as anti-hypertensive medicinal products if patients experience symptomatic bradycardia or life-threatening events. Symptomatic bradycardia can be managed with treatment interruption, dose reduction. If life-threatening, permanently discontinue if no contributing concomitant medicinal product is identified or upon recurrence. Gastrointestinal perforation: Cases of gastrointestinal perforations have been reported
in patients at increased risk (e.g., history of diverticulitis, metastases to the gastrointestinal tract, concomitant use of medicinal product with a recognized risk of gastrointestinal perforation) treated with Alecensa. Consider discontinuation of Alecensa in patients who develop gastrointestinal perforation. Inform patients of the signs and symptoms of gastrointestinal perforations and advise them to consult their HCP rapidly in case of occurrence. Photosensitivity: Photosensitivity has been reported. Avoid prolonged sun exposure during treatment and for at least 7 days after discontinuation. Advise to protect against sunburn. Women of child-bearing potential: Alecensa may cause foetal harm during pregnancy. Female patients of child bearing potential receiving Alecensa must use highly effective contraceptive methods during treatment and for at least 3 months following the last dose. Lactose intolerance: Patients with rare hereditary problems of galactose intolerance, congenital lactase deficiency or glucose-galactose malabsorption should not take Alecensa. Sodium content: Alecensa contains 48 mg sodium per daily dose (1200 mg), equivalent to 2.4% of the WHO recommended maximum daily intake of 2 g sodium for an adult. Interactions: Avoid grapefruit juice, grapefruit and Seville oranges. No dose adjustments are required when Alecensa is co-administered with CYP3A inducers, CYP3A inhibitors, CYP3A substrates, proton pump inhibitors or other medicinal products which raise gastric pH. Appropriate monitoring is recommended for patients taking concomitant strong CYP3A inducers, strong CYP3A inhibitors, P-gp substrates, BCRP substrates. The effectiveness of concomitant administration of oral contraceptives may be reduced. Refer to SmPC. Fertility, Pregnancy and Lactation: Advise women of childbearing potential to avoid pregnancy during treatment. See Special Warnings and Precautions. Patients should be advised to report a pregnancy while taking Alecensa or during the 3 months following the last dose of Alecensa and should be advised of the potential harm to the foetus. Reproductive toxicity observed in animals. Do not breast-feed while taking Alecensa. Refer to SmPC. Effects on ability to drive and use machines: Exercise caution when driving or operating machines. Undesirable Effects: Safety evaluated in 405 patients in phase II and III clinical trials. Most common ADRs were constipation (35%), oedema (30%) and myalgia (28%). Very common: anaemia, constipation, nausea, diarrhoea, vomiting, increased bilirubin, increased AST, increased ALT, rash, myalgia, increased blood creatine phosphokinase, oedema, weight increased. Common: Dysgeusia, vision disorders, bradycardia, stomatitis, increased alkaline phosphatase, photosensitivity, blood creatinine increased, acute kidney injury. Uncommon: Severe interstitial lung disease (ILD)/pneumonitis, drug-induced liver injury. Refer to Alecensa SmPC for a full list of adverse reactions. See SmPC section 4.8 for instructions on reporting Suspected Adverse Reactions. Legal Category: Product subject to prescription which may not be renewed (A). Presentation and Marketing Authorization Number: 224 (4 packs of 56) hard capsules (EU/1/16/1169/001). Marketing Authorisation Holder: Roche Registration GmbH, Emil-Barell-Strasse 1, 79639 Grenzach-Wyhlen, Germany. Alecensa® is a registered trade mark. Further information is available from Roche Products (Ireland) Limited, 3004 Lake Drive, Citywest, Naas Road, Dublin 24. Telephone: (01) 4690700. Fax: (01) 4690791. Date of API Preparation: April 2020.
▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. In the event of a suspected adverse event, please report it to: The Drug Surveillance Centre Roche Products (Ireland) Limited Telephone: (01) 4690700 Fax: (01) 4690793 Email: email@example.com
Alternatively, suspected adverse reactions should be reported to: HPRA Pharmacovigilance The Health Products Regulatory Authority (HPRA) Telephone: (01) 6764971 Fax: (01) 6762517 Website: www.hpra.ie Email: firstname.lastname@example.org
Alecensa® Summary of Product Characteristics [SmPC] is available on www.medicines.ie. API (IE/ALEC/0217/0003(5) based on Alecensa SmPC dated 03rd April 2020.
(pembrolizumab) Injection 25mg/ml KEYTRUDA®: HELPING TO REDEFINE OVERALL SURVIVAL EXPECTATIONS for more patients with mNSCLC1-4 PD-L1 <1% or unknown
1st line Combination** Therapy3
1st line*** Monotherapy4
NON-SQUAMOUS AND SQUAMOUS
1st line Combination* Therapy2
* KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of metastatic non-squamous NSCLC in adults whose tumours have no EGFR or ALK positive mutations. ** KEYTRUDA, in combination with carboplatin and either paclitaxel or nab-paclitaxel, is indicated for the first-line treatment of metastatic squamous NSCLC in adults. *** KEYTRUDA, as monotherapy, is indicated for the first-line treatment of metastatic non-small cell lung carcinoma (NSCLC) in adults whose tumours express PD-L1 with a≥ 50% tumour proportion score (TPS) with no EGFR or ALK positive tumour mutations. skin adverse reaction on prior treatment with other immune- stimulatory anticancer agents. Other clinically significant immune-related adverse reactions: The following additional clinically significant, immune-related adverse reactions, have been reported in clinical studies or in post-marketing experience: uveitis, arthritis, myositis, myocarditis, pancreatitis, Guillain-Barré syndrome, myasthenic syndrome, haemolytic anaemia, sarcoidosis, encephalitis and myelitis. For Grades 3 or 4 myocarditis, encephalitis or Guillain Barré syndrome, pembrolizumab should be permanently discontinued. Refer to SmPC for information on management of significant immune-related adverse reactions. Solid organ transplant rejection has been reported in the post-marketing setting in patients treated with PD-1 inhibitors. The benefit of treatment with pembrolizumab versus the risk of possible organ rejection should be considered in these patients. Complications of allogeneic Haematopoietic Stem Cell Transplant (HSCT): Allogeneic HSCT after treatment with pembrolizumab: Cases of graft-versus-host-disease (GVHD) and hepatic veno-occlusive disease (VOD) have been observed in patients with classical Hodgkin lymphoma undergoing allogeneic HSCT after previous exposure to pembrolizumab. Until further data become available, careful consideration to the potential benefits of HSCT and the possible increased risk of transplant-related complications should be made case by case. Allogeneic HSCT prior to treatment with pembrolizumab: In patients with a history of allogeneic HSCT, acute GVHD, including fatal GVHD, has been reported after treatment with pembrolizumab. Patients who experienced GVHD after their transplant procedure may be at an increased risk for GVHD after treatment with pembrolizumab. Consider the benefit of treatment with pembrolizumab versus the risk of possible GVHD in patients with a history of allogeneic HSCT. Infusion-related reactions: For Grades 3 or 4infusion reactions including hypersensitivity and anaphylaxis, stop infusion and permanently discontinue pembrolizumab. With Grades 1 or 2 infusion reactions, infusion may continue with close monitoring. Premedication with antipyretic and antihistamine may be considered. Overdose: There is no information on overdose with pembrolizumab. In case of overdose, monitor closely for signs or symptoms of adverse reactions and treat appropriately. INTERACTIONS No formal pharmacokinetic drug interaction studies have been conducted with pembrolizumab. No metabolic drug-drug interactions are expected. The use of systemic corticosteroids or immunosuppressants before starting pembrolizumab should be avoided because of their potential interference with the pharmacodynamic activity and efficacy of pembrolizumab. Corticosteroids can be used as premedication, when pembrolizumab is used in combination with chemotherapy, as antiemetic prophylaxis and/or to alleviate chemotherapy-related adverse reactions. FERTILITY, PREGNANCY AND LACTATION Women of childbearing potential Women of childbearing potential should use effective contraception during treatment with pembrolizumab and for at least 4 months after the last dose of pembrolizumab. Pregnancy No data on use in pregnant women. Do not use during pregnancy unless the clinical condition of the woman requires treatment with pembrolizumab. Breast-feeding It is unknown whether pembrolizumab is secreted in human milk. A risk to newborns/ infants cannot be excluded. Fertility No clinical data available. SIDE EFFECTS Refer to SmPC for complete information on side effects. Pembrolizumab is most commonly associated with immune-related adverse reactions. Most of these reactions resolved with appropriate medical treatment or withdrawal of pembrolizumab. The most serious adverse reactions were immune-and infusion-related adverse reactions. Monotherapy: Very Common: anaemia, hypothyroidism, decreased appetite, headache, dyspnea, cough, abdominal pain, nausea, vomiting, constipation, musculoskeletal pain, arthralgia, asthenia, oedema, pyrexia, diarrhoea, rash, pruritus, fatigue. Common: pneumonia, thrombocytopaenia, lymphopaenia, hyponatraemia, hypokalaemia, hypocalcaemia, insomnia, neuropathy peripheral, lethargy, dry eye, cardiac arrhythmia (including atrial fibrillation), hypertension, hyperthyroidism, insomnia, dizziness, dysgeusia, pneumonitis, colitis, dry mouth, severe skin reactions, vitiligo, dry skin, alopecia, eczema, dermatitis acneiform, erythema, myositis, pain in extremity, arthritis, influenza like illness, chills, AST and ALT increases, hypercalcaemia, increase in blood alkaline phosphatase, blood bilirubin increased, blood creatinine increased, infusion related reaction. Frequency not known: solid organ transplant rejection. Combination with chemotherapy: Very Common: anaemia, neutropaenia, thrombocytopaenia, hypokalaemia, decreased appetite, dizziness, neuropathy peripheral, dysgeusia, headache, dyspnoea, cough, abdominal pain, alopecia, diarrhoea, nausea, vomiting, constipation, rash, pruritus, musculoskeletal pain, arthralgia, pyrexia, fatigue, asthenia, oedema, blood creatinine increased. Common: pneumonia, febrile neutropaenia, leukopaenia, lymphopaenia, infusion related reaction, hypothyroidism, hyperthyroidism, hyponatraemia, hypocalcaemia, insomnia, lethargy, dry eye, cardiac arrhythmia (including atrial fibrillation), hypertension, pneumonitis, colitis, dry mouth, severe skin reactions, erythema, dry skin, myositis, pain in extremity, arthritis, nephritis, acute kidney injury, chills, influenza-like illness, hypercalcaemia, ALT increase, AST increased, blood alkaline phosphatase increased. Combination with axitinib: Very Common: hyperthyroidism, hypothyroidism, decreased appetite, headache, dysgeusia, hypertension, dyspnoea, cough, dysphonia, diarrhoea, abdominal pain, nausea, vomiting, constipation, palmar-plantar erythrodysaesthesia syndrome, rash, pruritus, musculoskeletal pain, arthralgia, pain in extremity, fatigue, asthenia, pyrexia, alanine aminotransferase increased, aspartate aminotransferase increased, blood creatinine increased. Common: pneumonia, anaemia, neutropaenia, leukopaenia, thrombocytopaenia, infusion related reaction, hypophysitis, thyroiditis, adrenal insufficiency, hypokalaemia, hyponatraemia, hypocalcaemia, insomnia, dizziness, lethargy, neuropathy peripheral, dry eye, cardiac arrhythmia (including atrial fibrillation), pneumonitis, colitis, dry mouth, hepatitis, severe skin reactions, dermatitis acneiform, dermatitis, dry skin, alopecia, eczema, erythema, myositis, arthritis, tenosynovitis, acute kidney injury, nephritis, oedema, influenza like illness, chills, blood alkaline phosphatase increased, hypercalcaemia, blood bilirubin increased. PACKAGE QUANTITIES KEYTRUDA 25 mg/mL: 4 mL of concentrate in a 10 mL Type I clear glass vial. Legal Category: POM. Marketing Authorisation numbers: EU/1/15/1024/002. Marketing Authorisation holder: Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands. Date of revision: June 2020. © Merck Sharp & Dohme B.V. 2020. All rights reserved. Further information is available on request from: MSD, Red Oak North, South County Business Park, Leopardstown, Dublin D18 X5K7 or from www.medicines.ie. Date of Preparation: November 2020. PSUSA. Adverse events should be reported. Reporting forms and information can be found at www.hpra.ie. Adverse events should also be reported to MSD (Tel: 01-2998700) References 1. Keytruda Summary of Product Characteristics, July 2020, available at www.medicines.ie. 2. Gandhi L, et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med. 2018;378:2078-2092. 3. Paz-Ares L, et al. Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. N Engl J Med. 2018;379:2040–2051. 4. Reck, M et al. Pembrolizumab versus chemotherapy for PDL1 positive-non-small cell lung cancer, N Eng J Med 2016, 375(19)1823-1833. ALK=anaplastic lymphoma kinase; EGFR=epidermal growth factor receptor; mNSCLC=metastatic non–small cell lung carcinoma; PDL1=programmed death ligand 1.
Red Oak North, South County Business Park, Leopardstown, Dublin D18 X5K7 Ireland
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
HOSPITAL REVIEW: LUNG CANCER
Non-Small Cell Lung Cancer: Laying the Foundations for Personalised RNA Therapeutics As many readers will no doubt be aware, lung cancer is an enormous unsolved health challenge, being the greatest cancer killer in Ireland and worldwide. It does not just affect smokers: 20% of deaths occur in never-smokers. The tragically low survival rate (5-year survival <20%) spurs many laboratories around the world, including ours, on the quest for new therapies. Most tumours appear and thrive due to genetic “driver” mutations in genes encoding certain wellknown proteins. For example, in the most common non-small cell type of lung cancer (NSCLC), we frequently observe mutations in the KRAS oncoprotein that “switch on” signalling pathways to drive cell growth. Drug developers have leveraged this knowledge to develop “targeted therapies” based on small molecules that inhibit driver proteins, for example gefitinib for EGFR, another frequently mutated driver gene. There is a commonly held hope, that by analysing molecular and genetic signatures in individual tumours, we may design “personalised” therapies tailored to each patient.
Sadly, despite heroic efforts by physicians, researchers and drug developers, we have yet to reach this ideal. Firstly, we lack targeted molecules for many driver mutations, or else we cannot identify the driver mutation at all. Secondly, targeted therapies are highly effective in the short term, but are ultimately defeated by “therapy resistance”: the fiendish ability of tumours to “learn” to stop responding to drugs. More traditional chemotherapies, meanwhile, are toxic for patients. It is clear then, that new treatments are urgently needed. A solution may be on the horizon, in the form of three exciting scientific developments. These can be summarised as: new gene targets, new genomic screening technologies, and new drugs. Here we will briefly introduce how these advances are converging into a concept that has recently shot to prominence in the COVID-19 epidemic: RNA therapeutics (RNATX). Since the sequencing of our entire human genome 20 years ago, there has been a revolution in our understanding of what constitutes
Written by: Rory Johnson, Associate Professor at the School of Biology and Environmental Science / Conway Institute of University College Dublin; Adjunct Assistant Professor at the University Hospital of Bern, Switzerland; Recipient of Science Foundation Ireland’s ‘Future Research Leaders’ programme and Michela Coan, Postdoctoral Research Fellow at the School of Biology and Environmental Science of University College Dublin
our “genes”. We are all familiar with the idea that genes produce a messenger RNA (mRNA), which encodes a protein. However, in recent years we have discovered thousands of exotic genes that defy this norm: they produce RNA that encodes no protein. These rather obviously-named “long noncoding RNAs”, or lncRNAs (pronounced “link RNAs”), are one of the hottest - and most controversial - areas of molecular biology today. During our respective PhD studies, we both became hooked on these mysterious genes and have studied them ever since. While we still do not understand precisely the biological roles or molecular mechanisms of most lncRNAs, it is clear that certain “onco-lncRNAs” play striking roles in promoting cancer. When researchers inhibit onco-lncRNAs, tumour cells die. In addition, while most conventional drug targets (including KRAS) are expressed in cells throughout the body, lncRNAs often have exquisite specificity in tumours. A great example is the onco-lncRNA “SAMMSON”, which is specific to melanoma cells. SAMMSON inhibition (SAMMSONi) kills tumour cells, while leaving normal melanocytes unaffected.
Strikingly, combination with SAMMSONi also potentiates the widely-used BRAF (V600E) targeted therapy, vemurafenib. These features make lncRNAs promising personalised drug targets with potentially low sideeffects, spurring researchers and companies worldwide to hunt for more onco-lncRNA targets. So how can we search this genomic haystack for the ideal “needle”, or onco-lncRNA drug target? In our research group, first in the University Hospital of Bern (Switzerland), and since 2020 at University College Dublin, we have developed new approaches to screen for tumour-promoting lncRNAs. In one project carried out with the international consortium PCAWG (PanCancer Analysis of Whole Genomes), we have developed software to analyse millions of DNA mutations from thousands of patients’ tumours, to identify highly mutated lncRNAs. We could show that inhibition of these “driver lncRNAs” represses tumour cell growth and is a promising therapeutic strategy. However our main project, which was recently supported by Science Foundation Ireland’s ‘Future Research Leaders’ programme, has a more direct
HOSPITALPROFESSIONALNEWS.IE | HPN • AUGUST - 2021
38 HOSPITAL REVIEW: LUNG CANCER used to hybridise to and degrade onco-lncRNAs. We have designed ASOs in the lab to target lncRNAs discovered in the above projects, and which are capable of inhibiting tumour cell growth and sensitise them to chemotherapeutics. Importantly, ASOs can, in principle, be used safely and effectively in humans, and the first ASO drugs have been approved by the European Medicines Agency. Nevertheless, significant challenges remain to be overcome, not least how to specifically deliver ASOs into tumours, without damaging the patient’s liver or provoking inflammatory responses. However, there is a growing hope that in the coming years, a growing RNATX pipeline will begin delivering ASOs and other oligonucleotide drugs that can be personalised for every patient, either in combination to potentiate existing therapies, or as a lowtoxicity, durable and effective standalone treatment.
approach borrowed from the world of CRISPR genome editing. We employ CRISPR molecular “scissors” to delete thousands of lncRNA genes from NSCLC cells, and measure the outcome on a variety of disease phenotypes. This approach enables us to rapidly and economically screen
for onco-lncRNAs. This “CRISPRscreening” pipeline has enabled us to compile the first catalogue of lncRNA drug targets in NSCLC. With these new targets in hand, a final big question remains: How can we drug these genes in patients? This is where “RNA
therapeutics” (RNATX) comes in. From dementia, to rare diseases, to vaccine development, to oncology, a new generation of bioactive molecules based on programmed, chemically-modified oligonucleotides is underway. For our purposes, small antisense oligonucleotides (ASOs) can be
Our lab and many others have recently embarked on this exciting journey. However, this is a team effort and we cannot succeed alone. Our collaborators in the medical world provide an invaluable input in guiding us towards the patients’ needs. We are always delighted to make new contacts with physicians, care-givers and patients, so please get in touch!
Hospital Review News IVF Success Rate Greatly Enhanced By Embryo Chromosome Testing A recent American study has found that women undergoing IVF achieved a 95% pregnancy success rate over the course of 3 consecutive frozen embryo transfers, when a test to identify embryos carrying the correct number of chromosomes was utilised. Over 4000 women with a median age of 35.4 years took part in the retrospective study from the RMA clinic in New Jersey, as reported by the European Society of Human Reproduction. Only 5% of patients in the study failed to achieve a pregnancy result after 3 consecutive single embryo transfers using the chromosomally sound embryos. Dr Bart Kuczera from Beacon CARE Fertility explains why this test (called PGT-A) can be effective in reducing the number of unsuccessful embryo transfers saying, “When a sperm fertilises an egg, the embryo should result in having 23 pairs of chromosomes,
i.e., one from the egg and one from the sperm in each pair, for a total of 46 chromosomes. “The PGT-A test can help identify embryos carrying this number of chromosomes and therefore the best chance of developing into a healthy pregnancy.” When asked what happens when an embryo doesn’t have 46 chromosomes, Dr Kuczera notes, “An embryo that doesn’t have the correct number of chromosomes will most likely fail to implant and if it does implant, it will most likely miscarry.” Dr Kuczera points out that the test may not be appropriate for all women, however women with a history of repeated miscarriages or failed IVF treatments can benefit from this screening. Women of older maternal age may also benefit from the test. The study concluded that recurrent implantation failure was rare and more likely to be embryonic in nature than endometrial.
AUGUST - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE
CONFRONT R/R CLL
VENCLYXTO® + rituximab provides superior PFS to bendamustine + rituximab with a
2-YEAR FIXED TREATMENT DURATION*2
VENCLYXTO® in combination with rituximab is NOW AVAILABLE for the treatment of adult patients with CLL who have received at least one prior therapy1 * 81% risk reduction of progression or death with VEN+R vs BR (HR=0.19;95% CI:0.15-0.26, P<0.0001) at 5 year median follow up. as appropriate. Immunisation: Live vaccines should not be administered during treatment and thereafter until B-cell recovery as the 2-year fixed treatment following 5-week dose titration period.2 PFS = Progression-Free Survival, R/R = relapsed/refractory safety and efficacy has not yet been established. CYP3A inducers: Co-administration of CYP3A4 inducers may lead to decreased VENCLYXTO®▼ (venetoclax) 10 mg/50 mg/100 mg film-coated tablets. PRESCRIBING INFORMATION. PRESENTATION: Venclyxto exposure and consequently a risk for lack of efficacy. Concomitant use of Venclyxto with strong or moderate CYP3A4 inducers Each film-coated tablet contains 10mg, 50mg or 100mg of venetoclax. Please refer to the Summary of Product Characteristics (SmPC) should be avoided. Women of childbearing potential: Women of childbearing potential must use a highly effective method of before prescribing. INDICATION: Venclyxto in combination with obinutuzumab is indicated for the treatment of adult patients with contraception while taking Venclyxto. INTERACTIONS: See SmPC for full details. Venetoclax is predominantly metabolised by CYP3A. previously untreated chronic lymphocytic leukaemia (CLL) (see section 5.1)†. Venclyxto in combination with rituximab is indicated for the CYP3A inhibitors: Concomitant use of Venclyxto with strong CYP3A inhibitors at initiation and during the dose titration phase is treatment of adult patients with CLL who have received at least one prior therapy*. Venclyxto monotherapy is indicated for the treatment contraindicated due to increased risk for TLS. At initiation and during the dose-titration phase, concomitant use with moderate CYP3A of CLL in the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B cell receptor pathway inhibitors should be avoided. Alternative treatments should be considered. If a moderate CYP3A inhibitor must be used, the doses must inhibitor or in the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B cell be reduced and patients should be monitored more closely. Refer to SmPC for full details. Grapefruit, Seville oranges and starfruit receptor pathway inhibitor*. DOSAGE AND ADMINISTRATION: Oral. Treatment to be initiated and monitored by a physician should be avoided during treatment. P-gp and BCRP inhibitors: Concomitant use of Venclyxto with P-gp and BCRP inhibitors at initiation experienced in the use of anticancer medicinal products. See SmPC for full posology. Posology: Dose-titration schedule: the starting and during the dose titration phase should be avoided; if a P-gp and BCRP inhibitor must be used, patients should be monitored closely dose is 20 mg of venetoclax, once daily for 7 days. The dose must be gradually increased over a period of 5 weeks up to the daily dose for signs of toxicities. CYP3A inducers: Concomitant use of Venclyxto with strong or moderate CYP3A inducers should be avoided. of 400 mg. Post-titration dose for venetoclax in combination with rituximab: the recommended dose of venetoclax in Alternative treatments with less CYP3A induction should be considered. Preparations containing St. John’s wort are contraindicated combination with rituximab is 400 mg once daily. Administer Rituximab after the patient has completed the dose-titration schedule and during treatment with venetoclax. Bile acid sequestrants: Co-administration of bile acid sequestrants with Venclyxto is not has received the recommended daily dose of 400 mg venetoclax for 7 days. Venetoclax is taken for 24 months from Cycle 1 Day 1 of recommended as this may reduce the absorption of venetoclax. If a bile acid sequestrant is to be co-administered with Venclyxto, the rituximab. Venetoclax in combination with obinutuzumab: Venetoclax is given for a total of 12 cycles, each cycle consisting of 28 SmPC for the bile acid sequestrant should be followed to reduce the risk for an interaction, and Venclyxto should be administered at days: 6 cycles in combination with obinutuzumab, followed by 6 cycles of venetoclax as a single agent. Administer obinutuzumab 100 least 4-6 hours after the sequestrant. Warfarin: It is recommended that the international normalised ratio be monitored closely in mg on Cycle 1 Day 1, followed by 900 mg which may be administered on Day 1 or Day 2. Administer 1000 mg on Days 8 and 15 of Cycle patients receiving warfarin. Substrates of P-gp, BCRP, and OATP1B1; Co-administration of narrow therapeutic index P-gp, or BCRP 1 and on Day 1 of each subsequent 28-day cycle, for a total of 6 cycles. Start the 5-week venetoclax dose-titration schedule (see Table 1) substrates with Venclyxto should be avoided. If a narrow therapeutic index P-gp or BCRP substrate must be used, it should be used with on Cycle 1 Day 22 and continue through Cycle 2 Day 28. After completing the dose-titration schedule, the recommended dose of caution. For an orally administered P-gp or BCRP substrate sensitive to inhibition in the gastrointestinal tract its administration should venetoclax is 400 mg once daily from Cycle 3 Day 1 of obinutuzumab to the last day of Cycle 12. Post-titration dose for venetoclax be separated from Venclyxto administration as much as possible to minimise a potential interaction. If a statin is used concomitantly monotherapy: the recommended dose of venetoclax is 400 mg once daily. Treatment should be continued until disease progression with Venclyxto, close monitoring of statin related toxicity is recommended. FERTILITY PREGNANCY AND LACTATION: Women of or no longer tolerated by the patient. Patients should swallow the tablets whole with water at approximately the same time each day. childbearing potential/Contraception in females: Women should avoid becoming pregnant while taking Venclyxto and for at least 30 The tablets should be taken with a meal. Prevention of tumour lysis syndrome (TLS): Prior to initiating Venclyxto, tumour burden days after ending treatment. Pregnancy: Venclyxto is not recommended during pregnancy and in women of childbearing potential not assessment, including radiographic evaluation must be performed for all patients. The following prophylaxis measures should be using highly effective contraception. Breast-feeding: Breast-feeding should be discontinued during treatment with Venclyxto. Fertility: followed to minimise the risk of TLS and more intensive measures should be employed as overall risk increases; adequate hydration, Before starting treatment, counselling on sperm storage may be considered in some male patients. SIDE EFFECTS: See SmPC for full administration of anti-hyperuricaemic agents if necessary, blood chemistry monitoring and correction of abnormalities. Monitoring details on side effects. Very common side effects (≥1/10): Pneumonia, upper respiratory tract infection, neutropenia, anaemia, should be increased for patients at high risk of TLS. Temporary hospitalisation and close monitoring may be required in some patients, lymphopenia, hyperphosphataemia, hyperkalaemia, hypocalcaemia, diarrhoea, vomiting, nausea, constipation and fatigue. Common especially those at greater risk of TLS. Dose modifications for TLS or other toxicities may need to be considered during treatment. See side effects (≥1/100 to <1/10): Sepsis, urinary tract infection, febrile neutropenia, tumour lysis syndrome, hyperuricaemia and blood SmPC for full details of prophylaxis measures. Special Populations: Elderly: No dose adjustment required. Renal impairment: No creatinine increased. Tumour lysis syndrome (TLS): TLS is an important identified risk when initiating Venclyxto. dose adjustment required in patients with mild or moderate renal impairment. Patients with reduced renal function may require more ▼ This medicinal product is subject to additional monitoring. This will allow quick identification of new intensive prophylaxis to reduce the risk of TLS and closer monitoring. Safety in patients with severe renal impairment or on dialysis has not been established, and a recommended dose for these patients has not been determined. Hepatic impairment: No dose adjustment safety information. Healthcare professionals are asked to report any suspected adverse reactions via HPRA is recommended in patients with mild or moderate hepatic impairment. Patients with moderate hepatic impairment should be Pharmacovigilance; Website: www.hpra.ie. Suspected adverse events should also be reported to AbbVie Limited monitored more closely for signs of toxicity. A dose reduction of at least 50% throughout treatment is recommended for patients with on 01-4287900. severe hepatic impairment. These patients should be monitored more closely for signs of toxicity. Paediatric Population: The safety and efficacy of Venclyxto in children aged less than 18 years has not been established. CONTRAINDICATIONS: Hypersensitivity to any of the active substances or excipients. Concomitant use of strong CYP3A inhibitors at initiation and during the dose-titration phase Preparations containing St. John’s wort. SPECIAL WARNINGS AND PRECAUTIONS: Tumour lysis syndrome (TLS): Patients with high tumour burden (any lymph node with a diameter ≥5 cm) or those with a high absolute lymphocyte count (≥25 x 109/L), are at greater risk of TLS when initiating Venclyxto. Reduced renal function (CrCL < 80mL/min) further increases the risk. Patients should be assessed for risk and should receive appropriate prophylaxis for TLS, including hydration and anti-hyperuricaemics. Blood chemistries should be monitored and abnormalities managed promptly. Dosing should be interrupted if needed. More intensive measures should be employed as overall risk increases. Neutropenia and infections: Grade 3 or 4 neutropenia has been reported. Complete blood counts should be monitored throughout the treatment period. Dose interruptions or reductions are recommended for patients with severe neutropenia. Serious infections, including sepsis with fatal outcome, have been reported. Monitoring of any signs and symptoms of infection is required. Suspected infections are to receive prompt treatment, including antimicrobials and dose interruption or reduction
LEGAL CATEGORY: POM (S1A). MARKETING AUTHORISATION NUMBERS/PRESENTATIONS: 10mg film-coated tablet, 14 tablets, EU/1/16/1138/002; 50mg film-coated tablet, 7 tablets, EU/1/16/1138/004; 100mg film-coated tablet, 7 tablets, EU/1/16/1138/005;100mg film-coated tablet, 14 tablets, EU/1/16/1138/006; 100mg film-coated tablet, 112 tablets, EU/1/16/1138/007. MARKETING AUTHORISATION HOLDER: AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany. Further information is available fromAbbVie Limited,14 Riverwalk,Citywest Business Campus,Dublin 24,Ireland.†This indication is not reimbursed. * Indications are reimbursed. DATE OF REVISION: June 2020. PI/1138/008. References: 1. VENCLYXTO® Summary of Product Characteristics, available at www.medicines.ie. 2. Kater AP, Kipps TJ, Eichhorst B, et al. Five-year analysis of MURANO study demonstrates enduring undetectable minimal residual disease (uMRD) in a subset of relapsed/refractory chronic lymphocytic leukemia patients following fixed-duration venetoclax-rituximab therapy. Oral presentation (125) presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; Virtual meeting IE-VNCLY-210002 Date of Preparation: January 2021
Flexible scheduling for your second-line non-small cell lung cancer patients*1-3 Every 3 weeks: Fixed dose 1200 mg IV (1 vial)
Every 4 weeks: Fixed dose 1680 mg IV (2 x 840 mg vials)3
Once prepared, TECENTRIQ remains stable for up to 30 days at 2-8°C. However, to avoid the risk of contamination, immediate use is always recommended.2,3 Please see Summary of Product Characteristics for further details.2,3 *A study examined the exposure-response relationship between TECENTRIQ’s efficacy and safety in patients with non-small cell lung cancer using data from pooled Phase I and III studies in non-small cell lung cancer and urothelial carcinoma. Population pharmacokineticsimulated exposures for the 1680mg Q4W were compared with the previously approved 1200mg Q3W. The results from the study support the interchangeable use of 1200mg Q3W and 1680mg Q4W dosing regimens for atezolizumab, as they are anticipated to demonstrate comparable efficacy and safety profiles while offering patients greater flexibility and convenience in their treatment.1
TECENTRIQ as monotherapy is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after prior chemotherapy. Patients with EGFR mutant or ALK-positive NSCLC should have received targeted therapies before receiving TECENTRIQ.2,3 2L, 2nd line. References: 1. Morrissey, K.M et al. Cancer Chemother Pharmacol 2019; 84: 1257–1267. 2. TECENTRIQ 1,200 mg concentrate for solution for infusion Summary of Product Characteristics 30 April 2021 available on www.medicines.ie. 3. TECENTRIQ 840 mg concentrate for solution for infusion Summary of Product Characteristics 30 April 2021, available on www.medicines.ie. Date of item: June 2021. M-IE-00000721. ABRIDGED PRESCRIBING INFORMATION (API). For full prescribing information refer to the Summary of Product Characteristics
▼ 1,200 mg concentrate for solution for infusion (One 20 ml vial of concentrate contains 1,200 mg atezolizumab) and 840 mg concentrate for solution for infusion (One 14 ml vial of concentrate contains 840mg of atezolizumab).▼ This medicinal product is subject to additional monitoring. This will allow quick
[SmPC]. Tecentriq® (atezolizumab)
identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See box below for details on how to report. Therapeutic Indications: Tecentriq 1,200mg and 840mg: As monotherapy for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma (UC) after prior platinumcontaining chemotherapy, or who are considered cisplatin ineligible and whose tumours have a PD-L1 expression ≥ 5%. As monotherapy for the first-line (1L) treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumours have a PD-L1 expression ≥ 50% tumour cells (TC) or ≥ 10% tumour-infiltrating immune cells (IC) and who do not have EGFR mutant or ALK-positive NSCLC. As monotherapy for the treatment of adult patients with locally advanced or metastatic NSCLC after prior chemotherapy. Patients with EGFR mutant or ALK-positive NSCLC should also have received targeted therapies before receiving Tecentriq. Tecentriq 1,200mg: In combination with bevacizumab, paclitaxel and carboplatin for the 1L treatment of adult patients with metastatic non-squamous NSCLC. In combination with bevacizumab, paclitaxel and carboplatin, for patients with EGFR mutant or ALK-positive NSCLC, is indicated only after failure of appropriate targeted therapies. In combination with nab-paclitaxel and carboplatin, for the 1L treatment of adult patients with metastatic NSCLC who do not have EGFR mutant or ALK-positive NSCLC. In combination with carboplatin and etoposide, for the 1L treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC). In combination with bevacizumab, is indicated for the treatment of adult patients with advanced or unresectable hepatocellular carcinoma (HCC) who have not received prior systemic therapy. Tecentriq 840mg: In combination with nab-paclitaxel for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) whose tumours have PD-L1 expression ≥ 1% and who have not received prior chemotherapy for metastatic disease. Posology and Method of Administration: The initial dose must be administered over 60 minutes and if well tolerated, subsequent infusions may be administered over 30 minutes. It must not be administered as an intravenous push or bolus. For instructions on dilution and handling, refer to SmPC. For combination therapies refer to the full prescribing information for the combination products. Recommended to treat patients until loss of clinical benefit or unmanageable toxicity for (2L) NSCLC, 2L UC and HCC; or until disease progression or unmanageable toxicity for 1L NSCLC, 1L UC, 1L ES-SCLC and TNBC. Atypical responses (i.e., an initial disease progression followed by tumour shrinkage) have been observed with continued Tecentriq treatment after disease progression. Treatment beyond disease progression may be considered at the discretion of the physician, for 1L NSCLC (Tecentriq in combination therapy) and 1L ES-SCLC. Administer Tecentriq as soon as possible if a planned dose is missed and adjust administration schedule to maintain a regular schedule. Dose reduction is not recommended. Dose delay or discontinuation may be required based on individual safety and tolerability, refer to SmPC. The safety and efficacy of Tecentriq in children and adolescents (< 18 years) has not been established, and no posology recommendation can be made. PD-L1 testing: Tecentriq monotherapy: Patients with 1L (cisplatin ineligible) UC and 1L NSCLC should be selected for Tecentriq treatment based on the tumour expression of PD-L1 by a validated test (1L (cisplatin ineligible) UC: PD-L1 ≥ 5%, 1L NSCLC: PD-L1 ≥ 50% TC or >10% IC). Tecentriq in combination therapy: Patients with previously untreated TNBC should be selected for treatment based on the tumour expression of PD-L1 ≥1% confirmed by a validated test. Refer to 1,200mg SmPC (1L UC and 1L NSCLC). Refer to 840mg SmPC (UC, TNBC or NSCLC). UC, 1L NSCLC and 2L NSCLC: Tecentriq monotherapy: 1,200mg administered intravenously every three weeks, or 840mg administered intravenously every 2 weeks, or 1,680 mg administered intravenously every 4 weeks. 1L NSCLC: Tecentriq in combination with bevacizumab, paclitaxel, and carboplatin: Induction phase recommended dose of Tecentriq is 1,200 mg administered by intravenous infusion, followed by bevacizumab, paclitaxel, and then carboplatin every 3 weeks for 4 or 6 cycles; followed by a maintenance phase without chemotherapy in which 1,200 mg Tecentriq followed by bevacizumab, is administered by intravenous infusion every 3 weeks. Tecentriq in combination with nab-paclitaxel and carboplatin: Induction phase recommended dose of Tecentriq is 1,200 mg administered by intravenous infusion, followed by nab-paclitaxel and carboplatin every three weeks for 4 or 6 cycles. For each 21-day cycle, Tecentriq, nab-paclitaxel, and carboplatin are administered on day 1. Nab-paclitaxel is administered on days 8 and 15. The induction phase is followed by a maintenance phase without chemotherapy in which 1,200 mg Tecentriq is administered by intravenous infusion every three weeks. ES-SCLC: Tecentriq in combination with carboplatin and etoposide:
Induction phase recommended dose of Tecentriq is 1,200 mg administered by intravenous infusion followed by carboplatin, and then etoposide administered by intravenous infusion on day 1. Etoposide is also administered by intravenous infusion on days 2 and 3. This regimen is administered every three weeks for four cycles; followed by a maintenance phase without chemotherapy in which 1,200 mg Tecentriq is administered by intravenous infusion every three weeks. TNBC: Tecentriq in combination with nab-paclitaxel: The recommended dose of Tecentriq is 840 mg administered by intravenous infusion, followed by 100mg/m2 nab-paclitaxel. For each 28-day cycle, Tecentriq is administered on days 1 and 15, and nab-paclitaxel is administered on days 1, 8, and 15. HCC: Tecentriq in combination with bevacizumab: The recommended dose of Tecentriq is 1,200 mg followed by bevacizumab 15 mg/kg of body weight, administered by intravenous infusion every three weeks. Contraindications: Hypersensitivity to Tecentriq or to any of the excipients listed in the SmPCs. Special Warnings and Precautions for Use: Refer to Tecentriq 1,200mg and 840 mg SmPCs for full description of Special Warnings and Precautions. Tecentriq is associated with immune-related adverse reactions. For suspected immune-related adverse reactions, thorough evaluation should be performed to confirm aetiology or exclude other causes. Based on the severity of the adverse reaction, Tecentriq should be withheld and corticosteroids administered. Upon improvement to Grade ≤ 1, corticosteroids should be tapered over ≥ 1 month. Permanently discontinue treatment with Tecentriq for any recurrent Grade 3 immune-related adverse reactions, and for any Grade 4, except for endocrinopathies that are controlled with replacement hormones. Immune-related pneumonitis: Monitor patients for signs and symptoms of pneumonitis and causes other than immune-related pneumonitis should be ruled out. Treatment with Tecentriq must be permanently discontinued for Grade 3 or 4 pneumonitis. Immune-related colitis: Monitor patients for signs and symptoms of colitis. Treatment with Tecentriq must be permanently discontinued for Grade 4 (life threatening; urgent intervention indicated) diarrhoea or colitis. Immune-related hepatitis: Monitor patients for signs and symptoms of hepatitis, transaminase and bilirubin elevation. In patients without HCC, treatment with Tecentriq must be permanently discontinued for Grade 3 or Grade 4 events (ALT or AST>5.0 x ULN or blood bilirubin>3xULN). In patients with HCC, treatment with Tecentriq must be permanently discontinued if ALT or AST increases to > 10 x ULN or total bilirubin increases > 3 x ULN. Immune-related endocrinopathies: Monitor patients for clinical signs and symptoms of endocrinopathies. Thyroid function should be monitored prior to and periodically during treatment with Tecentriq. Treatment with Tecentriq should be permanently discontinued for Grade 4 hypophysitis. Immune-related meningoencephalitis: Monitor patients for clinical signs and symptoms of meningitis or encephalitis. Treatment with Tecentriq must be permanently discontinued for any grade of meningitis or encephalitis. Immune-related neuropathies: Monitor patients for symptoms of motor and sensory neuropathy. Treatment with Tecentriq must be permanently discontinued for any grade of myasthenic syndrome/myasthenia gravis or Guillain-Barré syndrome. Immune-related pancreatitis: Monitor patients closely for signs and symptoms suggestive of acute pancreatitis. Treatment with Tecentriq should be permanently discontinued for Grade 4, or any grade of recurrent pancreatitis. Immune-related myocarditis: Monitor patients for signs and symptoms of myocarditis. Treatment with Tecentriq must be permanently discontinued for Grade 3 or 4 myocarditis. Immune-related nephritis: Monitor patients for changes in renal function. Treatment with Tecentriq must be permanently discontinued for Grade 3 or 4 nephritis. Immune-related myositis: Monitor patients for signs and symptoms of myositis. Treatment with Tecentriq should be permanently discontinued for Grade 4 or 3 recurrent myositis. Infusion-related reactions (IRRs): Severe IRRs have been observed. Tecentriq must be permanently discontinued for grade 3 or 4 IRRs. Immune-related severe cutaneous adverse reactions (SCARs): (SCARs), including cases of StevensJohnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in patients receiving Tecentriq. Monitor patients for suspected severe skin reactions and other causes should be excluded. For suspected SCARs, refer patients to a specialist for further diagnosis and management. Based on the severity of the adverse reaction, Tecentriq should be withheld for Grade 3 skin reactions and treatment with systemic corticosteroids at a dose of 1-2 mg/kg/day of prednisone or equivalent should be started. Treatment may be resumed if the event improves to ≤ Grade 1 within 12 weeks, and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day. Treatment with Tecentriq should be permanently discontinued for Grade 4 skin reactions, and corticosteroids should be administered. Tecentriq should be withheld for patients with suspected SJS or TEN. For confirmed SJS or TEN, Tecentriq should be permanently discontinued. Caution should be used when considering the use of Tecentriq in a patient who has previously experienced a severe or life-threatening skin adverse reaction on prior treatment with other immune-stimulatory anticancer agents. Tecentriq in combination with bevacizumab, paclitaxel and carboplatin in metastatic NSCLC: Carefully consider the combined risks of the four-drug regimen of Tecentriq, bevacizumab, paclitaxel, and carboplatin before initiating treatment, refer to SmPC. Tecentriq in combination with nab-paclitaxel in metastatic TNBC: Neutropenia and peripheral neuropathies occurring during treatment with Tecentriq and nabpaclitaxel may be reversible with interruptions of nab-paclitaxel. Consult the nab-paclitaxel SmPC for specific precautions and contraindications. Tecentriq in combination with bevacizumab in HCC: Severe gastrointestinal haemorrhage, including fatal events, were reported. Screening for and subsequent treatment of oesophageal varices should be performed as per clinical practice prior to starting treatment. Bevacizumab should be permanently discontinued in patients who experience Grade 3 or 4 bleeding with the combination treatment. Diabetes mellitus can occur. Monitor blood glucose levels prior to and periodically during treatment. Please refer to the bevacizumab SmPC. Tecentriq as monotherapy for 1L treatment in metastatic NSCLC: The delayed onset of Tecentriq effect should be considered before initiating 1L treatment as monotherapy in patients with NSCLC. A higher number of deaths within 2.5 months after randomisation followed by a long-term survival benefit was observed with Tecentriq compared with chemotherapy. No specific factor(s) associated with early deaths could be identified, refer to SmPC. Special Populations: Patients excluded from clinical trials included; baseline performance status ≥ 2, history of autoimmune disease and pneumonitis, active brain metastasis, HIV, hepatitis B or C infections, significant cardiovascular disease and patients with inadequate hematologic and end–organ function, patients who were administered a live attenuated vaccine within 28 days prior to enrolment, systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive medicinal products within 2 weeks prior to study entry; therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment. Use Tecentriq with caution in these populations, refer to SmPC for full list of specific precautions. Interactions: No formal pharmacokinetic drug interaction studies have been performed. Since Tecentriq is cleared from the circulation through catabolism, no metabolic drug-drug interactions are expected. The use of systemic corticosteroids or immunosuppressants should be avoided before starting Tecentriq. However systemic corticosteroids or other immunosuppressants can be used to treat immune-related adverse events after starting Tecentriq, refer to SmPC. Fertility, Pregnancy and Lactation: The effect of Tecentriq on fertility and pregnancy is unknown. Women of childbearing potential must use effective contraception methods during and for 5 months after treatment with Tecentriq. Tecentriq should not be used during pregnancy, unless the clinical condition of the woman requires treatment. It is not known whether Tecentriq is excreted in human milk. A risk to newborns/infants cannot be excluded. Effects on ability to drive and use machines: Tecentriq has minor influence on the ability to drive and use machines. Advise patients experiencing fatigue not to drive and use machines until symptoms abate Undesirable Effects: Tecentriq monotherapy: Very common (≥ 1/10): cough, decreased appetite, headache, dyspnoea, musculoskeletal pain, nausea, vomiting, diarrhoea, urinary tract infections, rash, pruritus, arthralgia, back pain, pyrexia, fatigue, asthenia. Common (≥1/100 to <1/10): thrombocytopenia, hypothyroidism, hyperthyroidism, hypokalaemia, hyponatremia, hyperglycaemia, hypotension, pneumonitis, hypoxia, nasal congestion, nasopharyngitis, abdominal pain, colitis, dysphagia, oropharyngeal pain, infusion–related reaction, AST increased, ALT increased, hepatitis, dry skin, blood creatinine increased, influenza like illness, chills. Tecentriq in combination therapy: Very common (≥ 1/10): anaemia, thrombocytopenia, neutropenia, hypothyroidism, lung infection, leukopenia, decreased appetite, peripheral neuropathy, dyspnoea, nausea, diarrhoea, back pain, constipation, rash, pruritus, alopecia, arthralgia, pyrexia, oedema peripheral, headache, hypertension, fatigue, musculoskeletal pain, vomiting, cough, asthenia. Common (≥1/100 to <1/10): hypokalaemia, hyponatremia, dysgeusia, dysphonia, stomatitis, sepsis, infusion-related reaction, hypomagnesaemia, dizziness, lymphopenia, hyperthyroidism, syncope, AST increased, ALT increased, proteinuria, blood creatinine increased, blood alkaline phosphatase increased. Immunogenicity: 13.1%-54.1% of patients developed treatment-emergent anti-drug antibodies (ADAs), refer to SmPC for details. Tecentriq in combination with bevacizumab, paclitaxel and carboplatin: Other clinically significant adverse events which were observed more frequently in the Tecentriq, bevacizumab, paclitaxel, and carboplatin arm were epistaxis, haemoptysis, cerebrovascular accident, including fatal events. Refer to SmPC for full listings of adverse events. Refer to SmPC section 4.8 for instructions on reporting of suspected adverse events. Legal Category: Product subject to medical prescription which may not be renewed (A). Presentation(s) and Marketing Authorization Number(s): 1,200 mg of atezolizumab in 20 mL, pack of one vial (EU/1/17/1220/001); 840 mg atezolizumab in 14 ml, pack of one vial (EU/1/17/1220/002). Marketing Authorisation Holder: Roche Registration GmbH, Emil-Barell-Strasse 1, 79639 Grenzach-Wyhlen, Germany. Tecentriq® is a registered trademark. Further information is available from Roche Products (Ireland) Limited, 3004 Lake Drive, Citywest, Naas Road, Dublin 24. Telephone: (01) 4690700. Date of API Preparation: May 2021.
▼ This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. In the event of a suspected adverse reaction, The Drug Surveillance Centre Roche Products (Ireland) Limited Telephone: (01) 4690700 Email: email@example.com
Or alternatively, report to: HPRA Pharmacovigilance Website: www.hpra.ie
Tecentriq® Summary of Product Characteristics [SmPC] is available on www.medicines.ie. API M-IE-00000644 based on Tecentriq 840mg and 1,200mg SmPCs dated 30 Apr 2021
42 HOSPITAL REVIEW: OBESITY
Obesity is Associated with Reduced Blood Supply to the Brain Professor Rose Anne Kenny, Principal Investigator of TILDA, and co-author of the study
RECCOMENDATIONS The study recommends at least 1.5 to 2 hours of ‘being active’ throughout the day, engaging in activities that require moderate effort. These include activities that cause one to breathe harder than normal, such as fast walking or cycling. However, any increase in physical activity, particularly if integrated into daily or weekly habits, such as gardening, should help maintain and potentially improve brain blood flow.
A new study from scientists at The Irish Longitudinal Study on Ageing (TILDA) reveals important findings, indicating that being overweight or obese significantly reduces blood flow in the brain. The study also shows that increased physical activity can positively modify, or even negate, this reduction in brain blood flow. The study contains important and relevant information which is of great interest to the general public; since reduced blood flow in the brain, or ‘cerebral hypoperfusion’, is an early mechanism in vascular dementia and Alzheimer’s disease. Obesity and Health Problems According to the World Health Organization (WHO), obesity is a worsening health crisis that has reached epidemic proportions globally, with over 1 billion adults overweight – and at least 300 million clinically obese. It continues to be a major contributor to global rates of chronic disease and disability, affecting overall quality of life, while placing increased strain on the immune system which is of the upmost importance given the current COVID-19 situation. Obesity is also a significant public health concern given its negative impact on physiological function, especially as we age. Finding easily implemented and costeffective ways to tackle the impact of obesity is particularly important
to help protect against negative health outcomes in later life. What are the findings of TILDA's study? The study investigates three different measures of obesity body mass index (BMI), waist-tohip ratio and waist circumference, as well as physical activity, in adults over 50 years. Brain blood flow was measured using cuttingedge MRI scanning and analysis techniques. The findings reveal that being overweight or obese is associated with reduced blood supply to the brain. Whereas brain blood flow is known to decline with age, in this study the negative influence of obesity on brain blood flow was shown to be greater than that of age. However, being physically active helps to cancel out the negative effects of obesity on brain blood flow. KEY FINDINGS • Increased BMI, waist-tohip ratio, and waist size are associated with less blood supply to the brain. • A waist size increase of +1cm is associated with the same reduction in brain blood flow as +1 year of age. • Higher levels of physical activity modify the associations between reduced brain blood flow and obesity.
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Dr Silvin Knight, Research Fellow at TILDA and lead author, said, “Consistent, healthy blood supply to the brain is critical, as it ensures that the brain is provided with enough oxygen and nutrients to function correctly. If brain blood flow becomes impaired, it can lead to serious health issues as we age, such as increasing the risk of dementia and Alzheimer’s disease. We know that obesity can predispose a person to age-related conditions, illness, and disease, and even reduce life expectancy by up to 6 years in men and 7 years in women, after the age of forty. Our study reveals clear associations between obesity and reduced blood supply to the brain in an older population. The study also shows the importance of being physically active for older overweight or obese individuals, as this may help to protect against
reduced brain blood flow and the poor health outcomes that can arise from this.” Professor Rose Anne Kenny, Principal Investigator of TILDA, and co-author of the study, said, “Many experts have shown that obesity and ageing have very similar effects on the biology of ageing; diseases associated with obesity are similar to those of ageing and age-related diseasesheart disease, diabetes, high blood pressure, kidney failure, arthritis, susceptibility to infectionsincluding Covid-19. “Our study not only shows that there is a link between obesity and reduced brain blood flow, but also that it is possible to protect against the negative consequences of obesity through regular physical exercise. Whereas these findings are of relevance in the global context, because of the rapidly evolving global burden of obesity, the research is especially important to Irish adults because obesity and being overweight is a considerable health issue in Ireland. “Previous TILDA research has shown that over one-third of Irish adults aged 50 and older are obese and a further 43% overweight. As we prepare our society for a growing ageing population, we can use this evidence to prepare meaningful public health policies that will promote impactful and positive lifestyle habits, such as regular physical activity, to mitigate against some of the negative consequences of the growing obesity crisis.”
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Job code: IV/ONCO/010/2020. Date of Preparation: November 2020.
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44 HOSPITAL REVIEW: CARDIOLOGY
Late Breaking Clinical Trials in Cardiology Update from the American College of Cardiology Annual Scientific Meeting 2021 Written by Robert A. Byrne, Himanshu Rai and Laurna McGovern Cardiovascular Research Institute (CVRI) Dublin, Mater Private Network, Dublin, Ireland (RAB, HR, LMcG); School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland (RAB, HR, LMcG)
Corresponding author: Professor Robert A. Byrne Cardiovascular Research Institute (CVRI), Mater Private Network and School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland firstname.lastname@example.org
This year’s meeting of the American College of Cardiology took place from 15th to 17th May 2021 and was an all virtual meeting. The meeting was highly successful, and a host of highquality late breaking clinical trials were presented along with simultaneous publication of a large number of accompanying manuscripts in high impact journals including New England Journal of Medicine and Lancet. The trials discussed in this article the subject of an online lecture as part of the Dublin Cardiovascular Research Forum (DCRF). DCRF is a weekly meeting hosted by the Cardiovascular Research Institute at Mater Private Network in association with RCSI University of Medicine and Health Sciences. A recording of the lecture is available at the following link: https://www.cvridublin.ie/ education-and-publication/ dublin-cardiovascular-researchforum/past-events/. To register for notification of upcoming lectures please visit www.cvridublin.ie or send an e-mail to email@example.com. ADAPTABLE (Aspirin Dosing: A Patient-Centric trial Assessing Benefits and Long-term Effectiveness)1 compared the effectiveness of two doses of aspirin in patients with known
atherosclerotic cardiovascular disease and at least one other risk factor or enrichment factor. The study was remarkable for its largescale design, screening more than 400,000 and enrolling more than 15,000 patients, and also for using an innovative approach to patient enrolment, largely bypassing study centres and communicating with potential candidates via a participant portal, which included facility for electronic consent and self-randomization. Treatment was randomly allocated with either aspirin 81 milligrams once a day or aspirin 325 milligrams once a day. Follow up was done electronically by direct contact with the patient as well as via electronic health records and health plans. The primary endpoint was a composite of all-cause mortality, hospitalisation for myocardial infarction or stroke. The primary safety endpoint was hospitalization for major bleeding. The main finding was that there was no difference between the groups, hazard ratio (HR) = 1.02 (95% CI 0.91 - 1.14, P = 0.75). The main safety endpoint also showed a similar rate between the groups. Tolerability was better and rates of discontinuation were lower in patients receiving low dose aspirin. These findings are limited by the open label design of the trial. The results are of interest to the community, particularly in the United States, where two
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different doses of aspirin are frequently prescribed, suggesting that low dose is the best option for patients taking aspirin for secondary prevention. The other main learning from the trial is that it is feasible to do large scale trials with direct patient screening, consenting and enrolment. This design might be used for other studies in the future. The LAAOS III (Left Atrial Appendage Occlusion Study III)2 was an important study examining the efficacy and safety of routine left atrial appendage exclusion at the time of surgery in patients with atrial fibrillation undergoing cardiac surgery for another indication. Patients were randomly allocated to routine LAA exclusion versus usual care. All patients received anticoagulation during follow up. This study was stopped early at the time of the planned interim analysis by the Data Safety Monitoring Board after enrolment of 4811 patients and at a median follow-up of 3.8 years. There was a clear efficacy advantage for LAA exclusion with a 33% reduction in the primary endpoint of stroke or systemic embolism (HR= 0.67, 95% CI 0.53 - 0.85, P = 0.001). The benefit appears additive to oral anticoagulation. There was no difference in the primary safety endpoint of hospitalization for heart failure, which might theoretically have been different in the presence of relevant
neurohormonal influence of the left atrial appendage. Unfortunately, the study doesn't inform us as to whether, if this strategy is adopted going forward, there continues to be a requirement for oral anticoagulation. Currently, perhaps somewhat counterintuitively, ESC clinical practice guidelines suggest against discontinuation of oral anticoagulant in patients who have surgical LAA exclusion (due in part to unconvincing results from earlier studies and varying completeness of exclusion depending on the surgical method used). In contrast, patients who received percutaneous LAA exclusion, usually discontinue oral anticoagulation. The FLOWER-MI (FLOW Evaluation to Guide Revascularization in Multi-vessel ST-elevation Myocardial Infarction)3 investigated patients undergoing primary angioplasty for ST-elevation myocardial infarction who turn out to have multivessel disease rather than disease restricted to the culprit lesion. Earlier studies, done predominantly in patients with stable chronic coronary syndrome, suggests that in multivessel disease, pressure wire guided intervention is superior to and results in fewer stents implanted compared with intervention based on stenting of all high-grade lesions. The generalizability of this data to patients with catheterization and intervention in the settings of an acute myocardial infarction is open to question, making the study of high clinical relevance. The primary endpoint was a composite of all-cause mortality, nonfatal myocardial infarction, or unplanned hospitalization leading to urgent revascularization at 1 year. The main finding was that there was no difference between the groups in terms of the primary endpoint, hazard ratio= 1.32 ( 95% CI 0.78-2.23, P = 0.31). The main conclusion that can be drawn from the trial is that in patients presenting with STelevation myocardial infarction,
45 pressure wire guided intervention is comparable to intervention of all angiographically high-grade lesions in terms of major clinical adverse events at 1-year follow-up timepoint. REHAB-HF (An Innovative Physical Function Intervention for Older Patients Hospitalised for Acute Decompensated Heart Failure)4 examined the effects of a rehabilitation intervention that included multiple physical-function domains in frail, older patients who were hospitalised for acute decompensated heart failure. The primary outcome was the score on the Short Physical Performance Battery (total scores range from 0 to 12, with lower scores indicating more severe physical dysfunction) at 3 months. The secondary outcome was the 6-month rate of rehospitalisation for any cause. A total of 349 patients underwent randomisation; 175 were assigned to the rehabilitation intervention and 174 to usual care (control). The Short Physical Performance Battery at 3 months was 8.3±0.2 in the intervention group and 6.9±0.2 in the control group (mean between-group difference, 1.5; 95% confidence interval [CI], 0.9 to 2.0; P<0.001). At 6 months, the rates of rehospitalisation for any cause were 1.18 in the intervention group and 1.28 in the control group (rate ratio, 0.93; 95% CI, 0.66 to 1.19). This study demonstrated that in a diverse population of older patients who were hospitalised for acute decompensated heart failure, an early, tailored, rehabilitation intervention resulted in greater improvement in physical function than usual care. In recent years there has been renewed debate regarding the optimal antiplatelet agent in the chronic maintenance period in patients who undergo coronary stenting with drug eluting stents. The HOST-EXAM (Harmonizing Optimal Strategy for Treatment of Coronary Artery Stenosis- EXtended Antiplatelet Monotherapy) trial5 aimed to compare the efficacy and safety of aspirin and clopidogrel monotherapy. This prospective, randomised, open-label, multicentre trial enrolled 5,530 patients at 37 study sites in South Korea. Patients were randomly assigned (1:1) to receive a monotherapy agent of clopidogrel 75 mg once daily or aspirin 100 mg once daily for 24 months. The primary endpoint was a composite of all-cause death, non-fatal myocardial infarction, stroke, readmission due to acute coronary syndrome, and Bleeding Academic Research Consortium (BARC) bleeding type 3 or greater, in the intention-to-treat population. During follow-up, the primary outcome occurred in 152 (5·7%)
patients in the clopidogrel group and 207 (7·7%) in the aspirin group (hazard ratio 0·73 [95% CI 0·59–0·90]; p=0·0035). This trial showed that among patients who were event free for 6–18 months post-PCI and successfully received the intended duration of DAPT, clopidogrel monotherapy compared with aspirin monotherapy significantly reduced the risk of the composite of all-cause death, non-fatal myocardial infarction, stroke, readmission due to acute coronary syndrome, and BARC type bleeding of 3 or more. This trial has important clinical implications for patients requiring indefinite antiplatelet monotherapy after percutaneous coronary intervention though must be interpreted against the background of prior studies, which failed to demonstrate an advantage of P2Y12 inhibitors over aspirin.6 Enthusiasm for renal denervation faded with the observation of lack of efficacy in the first large sham-controlled clinical trial in the field some years ago. Recent trials incorporating sham control, however, have showed encouraging results. The RADIANCE-HTN TRIO trial (A Study of the ReCor Medical Paradise System in Clinical Hypertension: TRIO cohort)7 investigated efficacy and safety of endovascular ultrasound renal denervation in patients with office blood pressure of at least 140/90 mm Hg despite on three or more antihypertensive medications. Earlier published evidence from several meta-analyses, suggested efficacy of renal denervation in reducing 24-h ambulatory systolic blood pressure as compared to the sham procedure. A total of 136 participants were randomly assigned to either renal denervation (n=69) or a sham procedure (n=67) and were compared for a primary endpoint of change in daytime ambulatory systolic blood pressure at 2 months post procedure. The main finding was that renal denervation reduced daytime ambulatory systolic blood pressure
more than the sham procedure (–8·0 mmHg [IQR –16·4 to 0·0] vs –3·0 mmHg [–10·3 to 1·8]; median between-group difference –4·5 mm Hg [95% CI –8·5 to –0·3]; adjusted p=0·022). The results can be of interest for patients with resistant hypertension, as this study showed renal denervation induced blood pressure reduction at 2-month follow-up timepoint. Evidence of long-term reduction in blood pressure after ultrasound renal denervation is still awaited. The next major international cardiology meeting is the annual meeting of the European Society of Cardiology which will take place between 27th and 31st of August 2021. Next year the American College of Cardiology meeting is scheduled to take place between 2nd and 4th April 2022. References: 1. Jones WS, Mulder H, Wruck LM, Pencina MJ, Kripalani S, Munoz D, et al. Comparative Effectiveness of Aspirin Dosing in Cardiovascular Disease. N Engl J Med. 2021;384(21):1981-90. 2. Whitlock RP, Belley-Cote EP, Paparella D, Healey JS, Brady K, Sharma M, et al. Left Atrial Appendage Occlusion during Cardiac Surgery to Prevent Stroke. N Engl J Med. 2021;384(22):2081-91.
3. Puymirat E, Cayla G, Simon T, Steg PG, Montalescot G, DurandZaleski I, et al. Multivessel PCI Guided by FFR or Angiography for Myocardial Infarction. N Engl J Med. 2021. 4. Kitzman DW, Whellan DJ, Duncan P, Pastva AM, Mentz RJ, Reeves GR, et al. Physical Rehabilitation for Older Patients Hospitalized for Heart Failure. N Engl J Med. 2021. 5. Koo B-K, Kang J, Park KW, Rhee T-M, Yang H-M, Won K-B, et al. Aspirin versus clopidogrel for chronic maintenance monotherapy after percutaneous coronary intervention (HOSTEXAM): an investigator-initiated, prospective, randomised, openlabel, multicentre trial. The Lancet. 2021;397(10293):2487-96. 6. Byrne RA, Colleran R. Aspirin for secondary prevention of cardiovascular disease. Lancet. 2020;395(10235):1462-3. 7. Azizi M, Sanghvi K, Saxena M, Gosse P, Reilly JP, Levy T, et al. Ultrasound renal denervation for hypertension resistant to a triple medication pill (RADIANCEHTN TRIO): a randomised, multicentre, single-blind, shamcontrolled trial. The Lancet. 2021;397(10293):2476-86.
HOSPITALPROFESSIONALNEWS.IE | HPN • AUGUST - 2021
46 HOSPITAL REVIEW: PEER NEWS
Revolution in Treatment of Genetic Disorders Professor Julian Gillmore, UCL National Amyloidosis Centre
known as ‘precursor proteins’. Amyloid deposits cause disease by gradually accumulating within organs and thereby disrupting the structure and damaging the function of the affected tissues. Different types of amyloidosis are named according to the precursor proteins which form the amyloid fibrils. All have the initial ‘A’ denoting amyloidosis and letter(s) identifying the particular precursor protein which forms amyloid fibrils within the amyloid deposits.
The development of an investigational therapy which ‘edits’ a harmful gene in patients with a debilitating condition called amyloidosis could pave the way for a revolution in the treatment of genetic disorders, finds a new study led by University College London scientists. People with hereditary transthyretin (ATTR) amyloidosis have a mutation in the transthyretin (TTR) gene, which means they produce an abnormal protein that gradually builds up in the heart and nerves. Symptoms include numbness in the hands and feet, loss of control of the bowel and bladder and immobility. The
condition gets progressively worse and is ultimately fatal. Amyloidosis is a rare disease caused by abnormal deposition and accumulation of proteins in the tissues of the body. Amyloid deposits are primarily made up of protein fibres known as amyloid fibrils. These amyloid fibrils are formed when normally soluble body proteins aggregate (clump together) and then remain in the tissues instead of safely going away. About 30 different proteins are known to form amyloid deposits in humans. These amyloid forming (‘amyloidogenic’) proteins are
In ATTR amyloidosis, a blood protein called transthyretin (TTR) is the amyloid precursor protein that forms the amyloid deposits. ATTR amyloidosis can be either hereditary or acquired (nonhereditary, known as wild-type ATTR amyloidosis) Most of the treatment options available to patients have involved managing the symptoms and preventing progression of the disease. But following strong interim results from the first six patients in a Phase 1 clinical trial of a geneediting treatment led by the UCL National Amyloidosis Centre at the Royal Free Hospital, London it is hoped this therapy will be a breakthrough for patients suffering from this debilitating condition. Patients on the trial receive, via a one-off infusion, a molecule known as CRISPR/Cas9, which
inactivates the incorrect gene within the liver cells. With the gene no longer active in the liver, it is expected that the patient will only produce negligible levels of the harmful transthyretin protein. In the first six patients, the investigational therapy reduced production of the harmful protein by up to 96% by day 28 following treatment. There were no serious adverse events observed. The data were published today in the New England Journal of Medicine. As the trial progresses, patients will be given higher doses of the gene editing therapy with the hope that will drive the levels of toxic protein even lower. CRISPR/Cas9, a Nobel Prizewinning technology, has been used in the past to edit cells outside the body. These are the first clinical data for an investigational therapy in which CRISPR/Cas9 is used as a medicine itself, infused intravenously to inactivate a target gene in a specific organ - in this case, the liver. Trial lead, Professor Julian Gillmore, of the UCL National Amyloidosis Centre, part of the UCL Centre for Amyloidosis and Acute Phase Proteins, said: “This is wonderful news for patients with this condition. If this trial continues to be successful, the treatment may permit patients who are diagnosed early in the course of the disease to lead completely normal lives without the need for ongoing therapy. “Until very recently, the majority of treatments we have been able to offer patients with this condition have had limited success. If this trial continues to go well, it will mean we can offer real hope and the prospect of meaningful clinical improvement to patients who suffer from this condition.”
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S U S P E C T AT T R - C M ( T R A N S T H Y R E T I N A M Y L O I D C A R D I O M YO PAT H Y )
A L I F E - T H R E AT E N I N G D I S E A S E T H AT C A N G O U N D E T E C T E D Life-threatening, underrecognized, and underdiagnosed, ATTR-CM is a rare condition found in mostly older patients in which misfolded transthyretin proteins deposit in the heart.1-7 It is vital to recognize the diagnostic clues so you can identify this disease.
C O N S I D E R T H E F O L L O W I N G C L I N I C A L C L U E S , E S P E C I A L LY I N C O M B I N AT I O N , T O R A I S E S U S P I C I O N F O R AT T R - C M A N D T H E N E E D F O R F U R T H E R T E S T I N G
HFpEF INTOLERANCE DISCORDANCE DIAGNOSIS ECHO NERVOUS SYSTEM heart failure with preserved ejection fraction in patients typically over 60 years old5-7
to standard heart failure therapies (ACEi, ARBs, and beta blockers)8-10 between QRS voltage and left ventricular (LV) wall thickness11-13
of carpal tunnel syndrome or lumbar spinal stenosis3,8,14-20
showing increased LV wall thickness6,13,16,21,22
—autonomic nervous system dysfunction-including gastrointestinal complaints or unexplained weight loss6,16,23,24
L E A R N H O W T O R E C O G N I Z E T H E C L U E S O F AT T R - C M AT :
References 1. Sipe JD, Benson MD, Buxbaum JN, et al. Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines. Amyloid. 2016;23(4):209-213. 2. Maurer MS, Elliott P, Comenzo R, Semigran M, Rapezzi C. Addressing common questions encountered in the diagnosis and management of cardiac amyloidosis. Circulation. 2017;135(14):1357-1377. 3. Connors LH, Sam F, Skinner M, et al. Heart failure due to age-related cardiac amyloid disease associated with wild-type transthyretin: a prospective, observational cohort study. Circulation. 2016;133(3):282-290. 4. Pinney JH, Whelan CJ, Petrie A, et al. Senile systemic amyloidosis: clinical features at presentation and outcome. J Am Heart Assoc. 2013;2(2):e000098. 5. Mohammed SF, Mirzoyev SA, Edwards WD, et al. Left ventricular amyloid deposition in patients with heart failure and preserved ejection fraction. JACC Heart Fail. 2014;2(2):113-122. 6. Maurer MS, Hanna M, Grogan M, et al. Genotype and phenotype of transthyretin cardiac amyloidosis: THAOS (Transthyretin Amyloid Outcome Survey). J Am Coll Cardiol. 2016;68(2):161-172. 7. González-López E, Gallego-Delgado M, Guzzo-Merello G, et al. Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction. Eur Heart J. 2015;36(38):2585-2594. 8. Narotsky DL, Castano A, Weinsaft JW, Bokhari S, Maurer MS. Wild-type transthyretin cardiac amyloidosis: novel insights from advanced imaging. Can J Cardiol. 2016;32(9):1166.e1-1166.e10. 9. Brunjes DL, Castano A, Clemons A, Rubin J, Maurer MS. Transthyretin cardiac amyloidosis in older Americans. J Card Fail. 2016;22(12):996-1003. 10. Castaño A, Drach BM, Judge D, Maurer MS. Natural history and therapy of TTR-cardiac amyloidosis: emerging disease-modifying therapies from organ transplantation to stabilizer and silencer drugs. Heart Fail Rev. 2015;20(2):163-178. 11. Carroll JD, Gaasch WH, McAdam KP. Amyloid cardiomyopathy: characterization by a distinctive voltage/mass relation. Am J Cardiol. 1982;49:9-13. 12. Cyrille NB, Goldsmith J, Alvarez J, Maurer MS. Prevalence and prognostic significance of low QRS voltage among the three main types of cardiac amyloidosis. Am J Cardiol. 2014;114(7):1089-1093. 13. Quarta CC, Solomon D, Uraizee I, et al. Left ventricular structure and function in transthyretin-related versus light-chain cardiac amyloidosis. Circulation. 2014;129(18):1840-1849. 14. Connors LH, Prokaeva T, Lim A, et al. Cardiac amyloidosis in African Americans: Comparison of clinical and laboratory features of transthyretin V122I amyloidosis and immunoglobulin light chain amyloidosis. Am Heart J. 2009;158(4):607-614. 15. Nakagawa M, Sekijima Y, Yazaki M, et al. Carpal tunnel syndrome: a common initial symptom of systemic wild-type ATTR (ATTRwt) amyloidosis. Amyloid. 2016;23(1):58-63. 16. Rapezzi C, Merlini G, Quarta CC, et al. Systemic cardiac amyloidoses: disease profiles and clinical courses of the 3 main types. Circulation. 2009;120(13):1203-1212. 17. Sperry BW, Reyes BA, Ikram A, et al. Tenosynovial and cardiac amyloidosis in patients undergoing carpal tunnel release. J Am Coll Cardiol. 2018;72(17): 2040-2050. 18. Westermark P, Westermark GT, Suhr OB, Berg S. Transthyretin-derived amyloidosis: probably a common cause of lumbar spinal stenosis. Ups J Med Sci. 2014;119(3):223-228. 19. Yanagisawa A, Ueda M, Sueyoshi T, et al. Amyloid deposits derived from transthyretin in the ligamentum flavum as related to lumbar spinal canal stenosis. Mod Pathol. 2015;28(2):201-207. 20. Sueyoshi T, Ueda M, Jono H, et al. Wild-type transthyretin-derived amyloidosis in various ligaments and tendons. Hum Pathol. 2011;42(9):1259-1264. 21. Phelan D, Collier P, Thavendiranathan P, et al. Relative apical sparing of longitudinal strain using two-dimensional speckle-tracking echocardiography is both sensitive and specific for the diagnosis of cardiac amyloidosis. Heart. 2012;98(19):1442-1448. 22. Ternacle J, Bodez D, Guellich A, et al. Causes and consequences of longitudinal LV dysfunction assessed by 2D strain echocardiography in cardiac amyloidosis. JACC Cardiovasc Imaging. 2016;9(2):126-138. 23. Coelho T, Maurer MS, Suhr OB. THAOS - The Transthyretin Amyloidosis Outcomes Survey: initial report on clinical manifestations in patients with hereditary and wild-type transthyretin amyloidosis. Curr Med Res Opin. 2013;29(1):63-76. 24. Swiecicki PL, Zhen DB, Mauermann ML, et al. Hereditary ATTR amyloidosis: a single-institution experience with 266 patients. Amyloid. 2015;22(2):123-131.
The health information contained in this ad is provided for educational purposes only. Date of Preparation: February 2021 GCMA code: PP-RDP-IRL-0105
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For more information visit www.FreeStyleDiabetes.ie Images are for illustrative purposes only. Not actual patient or data. 1. Scanning the sensor does not require lancets. 2. The LibreView website is only compatible with certain operating systems and browsers. Please check www.libreview.com for additional information. 3. The FreeStyle LibreLink app is only compatible with certain mobile devices and operating systems. Please check the website for more information about device compatibility before using the app. Use of FreeStyle LibreLink requires registration with LibreView. 4. The LibreLinkUp app is only compatible with certain mobile device and operating systems. Please check www.librelinkup.com for more information about device compatibility before using the app. Use of LibreLinkUp and FreeStyle LibreLink requires registration with LibreView. The LibreLinkUp mobile app is not intended to be a primary glucose monitor: home users must consult their primary device(s) and consult a healthcare professional before making any medical interpretation and therapy adjustments from the information provided by the app. © 2021 Abbott. FreeStyle, Libre, and related brand marks are marks of Abbott. ADC-41796 v1.0 06/21.
HOSPITAL REVIEW: RESEARCH
Pinpointing How a Mutation causes Childhood Cancer Researchers from Trinity have discovered how a specific genetic mutation (H3K27M) causes a devastating, incurable childhood cancer, known as diffuse midline glioma (DMG), and – in lab studies working with model cell types – successfully reversed its effects to slow cancer cell growth with a targeted drug.
Adrian Bracken, Professor in Trinity’s School of Genetics and Microbiology
Their landmark work, supported by Worldwide Cancer Research and The Brain Tumour Charity, translates crucial new understanding of the genetics of DMG progression into a highly promising, targeted therapeutic approach and offers significant hope of improved treatments in the future. The scientists now call for clinical trials to begin imminently, in which an already approved class of drugs called “EZH2 inhibitors” can be assessed. These drugs target the same key biological pathway involved in DMG as they do successfully in lymphomas and sarcomas — two cancers common in adults. Adrian Bracken, Professor in Trinity’s School of Genetics and Microbiology, led the exciting research. He said, “We’ve taken a huge step forward in our study of DMG tumours and hope that the insights will help us design and implement precision oncologybased treatment approaches in DMG patients in the future. Crucially, ‘EZH2 inhibitor’ drugs have already received approval from the United States Food and Drug Administration for the treatment of two types of adult cancer. We propose these drugs could be impactful for children with DMG and, as a result, call for clinical trials to begin next. “Ultimately, we hope that our work – together with that of others focused in this area – will lead to curative clinical approaches for what is a truly terrible disease that can devastate families and for which there are currently no therapeutic options.” Paediatric gliomas – harrowing, devastating cancers Paediatric gliomas like DMG are among the most devastating of childhood cancers. Tumours
typically arise in the brain and are very challenging to treat, with prognosis extremely poor. As such, effective therapeutic options are urgently needed. Dr Jane Pears, paediatric consultant oncologist at Our Lady’s Children’s Hospital, Crumlin, who treats children with this disease, said, “Despite combined best efforts, these tumours remain a devastating diagnosis for children and their families. The best treatment we can currently offer may extend survival for a few months but is not curative. “We are now entering an exciting era of expansion of our knowledge of this disease at a molecular level, which in turn will lead us towards more targeted treatments. Thanks to collaborative translational efforts between scientists, such as Prof. Bracken and his team working in the laboratory, and doctors in the clinical setting, this will hopefully lead to the improved outcomes that we all so dearly wish to see.” Speaking to the importance of the work, Maeve Lowery, Professor of Translational Cancer Medicine at Trinity, and Academic Director of the Trinity St James’s Cancer Institute (TSJCI) said, “These findings have the potential to transform the treatment landscape of DMG tumours and improve outcomes for children with this challenging disease. Importantly, this pivotal work illustrates the
“Ultimately, we hope that our work will lead to curative clinical approaches for what is a truly terrible disease that can devastate families and for which there are currently no therapeutic options” success of a precision oncology approach – where understanding how cancers develop on a genomic level can accelerate the development of more effective treatments with less side effects. “The Precision Oncology Research Program at TSJCI, led by Prof Bracken, will build on this success to continue to develop new and innovative treatment strategies for adult and childhood cancers.” Dr Becky Birch, Head of Research at The Brain Tumour Charity, which helped fund the study, said, “This is a really promising discovery that we hope will now pave the way for new and targeted treatments to be developed for children with diffuse midline gliomas
(DMGs). With average survival still heartbreakingly short at less than 12 months, we urgently need to find new options to help slow the growth of this rare and often-inoperable cancer and give children diagnosed more time to live. “It’s really exciting that we now better understand how a specific genetic mutation may be driving the disease, and even more so that drugs that may inhibit this process have already been tested in other cancers. If further research can now design EZH2 inhibitors to more effectively target DMG cells, we hope these drugs can be quickly advanced into clinical trials for children diagnosed with this devastating disease.”
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50 HOSPITAL REVIEW: RHEUMATOID ARTHRITIS
Rheumatoid Arthritis Clinical Presentation, Diagnosis and Pharmacological Treatment (DMARD’s) Written by Theresa Lowry-Lehnen (PhD)
Rheumatoid arthritis (RA) is a chronic systemic inflammatory autoimmune condition with periods of exacerbation and remission, characterized by synovitis and joint destruction mediated by cytokines, chemokines, and metalloproteases. RA can affect any body part but most commonly the peripheral joints, interphalangeal, metacarpophalangeal and wrist, as well as the ankles and metatarsophalangeal joints, leading to progressive destruction of articular structures and accompanied by systemic symptoms. Triggers and etiology of RA are unclear but hormones, genetics, stress, smoking and environmental factors are thought to be contributing factors. An autoimmune etiology is currently the most widely accepted.
Criteria for diagnosis of rheumatoid arthritis
Therefore, a knowledge of lifestyle factors is also important in the diagnosis and treatment of RA.
A diagnosis of RA is based on CNS, GPN, RNP and National PRO Physical examination is a key specific clinical, laboratory and Irish General Practice Nurses part of the assessment process. imaging features and the ACR/ Educational Association illnesses will be discussed as some medical problems tend to occur along to with RA and may be In addition checking general EULAR Classification Criteria. vital signs, including temperature, suggestive of the disease. A family medical history is important due to the hereditary The ACR ‘RA Disease Activity blood pressure, pulse rate, heart Measures’, the ranges component to RA, and information aboutdefine any close relative with the condition or any other and lung function, the doctor will and level of disease activity. autoimmune disease will provideAllmore information onRA the individual’s risk.patient’s Smoking isina high evaluate the joints patients with suspected detail, paying particular attention should the be referred to a risk factor, and alcohol which effects liver, urgently can promote inflammation and interact with to function, swelling, and pain. The rheumatologist. some NSAID and methotrexate medication. Therefore, a knowledge of exam lifestyle factors is also physical will help determine Medical history refers to current the severity of the illness and help important in the diagnosis and treatment of RA. presenting symptoms, past guide treatment decisions. medical history, family medical blood tests required history, medications including Physical examination is a key part of the assessment process. InLaboratory addition to checking general to determine a diagnosis any OTC medications, allergies vital signs, including temperature, rate, suggestive heart andof lung the RA or function, inflammatory and blood lifestyle pressure, factors suchpulse as disease include: smoking andinalcohol intake. doctor will evaluate the patient’s joints detail, paying particular attention to function, Presenting symptom history • Rheumatoid (RF)and help swelling, and pain. The physical includes exam will help determine the severity of thefactor illness questions about the type, duration, location and pattern of guide treatment decisions. • Anti-citrullinated protein (synovitis) which affects the hands pain experienced, how it affects antibodies and/or feet, although any joint mobility and lifestyle, and whether (ACPA) (including anti-CCP and lined by a synovial membrane Laboratory blood tests requiredit to determine diagnosis of RA or inflammatory is affecting sleepaand causing suggestive anti-MCV antibody tests) may be involved. Severity fatigue. Past medical history disease include: • Erythrocyte sedimentation rate fluctuates over time, but chronic and other medical illnesses will (ESR) • Rheumatoid factor (RF) be discussed as some medical RA results in the progressive development of various degrees problems tend to occur along with • Anti-citrullinated protein antibodies (ACPA) (including anti-CCP and anti-MCV antibody • C-reactive protein (CRP) tests) of joint destruction, deformity, and RA and may be suggestive of the • Erythrocyte rate (ESR) a significant decline insedimentation functional • Antinuclear antibody (ANA) disease. A family medical history status. involvement • Extra-articular C-reactive protein (CRP) is important due to the hereditary • Full blood count (FBC) of organs such as the skin, heart, • and Antinuclear antibody (ANA)component to RA, and information lungs, eyes can also be about any close relative with the Imaging tests include x-rays • Full blood count (FBC) significant. condition or any other autoimmune taken of symptomatic joints disease will provide more which can reveal signs of joint Patients with RA are at an information on the individual’s involvement (inflammation) andjoint increased tests risk of co-morbidities Imaging include x-rays taken of symptomatic joints which can reveal signs of risk. Smoking is a high risk factor, damage (bone erosion) indicative such as CVD, severe infections, involvement (inflammation) andand damage erosion) of Other RA. Other imaging tests alcohol(bone which effects the indicative of RA. imaging tests and over-lapping autoimmune can promote inflammation usefuland in diagnosis of RA include disease,ine.g. mixed connective useful diagnosis of RA includeliver, magnetic resonance imaging (MRI) ultrasound. magnetic resonance imaging (MRI) and interact with some NSAID tissue diseases, autoimmune and ultrasound. and methotrexate medication. thyroiditis and lymphoma.
The ACR/EULAR Classification Criteria, is associated with a point value. Diagnosis of RA can be made when a total of 6 points or more is reached across the separate criteria.
Clinical features and presentation of rheumatoid arthritis Approximately 10% of patients with rheumatoid arthritis have an abrupt onset, but in most cases onset is insidious and initial presenting symptoms can be vague, including fatigue, malaise, morning stiffness, weight loss and low-grade fever. Progression of the illness leads to joint inflammation and swelling which causes difficulty performing activities of daily living, such as dressing, standing, walking, or use of the hands. Clinical features of RA are persistent symmetric polyarthritis
AUGUST - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE
51 ACR recommendations for the measurement of RA disease activity. ACR recommendations for the measurement of RA disease activity
with bDMARDs is however contraindicated and tsDMARDs cannot be used with live vaccines. Combination therapy which allows for lower dosage of an individual drug, may reduce the risk of adverse effects that can occur with higher doses. Methotrexate, leflunomide and sulfasalazine have similar efficacy, however methotrexate is considered the ‘anchor drug’ for the treatment of RA. It is prescribed in up to 70% of patients as a monotherapy or as combination therapy with other DMARDs. Methotrexate as the DMARD of choice in the treatment of rheumatoid arthritis
DMARD’s and the pharmacological treatment of rheumatoid arthritis
using corticosteroids. NSAIDs are then further subdivided and The ACR/EULAR Classification Criteria, is associated with a point typically prescribed to control pain classed as conventional synthetic value. Diagnosis of RA can be management Current pharmacological of RA includes the (csDMARDs) initiation of DMARDs by a and inflammation in the RA patient. or targeted synthetic made when a total of 6 points The symptom ACR and EULAR guidelines (tsDMARDs). Conventional rheumatologist and medication for control such as a corticosteroid. The lowest dose or more is reached across the recommend that if used NSAIDs synthetic (csDMARDs) include separate criteria. possible for the shortest period be of prescribed time is recommended when methotrexate, using corticosteroids. in the lowest dose leflunomide NSAIDs that provides symptom relief, and in the and sulfasalazine. are typically prescribed to control pain and inflammation RA patient. The ACR and DMARD’s and the the dose reduced when a good pharmacological treatment of Targeted synthetic DMARDs EULAR guidelines recommend response that if used NSAIDs be prescribed in the lowest dose that to DMARDs is achieved. rheumatoid arthritis (tsDMARDs) example Tofacitinib provides symptom relief, and the dose reduced when a good response to DMARDs is DMARDs, (Disease-modifying and Baricitinib are a new Current pharmacological anti-rheumatic drugs) are also therapeutic class that inhibit JAK achieved. management of RA includes called immune-suppressive or (Janus kinase inhibitors). They the initiation of DMARDs by a slow-acting anti-rheumatic drugs can be used in combination with rheumatologist and medication DMARDs, anti-rheumatic drugs) are also called immune-suppressive (SAARDs). They are classed methotrexate or as monotherapy or for symptom(Disease-modifying control such as a in two major groups; patients havegroups; contraindications corticosteroid. anti-rheumatic The lowest dose drugs slow-acting (SAARDs). Theysynthetic are classed iniftwo major synthetic (sDMARDs) and biological or are intolerant of methotrexate. possible for the shortest period (sDMARDs) and biological These groups subdivided and classed of time is recommended when (bDMARDs). (bDMARDs). These groupsare are then further Concurrent use of tsDMARDS
as conventional synthetic (csDMARDs) or targeted synthetic (tsDMARDs). Conventional synthetic (csDMARDs) include methotrexate, leflunomide and sulfasalazine.
Methotrexate (MTX), a diseasemodifying anti-rheumatic drug (DMARD), interferes with the production and maintenance of DNA, the genetic material in the cells of the body. It is not known exactly how methotrexate works in rheumatoid arthritis, but it can reduce inflammation and slow progression of the illness. Methotrexate is the most common DMARD used to treat rheumatoid arthritis. It may be used in the early stages to prevent progression of the illness and in combination with other DMARDs. It is effective in relieving joint inflammation and pain, slowing RA progression, and preventing disability by delaying joint destruction.
Targeted synthetic DMARDs (tsDMARDs) example Tofacitinib and Baricitinib are a new therapeutic class that inhibit JAK (Janus kinase inhibitors). They can be used in combination with methotrexate or as monotherapy if patients have contraindications or are intolerant of methotrexate. Concurrent use of tsDMARDS with bDMARDs is however contraindicated and tsDMARDs cannot be used with live vaccines. Combination therapy which allows for lower dosage of an individual drug, may reduce the risk of adverse effects that can occur with higher doses. Methotrexate, leflunomide and sulfasalazine have similar efficacy, however methotrexate is considered the ‘anchor drug’ for
HOSPITALPROFESSIONALNEWS.IE | HPN • AUGUST - 2021
52 HOSPITAL REVIEW: RHEUMATOID ARTHRITIS
Methotrexate produces a beneficial effect in 2-6 weeks and is given once weekly. The initial weekly dose is 7.5-15 mg but can be increased up to 25mg per week if required, based on assessment of response and side effects. It can be administered by oral, intramuscular or subcutaneous routes. Rheumatoid arthritis patients taking methotrexate must be monitored closely for signs of infection and require regular FBC, LFT and renal function blood tests. Intensive monitoring is required when initiating therapy, changing doses and in patients with co-morbidities. FBC, LFTs and U&Es are required every two
weeks when initiating therapy until blood tests are stable for 6 weeks. This is followed by monthly blood tests until the dosage and illness is stable for 1 year. Thereafter, blood test monitoring may be reduced in frequency to every 2-3 months based on clinical judgement and discussion with the specialist team. Patients must be closely monitored when taking methotrexate as it is associated with many adverse side effects including infections, gastrointestinal problems, leukopenia, headache, dizziness; fatigue, raised LFTs, rash and alopecia. Some side effects may be reduced by taking folic acid at a dose of at least 5mg/week, taken on a different day from the methotrexate.
Patient education about their weekly methotrexate regimen, folic acid requirement and the risk of drug interactions is important as a number of medications such as salicylates, hypoglycaemics, sulphonamides, phenytoin, and trimethoprim have the potential to interact with methotrexate. Drug interactions can enhance the action of methotrexate resulting in an increased risk of methotrexate toxicity. Live vaccines should be avoided, however, flu and pneumococcal vaccination is recommended. Screening for TB and infections such as hepatitis B and C should be performed prior to initiating treatment and screening for varicella zoster is also recommended by some experts. It is advisable that if a person with RA develops an infection, requires antibiotic
treatment or develops shingles or chicken pox, that they stop taking their anti-rheumatic medication until the infection has cleared. Advice on smoking cessation, contraception when applicable, and the risks associated with alcohol consumption while taking methotrexate should be provided for the patient. Assessment, monitoring, audit and evaluation for disease activity, progression, and effects of the therapeutic regime on a patient with rheumatoid arthritis is a continuous process. Implementing person-centred care, monitoring and evaluating symptoms, outcomes and responses to therapy plays a pivotal role in managing the illness and improving the patient’s quality of life. References available on request
Hospital Review News Waiting Lists Soar in Cork Hospitals IHCA President Dr Alan Irvine
patients. These growing waiting lists are not simply a result of Covid-19 but demonstrate the impact of years of consultant shortages and underinvestment in capacity across public hospitals in the region. “We have a chronic recruitment and retention crisis with 1 in 5 permanent hospital consultant posts not filled. These posts in the SSWHG region are either vacant or filled on a temporary basis.
The Irish Hospital Consultants Association (IHCA) has warned that the ongoing shortage of hospital consultants across a large number of specialties in the South/ South West Hospital Group is restricting patients from accessing timely, high-quality medical and surgical care and is contributing massively to growing waiting list. Hospitals in the South of the country have seen their outpatient waiting lists increase by more than 11% in the past year, with more than 13,500 additional people in the South/South West Hospital Group (SSWHG)* now waiting to see a hospital consultant. There were over 131,000 people on public hospital outpatient waiting lists in the SSWHG in May 2021, the latest available figures from the National Treatment Purchase Fund reveal**. However, consultants fear this figure could
in fact be higher as the NTPF has been unable to release new figures for the end of June due to the HSE cyber-attack that took place on 14 May. The most recent data shows that the waiting list for an appointment to see a hospital consultant in the SSWHG has increased by 35,000 (37%) in six years.
The number of patients waiting longer than a year for treatment in the Group has increased to more than 2,900 compared with 982 six years ago and just 95 in 2012 - a 30-fold increase in almost 9 years. Cork hospitals now have over 1,250 patients waiting longer than a year for treatment, almost a 4-fold increase in 6 years.
Of the current total, over 69,000 are on waiting lists in Cork hospitals, which have seen their outpatient waiting lists increase by 11,000 (19%) since May 2015.
These waiting lists are likely to worsen in the coming months as more people who have put off seeking care during the pandemic enter the system, and as a result of the ongoing impact of the cyberattack on the HSE.
Inpatient and day-case numbers waiting have increase by 17% in SSWHG and by 42% in Cork Hospitals since 2015. Of the 11,190 currently awaiting hospital treatment in the SSWHG, more than half (6,293) are on Cork hospital waiting lists.
Commenting on the waiting lists, IHCA President Professor Alan Irvine, said, "The severe shortage of hospital consultants in our public health service in Cork and the southern region is the main contributor to the unacceptable delays in providing care to
AUGUST - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE
“Reducing the record 885,000 people on some form of waiting list to be treated or seen by a consultant will only be possible by filling the 1 in 5 permanent hospital consultant posts that are currently unfilled and appointing significant additional consultants. Unfortunately, the current recruitment and retention crisis is being exacerbated further by the health services' current approach to impose a new consultant contract without full negotiations with the IHCA. “Last October, the Minister for Health gave his 'unambiguous commitment' to address the root causes of Ireland's chronic consultant recruitment and retention crisis, including the restoration of full pay parity. Failure to uphold that commitment and to engage in meaningful negotiations with hospital consultant representative organisations have contributed to the addition of 40,000 people to hospital waiting lists across the country in the period since.”
For the treatment of diabetes mellitus in adults, adolescents and children from the age of 6 years1 Prescribing Information: Toujeo ® (insulin glargine 300 units/ml) Please refer to Summary of Product Characteristics (SmPC) before prescribing. Presentation: Toujeo SoloStar and DoubleStar pre-filled pens. Each ml contains 300 units of insulin glargine. SoloStar pen contains 1.5ml (450 units) of solution for injection. DoubleStar pen contains 3ml (900 units) of solution for injection. Indication: Treatment of diabetes mellitus in adults, adolescents and children from the age of 6 years. Dosage and ® Administration: Toujeo is administered subcutaneously, by injection into the abdominal wall, the deltoid or the thigh, once daily, at any time of the day, preferably at the same time every day. Injection sites must be rotated within a given injection area from one injection to the next in order to reduce the risk of lipodystrophy and cutaneous amyloidosis. The dose regimen (dose and timing) should be adjusted according to individual response. Do not administer intravenously. In type 1 diabetes mellitus, Toujeo must be combined with short-/rapid-acting insulin to cover mealtime insulin requirements. In patients with type 2 diabetes mellitus, recommended daily starting dose is 0.2 units/kg followed by individual dose adjustments. Toujeo can also be given together with other anti-hyperglycaemic medicinal products. Switch between insulin glargine 100 units/ml and Toujeo: Insulin glargine 100 units/ml and Toujeo are not bioequivalent and are not directly interchangeable. When switching from insulin glargine 100 units/ml to Toujeo, this can be done on a unit to unit basis, but a higher Toujeo dose (approximately 10-18%) may be needed to achieve target ranges for plasma glucose levels. When switching from Toujeo to insulin glargine 100 units/ml, the dose should be reduced (approximately by 20%). Switching from other basal insulins to Toujeo: A change of dose and/or timing of the basal insulin and concomitant anti hyperglycaemic treatment may be required. Dose adjustments may also be required if the patient’s weight or lifestyle changes, the timing of insulin dose is changed or other circumstances arise that increase susceptibility to hypo- or hyperglycaemia. Toujeo must not be mixed or diluted with any other insulin or other medicinal products. Close metabolic monitoring is recommended during a switch and in the initial weeks thereafter. SoloStar 1-80 units per single injection in steps of 1 unit and DoubleStar 2-160 units in steps of 2 units. When changing from Toujeo SoloStar to Toujeo DoubleStar, if the patient’s previous dose was an odd number then the dose must be increased or decreased by 1 unit. Toujeo DoubleStar prefilled pen is recommended for patients requiring at least 20 units per day. Special Populations: Insulin requirements may be diminished in the elderly or patients with renal or hepatic impairment. Paediatric: When switching basal insulin to Toujeo, dose reduction of basal and bolus insulin needs to be considered on an individual basis, in order to minimise the risk of hypoglycaemia. The safety and efficacy of Toujeo in children and adolescents below 6 years of age have not been established. Contraindications: Hypersensitivity to insulin glargine or any excipients. Precautions and Warnings: Traceability: In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Toujeo is not the insulin of choice for treatment of diabetic ketoacidosis. Patients must be instructed to perform continuous rotation of the injection site to reduce the risk of developing lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and worsened glycaemic control following insulin injections at sites with these reactions. A sudden change
References: 1. Toujeo® Summary of Product Characteristics Date of preparation: August 2020 | MAT-IE-2000822 (v1.0)
in the injection site to an unaffected area has been reported to result in hypoglycaemia. Blood glucose monitoring is recommended after the change in the injection site, and dose adjustment of antidiabetic medications may be considered. Hypoglycaemia: In case of insufficient glucose control or a tendency to hyper/hypoglycaemic episodes, the patient’s adherence to the prescribed treatment regimen, injection sites and proper injection technique and all other relevant factors must be reviewed before dose adjustment is considered. Particular caution should be exercised, and intensified blood glucose monitoring is advisable for patients in whom hypoglycaemic episodes might be of clinical relevance and in those where dose adjustments may be required. Warning signs of hypoglycaemia may be changed, less pronounced or absent in certain risk groups, potentially resulting in severe hypoglycaemia and loss of consciousness. Risk groups include patients in whom glycaemic control is markedly improved, hypoglycaemia develops gradually, an autonomic neuropathy is present, or who are elderly. The prolonged effect of subcutaneous insulin glargine may delay recovery from hypoglycaemia. Intercurrent illness: Requires intensified metabolic monitoring and often it is necessary to adjust the insulin dose. Insulin antibodies: administration may cause insulin antibodies to form. Use with pioglitazone: Cases of cardiac failure have been reported when pioglitazone was used in combination with insulin, especially in patients with risk factors for development of cardiac heart failure. If the combination is used, patients should be observed for signs and symptoms of heart failure, weight gain and oedema. Pioglitazone should be discontinued if any deterioration in cardiac symptoms occurs. Medication errors: Insulin labels must always be checked before each injection to avoid errors between Toujeo and other insulins. Patients must be instructed to never use a syringe to remove Toujeo from the SoloStar or DoubleStar pre-filled pen, A new sterile needle must be attached before each injection. Needles must not be re-used. Pregnancy and lactation: There is no data from exposed pregnancies in controlled clinical trials. However, there is a large amount of data on use of insulin glargine 100 units/ml in pregnant women indicating no specific adverse effects on pregnancy and no specific malformative nor feto/neonatal toxicity. The use of Toujeo may be considered during pregnancy, if clinically needed. Careful monitoring of glucose control is essential. It is unknown if insulin glargine is excreted in breast milk. Interactions: Substances that affect glucose metabolism may require adjustment of insulin glargine. Adverse Reactions: Very common: Hypoglycaemia. Prolonged or severe hypoglycaemia may be life-threatening. Common: Lipohypertrophy, injection site reactions, including redness, pain, itching, hives, swelling, or inflammation. Legal Category: POM. Marketing Authorisation Number: SoloStar 3 Pen pack: EU/1/00/133/034, DoubleStar EU/1/00/133/038. Marketing Authorisation Holder: Sanofi Aventis Deutschland GmbH, D-65926 Frankfurt am Main, Germany. Further information is available from: Medical Information, Sanofi 18 Riverwalk, Citywest Business Campus, Dublin 24 or contact IEmedinfo@sanofi.com. Date of preparation: July 2020. Adverse events should be reported. Reporting forms and information can be found at www.hpra.ie; email: firstname.lastname@example.org Adverse events should also be reported to Sanofi Ireland Ltd. Tel: 01 403 5600. Alternatively, send via email to IEPharmacovigilance@sanofi.com
54 HOSPITAL REVIEW: BREAST CANCER
A Focus On Advances In Breast Surgery: MMUH Breast Team Perspective Written by Professor Malcolm Kell, and Aoife Sartini-Bhreathnach Professor Malcolm Kell is Consultant Breast Surgeon in Breastcheck, Mater Misericordiae University Hospital and Mater Private, Dublin.
Aoife Sartini-Bhreathnach, Physician Associate PA-IC, Mater Misericordiae University Hospital
Professor Kell has special interest in oncoplastic, aesthetic and reconstructive breast surgery. He is widely published; current research focuses on optimising outcome after breast surgery.
Breast surgery is ever advancing in terms of surgical procedures through the introduction of new techniques and the revival and improvement of the old. This article focuses on some of the advances adapted by the Breast team in the Mater Misericordiae Hospital to date. Advances are continually made to improve surgical options for our patients in both breast reconstruction and breast conserving surgeries. This article will discuss the pre-pectoral implant reconstruction technique, a procedure that has made a resurgence in recent years and the introduction of magseed guided surgery to our unit; a new localisation method for impalpable Breast lesions. Alongside surgical advancements the team have also been supportive in advancing new roles within Irish healthcare, such as that of the Physician associate (PA). Physician Associate Role The role of the PA in Ireland is a rapidly developing professional group where worldwide there are over 110,000 PAs now employed in the US. PAs are trained in the medical model and work under the consultant’s supervision. Miss Sartini-Bhreathnach graduated with her MSc in Physician associate studies in 2019 as part of the second cohort of Physician Associate’s in Ireland. Eligibility for the MSc programme requires a relevant undergraduate degree and previous experience is desirable. Miss Sartini-Bhreathnach obtained her undergraduate in Biomedical Sciences in 2012
and prior to commencing the PA programme worked with a number of research groups. A career as a Physician Associate has given the opportunity to pioneer a new profession within healthcare and be directly involved in the management of patients under the medical model. Aoife has been working for the Breast team in the Mater hospital for almost two years to date where she works alongside the surgical team. The opportunities she has availed of have included: educational progression and learning. Aoife assists in surgical cases; reviews patients post operatively and at their clinical appointments. She has also had the opportunity to continue with new research endeavours. Advancements In Implant Based Breast Reconstruction Globally there is an increase in patients availing of breast reconstruction, following mastectomy, with 80-95% of reconstruction being implant based. Breast reconstruction can be performed with the use of autologous tissue to reconstruct the breast in procedures such as latissimus dorsi (LD) reconstruction. The addition of an implant can be common in these procedures and may be placed to enhance the aesthetic outcome. Reconstruction options can also include the sole use of the implant without autologous tissue. Implant based reconstruction of the breast cavity is a popular surgical procedure of which was traditionally performed as part of a two stage process. Firstly the mastectomy was performed
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followed by the insertion of a tissue expander. A second procedure was scheduled to remove and replace the expander with a permanent prosthesis. While this 2-stage process may still provide a suitable reconstruction option for a select cohort of patients,the majority of implant reconstructions performed by the breast team in the MMUH are direct-to-implant, one stage procedures. Historically the use of an implant to reconstruct the breast cavity has been in practice since the 1970’s where, at this time, the implant was mostly positioned in front of the pectoralis muscle. Positioning in this pre-pectoral position,following mastectomy, allows for the implant to be placed directly into the cavity in front of the pectoralis muscle where there is no manipulation of the pectoralis muscle. Post-operative complications were high, following pre-pectoral reconstruction, with complications such as flap necrosis, implant extrusion and overall implant loss. Due to this there was a natural progression away from the placement of the implant directly in front of the pectoralis muscle and towards a subpectoral positioning. Subpectoral implant reconstruction differs from the pre-pectoral procedure due to the manipulation of the pectoralis muscle. Following mastectomy, the inferior border of the pectoralis muscle is released and the implant is positioned under the muscle. Elevation of the pectoralis muscle provides tissue coverage to the superior aspect of the implant and an additional layer
between the implant and skin, all of which was absent in the prepectoral technique. There is wide acceptance of subpectoral implant reconstruction and to this day it is a popular surgical procedure amongst reconstructive breast surgeons. Revival of Pre-Pectoral Implant Reconstruction In more recent years however, there has been a surge in the use of pre-pectoral implant reconstruction, with many surgeons favouring this technique once more. Recent studies have reported positive outcomes when comparing the pre-pectoral technique to the subpectoral equivalent. The literature has reported an overall reduction in post-operative complications when compared to the subpectoral implant reconstruction technique. Aesthetic outcomes have also been favourable for the prepectoral technique, where an independent evaluation of pre versus subpectoral aesthetic outcomes reported that bilateral pre-pectoral implant procedures scored highest on a visual analog scale of aesthetic outcomes. Research continues to report a positive trend of reduced post-operative complications and a move towards this surgical procedure. The breast team in the MMUH have also progressed towards the pre-pectoral reconstruction procedure acknowledging the potential advancements it can provide to improved patient outcomes and breast reconstruction.
55 By avoiding the manipulation of the pectoralis muscle there have been positive patient and surgical outcomes such as: • Decrease animation deformity
Fig 2: Placement of the mesh around the implant
• Reduced pain post op • Less widening of cleavage Advancing surgical techniques: Synthetic Mesh A contributing factor to the revival of the pre-pectoral procedure was the development and use of mesh material in implant reconstruction. Both biological and synthetic forms of mesh are approved for use in reconstruction procedures. Acellular dermal matrix (ADM), is a form of biological mesh that derives from biotechnologically engineered bovine or porcine tissue . ADMs are internationally the predominate form of mesh used in implant reconstruction of the breasts. The use of synthetic mesh in implant reconstruction is a newer advancement in breast surgery. Our Breast team solely use synthetic mesh, in the form of TIGR mesh, for all implant based reconstructions.
muscle and sutured to secure in place. A pain catheter and drain are placed with the latter remaining in situ until less than 30mls are drained within a 24hr period. Advancements in Breast Conservation Surgery: Magseed guided localization: Wire guided localization has been widely utilised as the standard method of pre-operative localization of breast lesions. Whilst it is a safe procedure there are some disadvantages associated with the use of wire guided procedures. Wires are placed pre-operatively which can cause delays to theatre
Fig 3: Implant placement in the prepectoral position
TIGR mesh is a bioresorbable synthetic material with a decreased cost in comparison to biological mesh material. To date the use of TIGR mesh has provided substantial support to the implant reconstruction procedure with minimal specific concerns post operatively.
Fig 4: Magseed
Pre-pectoral Surgical Technique using TIGR mesh
The paper details the results of a retrospective review of a prospective database of which was performed on the first 100 patients who underwent a Magseed guided breast surgery between November 2018 and November 2019.
Following mastectomy the implant and TIGR mesh are prepared ex-vivo prior to placement in the mastectomy cavity. The TIGR mesh is enveloped around the implant and both are immersed in antibiotic solution.
The aim was to measure the retrieval of the magseed and excision of the lesion. Data was also gathered on post-operative complications, time to theatre and re-excision rates.
The implant and mesh are then positioned in the mastectomy cavity in front of the pectoralis
and the additional possibility of dislodgment of the wire whilst transferring the patient. Patients have also reported discomfort following the procedure. Magnetic seeds (magseed) were developed to potentially eliminate some of the disadvantages associated with wires. The breast team in the Mater almost solely use the magnetic seeds for the localisation of impalpable breast lesions and have most recently published a paper on our experience to date. Fig 1: TIGR mesh following direct placement
Results have shown that over 50% of magseed guided cases are suitable as first theatre case procedures in comparison to wire guided procedures that are not ready morning of surgery. This can reduce delays to theatre. In regards to re-excision rates for margin clearance, in therapeutic Magseed guided cases, the rate was 9.4%. Overall the introduction of magseed guided surgery has had positive feedback from our unit . It has shown many benefits including efficient theatre planning, low re-excision rates and ease of localisation and excision. References on request
HOSPITALPROFESSIONALNEWS.IE | HPN • AUGUST - 2021
56 HOSPITAL REVIEW: PSYCHIATRY
The Impact of Covid 19 on the Mental Health of Healthcare Workers: What is the Evidence? Written by Professor Brendan Kelly, Professor of Psychiatry, Trinity College Dublin
Brendan Kelly is Professor of Psychiatry at Trinity College Dublin and author of ‘The Science of Happiness: The Six Principles of a Happy Life and the Seven Strategies for Achieving It’ (Gill Books, 2021).
The Covid-19 pandemic has had a significant impact on mental health, especially among healthcare workers. Research evidence over the course of 2020 indicated that the combined effect of the Covid-19 pandemic and associated restrictions was that approximately one person in every five in the general population experienced significantly increased psychological distress (e.g. anxiety or depression).1 Rates of significant psychological distress are higher among healthcare workers, at approximately 40%. Clearly, this is an area in need of careful consideration, continued study and urgent intervention. A series of systematic reviews and meta-analyses in early 2021 have assisted greatly in quantifying this issue, elucidating the nature of the problems, and suggesting potential solutions for healthcare workers and their employers, as the pandemic continues. In March, a systematic review and meta-analysis of the prevalence of depression, anxiety and post-traumatic stress disorder (PTSD) in healthcare workers during the pandemic examined 65 studies involving 97,333 health care workers.2 These studies were conducted between December 2019 and August 2020 across 21 countries This meta-analysis found a pooled prevalence of 21.7% for depression, 22.1% for anxiety
and 21.5% for PTSD. Studies conducted in the Middle-East provided the highest prevalence estimates for depression (34.6%) and anxiety (28.9%). These prevalences are notably high and the authors conclude that appropriate support is needed as a matter of urgency. Another systematic review and meta-analysis published the same month in Neuroscience and Biobehavioral Reviews looked at anxiety, depression, traumarelated and sleep disorders among healthcare workers during the pandemic.3 This analysis included 70 studies with 101,017 participants. The authors reported a pooled prevalence of 31.1% for depression, 30.0% for anxiety, 20.2% for PTSD, 56.5% for acute stress and 44.0% for sleep disorders. Again, these authors recommended the development of targeted prevention and support strategies, both now and in the future, for those affected. The high prevalence of problems with sleep is deeply concerning, as disturbances to sleep are strongly linked with poor physical health and diminished psychological wellbeing. To gain a deeper qualitative perspective on these problems, Kristina Newman and colleagues examined experiences and emotional strain among frontline workers in the National Health
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Service (NHS) during the peak of the pandemic.4 In this study, survey data from 395 NHS staff were developed into three key themes: (a) despair and uncertainty, with feelings of being overwhelmed; (b) behavioural and psychological impact, which affect wellbeing and functioning; and (c) coping and employer support, involving getting the help that is needed. These authors conclude that NHS staff felt enormous burdens during the peak of the pandemic. It is likely that these stresses will be sustained and even increase for as long as the pandemic persists. So, what can be done to support healthcare workers in these extraordinary circumstances? In addition to identifying the prevalence and nature of stresses and mental health problems during the pandemic, the literature has now started to identify factors relating to coping and support, in order to guide the interventions that are so clearly needed. One systematic review of quantitative studies of psychological resilience, coping behaviours and social support among healthcare workers during the pandemic identified 31 r elevant articles.5 This analysis found that healthcare workers used both problem-centred and emotion-centred coping to manage the stresses associated with the pandemic. Notwithstanding the unique nature of current circumstances, substantial evidence supports the effectiveness of certain coping behaviours, resilience and social support in this situation. This paper concludes that, in order to protect the mental health of healthcare workers, administrators should implement proactive measures to sustain resilience, develop coping skills and introduce creative ways to grow social support, using theory-based interventions, supportive leadership and building resilient work environments. Practical measures can make an enormous difference in these tasks: careful rostering and timetabling of work, ensuring staff can take the leave to which they are entitled, and employers providing organisational support where and when it is needed.1,6
In many circumstances, ‘psychological first aid’ is also useful, along with appropriate follow-on care for those who require further treatment and support.7 Finally, it is important to remember that, in addition to the effects of the pandemic on stresses at work, infection with Covid-19 also carries significant psychological and psychiatric risk. In April, Maxime Taquet and colleagues published data on 6-month neurological and psychiatric outcomes in 236,379 survivors of Covid-19 in Lancet Psychiatry, using electronic health records.8 This group found that the estimated incidence of a neurological or psychiatric diagnosis during the six months following Covid-19 infection was 33·6%, with 12·8% of people receiving their first such diagnosis during this period. For patients admitted to intensive care with Covid-19, the estimated incidence was 46·4%, with 25.8% receiving their first such diagnosis. The specific conditions seen in this study included anxiety disorder (17.4%), ischaemic stroke (2.1%), psychotic disorder (1.4%), dementia (0.7%), intracranial haemorrhage (0.6%) and parkinsonism (0.1%). Among those admitted to intensive care, incidences were generally higher: anxiety disorder (19.1%), ischaemic stroke (6.9%), psychotic disorder (2.8%), intracranial haemorrhage (2.7%), dementia (1.7%) and parkinsonism (0.3%). Most diagnostic categories were more common in patients who had Covid-19 compared to those who had influenza or other respiratory tract infections. Covid-19, it seems, has an especially high rate of psychological and psychiatric sequelae, especially after severe illness. Overall, the impact of Covid-19 on the mental health of healthcare workers has been substantial and will continue to be significant for some time to come. Ensuring practical support in the workplace, as well as appropriate follow-up care, will help manage the lingering psychological consequences of the pandemic as it subsides. References available on request
HOSPITAL REVIEW: COLORECTAL CANCER
Stromal cells in colorectal cancer – new immunotherapeutic targets? Authors: Hannah Egan1,4,5, Niamh A Leonard MSc1,4,5, Eileen Reidy MSc1,4,5, Oliver Treacy PhD1,4,5, Aisling M Hogan MB BCh BAO MD2,4,5*, Margaret Sheehan MB BCh MD3,4,5, Laurence Egan MD FRCPI1,4,5, Aoife Canney MB BCh MD3,4,5, Sean O. Hynes MB BCh PhD3,4,5* and Aideen E Ryan PhD1,4,5*, on behalf of: Galway Academic Intestinal cancer Network (GAIN) 1 Discipline of Pharmacology & Therapeutics, Lambe Institute for Translational Research, Galway University Hospitals 2 Department of Colorectal Surgery, Galway University Hospitals 3 Division of Anatomical Pathology, Galway University Hospitals 4 School of Medicine, National University of Ireland, Galway. 5 Galway Academic Intestinal cancer Network (GAIN) *Equal contributions
Colorectal Cancer Colorectal cancer (CRC) is a leading cause of death globally with increasing incidence in developing countries (Arnold et al., 2017). Whilst management of this disease has improved significantly, the ability to prognosticate CRC, in particular Stage II/III disease, remains challenging (Shah et al., 2016). Furthermore, predicting response to conventional therapies based on standard techniques is not always robust (Shah et al., 2016). Surgery and adjuvant chemotherapy +/- radiotherapy for
Sean O. Hynes MB BCh PhD
Aisling M Hogan MB BCh BAO MD
Aideen Ryan PhD
Figure 1. The immunosuppressive effects of the tumour microenvironment on various immune cells in colorectal cancer. Image created with Biorender
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58 HOSPITAL REVIEW: COLORECTAL CANCER
local control remain the mainstays of treatment. Morphological analysis along with microsatellite/ mismatch repair protein assessment +/- KRAS/NRAS variant analysis are the main tools available in the armamentarium of the histopathologist in trying to provide prognostic and predictive information useful for any particular tumour (Dobre et al., 2015). Soil and Seed Hypothesis The importance of the tumour and its microenvironment in relation to its ability to induce metastasis was highlighted as far back as 1889 by Paget. Paget introduced the soil and seed hypothesis with the seed (tumour) requiring a receptive environment (soil) in which to spread. Although this hypothesis was in relation to metastasis, it also holds true for the local tumour site with the tumour microenvironment and stromal interactions playing a crucial role in how CRC progresses (Fidler, 2003). Colorectal cancer molecular subtypes Based on transcriptomics, CRC can be classified into four molecular subtypes, as described by the Colorectal Cancer Subtyping Consortium (Dienstmann et al., 2015). These
include CMS1 (microsatellite instability), CMS2 (canonical), CMS3 (metabolic) and CMS4 (mesenchymal) (Fig. 1). The CMS4 subtype (accounting for approximately 23% of colorectal cancer cases) is associated with an overall poorer prognosis and this has been postulated to be due to an increased ability to induce an epithelial-to-mesenchymal transition by acquiring a stem cell characteristic, thereby increasing their propensity for invasion and metastases (Dienstmann et al., 2015). Although studies have questioned this dogma, given the contribution that can be made by stromal tissue to these genotyping methods (Dunne et al., 2017), research has demonstrated that variation in stromal content and stromal gene signatures may lead to inaccurate CRC subtyping using CMS. Moreover, this approach to tumour-typing has yet to be integrated into clinical practice, however, it holds promise for discovery of tumour subtypespecific treatments. Immunotherapy and colorectal cancer Until recently, cancer therapy had been based on targeting either rapidly growing colorectal cancer cells through non-specific chemotherapy or a single clone of cancer cells that carry a specific genetic variant/mutation. Although targeting a clone with a specific
variant or “biomarker” has proven helpful, it can lead to selection of another clone with a different variant and thereby resistance to therapy and recurrence of disease (Soucheray et al., 2015). The rate at which this clonal selection occurs depends upon how much of a primary “driver” gene is affected (Davis et al., 2019). A better long-term strategy would be to co-opt the body into fighting the cancer itself with its own immune cells. Cancer, with colorectal cancer being no exception, is constantly evolving and striving to survive at the expense of the host and it manages to avoid the host immune response through the upregulation of certain receptors on its surface. One of these so-called ‘immune checkpoints’ is termed programmed death-ligand 1 (PDL1). Its expression on the surface of cancer cells has been shown to dampen the immune response to these cells (Ju et al., 2020). Without this expression, cancer cells which express many non-self neo-antigens due to their genetic plasticity can be then targeted by the host immune system through its cytotoxic CD8 T cells (Ju et al., 2020). Expression of PD-L1, not only by cancer cells but also by stromal cells such as tumour-associated fibroblasts, can lead to deactivation of the immune cascade associated with CD8 cytotoxic T cells (O’Malley et al., 2018). In many cancers there has been significant promise in the use of
PD-L1 inhibitors to re-activate the immune system. However, this treatment cannot be applied to all cancers in a non-discriminatory way. Therapy is costly and has side effects. At present, the best method to predict response is through immunohistochemistry for PD-L1 (Incorvaia et al., 2019). There are layers of complexity, however, with regard to antibody used, staining platform and scoring systems that, based on trial data, requires a specific companion diagnostic for a tumour type. In the realm of colorectal cancer, immune checkpoint inhibitor therapy has proven useful in microsatellite unstable (MSIhigh) or mismatch repair protein expression-deficient tumours (dMMR) (Sahin et al., 2019). This shows the importance of the neoantigen load produced by certain colorectal cancers in inducing a prolonged immunebased therapeutic response. However, mesenchymal tumours (CMS4) do not seem to have the same response to this type of therapy as compared with MSI-high tumours (molecular subtype CMS1) (Roseweir et al., 2017). Currently, PD-L1 is being examined for its effectiveness as a marker in colorectal cancer. Stromal cell link to poor prognosis in colorectal cancer Not all advancements in colorectal cancer relate to molecular or antigenic biomarkers. The humble H&E slide, the standard tool in the histopathologist’s toolbox, can
Figure 2. The tumour microenvironment features and response to therapy of immunogenic colorectal tumours (CMS1) and immunosuppressive tumours (CMS4). Image created with Biorender
AUGUST - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE
For the treatment of pretreated mCRC
Make time for more moments that matter
Lonsurf® is licensed to Servier by Taiho, co-developed globally and marketed in their respective territories.
Lonsurf® (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 (20mg/m2/dose for patients with severe renal impairment). Dosage calculated according to body surface area, not exceeding 80 mg/dose. Possible dosing adjustments based on individual safety and tolerability: permitted dose reductions to a minimum dose of 20 mg/m2 twice daily (15mg/m2/dose for patients with severe renal impairment), 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 x 109/L, if platelet counts < 75 x 109/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 end-stage renal disease. Patients with renal impairment should be monitored closely; patients with moderate or severe 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-plantarerythrodysaesthesia 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, gastrooesophageal 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. Marketing Authorisation Holder LES LABORATOIRES SERVIER, 50 rue Carnot, 92284 Suresnes cedex France. www.servier.com. Marketing Authorisation: EU/1/16/1096/001-006. Legal Classification for Supply: POM. Further information available from: Servier Laboratories (Ireland) Ltd., Second Floor, 19 Lr. George’s Street, Dun Laoghaire, Co. Dublin A96 ER84, Ireland, Tel (01) 6638110, www.servier.ie. *For complete information, please refer to the Summary of Product Characteristics available on medicines.ie. Date of last revision of text: January 2021 (date of last approved SmPC: December 2020) Date of preparation of this item: February 2021. 2021c1LNPressA4Onc
60 HOSPITAL REVIEW: COLORECTAL CANCER Conclusion
prognosticate colorectal cancer somewhat, through identification of features in the tumour microenvironment such as stromal cells. This compartment includes mesenchymal stromal cells, cancer associated fibroblasts, and myofibroblasts (O’Malley et al., 2016). Recent research indicates that the stromal cell microenvironment in colorectal tumours has important prognostic and diagnostic relevance to patient outcomes. For example, the presence of more stroma globally has been found to indicate a worse prognosis in colorectal cancer patients (Roseweir et al., 2017; Hynes et al., 2017) The stromal populations of fibroblasts, connective tissue and immune cells contribute to preventing tumour cells being effectively targeted either by chemotherapy or immunotherapy strategies. Research through the Galway Academic Intestinal cancer Network is focussed on understanding the role of stromal cells in shaping immune responses in colorectal cancer (O’Malley et
al., 2018). Stromal cells regulate immune cell recruitment through chemokine and cytokine secretion as well as through regulation of angiogenesis in the tumour microenvironment. Regulation of both innate and adaptive immune cell phenotype and function by stromal cells in colorectal cancer facilitates an immunosuppressive tumour microenvironment (Turley et al., 2015). Mechanisms of stromal cell immunosuppression Stromal dense tumours, despite their association with a poorer prognosis, display a strong immune signature. Given the striking similarity between tumours and wounds, stromal cells in the tumour display some of the characteristics of a wound healing response to injury. In addition, Immune cells in this micro-environment display antiinflammatory and wound healing responses, including angiogenesis. and cell growth rather than their cytotoxic anti-tumour capabilities (Jackstadt et al 2019). PD-L1, an immune-supressing molecule, is increased on stromal cells conditioned by the colon cancer
cells, and these stromal cells can reduce the anti-tumour response of T-cells (O’Malley et al., 2018). Tumour-conditioned stromal cells release IL-8 to recruit macrophages to the tumour, then act on these phagocytic cells to alter their functions to induce a wound healing/tumourpromoting phenotype (Zhang et al., 2019). Stromal cells purified from colorectal carcinomas have been shown to modulate the function of natural killer cells, suppressing their ability to directly lyse cells (Li et al., 2013). These studies demonstrate how stromal cells can be altered in the tumour microenvironment. These cancer-associated stromal cells act directly to supress immune cell function and induce tumour-promoting inflammatory environments (Fig. 2). Targeting the immunosuppressive capacity of stromal cells could improve the efficacy of currently used therapies through altered stratification of patients and may identify novel therapeutic targets. Overcoming immunosuppression is a promising approach for novel cancer treatments. Therapies that target mechanisms of stromal-induced immunosuppression may offer novel opportunities to activate anti-tumour immune responses.
Advancing our knowledge on the location, complexity and diversity of immune cell subtypes, and functions within the colorectal tumour microenvironment and how they are shaped by stromal cells, is pivotal to validation of stromal cells as immunotherapy targets. This knowledge will increase the potential for developing diagnostic and predictive biomarkers and novel therapeutic strategies to potentiate anti-tumour immunity in colorectal cancer patients with stromal dense tumours. GAIN Galway Academic Intestinal cancer Network (GAIN) is a collaboration of scientists and academic clinicians. Based in National University of Ireland, Galway and Galway University Hospital, it is led by Dr Aideen Ryan (Tumour Immunologist), Dr Sean Hynes (Consultant Histopathologist) and Ms Aisling Hogan (Consultant Gastrointestinal Surgeon) who have a shared interest in translational gastrointestinal cancer research. We are indebted to our patients for their endless support and generosity. Without them, this research would not be possible. References available on request
Hospital Review News Protection of IP Rights for Covid Vaccines and Treatments The originator biopharmaceutical industry, in Dublin and Brussels, is pressing for the protection intellectual property as efforts intensify to waive inventors’ rights to own patents for Covid vaccines and treatments. The Irish Pharmaceutical Healthcare Association (IPHA), in partnership with EFPIA in Europe and with BPCI in Dublin, has urged the Government to partner with the industry in stepping up efforts to achieve equity of access to vaccines and treatments around the world and to surge production. The call comes following a proposal for consideration by the UN’s TRIPS Council of a temporary waiver for health products and technologies, including diagnostics, therapeutics, vaccines, medical devices and personal protective equipment to tackle Covid. The proposal is by India and South Africa, co-sponsored by some developing countries. The
US administration has supported the proposal. EU leaders have asked for an open discussion. Germany, Portugal, Estonia and Belgium oppose the Covid vaccines waiver proposal. Greece, France and Italy, with significant qualifications, support it. EU Commission President Ursula von der Leyen, in her plenary session speech last month, opposed the waiver, saying “intellectual property has to be protected because it is the idea behind the breakthrough, and it retains the incentives for innovation in research and development”. The industry has urged: Continued dose-sharing: Through COVAX, accelerate the redistribution of significant domestic supplies of Covid vaccine doses with low and lower middle-income countries. Optimised production: Onboard, on a voluntary basis, suitable manufacturing partners and invest in existing
AUGUST - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE
sites, meeting the highest regulatory standards. Removing trade barriers: Expedite the cross-border supply of raw materials, vaccines and skills needed for surged vaccines production. Backing country preparedness: Ensure countries, especially low and lower middle-income countries, are able to distribute Covid vaccine doses within their shelf-lives. Valuing innovation: support innovators’ efforts to find answers to Covid variants. Meanwhile, just 4% of people say they are unsure whether they will get vaccinated for Covid-19 – down by 14 points since January, according to the results of the latest tracker survey by Ipsos MRBI for IPHA. The number of people who either intend to get vaccinated for Covid-19, or who have already received a vaccine for the disease, has risen to 89%. The
results show that 34% of people will take a Covid-19 vaccine. But when combined with those who have received a Covid-19 vaccine, or 55% of the sample*, that number rises to 89%. Between January and June, the number of people who said they either won’t get vaccinated for Covid-19 or were unsure about taking a vaccine has declined. In January, 7% said they would refuse a Covid-19 vaccine and 18% were unsure. This month, 6% overall say they will refuse a Covid-19 vaccine and 4% are unsure.
HOSPITAL REVIEW: GERIATRICS
EDITH: Bringing Emergency Care to the Home for Older People living with Frailty Written by Conor Prendergast, Specialist Registrar in Emergency Medicine Dr Gareth Fitzpatrick, Consultant in Emergency Medicine - Dr Rosa McNamara, Consultant in Emergency Medicine & Dr Shane O’Hanlon, Consultant Geriatrician
Conor Prendergast, Specialist Registrar in Emergency Medicine
Dr Gareth Fitzpatrick, Consultant in Emergency Medicine
Dr Rosa McNamara, Consultant in Emergency Medicine
Dr Shane O’Hanlon, Consultant Geriatrician
team the decision was made to refer to the Emergency Department in the Home (EDITH) service. The intention was to keep the patient at home and avoid an admission if possible.
Units1 and prehospital falls and frailty response service operating in other areas.2
The service includes an Emergency Medicine (EM) doctor or Advanced Nurse Practitioner and an Occupational Therapist (OT) daily, supplemented by an Advanced Paramedic at weekends. A study in 2016 by the Royal College of Occupational Therapists found that by having OTs working in ED and frontline emergency services can decrease overall hospital admission by 70-80%.5 With over 3000 patients seen in the last 14 months and a transfer rate to hospital of less than 10%, the impact the service is having is apparent for all to see.6
A one hundred year old man was observed to have left sided weakness by his family and carers. The patient had celebrated his birthday just three days previously, with celebrations limited to drive-by cheers and waves from the front door secondary to social distancing restrictions. The patient and his family were very keen to stay at home but after over 24 hours of symptoms, the decision was made to call the National Ambulance Service (NAS). Normally this would be a straightforward scenario, the patient would be transferred to hospital and be admitted to the hospital for investigations for his possible stroke. However, this was not what the patient wanted, nor did his family. After consultation with the NAS
Emergency Department in the Home (EDITH) The EDITH service has been in operation since February 2020 with the goal to bring specialised emergency services to older people and divert attendances to the Emergency Department (ED) when appropriate. The service sees referrals from NAS (999 calls), GPs, local EDs and Nursing Homes of any patient over the age of 65 who would have otherwise attended ED that may be suitable to be treated at home. We also accept referrals for younger people living with frailty. The model uses elements of Physician Response
Approximately 13% of the Irish population are over the age of 65 with this number likely to increase by a further 59% by 20313. Furthermore, this cohort of patients accounts for almost 45% of all acute hospital admissions in Ireland.3 This population clearly represents an area where we as healthcare providers need to clarify what is the best and most efficient form of treatment. Even a small upgrade in the efficiency of service would cause a significant rippling effect due to large percentage of the population involved. The main facets of how EDITH works are: enabling early discharge from ED with follow-up home visits to avoid hospital admission, reviewing 999 calls deemed appropriate for the service, GP and nursing home referrals of patients that would have otherwise needed an ED attendance and supporting palliative care services in the community.4 On a personal level, the service helps maintain patient autonomy with a separate pathway that gives them the option to be treated at home and to avoid busy and noisy EDs.
Older Persons Rapid Assessment Hub (OPRAH) EDITH works in close proximity to our Older Persons Rapid Assessment Hub (OPRAH), which was established in SVUH in April 2019. This service was intended to identify older patients attending the ED who are likely to be discharged within the next 24-hour period. In its first eleven months of service, 1,395 patients were assessed, with an average age of 82, and 77% were discharged directly from the ED.6 OPRAH provides consultant-led care in a dedicated area of the ED, with rapid access to multidisciplinary input. This helps to avoid the
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62 HOSPITAL REVIEW: GERIATRICS
delays that are possible when a patient is admitted to hospital and care is handed over to a new team. Case continued On assessment of our patient, it was clear that he had developed left sided upper and lower limb weakness approximately 36 hours previously. The patient’s power was 4/5 in both limbs with his symptoms slowly improving. The patient had no other focal neurology, with a score on the National Institutes Health Stroke Scale (NIHSS) of 3. His vitals were stable, and an ECG was performed which demonstrated normal sinus rhythm. His regular medications already included adequate secondary prevention so no changes were made. The OT assessed his care needs including ability to transfer and perform personal hygiene, and his home environment. The patient had a fantastic support network at home, between his family and in home carers. After discussing the case with the patient, his family, the stroke team on call and our Clinical Lead Consultant for EDITH and with the stroke team on call and the decision was made for him to remain at home. The possible benefit of attending an acute hospital setting did not outweight the potential risks. The additional investigations that could be offered by admission were felt to be unlikely to change his management plan. The joinedup decision making followed the patient’s wishes and ensured his autonomy was maintained. The patient was reviewed for a second time by EDITH two days later due to concerns of increased density of the left sided weakness. On assessment power was once again found to be 4/5 with mild discoordination in the left upper limb. There was no other deterioration, and once again the shared decision between the EDITH team, the patient and the family was for conservative management. Providing an alternative to the ED This case is an example of the service that EDITH can provide some of our most vulnerable patients. Previously this scenario would have played out very
differently, the patient would have been transferred to hospital, to wait on a trolley in the ED to be assessed and then to wait for placement on a ward. He would then have waited to complete functional assessments. Instead he had clinical and functional assessment done at home at the onset of symptoms and again two days later. The Health in Ireland Key Trends 2018 reported that the average length of hospital stay was 5.6 days (6). A recent study in St James’s hospital found that those classified as severely frail on the Clinical Frailty Score (CFS) had an average length of hospital admission that was 8.5 days longer than those classified as non-frail.7 Since the start of the covid 19 pandemic we have increasingly met older people that are reluctant to go to hospital and our aim is to see and treat at home where possible and to arrange appropriate onward care as needed to inpatient, rehabilitation, or outpatient settings. Patients who require advanced investigations but who may not need admission can be transferred directed to the OPRAH service. The EDITH service aligns with the aims of Sláintecare, an indeed the weekend service has benefited from financial support from the Sláintecare innovation fund. Risks of hospital for older people In this scenario, especially given this man’s age and the risks associated with hospital admission, all were keen to avoid transfer. Hospitals can be disorientating for older people particularly those with cognitive problems. There are significant risks of falls, delirium, infections, deconditioning, and medication errors associated with hospital admission in this cohort.8 It can be a scary experience with a realistic fear of never returning home. This has been exacerbated by the restrictions due to the Covid-19 pandemic, with a reduction in visitors, and difficulty interacting with staff wearing Personal Protective Equipment (PPE) can make a hospital stay a very isolating experience, with little social interaction. Focusing on shared decision making This case also highlights the
AUGUST - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE
importance of shared decision making. It demonstrates a patientcentred approach where, once goals have been established collectively, the focus switches to the highest priority issue and decides how this aim can be achieved.9 This helps patients keep their autonomy, which can become more difficult for older people living with frailty to maintain. The end goal is to ensure the patient is enabled to make an informed choice that aligns with their preferences and wishes. This manner of service provision needs “buy-in” from all parties involved, with this case highlighting the importance of a good family support network with the patient’s best interests as the main focus point. Furthermore, this way of practice involves a change in mindset from healthcare staff. The easy and familiar decision would have been to admit the patient as admission diversion requires extra attention to the details of the plan to stay out of hospital. In our patients case he clinically had a stroke and although the resultant deficit was mild it still meant the patient required more help than previously. For us this means ensuring that the patient, and his family are happy with the plan in place and know what to do if something changes. Our team also activate other services in the community to help people remain at home often linking in with community intervention teams, public health nursing, general practitioners and with community therapists. Conclusion This case highlights the value a service such as EDITH provides. As demand for emergency healthcare continues to rise in Ireland, the goal is to ensure care remains patient-centred but can also be delivered in an efficient manner. EDITH provides the means for one way that this can be achieved. It is clear that keeping patients such as this gentleman in the comfort of their own homes and diverting admissions when appropriate should be the goal of our emergency services moving forward. References 1. Physician response units: is taking care to the patient the right thing to do? S. M Mason; EMJ Volume 37 Issue 9: http://dx.doi.org/10.1136/ emermed-2019-209315
2. The Rise and rise of an innovative falls project. Working together. South Central Ambulance Service. Reading. 2017 3. Health Service Capacity Review Executive Report (2018). Review of healthcare demand and capacity requirements in Ireland to 2031 – Findings and recommendations. HSE, Government of Ireland 4. Physician Response Unit Expansion Supports London’s Covid-19 Response: April 14, 2020 Ambulance Today: https://ambulancetoday.co.uk/ uncategorized/physicianresponse-unit-expansion-supports-londons-covid-19-response/ 5. Occupational therapy proves crucial for reducing hospital admissions in England; Royal College of Occupation Therapists 16/11/2016, https://www.rcot.co.uk/news/ occupational-therapy-provescrucial-reducing-hospitaladmissions-england 6. McNamara R, Donnelly K, Boyle N, et al. Community frailty response service: the ED at your front door. Emergency Medicine Journal 2020;37:714-716. 7. Government of Ireland; Health in Ireland: Key Trends 2018; https://assets.gov.ie/9441/ e5c5417ee4c544b384c262f99da77122.pdf 8. Association Between Clinical Frailty Scale Score and Length of Stay in a Complex Discharge Unit; A. McDermott et al, IMJ, 2021 Issue: Ir Med J; Vol 114; No. 1; P238 9. Occupational Therapists and Paramedics working together to reduced Admissions to the Emergency Department: A marriage of Opportunity: C Williams; https:// www.england.nhs.uk/southeast/wp-content/uploads/ sites/45/2018/12/2.-Rapidresponse-falls-service.pdf 10. The importance and challenges of shared decision making in older people with multimorbidity: T. Hoffmann, PLoS Med. 2018 Mar; 15(3): e1002530.
HOSPITAL REVIEW: SEXUAL HEALTH
Sex and Sexual Health During the Pandemic One Clinic’s Experience! Written by Salgaonkar. S1, Crowe. A2, Gorman. D1, Rowley. D1 1 Midland Regional Hospital Portlaoise, Ireland 2 King’s College Hospital, London
Introduction: COVID-19 has changed the way we live for the foreseeable future. The first few cases of COVID-19 originated in Wuhan, Hubei province, China in late 2019. (1) Although most cases were linked to the seafood wholesale market, there was a possibility that patients could have been infected by zoonotic or environmental exposures as it had been clear that human to human transmission had occurred which contributed to the growing epidemic in Wuhan.1 The first four cases diagnosed were all linked to the wholesale market, which also sold wild animals or mammals.1 The China Centres for Disease Control revealed a novel coronavirus was the causative pathogen of the outbreak.2 Chinese authorities shared the sequence of a novel coronavirus termed severe acute respiratory syndrome coronavirus 2 (SARSCoV-2).2 Since then, the disease has been called coronavirus 2019 (COVID-19).2 Consequently, Wuhan entered a three-month lockdown with restrictions entering and leaving the city to prevent further transmission of COVID-19.3 On the other side of the world, France was one of the first European countries to inform the WHO of three confirmed cases of COVID-19 from passengers who arrived from Wuhan before the implementation of the restrictions.4 Interestingly, it was later discovered that COVID-19 had been spreading one month before the official cases were reported in France.5 Italy became the next country to announce their first two cases of COVID-19 which originated from foreign travel which caused Italy to declare a State of Emergency.6 Italy’s first cluster of COVID-19 cases originated in the southern Lombardy region, Northern Italy.6 Ireland has a very close relationship with Italy especially for teenage ski holidays and indeed it was a returning traveller from this area that was the first person to be
diagnosed on the island of Ireland. Contact tracing and testing was the biggest concern as the traveller had travelled to Northern Ireland via Dublin by bus and train.7 In the Republic of Ireland, the first case of Covid-19 appeared in a male student in the east of Ireland in February 2020 after he had returned from Northern Italy.8 Shortly after, Ireland had its first cluster of cases when a family of four, contracted Covid-19 from foreign travel.9 Most of Ireland’s initial cases had come from travel abroad and not close contact or community transmission. On the 11th of March, the World Health Organisation (WHO) declared Covid-19 a pandemic with hundreds of thousands of people contracting the virus.10 The Irish government acted early by announcing a nationwide lockdown, just days before the WHO declared the Covid-19 pandemic. Daily case numbers peaked to 1508 during the first lockdown in the Republic of Ireland.11 Restrictions were slowly eased in May 2020 perhaps lending to an unusual situation over the summer with foreign travel still restricted but outdoor dining and shops reopening. Unfortunately, cases spiked again in late October peaking to 1000 cases per day leading to a second lockdown.12 It became apparent at this stage that the economy and people’s physical and mental health was suffering, and a government decision was made to reopen Ireland for Christmas and new year’s eve.13 Unfortunately, this decision to reopen for Christmas was controversial and many people were worried about the consequences and in January the country went into its third and longest lockdown with case numbers exploding to 8000 a day with over 1000 hospitalisations with acute COVID-19 infections.14 This lockdown has just recently come to an end with a cautious easing of restrictions. The variance in COVID-19 symptoms presentations have
been evident with the consistent emergence of asymptomatic positive COVID-19 cases that has created a wave of questions to the presentation of this viral illness. The transmission mode of the disease at this stage has become more difficult to pinpoint at this stage due to the appearance of these cases. In response to this, one method the National Public Health Emergency Team (NPHET) advised the introduction of random testing centres across the country to identify localised hotspots of infections.15 The race to find a vaccine had never been such a sprint with four vaccines approved within the European Union alone. Various vaccine companies have shown over 90% efficacy with rare side effects.16 Ireland along with other countries in the world are having an extremely successful rollout of vaccinations with over 1.2 million Irish being people fully vaccinated.17 We are in a time crunching competition with more transmissible strains of COVID-19 before they become established in the community. COVID-19 variants were renamed from country of origin to the Greek alphabet in order to avoid stigmatization and discrimination of countries where new strains were reported. Some examples of well – known variants include:
Alpha (British), Beta (South African), Gamma (Brazilian), and Delta (Indian) variant.18 Fortunately, they all appear to be vaccine responsive, but the world remains on tenterhooks. We decided to document the journey of our sexual health clinic and how we had to evolve multiple times as an essential service to provide optimal care for our patient population during this pandemic. Our sexual health clinic covers most of the Sexually Transmitted Infections (STIs) including Post Exposure Prophylaxis (PEP), PreExposure Prophylaxis (PrEP), all sexually transmitted infections and non-sexually related genitourinary conditions such as Needle Stick Injury (NSI) and genital dermatoses. The demand for our services has grown exponentially and we now provide 4 PrEP clinics and 4 general STI clinics a month to a wide geographical cohort. Method: We collected data retrospectively from patient files at the end of the first lockdown period (March-June 2020) in Ireland. Patients were assigned study numbers in Excel and divided into the following categories: diagnosis, gender, number of partners per patient, sexual orientation, asymptomatic versus symptomatic patients.
HOSPITALPROFESSIONALNEWS.IE | HPN • AUGUST - 2021
POWER POWER REIMAGINED REIMAGINED AN INNOVATIVE NEW TREATMENT FOR YOUR PATIENTS LIVING WITH HIV AN INNOVATIVE NEW TREATMENT FOR YOUR PATIENTS LIVING WITH HIV POWERFUL, DURABLE EFFICACY1,2
POWERFUL, DURABLE EFFICACY1,2 HIGH BARRIER TO RESISTANCE1,2
HIGH BARRIER TO RESISTANCE1,2 TDF, TAF AND ABC FREE1-3
TDF, TAF AND ABC FREE1-3 GEMINI-1 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 inRNA treatment-naïve patients:
DOVATO 86.0% (n=716) vs DTG + TDF/FTC 89.5% (n=717) (Proportion of patients with HIV-1 RNA <50 copies/mL)
WHY USE 3 IF 2 IS ALL HE NEEDS?
WHY USE 3 IF 2 IS ALL HE NEEDS?
DTG 50 mg + 3TC 300 mg used in the GEMINI studies.
DOVATO is indicated for the treatment of HIV-1 in adults and adolescents above weighing at least 40 kg, with no known or DTG 50 mg + 3TC 30012 mgyears used in the GEMINI studies. suspected resistance to the integrase inhibitor class, or lamivudine. DOVATO is indicated for the treatment of HIV-1 in adults and 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 counselled about the potential risk of neural tube defects including consideration of Dovato (dolutegravir 50mg/lamivudine 300mg) tablets dolutegravir and 300 mg lamivudine debossed with “SV-137” on one face. Indication: effective contraceptive measures. If a woman plans pregnancy, the benefits and the risks HIV-1 in adultsof&Product adolescents above 12 (SmPC) years ofbefore age weighing >40kg, with no known or of continuing treatment should be discussed with the patient. The safety and efficacy of a See Summary Characteristics prescribing. suspected resistance to the integrase inhibitor class, or lamivudine. Dosing: One tablet duel regime has not been studied in pregnancy. If a pregnancy is confirmed in the first counselled about the potential risk ofand neural defects including consideration Presentation: Film-coated tablet containing dolutegravir sodium equivalent to 50 mg trimester while on Dovato, the benefits riskstube of continuing Dovato versus switchingof once daily with or without food. Use an additional 50mg tablet of dolutegravir effective contraceptive measures. If ashould womanbeplans pregnancy, the risks dolutegravir and mgafter lamivudine “SV-137” on one face. another antiretroviral regimen discussed withthe thebenefits patientand taking the approximately 12 300 hours the dosedebossed of Dovatowith when co-administered withIndication: efavirenz, to of continuing treatment discussed the patient. The safety and efficacyinto of a HIV-1 in adults & adolescents above 12 years of age weighing >40kg, no known or gestational age and theshould criticalbe time periodwith of neural tube defect development nevirapine, tipranavir/ritonavir, etravirine (without boosted PI), with carbamazepine, duel regime has not been studied in pregnancy. If a pregnancy is confirmed in the suspected resistance to the integrase inhibitor class, or lamivudine. Dosing: One tablet in oxcarbazepine, phenytoin, phenobarbital, St John’s Wort or rifampicin. Elderly: Limited account (see SmPC section 4.6). There have been reports of mitochondrial dysfunctionfirst trimester while on Dovato, theinbenefits and risks of continuing Dovato versus switching onceindaily withNot or recommended without food. in Use an additional 50mg clearance tablet of <dolutegravir infants exposed utero and/or post-natally to nucleoside analogues. Do data 65+ yrs. patients with creatinine 50 mL/min. HIV-negative to another antiretroviral regimen should discussed with the patient taking the approximately 12 hours after the dose of Contraindications: Dovato when co-administered with efavirenz, breast-feed. Side effects: See SmPC forbefull details. Headache, GI disturbance, Caution in severe hepatic impairment. Hypersensitivity to any not gestational age anddreams, the critical time period of neural tube defect development into nevirapine, tipranavir/ritonavir, etravirine boosted PI), carbamazepine, abnormal depression, anxiety, dizziness, somnolence, rash, pruritus, ingredient. Co-administration with substrates of(without OCT-2 with narrow therapeutic windows, insomnia, account (see SmPC section myalgia, 4.6). There have been reports of mitochondrial dysfunction oxcarbazepine, phenytoin, St John’s Wort or hypersensitivity rifampicin. Elderly: Limited alopecia, fatigue, arthralgia, hypersensitivity, suicidal ideation or suicide attempt,in such as fampridine. Specialphenobarbital, warnings/precautions: Risk of reactions. HIV-negative infants exposed in utero and/or post-natally to nucleoside analogues. Do data in 65+ yrs. Not recommended in patients with creatinine clearance < 50 mL/min. Discontinue dolutegravir and other suspect agents immediately. Risks of osteonecrosis, hepatitis, blood dyscrasias, acute hepatic failure, pancreatitis, angioedema, not breast-feed.lactic Sideacidosis, effects:peripheral See SmPCneuropathy. for full details. Headache, GIAST disturbance, Caution reactivation in severe hepatic impairment. Contraindications: Hypersensitivity to any rhabdomyolysis, Elevations of ALT, and CPK. immune syndrome. Monitor LFTs in Hepatitis B/C co-infection and ensure insomnia, abnormal dreams, dizziness, rash, pruritus, ingredient.Hepatitis Co-administration with substrates OCT-2 withmonitor narrow therapeutic windows, Nr: EU/1/19/1370/001. MAdepression, holder: ViiV anxiety, Healthcare BV, Vansomnolence, Asch van Wijckstraat 55H, effective B therapy. Caution with of metformin: renal function and MA alopecia, fatigue, arthralgia, myalgia, hypersensitivity, suicidal ideation or suicide attempt, such as fampridine. warnings/precautions: Risk of hypersensitivity reactions. LP Amersfoort, Netherlands. Legal Category: POM A. Date of preparation of API: consider metforminSpecial dose adjustment. Use with etravirine requires boosted PI or 3811 hepatitis, blood acute information hepatic failure, pancreatitis, angioedema, Discontinue dolutegravir and other agents immediately. Risks requires of osteonecrosis, Code:dyscrasias, PI-6305. Further available from GlaxoSmithKline, increased dose of dolutegravir. Usesuspect with Mg/Al-containing antacids dosage January2021. rhabdomyolysis, lacticBusiness acidosis,Campus, peripheral neuropathy. Elevations of ALT, AST and CPK. immune reactivation syndrome. Monitor LFTs in Hepatitis B/C dosage co-infection and ensure Riverwalk, Citywest, Dublin 24. Tel: 01-4955000. separation. Use with calcium, multivitamins or iron also requires separation if not 12 effective Hepatitis B therapy. metformin: monitor renal function and MA Nr: EU/1/19/1370/001. MA holder: ViiV Healthcare BV, Van Asch van Wijckstraat 55H, taken at the same time with food.Caution Use withwith cladribine or emtricitabine not recommended. 3811 LP Amersfoort, Netherlands. Legal Category: POM A. Date of preparation of API: consider metformin dose adjustment. Use with etravirine requires boosted PI or When possible, avoid chronic co-administration of sorbitol or other osmotic acting Adverse events should be reported directly to the Health Products Regulatory January2021. Code: PI-6305. Further information available from GlaxoSmithKline, increased(see dose of dolutegravir. with Mg/Al-containing antacids requires dosage alcohols SmPC section 4.5).Use If unavoidable, consider more frequent viral load Authority (HPRA) on their website: www.hpra.ie . Adverse events should also be reported 12 Riverwalk, Citywest, Business Campus, Dublin 24. Tel: 01-4955000. separation. Use with calcium, multivitamins or iron alsofertility requires dosage if not monitoring. Fertility, pregnancy and lactation: Human - no data; separation animal fertility to GlaxoSmithKline on 1800 244 255. taken at indicate the same no time with food. Use with cladribine or emtricitabine not recommended. studies effects. Women of childbearing potential (WOCBP) should be When possible, avoid chronic co-administration of sorbitol or other osmotic acting Adverse events should be reported directly to the Health Products Regulatory alcohols (see 4.5). Immunde If unavoidable, consider more frequent2.viral loadJ et al. Clin Authority on their website:3. www.hpra.ie . Adverse of events should also be reported References: 1. SmPC Cahn Psection et al. J Acquir Defic Syndr. 2020;83(3):310-318. van WYK Infect (HPRA) Dis. 2020;ciz1243:1-10 DOVATO Summary Product monitoring. Fertility, pregnancy and lactation: Human fertility - no data; animal fertility to GlaxoSmithKline on 1800 244 255. Characteristics. June 2020. studies indicate no effects. Women of childbearing potential (WOCBP) should be
References: 1. Cahn P et al. J Acquir Immunde Defic Syndr. 2020;83(3):310-318. 2. van WYK J et al. Clin Infect Dis. 2020;ciz1243:1-10 3. DOVATO Summary of Product Characteristics. June 2020. is owned by or licensed to the ViiV Healthcare group of companies. DOVATO ©2021 ViiV Healthcare group of companies or its licensor.
DOVATO is owned by or licensed to the ViiV Healthcare group of companies. ©2021 ViiV Healthcare group of companies or its licensor.
Date of preparation: April 2021. PM-IE-DLL-ADVT-200002
Date of preparation: April 2021. PM-IE-DLL-ADVT-200002
lockdown period (March-June 2020) in Ireland. Patients were assigned study numbers in Excel and divided into the following categories: diagnosis, gender, number of partners per patient, sexual orientation, asymptomatic versus HOSPITAL REVIEW: symptomatic patients.
Discussion: The impact of COVID-19 has impacted the entire health service with new emergency pathways being developed to deal with pressures of the pandemic, A COVID-19 pathway was urgently developed to increase the provision of ICU beds, endoscopy units and operating theatres were turned into temporary intensive care beds. However, it had negative consequence with the disruption of cancer services, cancellation of elective procedures and pausing of vital clinical trials. Figure 1
Our Sexual Health clinic was one of few public clinics to remain operational throughout the lockdown period. The nurses from our clinic were redeployed overnight to the emergency department and midwifery department which were deemed as essential services leaving STI services with a skeletal staffing level.
With limited staff, our team had to evolve to a new way of consulting with patients. Our first novel shift was implementing a Covid-19 screening questionnaire for teleconsultations and for those patients who were required to attend in person. These questionnaires which all health settings had to initiate had to be updated on an almost weekly basis Figure 2: Figure 2: as new symptoms emerged such as loss of smell or taste. Personal Protective Equipment and masks Results: were provided if patients had to they were self-reporting that they Results: clinic. Virtual consulting were still having sex with multiple With regards to chlamydia and Human Papilloma Virus (HPV)attend 29% the of patients With regards to chlamydia and became the backbone of the partners from different households, were with(HPV) both conditions compared to 16% and 6%service. respectively in staff provided Humandiagnosed Papilloma Virus Health care they were also breaking the law. these services remotely, which 29%period of patients were diagnosed2020. In 2019, 12% of people presented the of March-June with was consistent with lockdown There was a steep decline in the with both conditions compared gonorrhea versus 1% in 2020. Interestingly Herpes Simplex (HSV)From ratesa practical point regulations. number of people presenting with Virus to 16% and 6% respectively of view, wenon triaged chlamydia andpresentations gonorrhoea in the period of March-June doubled between 2019-2020 (4% vs 8%).(16%) Other included - symptomatic versus asymptomatic patients (1%) during the lockdown 2020. In 2019, 12% of people STI diagnoses 11% inversus 2019 andcompared 53% in 2020. diagnosis and in-person appointments were to 29%Examples and 12% in of non-STI presented with gonorrhea given to and symptomatic patients or 2019, respectively. One theory 1% in 2020. Interestingly Herpes epididymitis, included genital dermatoses, urethritis, NSI,wefolliculitis, PEP. those requiring PEP. concluded was due to the fact Simplex Virus (HSV) rates doubled women are often asymptomatic between 2019-2020 (4% vs 8%). There were still an unexpectedly high number of symptomatic patients Our PrEP clinic was run virtually due to chlamydia and may not Other presentations included via telephone with the PrEP 19 presenting to our physical clinic with 129 people seen during the first lockdown notice any symptoms. non - STI diagnoses 11% in 2019 proforma being completed this and 53% in 2020. Examples waybreaking and scriptsaposted out or period. We hypothesize that these figures are due to people Surprisingly, HSVeither rates doubled of non-STI diagnosis included emailed. We also advised our from 4% to 8% in 2020. The national lockdown and continuing to have sex or that reinfections could genital dermatoses, epididymitis, patients to monitor for any side long-standing interest in the urethritis, NSI,be folliculitis, and PEP. effects, if they were commenced potentially secondary to stress associated withHSV isolation It was relationship between and in lockdown. new medication, if there was acutethere or chronic There were still an unexpectedly intriguing to discover during thiswhether time that wasstress still aisgreatany degree of nonany concern of a seroconversion a causative factor, however a link high number of symptomatic illness still or if ahaving new medical compliance and the fact that they were that they were has neverself-reporting been clearly established patients presenting to our physical condition had been diagnosed the discussion continues. It is awere also breaking clinicwith with 129 peoplepartners seen during sex multiple from as different households, they in the interim to contact us well-documented fact the Human the first lockdown period. We immediately. the law. that these figures are Immunodeficiency Virus (HIV) hypothesize either due to people breaking a can reactivate latent infections There were a few limitations to There a steep in theand number ofnatural people presenting with chlamydia nationalwas lockdown anddecline continuing alter the history in this study, it was a retrospective to have sex or that reinfections particular syphilis. However, recent case and itin may not have (16%) and gonorrhoea (1%) during the lockdown compared to 29%review, and 12% could potentially be secondary to publications are emerging showing represented the actual number 2019, respectively. One theory we was to the womenthat areaccessed the stress associated with isolation thatconcluded Covid-19 may be adue trigger for fact of patients in lockdown. It was intriguing recurrence latentnot HSVnotice infections sexual health(19) services. This may often asymptomatic due to chlamydia andofmay any symptoms. to discover during this time that as well as Hepatitis B Virus, be for various reasons: firstly, there was still a great C Virus and in Varicella there was a nationwide high level Surprisingly, HSVdegree rates of doubledHepatitis from 4% to 8% 2020. The long-standing of anxiety during the lockdown non-compliance and the fact that Zoster Virus.20, 21, 22
interest in the relationship between HSV and whether acute or chronic stress is a
and fear of patients breaking regulations. Secondly, it was felt on discussion with the team it was harder to elicit sexual histories than before lockdown as different households were strictly forbidden to mix and thus perhaps creating an atmosphere of stigma around people’s ability to tell their complete sexual history. Thirdly, another limitation we were concerned about was in determining our true case numbers i.e., Patients with pre-existing STIs either those who had delayed seeking medical attention and perhaps more importantly the fear of contracting COVID-19 on arriving to the hospital. There is a huge drive however, in resuming all health services across Ireland, in particular cancer screening, out-patient appointments, and mental health services. However, most departments are still running virtual clinics due to the uncertainty of this pandemic. Hospitals and nursing homes still have limited visiting restrictions to limit the spread of the disease. Sadly, the fallout of Covid-19 is that every medical/surgical specialty are desperately aware that their waiting lists are growing with almost one million hospital appointment cancelled by the pandemic, and it is certain people are dying due to lack of access to services.23 Covid-19 was something the world was not prepared for however one could argue that the Italians gave us plenty of warning. Sexual health services have proven to be an essential service, and we have found ourselves in an unique position to provide continuous health care to an often marginalized cohort of patients. This was due to a very supportive hospital management who recognized its importance. As we have come to live with Covid-19, however challenging and traumatic it has been; it has ironically accelerated many facets of our health care system that had been in serious need of modernization and interestingly we received very positive feedback as the corner of all health systems has been face to face consultations. We now must acknowledge that people will continue to be people, all human frailties included, and they will continue to break curfew no matter how strict government regulations are and it is our responsibility as sexual health specialists to acknowledge human nature and to adjust our practice accordingly. References available on request
HOSPITALPROFESSIONALNEWS.IE | HPN • AUGUST - 2021
For treatment of 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/lamivudine/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). Lactic acidosis Cases of lactic acidosis have been reported with tenofovir disoproxil alone or in combination with other antiretrovirals. Patients with predisposing factors such as patients with decompensated liver disease, or patients receiving concomitant medications known to induce lactic acidosis are at increased risk of experiencing severe lactic acidosis during tenofovir disoproxil treatment, including fatal outcomes. 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: June 2020. © Merck Sharp & Dohme B.V., 2020. All rights reserved. Further information is available on request from: MSD, Red Oak North, South County Business Park, Leopardstown, Dublin D18 X5K7 or from www.medicines.ie. Date of Preparation: April 2021. IB/0019. References: 1. DELSTRIGO Summary of Product Characteristics, June 2020. 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
PIFELTRO® ▼ (Doravirine) DELSTRIGO® ▼ (Doravirine/Lamivudine/Tenofovir disproxil fumarate)
HOSPITAL REVIEW: HIV
HIV Prevention : What is PrEP? Authors: Crowe. A1, Salgaonkar. S2, Gorman. D2, Rowley. D2 1 King’s College Hospital, Denmark Hill, London, UK 2 The Sexual Health Clinic, Midlands Regional Hospital, Portlaoise, Ireland
HIV, which has been directly responsible for millions of deaths worldwide, is now a preventable condition. The AIDS epidemic of the last four decades has caused immeasurable loss and grief to all that it has touched. However, the world of HIV medicine has progressed dramatically in recent times. Previously, a new diagnosis of HIV would often lead to early death from AIDS, but nowadays people living with HIV have a near normal life expectancy if diagnosed promptly and treated appropriately (May 2014). Some of the most exciting recent advances in HIV pharmacology are the therapeutics that prevent the acquisition of HIV, most notably, PEP and PrEP. Many medics are aware of PEP or Post Exposure Prophylaxis. This regimen is given within 72 hours after exposure and reduces risk of HIV acquisition. Indeed, many medics have taken it after a needlestick injury. However, far fewer are aware of PrEP. (Petroll 2017)
reduces risk of acquisition of HIV. PrEP is taken by HIV negative patients who are expected to be exposed to HIV, for example, through sexual contact or IV drug use. If exposed to HIV, and provided drug concentration levels are adequate, PrEP prevents replication of HIV within the body, allowing the immune system to clear it naturally.
Dr Andrew Crowe, King’s College Hospital, Denmark Hill, London, UK
This article will describe the evidence behind PrEP, along with some key learning points for clinicians who may find themselves caring for patients taking PrEP. The iPREX study was the first landmark study to demonstrate the efficacy of PrEP (Grant et al. 2010). This multicentre international Randomised Control Trial assigned 2,499 patients to received either Truvada (Emtricitabine and Tenofovir Disoproxil Fumarate) or placebo with results showing a 42% risk reduction in new diagnosis of HIV in the Truvada arm. However, efficacy was strongly correlated with adherence. In patients with good adherence, who had persistently therapeutic drug levels, the risk reduction of acquiring HIV was estimated
at 92%, suggesting the former figure was low due to poor medication compliance. The UK based PROUD study, an open label randomised trial using Truvada (TDF/FTC), showed an 86% reduction in risk of acquiring HIV amongst men who have sex with men. In this trial, the patients in the treatment arm took Truvada every day, known as the “daily regimen”. (McCormack et al. 2016)
men who have sex with men, also showed an 86% reduction in risk of acquiring HIV. The patients in the treatment arm took Truvada in the days before and after potential exposure. This is also known as the “event based” regimen or “PrEP on demand” and is shown in diagram 1. (Molina et al. 2015) These studies demonstrated the efficacy of PrEP in men who have sex with men, but the efficacy has also been shown in a heterosexual population. The Partner PrEP study of heterosexual serodiscordant couples randomised 4758 patients
Dosing Schedule for “Event based PrEP”
PrEP, or Pre Exposure Prophylaxis, is a regimen of medications taken before potential exposure that
ram 1Diagram 1
2 tablets (Truvada) 2-24 hours before sex
The IPERGAY study in France and Canada, a double blind randomised control trial of PrEP in
1 tablet (Truvada) 24 hours later
1 tablet (Truvada) 48 hours later
1 tablet Thursday (Truvada) 24 hours later
1 tablet Friday (Truvada) 48 hours later
Dosing Schedule for “Event based PrEP” Monday
2 tablets (Truvada) Sexual 2-24 hours before sex Wednesday Event Tuesday
• “Event based PrEP” was shown to reduced risk of HIV acquisition by 86% in the IPERGAY study
• “Event based PrEP” was shown to reduced risk of HIV acquisition by 86% in the IPERGAY study Molina J, et al. CROI 2015; Seattle, WA. #23LB http://www.cdc.gov/nchhstp/newsroom/2015/IPERGAY-2015-Media-Statement.html
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Adherence is proportionate to Efficacy Partners PrEP3 81% adherence/ 75% efficacy
68 HOSPITAL REVIEW: HIV
iPrEx1 51% adherence/ 44% efficacy
TDF24 84% adherence/ 63% efficacy Bangkok2 67% adherence/ 49% efficacy
HIV protection effectiveness Multiple trials demonstrate that efficacy of PrEP is directly proportionate to adherence 1. Grant R, et al. N Engl J Med 2010;363:2587-99. 2. Choopanya K, et al The Lancet. June 13, 2013. 3. Baeten J, et al. N Engl J Med 2012;367:399-410. 4. Thigpen M, et al. N Engl J Med 2012;367:423-34.
to either Truvada or placebo. The results showed a reduction of 75% in risk of acquiring HIV compared to placebo. (Baeten et al. 2012) The overall conclusion from multiple large scale trials is that PrEP is effective in preventing HIV infection in high risk patients, and that efficacy is strongly correlated with medication compliance. We now know that efficacy is directly proportionate to compliance and this is shown in diagram 2. In Ireland, PrEP has been available free of charge since 2019. Specialist doctors prescribe PrEP to patients who meet eligibility criteria, and then monitor them in clinic every 3 months (HIV testing, STI screen and bloods for renal function). Around 1 in 10 may experience GI side effects such a nausea and diarrohea which tend to resolve after the first month. The other notable side effects are potential renal dysfunction (hence the need for 3 monthly bloods) and possible reduction in bone mineral density although this has generally been associated with longterm use of Truvada. For patients who experience
side effects, other alternatives such a Descovy (Emtricitabine and Tenofovir Alafenamide) are available. Descovy is similar to Truvada but with less renal and bone complications. Despite the plethora of evidence, PrEP has faced criticism with some claiming it will increase risky sexual behaviour. However, the PROUD study showed that MSM are not more likely to acquire bacterial sexually transmitted infections when on PrEP (McCormack et al. 2016). It is also crucial to highlight that patients in clinic are always informed that PrEP is not 100% effective and are advised to use protection alongside PrEP. Additionally, critics claim that PrEP will induce drug resistance. However, the evidence shows the overall risk appears very low and occurs mainly in people with unknown HIV who are then started on PrEP. To reduce this risk, all patients must have HIV testing before starting and Truvada as PrEP is contraindicated in patients with active HIV infection or unknown HIV status (NICE 2016)
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In conclusion, PrEP is an evidence based therapeutic for the prevention of HIV. It is safe, effective and free of charge in Ireland. The incidence of HIV in Ireland continues to rise year on year, in contrast to other European countries where rates are declining. The onus is on all doctors to encourage patients to take PrEP where indicated. Failure to do so will lead to more unnecessary HIV infections and deaths. References 1. May et al. UK Collaborative HIV Cohort (UK CHIC) Study. Impact on life expectancy of HIV-1 positive individuals of CD4+ cell count and viral load response to antiretroviral therapy. AIDS; 28(8):1193-202. 2014 2. Petroll, A. E., Walsh, J. L., Owczarzak, J. L., McAuliffe, T. L., Bogart, L. M., & Kelly, J. A. (2017). PrEP Awareness, Familiarity, Comfort, and Prescribing Experience among US Primary Care Providers and HIV Specialists. AIDS and behavior, 21(5), 1256–1267. https://doi. org/10.1007/s10461-016-1625-1
3. Grant et al. December 30, 2010. Preexposure Chemoprophylaxis for HIV Prevention in Men Who Have Sex with Men. New England Journal of Medicine; 363:2587-2599 DOI: 10.1056/NEJMoa1011205 4. McCormack S et al. Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trial. The Lancet, early online publication. DOI: http://dx.doi.org/10.1016/ S0140-6736(15)00056-2. 2015. 5. Molina J-M et al. On-demand preexposure prophylaxis in man at high risk for HIV-1 infection. NEJM early online publication, DOI: 10.1056/NEJMoa1506273. 2015 6. Baeten et al. 2012. Antiretroviral Prophylaxis for HIV Prevention in Heterosexual Men and Women. August 2, 2012. New England Journal of Medicine 2012; 367:399-410 DOI: 10.1056/NEJMoa1108524 7. NICE Evidence Summary 2016. Pre-exposure prophylaxis of HIV in adults at high risk: Truvada (emtricitabine/tenofovir disoproxil). Evidence summary [ESNM78] Published: 05 October 2016
HOSPITAL REVIEW: LONG COVID
Post Covid Syndromes and the Dyspnoeic Patient Written by Dr Oisin O’Connell, Consultant Respiratory Physician, Bon Secours Hospital; Dr Dervla Devine & Dr Michael Killian
SARS-CoV-2 belongs to the β subgroup of coronaviruses, along with SARS-CoV that was initially reported in China’s Guangdong Province in 2003, and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) first described in 2012. Genomic sequencing revealed a 93.1% identity between SARS-CoV-2 and the coronavirus RaTG12 isolated from the common horseshoe bat (Rhinolophus affinis) in Yunnan, China in 2013. Located within the S1 subunit of SARS-CoV-2 is the receptor binding domain that is responsible for attaching to the host cell angiotensin converting enzyme 2 (ACE2) receptors which facilitates viral entry into the target cells. This article will summarize some of the symptoms people experience after covid, their duration with a particular focus on the evaluation of the persistently breathless patient and their management. Post Covid-19 signs and symptoms are becoming more topical in medical research as we move further from the first case of Covid-19, detected over 18 months ago. Following a severe primary infectious disease like COVID-19, a systemic inflammatory response syndrome or SIRS is predominant in the acute stages, but has a concomitant and potentially overwhelming and long-lasting counterbalancing compensatory anti-inflammatory response syndrome (CARS) which can result in long term clinical sequelae and symptoms. Genome wide association studies (GWAS) studies have already highlighted a number of innate immune system polymorphisms associated with worse acute clinical outcomes in patients infected with Covid-19. It is likely in the future, other immune and haemostatic dysregulation and polymorphisms might help identify specific phenotypes of postcovid syndromes. The majority of patients with covid experience a short transient illness and are not left with long term symptoms, but current research is starting to show the number of symptoms and notably symptoms across multiple systems in the body at initial presentation can result in an increased risk of a Post Covid syndrome.
Dr Oisin O'Connell MD, FRCPI, Consultant Respiratory Consultant, Bon Secours Hospital Cork, Medical Director for HospitalBuddy medical education phone App for hospital doctors in Ireland
Dr Dervla Devine graduated from UCC in 2019, worked as an intern and SHO in Beaumont Hospital, Dublin and Bon Secours, Cork
Having graduated from UCC in 2016 and spending some time working abroad in New Zealand, Dr Michael Killian has been working as a medical senior house officer in the Bon Secours Hospital Cork for the last 3 years. He aims to complete further training commencing July 2021 in Dublin
‘Acute Covid-19’ is defined as 0-4 weeks from first day of symptoms or a positive Covid-19 test if asymptomatic, ‘Ongoing symptomatic Covid-19’ is defined as continued symptoms between 4-12 weeks post initial diagnosis and finally, ‘post Covid-19 syndrome’ is described as ‘signs and symptoms that develop during or following an infection consistent with Covid-19, continue for more than 12 weeks and are not explained by an alternative diagnosis. It usually presents with clusters of symptoms, often overlapping, which can fluctuate and change over time and can affect any system in the body’ (1). Post Covid-19 syndrome is a multiorgan disorder with conflicting evidence on whether the severity of an individuals’ acute Covid experience has an identifiable relationship for the prediction of developing post Covid-19 syndrome and the severity of this post viral illness. It is important to realise a positive Covid-19 test result, hospital admission or multiple medical comorbidities are not prerequisites to post-acute Covid-19 syndrome diagnosis and that functional disability can
often appear out of proportion to the degree of imaging and clinical findings. (2). Broadly speaking, the majority of patients with post Covid-19 syndrome will likely be managed in primary and secondary care through a wholepatient approach involving the treating physician, physiotherapist, occupational therapist, medical social worker and psychologist as necessary (2,5).
sectional population studies are carried out(4). It is not clear why some patients suffer a protracted course of illness however medical comorbidities particularly cardiovascular and respiratory disease, high BMI, sarcopenia, poor nutritional status, relapse and reinfection are hypothesised to be significant risk factors for long-Covid (4). In an Egyptian study examining post Covid-19 syndrome it was found to be more common in women than men with 64% of patients being female while 36% of patients were male. In this particular study, 73% of patients were either overweight or obese (BMI >30), while 90.2% were nonsmokers and 70% had no other diagnosed comorbidities at the time(2). Prolonged multisystem pathology of the cardiovascular, respiratory and musculoskeletal systems have been described in other coronaviruses – SARS and MERS – which have similar aetiopathogenesis to Covid-19. As time passes, managing post Covid-19 syndrome is going to become an increasingly prevalent phenomenon in both primary and secondary healthcare services.
It is estimated that approximately 10% of individuals who contract Covid-19 will go on to develop a post Covid-19 syndrome, although there are large variations in the reported prevalence of same pending how study populations are identified. This 10% figure originates in a UK study whereby patients diagnosed with Covid-19 entered their symptoms in an ongoing symptom-tracker application throughout recovery, however observational studies quote a much higher prevalence, with up to 65% of patients describing a long-Covid phenomenon(1). It is impossible to currently accurately estimate the prevalence of long-Covid and it will be challenging until large cross-
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Respiratory • Persistent Dyspnoea • Chronic Cough • Tracheal burning sensation • Burning sensation in lung Systemic • fatigue • Sensation of increased body temp • Fevers over 38 deg • Lymphadenopathy Cardiovascular • Chest pain • Palpitations • Interscapular pain Musculoskeletal • Muscle Pains • Arthralgia • Weakness/deconditioning • Muscle wasting/sarcopenia
Goertz et al (Symptom prevalence at day 79 post covid, n=2113)
Neurological/Neuropsychiatric • Headache • Dizziness • Ocular Disturbance • Neurocognitive deficits • Mood Changes • Chronic fatigue • Sleep Deprivation Haematological • Persistent or recurrent thrombosis Dermatological • Hair Loss Gastrointestinal/Hepatobilary • Nausea • Diarrhoea • Abnormal Liver function ENT • Anosmia • Ageusia • Ear pain • Sore throat Other
71% 29% 20% 24% 87% 20% 2% <1% 44% 32% 33% 36% 22%
38% 27% 12% 29% 57%
12% 10% 13% 6% 8% 27%
Persistent symptoms 3 months after a SARS-CoV-2 infection as adapted from Goërtz YM et al, ERJ Open Res. 2020 Oct; 6(4): 00542-2020 with other sources
Symptoms: There is a wide variety in the symptoms described as part of ‘Long Covid’ or ‘post-acute Covid-19 syndrome’ and as such symptoms can broadly be
divided into 2 main groups – mild symptoms and critical or serious symptoms. Most frequently reported symptoms were mild including fatigue (73 to 87%%), anxiety (38%), myalgia (31 to
AUGUST - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE
36%), continuous headache (29 to 38%), chest pain (29 to 44%), depression (28.9%) and dyspnoea (28 to 71%). Rarer but critical sequelae such as myocarditis (1.4%), pulmonary fibrosis
(4.9%), stroke (2.8%), chronic thromboembolic disease and renal impairment (1.4%), have also been described. Looking at previous models used for SARS, studies describe chronic fatigue and psychiatric complaints persisting up to 4 years post-acute viral infection. Some studies suggest that the severity of post-Covid 19 syndrome is related to the comorbidities of the individual predating diagnosis with acute Covid-19, as well as the course of the acute illness itself, be that mild - treated at home, moderate - requiring oxygen, or severe needing ICU admission. It is clear that a negative PCR test in no way indicates completed disease course(5). No current guidelines exist for the management of long Covid, however with services sporadic and an already stretched healthcare system there is much room for implementation for up to date guidelines to manage the expected increased demands on the healthcare service in the near future. The lungs are the organ most affected by COVID-193 with different pathophysiological events that include diffuse alveolar epithelium destruction, hyaline membrane formation, capillary damage and bleeding, alveolar septal fibrous proliferation, and pulmonary consolidation (1). A characteristic of COVID-19 is the extensive injury to alveolar epithelial cells and endothelial cells with secondary fibroproliferation,5 indicating a potential for chronic vascular and alveolar remodeling leading to lung fibrosis and/ or pulmonary hypertension.6 Similarly, patients with preexisting respiratory diseases such as COPD and interstitial lung disease suffer increased morbidity and mortality post covid. These findings generate concerns regarding the assessment of lung injury for discharged patients. Persistent dyspnoea post Covid The BTS guidelines suggest following up patients with severe pneumonia due to COVID-19 with full pulmonary function testing (PFT) 12 weeks after discharge (2). In the case of mild to moderate pneumonia related to Covid-19, the PFTs should be conducted if the chest radiograph is abnormal. The BTS guidelines suggest if any abnormality in lung function, together with a CT abnormality, is found, the patient must be referred to a respiratory specialist with expertise in interstitial lung disease (2). The first reports on lung function related to COVID-19 indicated that patients have a restrictive defect and a small airways dysfunction that can be persistent and not related to the disease severity (3). In the largest meta-analysis of full PFT’s to date post Covid, there was altered
73 diffusion capacity in 39% at 1 month post Covid, 15% showed a restrictive pattern PFT’s and 7% showed an obstructive pattern PFT’s at 1 month post Covid. Zhao found a 16% prevalence of significantly reduced diffusion measured by DLCO at 3 months post-Covid (4). They found a very high prevalence (66%) of altered diffusion capacity of carbon monoxide (DLCO) in severe covid patients, especially those with high inflammatory indicators who are more likely to develop long-term pulmonary fibrosis, thought related to the pulmonary fibrogenesis related to IL-6 and other profibrotic cytokines (5). An initial screening for ‘post-covid syndrome’ patients reporting significant dyspnoea should consider CXR and Full PFT’s to include a DLCO at 3 months post Covid evaluation. If these tests are abnormal, then consideration should be given for further evaluation which may include HRCT/ECHO/Exercise stress test and ventilation-perfusion imaging in a specialist respiratory center may be considered. There are rare but serious and treatable consequences described causing persistent dyspnoea post covid, including post-Covid chronic thromboembolic disease. If there are mismatched or reverse mismatched ventilation perfusion findings on the perfusion scan at 3 months, then consideration for an opinion from the a pulmonary hypertension expert may need to be sought (6). It is speculated that hypercoagulability and immune thrombus associated with Covid can result in acute, delayed and chronic thromboembolic
complications and manifest as dyspnoea and reduced exercise tolerance in patients with pulmonary hypertension (7). There are various targeted therapies used in pulmonary hypertension specialty centers than can improve the dyspnoea and exercise tolerance of such patients including Sildenafil, Modafinil, Macitentan and inhaled prostanoids, as well as the potential for some very rare patients post Covid to require pulmonary end-arterectomy (8). Van Linthout et al. 1 in a wellwritten and expansive editorial outlined 11 cases of ‘probable’ SARS-CoV-2-associated myocarditis, highlighting a rather heterogeneous presentation but all showing acute troponin elevation in the acute Covid infection (9). The gold standard for diagnosing viral myocarditis, requiring identification of viral inclusion structures in endothelial cells is not required to diagnose Covid Myocarditis. Diagnostic tests suggestive of Covid myocarditis may include BNP, Troponin, ECG, Echo, Cardiac MRI, Cardiac Biopsy, holter or Loop recorder. On cardiac MRI imaging, the Lake Louise Criteria (LLC v2018) requires both (1) myocardial edema on T2-mapping of T2W images and (2) non-ischemic myocardial injury signified by abnormal T1, extracellular volume, or late gadolinium enhancement to diagnose viral myocarditis, and these rules hold through today for Covid-19 related Myocarditis: There are several studies
underway to evaluate what may influence the course for long term outcomes in patients with Covid. This includes the “STerOids in Covid-19 Study” (STOIC) which has suggested a reduction in post Covid symptoms at day 14 and day 28 after initiating of inhaled Budesonide 800mcg BD in patients diagnosed with Covid (10) and the recently published Principle study, also showing potential beneficial effects of Inhaled Corticosteroids. Post Covid Syndrome self-management and symptom control: Management of post COVID syndrome remains challenging. NICE guidelines were recently published for the management of post COVID syndrome which suggests that a multidisciplinary approach should be considered. (1) Many strategies have been explored including multidisciplinary input to include physiotherapy, psychology, rehabilitation medicine, occupational therapy, breathing techniques and exercises for symptom management, graded exercise programs and other specific medical therapies (1,2). Comprehensive assessments may include PFT’s, radiological imaging, respiratory muscle strength assessments. The severe and prolonged impact post COVID syndrome can have and in the absence of any proven effective pharmacological treatment, supportive therapies
are the mainstay of management. These specialities can assist patients in self-management of symptoms and provide a much needed resource, education, emotional and physical support for patients. The multidisciplinary approach also allows the sharing of knowledge, skills and training between services to help practitioners in the community provide assessments and interventions, such as 1‑minute sit‑to‑stand tests and breathlessness training. (3, 2,4,5). The focus of rehabilitation should aim to reverse the decline from deconditioning, increase muscle strength, reduce dyspnoea and fatigue, improve balance and endurance and return the patient towards functional independence. With regard to breathlessness, breathing exercises and posture positional awareness can be helpful. Physiotherapy plays an important role with regard to education, understanding and utilisation of these aspects of symptom relief. There are also online resources where patients can obtain illustrations and background information which may be of assistance. (2) Persistent cough can be a particularly frustrating persistent symptom with many patients achieving alleviation using simple techniques such as taking small sips of water, using honey and lemon drinks or steam inhalation. Fatigue is also a very common persistent symptom and managing patient expectations is important. It may be more prudent to discuss setting daily targets and achievable goals for patients, whilst providing reassurance that symptoms will improve with time. Initially planning and prioritising daily activities may be helpful, whilst focusing on the likely energy expenditure for each task. Some may find that they may have to pace themselves during activities. Sleep hygiene, limitation of alcohol and caffeine are also beneficial, and there is emerging evidence that lock-downs and poorer diet and reduced exercise have had an effect on increasing the prevalence of Obstructive Sleep apnoea. Smoking cessation should be advised. Diet and exercise are also important aspects of patient recovery. Increased protein intake is necessary after a debilitating illness such as COVID, especially in the elderly or those who have endured long hospitalisations as sarcopenia can contribute to fatigue, reduced exercise tolerance and breathlessness. (6)
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74 HOSPITAL REVIEW: LONG COVID 6];42(6):1547–78. Available from: 10.1007/s11357-020-00272-3
With regard to return to work, this should be done on a phased basis and considered on an individual level with respect to number of hours worked and amount of physical activity involved. It is important to recognise the impact of post COVID syndrome on mental health and provide emotional support for patients. Simple relaxation and breathing techniques and peer support groups may be of help for managing anxiety, as can take up a new hobby such as Yoga. Cognitive behavioural therapy has been shown to be of benefit for patients with other conditions, however its role in post COVID syndrome is controversial and may not be of particular benefit to the majority. (7) Consideration for this modality should be on a caseby-case basis and appropriate referrals to clinical psychology or psychiatry should be considered. Patients need regular follow up and multidisciplinary care. Whilst inhaled and oral steroid therapy in acute COVID infection have been shown to be of benefit in select cases, steroid use beyond 10 days in the acute setting is detrimental to the majority of patients. (8) Evidence suggests that prolonged steroid use in acute COVID infection may contribute to post COVID syndrome, increasing the risk of myopathy, neuromuscular weakness and psychiatric symptoms. (8) This likely explains the lack of available evidence for commencement of steroid therapy in the post COVID syndrome. There is an exception for a small subgroup of patients however where prolonged steroid therapy may be indicated. (9) This subgroup consists of patients with post disease pulmonary fibrosis. These patients have usually had a very severe illness with radiological evidence of persistent ground glass change and respiratory specialist input is required. With regard to vitamin D, there is also limited data for post COVID syndrome. Correlations have been made between acute COVID infection and low vitamin D levels. (10,11) In addition, vitamin D is well known to contribute to host immune responses and has a role in defence against pathogens such as mycobacterium tuberculosis. (12) This lends some theoretical scientific plausibility for vitamin D supplementation in acute COVID infection. Both COVID and low vitamin D levels can contribute to sarcopenia and fatigue, so it
is not unreasonable to suggest replacement in those that have proven deficiency in the setting of post COVID syndrome, despite a lack of evidence in this particular cohort. This also highlights the importance of overall nutrition in those with post COVID syndrome. The importance of using low molecular weight heparin in acute COVID infection, a proven prothrombotic state, has been highlighted in a number of recent studies. (13,14). It is also well established that patients are at risk of thromboembolic events in the weeks of recovery post COVID 19 infection. Again, there are limited guidance and advice for continuation of low molecular weight heparin on discharge from hospital or initiation of same for community-based cases, but risk assessment should be done on a case by case basis, notably in patients with active cancers. For younger, ambulatory patients with post COVID syndrome with few risk factors for thromboembolism, prophylactic low molecular weight heparin may not be considered. However, for elderly patients, particularly those who are bedbound or nursing home residents, with comorbidities, it may be prudent to initiate low molecular weight heparin prophylaxis on a case-by-case basis. Finally, it is important to optimise patient care in relation to comorbidities in patients with post COVID syndrome. Exploring symptoms with regard to contribution to or from known existing medical conditions such as heart and lung diseases, neurological conditions, diabetes and thyroid disorders is important. Symptom control may be achieved by reviewing and adjusting existing therapies and these patients should not be overlooked as solely a post COVID syndrome. References 1. Greenhalgh T, Knight M, A’Court C, Buxton M, Husain L. Management of post-acute Covid-19 in primary care. BMJ. 2020;370. 2. Kamal M, Abo Omirah M, Hussein A, Saeed H. Assessment and characterisation of post-COVID-19 manifestations. Int J Clin Pract. 2021;75(3):1–5. 3. Huang C, Huang L, Wang Y, Li X, Ren L, Gu X, et al. 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. Lancet [Internet]. 2021;397(10270):220–32. Available from: http://dx.doi.org/10.1016/ S0140-6736(20)32656-8 4. Vindegaard N, Benros ME. Since January 2020 Elsevier has created a COVID-19 resource centre with free
AUGUST - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE
information in English and Mandarin on the novel coronavirus COVID19. The COVID-19 resource centre is hosted on Elsevier Connect , the company ’ s public news and information. Brain Behav Immun. 2020;89(January):531–42. 5. Ladds E, Rushforth A, Wieringa S, Taylor S, Rayner C, Husain L, et al. Developing services for long COVID: lessons from a study of wounded healers. Clin Med J R Coll Physicians London. 2021;21(1): 59–65. 1. Mo X., Jian W., Su Z., Chen M., Peng H., Peng P. Abnormal pulmonary function in COVID-19 patients at time of hospital discharge. Eur Respir J. 2020;55. 2. British Thoracic Society. British Thoracic Society Guidance on Respiratory Follow Up of Patients with a Clinico-Radiological Diagnosis of COVID-19 Pneumonia [Internet]. 2020. Available from: https://www.britthoracic.org.uk/document-library/ quality-improv. 3. You J., Zhang L., Ni-jia-Ti M., Zhang J., Hu F., Chen L. Anormal pulmonary function and residual CT abnormalities in rehabilitating COVID-19 patients after discharge. J Infect. 2020. 4. Zhao Y., Shang Y., Song W., Li Q., Xie H., Xu Q. Follow-up study of the pulmonary function and related physiological characteristics of COVID-19 survivors three months after recovery. EClinicalMedicine. 2020. 1. 5 Management | COVID-19 Rapid Guideline: Managing The Long-term Effects Of COVID-19 | Guidance | NICE [Internet]. [cited 2021 Apr 6]. Available from: https://www.nice. org.uk/guidance/ng188/chapter/5Management 2. https://www. tamesideandglossopccg.org/ getmedia/82823843-620a-4513b378-9265f871127b/Tameside-andGlossop-Post-COVID19-PatientInformation-Pack. 3. Shah W, Hillman T, Playford ED, Hishmeh L. Managing the long term effects of Covid-19: summary of NICE, SIGN, and RCGP rapid guideline. BMJ [Internet]. 2021;n136. Available from: 10.1136/ bmj.n136 4. Your COVID Recovery [Internet]. [cited 2021 Apr 6]. Available from: https://www.yourCovidrecovery.nhs. uk/ 5. Sleeping Well | Royal College Of Psychiatrists [Internet]. RC PSYCH ROYAL COLLEGE OF PSYCHIATRISTS. [cited 2021 Apr 6]. Available from: https://www. rcpsych.ac.uk/mental-health/ problems-disorders/sleeping-well 6. Kirwan R, McCullough D, Butler T, Perez de Heredia F, Davies IG, Stewart C. Sarcopenia during COVID-19 lockdown restrictions: long-term health effects of shortterm muscle loss. GeroScience [Internet]. 2020 [cited 2021 Apr
7. Vink M, Vink-Niese A. Could Cognitive Behavioural Therapy Be an Effective Treatment for Long COVID and Post COVID-19 Fatigue Syndrome? Lessons from the Qure Study for Q-Fever Fatigue Syndrome. Healthcare [Internet]. 2020 [cited 2021 Apr 6];8(4):552. Available from: 10.3390/ healthcare8040552 8. Mishra GP, Mulani J. Corticosteroids for COVID-19: the search for an optimum duration of therapy. The Lancet Respiratory Medicine [Internet]. 2021 [cited 2021 Apr 6];9(1):e8. Available from: 10.1016/ s2213-2600(20)30530-0 9. Vasarmidi E, Tsitoura E, Spandidos D, Tzanakis N, Antoniou K. Pulmonary fibrosis in the aftermath of the Covid-19 era (Review). Exp Ther Med [Internet]. 2020 [cited 2021 Apr 6]; Available from: 10.3892/etm.2020.8980 10. Mok CK, Ng YL, Ahidjo BA, Hua Lee RC, Choy Loe MW, Liu J, et al. Calcitriol, the active form of vitamin D, is a promising candidate for COVID-19 prophylaxis. [cited 2021 Apr 6]; Available from: 10.1101/2020.06.21.162396 11. Ebadi M, Montano-Loza AJ. Perspective: improving vitamin D status in the management of COVID-19. Eur J Clin Nutr [Internet]. 2020 [cited 2021 Apr 6];74(6):856–9. Available from: 10.1038/s41430-020-0661-0 12. Gombart AF. The vitamin D– antimicrobial peptide pathway and its role in protection against infection. Future Microbiology [Internet]. 2009 [cited 2021 Apr 6];4(9):1151–65. Available from: 10.2217/fmb.09.87 13. Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F, et al. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. N Engl J Med [Internet]. 2020 [cited 2021 Apr 6];383(2):120–8. Available from: 10.1056/nejmoa2015432 14. Ambrosino P, Di Minno A, Maniscalco M, Di Minno MND. COVID-19 and venous thromboembolism: current insights and prophylactic strategies. Annals of Medicine [Internet]. 2020 [cited 2021 Apr 6];52(6):239–42. Available from: 10.1080/07853890.2020.1791355 15. Klok FA, Kruip MJHA, van der Meer NJM, Arbous MS, Gommers D, Kant KM, et al. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis. Thrombosis Research [Internet]. 2020 [cited 2021 Apr 6];191:148– 50. Available from: 10.1016/j. thromres.2020.04.041 Casagrande M, Favieri F, Tambelli R, Forte G. The enemy who sealed the world: effects quarantine due to the COVID-19 on sleep quality, anxiety, and psychological distress in the Italian population. Sleep Med. 2020.
Dexmedetomidine EVER Pharma 100 micrograms/ml concentrate for solution for infusion For sedation of adult ICU patients requiring sedation level not deeper than arousal in response to verbal stimulation (corresponding to Richmond Agitation-Sedation Scale (RASS) 0 to -3). For sedation of non-intubated adult patients prior to and/or during diagnostic or surgical procedures requiring sedation, i.e., procedural/awake sedation. Patient ability to communicate and cooperate with staff significantly improved1 Provides relatively fast onset of sedative properties paralleling natural sleep with easy reversibility providing improved patient safety1 Low rates of respiratory depression2 Similar cardio-respiratory safety profile to midazolam with more efficacious sedation than midazolam in the peri-procedural period2
References: 1. Weerink MAS, Struys MMRF, Hannivoort LN, Barends CRM, Absalom AR, Colin P. Clinical Pharmacokinetics and Pharmacodynamics of Dexmedetomidine. Clin Pharmacokinet. 2017 Aug;56(8):893-913. doi: 10.1007/s40262-017-0507-7 2. Barends, C.R., et al., Dexmedetomidine versus Midazolam in Procedural Sedation. A Systematic Review of Efficacy and Safety. PLoS One, 2017. 12(1): p. e0169525.
(Please refer to the Summary of Product Characteristics before prescribing). Dexmedetomidine EVER Pharma 100 micrograms/ml concentrate for solution for infusion. Therapeutic indications: Dexmedetomidine EVER Pharma is indicated for the treatment of: For sedation of adult ICU (Intensive Care Unit) patients requiring sedation level not deeper than arousal in response to verbal stimulation (corresponding to Richmond Agitation-Sedation Scale (RASS) 0 to -3). For sedation of non-intubated adult patients prior to and/or during diagnostic or surgical procedures requiring sedation, i.e. procedural/awake sedation. Posology and method of administration: Method of administration: Hospital use only. Dexmedetomidine EVER Pharma must be administered only as a diluted intravenous infusion using a controlled infusion device. Indication 1. For sedation of adult ICU (Intensive Care Unit) patients requiring a sedation level not deeper than arousal in response to verbal stimulation (RASS 0 to -3). It should be administered by healthcare professionals skilled in the management of patients requiring intensive care. A lower starting infusion rate should be considered for frail patients. It is very potent and the infusion rate is given per hour. After dose adjustment, a new steady state sedation level may not be reached for up to one hour. The maximum dose of 1.4 micrograms/kg/h should not be exceeded. Patients failing to achieve an adequate level of sedation with the maximum dose of the product should be switched to an alternative sedative agent. Duration: There is no experience in the use for more than 14 days. The use for longer than this period should be regularly reassessed. Indication 2. For sedation of non-intubated adult patients prior to and/or during diagnostic or surgical procedures requiring sedation, i.e. procedural/awake sedation. Dexmedetomidine EVER Pharma should be administered only by health care professionals skilled in the anaesthetic management of patients in the operating room or during diagnostic procedures. Patients should be monitored continuously for early signs of hypotension, hypertension, bradycardia, respiratory depression, apnoea, dyspnoe and/or oxygen desaturation (see section 4.8 of the SmPC). Initiation of Procedural Sedation: For adult patients: A loading infusion of 1.0 microgram/kg over 10 minutes. For less invasive procedures such as ophthalmic surgery, a loading infusion of 0.5 micrograms/kg given over 10 minutes may be suitable. For awake beroptic intubation in adult patients: A loading infusion of 1 microgram/kg over 10 minutes. For patients >65 years of age: A dose reduction should be considered. For adult patients with impaired hepatic function: A dose reduction should be considered. Maintenance of Procedural Sedation: For adult patients: The maintenance infusion is generally initiated at 0.6 microgram/kg/hour and titrated to achieve desired clinical effect with doses ranging from 0.2 to 1 microgram/kg/hour. The rate of the maintenance infusion should be adjusted to achieve the targeted level of sedation. For awake beroptic intubation in adult patients: A maintenance infusion of 0.7 microgram/kg/hour is recommended until the endotracheal tube is secured. For patients > 65 years of age: A dose reduction should be considered. Special populations Elderly: A dose reduction should be considered. Please refer to section 4.4 of the SmPC Renal impairment: No dose adjustment is required. Hepatic impairment: Metabolised in the liver, caution advised, consider reduced dose (see sections 4.4 and 5.2 of the SmPC). Paediatric population: The safety and efficacy in children aged 0 - 18 years have not been established. Contraindications: Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 of SmPC. Advanced heart block (grade 2 or 3) unless paced. Uncontrolled hypotension. Acute cerebrovascular conditions. Special warnings and precautions for use: Not recommended in malignant hyperthermia-sensitive individuals. Discontinue in the event of a sustained unexplained fever. Monitoring: intended for use in an intensive care setting, operating room and during diagnostic procedures. The use in other environments is not recommended. All patients should have continuous cardiac monitoring. Patients with impaired peripheral autonomic activity (e.g. due to spinal cord injury) may have more pronounced haemodynamic changes after starting and so should be treated with care. General precautions: Do not give as a bolus dose. Some patients receiving Dexmedetomidine EVER Pharma have been observed to be arousable and alert when stimulated. Do not use as induction agent for intubation or to provide sedation during muscle relaxant use. Dexmedetomidine lacks the anticonvulsant action of some other sedatives and so will not suppress underlying seizure activity. Care should be taken if combining dexmedetomidine with other substances with sedative or cardiovascular actions as additive effects may occur. Not recommended for patient controlled sedation. Elderly patients over 65 years of age are more prone to hypotension with the administration of dexmedetomidine. A dose reduction should be considered. Please refer to section 4.2 of the SmPC. Cardio-vascular effects and precautions: Reduces heart rate and blood pressure through central sympatholysis but at higher concentrations causes peripheral vasoconstriction leading to hypertension (see section 5.1 of the SmPC). Caution should be exercised when administering dexmedetomidine to patients with pre-existing bradycardia. High physical fitness and slow resting heart rate, pre-existing hypotension. Hypotension, Hypovolaemia, chronic hypotension or reduced functional reserve, severe ventricular dysfunction and the elderly. Pregnancy: Not recommended during pregnancy and in women of childbearing potential not using contraception. Breastfeeding: A risk to infants cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue dexmedetomidine therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman. Undesirable effects: Adverse reactions (Indication 1 and Indication 2): Very common (≥1/10): Bradycardia, hypotension, hypertension, respiratory depression, Common (≥1/100 to <1/10):: hyperglycaemia, Hypoglycaemia, agitation, myocardial ischaemia or infarction, tachycardia, nausea, vomiting, dry mouth, withdrawal syndrome, hyperthermia, Uncommon (≥1/1,000 to <1/100): Metabolic acidosis, hypoalbuminemia, hallucination, atrioventricular block first degree, cardiac output decreased, dyspnoea, apnoea, abdominal distension, drug ineffective, thirst. Legal classification: POM. Marketing authorisation number: PA1774/002/001. Marketing Authorisation Holder: EVER Valinject GmbH, Oberburgau 3, 4866 Unterach am Attersee, Austria. For a copy of the SmPC or further medical information, please contact (090) 666 1109 or email@example.com. Ref: IE21/001/SmPC-April 2020.
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. Health care 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) or by email firstname.lastname@example.org. Adverse events should also be reported to Kent Athlone Pharma Group on (090) 666 1109 or email@example.com. Additional information available on request.
For further information on this product, please contact Gavin Butler, Key Account Manager, Athlone Pharmaceuticals Ltd., Ballymurray, Co. Roscommon Tel: + 353 (0) 87 3354523 | Email: Gavin.Butler@kent-athlone.com
Date of preparation: June 2021 Ref: IE2021/011/00
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Current Options for Medical Management of aetiology of IBD is not entirely understood, however, involves an inte Crohn’s Disease, anThe Update mune system, genetic and environmental factors. In people with IBD, the
Written by Dr Michael Hanly, Gastroenterology Specialist andinappropriate Dr Orlaith B Kelly, immune systemRegistrar mounts an response to a stimulus in the inte Consultant Gastroenterologist inflammation. IBD is a life-long condition and apart from a total proctocole
is no ,cure. IBD can be treated with a myriad of medications that induce Institute: Gastroenterology Department Connollythis Hospital RCSI group, Blanchardstown, Dublin 15 Key terms (MeSH): inflammatory bowel disease,targeting Crohn’s disease, variousmedical points management along the disordered immune pathway implicated in
stabilising, the burden remains high as prevalence exceeds 0.3%. The age of onset is between 15 and 30 years although some studies suggest a bimodal age distribution with a second peakan update. Title: Current options for medical management of Crohn’s disease, between 50 and 80. However, Written by there is an in Dr Michael Hanly, Gastroenterology Specialist Registrar increase the paediatric Dr Orlaith B Kelly, Consultant Gastroenterologist population with cases of very Institute: early onset Gastroenterology Department Connolly Hospital , RCSI group, Dublin 15 IBDBlanchardstown, in neonates described. Small Contact email: firstname.lastname@example.org gender differences Key terms (MeSH): inflammatory bowel disease, Crohn’s disease, medical exist , with a slight management Dr Michael Hanly, Gastroenterology Dr Orlaith B Kelly, female predominance Specialist Registrar Consultant Gastroenterologist in CD and slight male in UC. Overinvolved the Figure 2 Vennpredominance Diagram of factors in 2the of IBD  Figure Vennaetiology Diagram of factors last 30 years, IBD has accelerated involved in the aetiology of IBD  Background: commonly occurs in the distal Background: in newly industrialised countries. ileum and colon,(UC) whereas Crohn’s (CD) colitis areUCchronic inflammatory diseases gastroinReports of IBD appear higher inof the Therapeutic choice depends on multiple factors; disease location, severity, Crohn’sdisease disease (CD) and and ulcerative affects only the colon. urban areas and in highercommonly socioulcerative colitis (UC) are chronic testinal tract. While CD can affect any part ofence, the gastrointestinal tract, it most occurs in co-morbidities, local availability, cost, and the balance of medication ri economic classes. Individuals who Although the incidence of inflammatory diseases of the thegastroin-testinal distal ileum tract. and While colon, whereas UC affects only the colon. immigrate to industrial urbanised inflammatory bowel disease (IBD) controlled IBD. This treatment paradigm shifts, depending on the with poorly nations be-fore adolescence and to a low-incidence population in North America and Europe CD can affect any part of the flare vs This who article will focus onshow some current and novel medic immigrants initially belonged a sig-nificantly higher gastrointestinal tract, it most is cur-rently reported to be remission. incidence of IBD . This rise has been attributed to the rapid modernisation and westernisation of the population. Aminosalicylates +/- Sulfasalazine
The aetiology is not entirely Arthrit This group of drugs were originally developed to treatof IBD Rheumatoid understood, however, involves an beneficial for IBD patients. They can be used to treat mild-moderate activ interaction between the im-mune system, genetic and environmental used as maintenance. 5-ASA’s are a well-established treatment option for U factors. In people with IBD, the equivocal and we limit its use in Crohn’s to patients with mild limited colon immune system mounts an The precise mechanism of action is not known but theyresponse are thought inappropriate to a to act topi stimulus in the intestinal tract, to have multiple anti-inflammatory effects, including inhibition of cyclooxyg resulting in inflammation. IBD is cells, several key inflammatory cytokines and activation selective perox a life-long conditionof and apart a total that proctocolectomy for prolife vated receptor ligand-γ (PPAR-γ), a nuclear from receptor controls cell UC, currently this is no cure. IBD There are multiple preparations of 5-ASA can available which alter release in be treated with a myriad medications that induce and ASA’s enemas and suppositories are highlyof efficacious first-line treatment f maintain remission targeting ease. various points along the disordered immune pathway implicated in IBD pathogenesis.
Immunomodulators (Azathioprine, MTX, 6-MP) In the pre-biologic era, Azathioprine, 6-MP and methotrexate were second patients with a step-up approach. The place of immunomodulators in the trea has been debated over the past decade. In a meta-analysis, patients Figure 1 IBD Demographics  treated w ciated higher rates of steroid-free clinical remission compared to patients tr ASA (RR, 1.25; 95% CI, 1.01–1.56)  Figure 1 IBD Demographics  One challenge facing IBD patients is loss of response to anti-TNF treatmen AUGUST - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE cussed on predicting loss of response to Anti-TNF. Combination immunom
78 HOSPITAL REVIEW: CROHN’S DISEASE
Therapeutic choice depends on multiple factors; disease location, severity, duration, patient prefer-ence, co-morbidities, local availability, cost, and the balance of medication risks with risks associat-ed with poorly controlled IBD. This treatment paradigm shifts, depending on the disease phase e.g. acute flare vs remission. This article will focus on some current and novel medical treatments for IBD. Aminosalicylates +/Sulfasalazine This group of drugs were originally developed to treat Rheumatoid Arthritis and were found to be beneficial for IBD patients. They can be used to treat mildmoderate active disease but are mainly used as maintenance. 5-ASA’s are a well-established treatment option for UC, data for use in CD is equivocal and we limit its use in Crohn’s to patients with mild limited colonic involvement.
There are multiple preparations of 5-ASA available which alter release in the GI tract. Topical 5-ASA’s enemas and suppositories are highly efficacious first-line treatment for limited left sided disease. Immunomodulators (Azathioprine, MTX, 6-MP) In the pre-biologic era, Azathioprine, 6-MP and methotrexate were second-line treatment for IBD patients with a step-up approach. The place of immunomodulators in the treatment algorithm of IBD has been debated over the past decade. In a meta-analysis, patients treated with thiopurines had associated higher rates of steroid-free clinical remission compared to patients treated with pla-cebo or 5-ASA (RR, 1.25; 95% CI, 1.01–1.56). 
rate of lymphoma in thiopurinetreated patients was 4.9 (95% CI, 3.1–7.8) . Methotrexate has also been variably associated with either no significant or a 1.5–5.0-times increased risk of lymphoproliferative disease, based on studies in patients with rheumatoid arthritis.  Tumor necrosis factor (TNF)-alpha inhibitors, including infliximab, adalimumab, golimumab and certolizumab pegol Anti-TNF’s are a first line biologic treatment for IBD. They are monoclonal antibodies directed against tumor necrosis factor (TNF)-alpha. (TNF)-alpha has several biologic activities that appear to be directly related to the pathogenesis of IBD.
as the original monoclonal antibodies . Biosimilars offer a considerable cost-saving to the health ser-vice allowing provision of this valuable resource to more patients Anti-Integrin Therapy Vedolizumab and originally natilizumab (discontinued due to JC Virus related PML) Vedolizumab is a humanized monoclonal antibody that antagonizes α4β7 integrin, by inhibiting its binding to the gutspecific intestinal mucosal address in MAdCAM-1.Vedolizumab is an eight weekly infusion licensed for the treatment of IBD. Of note, there will be a subcutaneous injection available soon. Good clinical and endoscopic response/ remission rates have been observed in UC and CD patients (65%clinical response in CD at Week 14, 59% in UC at Week 10). with no significant differences in response rates between UC and CD patients. 
There is now over twenty years of experience and data for antiTNF use in treatment of IBD. There are a number of different Hupe et al compared efficacy formulations, that can be given One challenge facing IBD and safety of vedolizumab and subcutaneously or by infusion. patients is loss of response to infliximab in ulcerative colitis after There are clear guidelines on anti-TNF treatment. The PANTS failure of a first subcutaneous pre-screening patients before study fo-cussed on predicting anti-TNF agent. 225 patients were commencing biologics and on the loss of response to Anti-TNF. included, clinical remission at week safety of these drugs in pregnancy. The precise mechanism of action Combination immunomodulator 14 was achieved in 40/154 (26%) Therapeutic drug monitoring is not known but they are thought (thiopurine or methotrexate) patients treated with IFX and in allows clinicians to more precisely to act topically. 5-ASAs are likely therapy mitigated risk of 35/71 (49%) treated with VDZ (P = titrate the dose of the drugs and to have multiple anti-inflammatory developing anti-drug antibodies 0.001). With a median follow-up of monitor for development of drug effects, including inhibition of (hazard ratio 0·39 [95% CI 117 weeks, survival rates without resistance/ antibodies/ loss of cyclooxygenase, lipoxy-genase, 0·32–0·46] for infliximab; 0·44 treatment discon-tinuation at years response. Approx-imately 30% B-cells, several key inflammatory [0·31–0·64] for adalimumab; 1 and 3 were 50% and 29% with of patients are primary noncytokines and activation of p<0·0001 for both).  IFX,0·39 and 80% andCI 55% with VDZ, methotrexate) therapy mitigated risk of developing anti-drug (hazard [95% respondersantibodies to infliximab and not ratio selective peroxisome proliferaThe SONIC data in UC for adalimumab; all responders have a complete tors-activated receptor ligand-γ 0·32–0·46] for infliximab; 0·44trial [0·31–0·64] p<0·0001 for both) respectively (P < 0.001).  showed increased efficacy for response.  Secondary loss (PPAR-γ), a nuclear receptor et al year in the of VARSITY trial, The trial data combination in UC showed for combination inSands the first therapyincreased in the first efficacy of response to anti-TNF’s therapy and that controls cell SONIC proliferation compared vedolizumab with yearof of therapy withhealing higher rates development of antibodies and apoptosis . with higher rates therapy mucosal and higher infliximab levels. is also adalimumab in adults with modermucosal healing and higher a big problem for IBD patients. Thiopurines have beenof consistently associated with increased risk of lymphoproliferative In ulcerative ately todiseases. severely active infliximab levels. Over time, more data is becoming colitis. Vedolizumab was superior a meta-analysis of 18 studies, the standardised incidence of lymphoma available rate on developing strategiesin thiopurine-treated to adalimumab with respect to Thiopurines have been consistently to prevent loss of response. patients was 4.9 (95% associated CI, 3.1–7.8) Methotrexate has also this been variably associated with either no remission achievement of clinical with . increased risk of andstudies endoscopic improvement, but lymphoproliferative diseases. In lymphoproliferative There is now data from IBD based on significant or a 1.5–5.0-times increased risk of disease, in paFigure 3 Timeline of Development of meta-analysis of 18 studies, not corticosteroid-free and rheumatology patients that IBD Medications tientswith rheumatoidathe arthritis.  standardised incidence using biosimilars are as effective clinical remission. 
AUGUST - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE
Figure 4. Successful and failed treatments for IBD 
Figure 4. Successful and failed treatments for IBD 
oral form. It is a small molecule safety analysis of this trial until Janu-ary 2019, an excessive and has a short half -lifeTofacitinib rate of pulmonary embolism has had some safety concerns and all-cause mortality was transplansince released, specifically a inhibition, ongoing trials investigating novel treatments for IBD: Jak other MOAs, Faecal warning VTEOf (venous Tofacitinib is andietary attractive tation and measures forblack-box the treatment of for IBD. October 2019, there are 730 listed on clinitreatment option as it comes in thromboembolism). In the interim It is an attractive option as Figure 5 The therapeutic pipeline caltrials.gov related to IBD . an initial infusion then can be in Crohn’s disease. Drugs are switched to eight or twelve weekly categorized based on the Surgical interventions subcu-taneous injection. This mechanism of action and on the results in reduction in infusion suite Despite an improving treatment landscape, long-term rates of colectomy for ulcerative have phase of colitis clinical development.  use and patient treatment times. not declined over a 10-year period  Surgical interventions are necessary for a large proportion of The Unifi study demonstrated efficacy moderate There to severehave been advances in surgical techniques with laparoscopic colectomy, side-toIBDfor patients. UC patients compared to placebo. anastomosis Theside percentage of patientsand who J-Pouch formation. had clinical remission at week 44 was significantly higher among pa-tients assigned to 90mg of subcutaneous ustekinumab every 12 weeks (38.4%) or every Summary/ Key message: 8 weeks (43.8%) than among those assigned to placebo Biologic treatments have brought us a long way in the treatment of IBD with the target moving from (24.0%) (P=0.002 and P<0.001, respectively).  clinical remission to endoscopic and now histological remission. We still have primary non-respondUstekinumab an antagonist of the p40 subunit of interleukin-12 and interleukin-23, is approved for treatment of Crohn’s disease (CD) and more recently for UC.
cellular responses through gene expression. Tofacitinib is a potent JAK1 and JAK3 inhibitor but is less active against JAK2 and TYK2 .
ers and ishigh rates that of secondary loss of response to biologic treatments especially anti-TNF’s. We Ustekinumab a treatment is used in psoriasis and psoriatic have a lot to learn about other potential targets in IBD pathogenesis and about the interaction between arthropathy. So it is an ideal treat-ment option for patients our microbiome and the inflammatory process. The data suggests with greater understanding of the with these co-morbidities. Some aetiology andthat spectrum studies are showing it is more of the inflammatory bowel diseases ,and consequently the introduction of effica-cious than vedolizumab for more focussed treatment targets, closer non-invasive monitoring with faecal calprotectin or novel certain phenotypes of Crohn’s serum targets, therapeutic drug monitoring, and multiple biologics becoming available, that we will disease and may be a preferential second line treatment compared to see a more tailored individualized approach to IBD management. This may alter colectomy rates, vedolizumab.  but this is not the sole target for measuring success, rather we need data on reduced hospitalizations, of life and reduction in malignancies in IBD patients. There are multiple
Jak inhibitors Tofacitinib, an improvement in quality oral, small-molecule Janus kinase inhibitor. Many cytokines involved in IBD act on the JAK/signal transducer and activator of transcription (STAT) cell signaling pathway, generating
Figure5 The therapeutic pipeline in Crohn’s disease. Drugs are categorized on the mech| HPNbased HOSPITALPROFESSIONALNEWS.IE • AUGUST - 2021 anism of action and on the phase of clinical development. 
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identified in patients treated with tofacitinib 10mg twice/day as compared to patients treated with TNFα antagonists.
There have been advances in surgical techniques with laparoscopic colectomy, side-to-side anastomosis and J-Pouch formation.
Summary/ Key message:
Despite an improving treatment landscape, long-term rates of colectomy for ulcerative colitis have not declined over a 10-year period.  Surgical interventions are necessary for a large proportion of IBD patients.
Biologic treatments have brought us a long way in the treatment of IBD with the target moving from clinical remission to endoscopic and now histological remission. We still have primary non-responders and high rates of secondary loss
of response to biologic treatments especially anti-TNF’s. We have a lot to learn about other potential targets in IBD pathogenesis and about the interaction between our microbiome and the inflammatory process. The data suggests with greater understand-ing of the aetiology and spectrum of the inflammatory bowel diseases ,and consequently the intro-duction of more focussed treatment targets, closer non-invasive monitoring with faecal calprotectin or novel serum targets, therapeutic drug monitoring, and multiple biologics becoming available, that we will
see a more tailored individualized approach to IBD management. This may alter colectomy rates, but this is not the sole target for measuring success, rather we need data on reduced hospitali-zations, improvement in quality of life and reduction in malignancies in IBD patients. There are multiple ongoing trials investigating novel treatments for IBD: Jak inhibition, other MOAs, Faecal transplantation and dietary measures for the treatment of IBD. Of October 2019, there are 730 listed on clinicaltrials.gov related to IBD.  References available on request
Hospital Review News Dedicated Paediatric Epilepsy Unit The Bon Secours Hospital Cork has recently opened a dedicated Paediatric Epilepsy Monitoring Unit, the first of its kind in the Munster region and the first private unit in the country.
The launch of this unit was possible thanks to the joint effort of Consultant Paediatric Neurologist, Dr Niamh Lynch and the Neurophysiology Department, led by Dr Peter Kinirons.
This state of the art unit consists of one dedicated bed with continuous nurse supervision and video EEG recording, located in the Children’s Ward.
Direct referrals by Paediatricians are accepted and a referral letter with patient details (including a contact number) and reason for referral should be addressed to Ms. Claudia Leite, Senior Neurophysiologist, Neurophysiology Department, Bon Secours Hospital, College Road, Cork (Email: CALeite@bonsecours.ie).
Patients admitted to this unit will benefit from timely diagnosis and management of Epilepsy; all done in a safe environment and supervised by highly trained Paediatric nurses and Neurophysiologists.
Dr Peter Kinirons, Consultant Neurologist/Clinical Neurophysiologist, Dr Niamh Lynch, Consultant Paediatric Neurologist, Antonia Walsh, CNMII Children’s Ward, Claudia Leite, Senior Neurophysiologist and James Fisher, Physiologist
Role of Ketamine in Depression Researchers from Trinity and St Patrick’s Mental Health Services are trialing a new treatment option (ketamine) for people who are experiencing severe depression. Led by Declan McLoughlin, Research Professor of Psychiatry at Trinity, and Consultant Psychiatrist at St Patrick’s Mental Health Services, the team will investigate the role of ketamine in improving outcomes for people receiving inpatient treatment for depression. The randomised, controlled trial, entitled Ketamine as an Adjunctive Therapy for Major Depression (2) [KARMA-Dep-2], will mark the first clinical trial to be sponsored by Trinity, and is a definitive pragmatic trial informed by a previous smaller feasibility pilot trial. It will investigate the impact that a low dose of ketamine as an add-on treatment could have on people with severe depression. The trial is funded by the Health Research Board.
Depression has been recognised by the World Health Organisation as the leading cause of disability globally. In Ireland, over 200,000 people experience a depressive episode each year with approximately 6,000 requiring acute care.
first treatment for the condition with a type of antidepressant medication called a serotonin reuptake inhibitor. A further 30% of patients are resistant to this type of treatment. Moreover, these treatments can take many weeks to see the full benefit.
Neurotransmitters are chemical messengers in our bodies that play important roles in our moods, behaviours and functionality. Though there has been intense research in this area to date, pharmacological treatments for depression that target monoamine neurotransmitters, for example serotonin, dopamine and noradrenaline, have remained mostly unchanged over the past 60 years.
Ketamine works differently to widely used antidepressants and may change dysfunctional brain cell pathways and connections, a process called neuroplasticity. Its effects come about by the way it acts on the signals of a particular chemical messenger, glutamate, in the brain. Crucially, and in comparison to current treatments, ketamine has a rapidonset antidepressant effect with symptoms improving within onehour of single infusions and peak benefits after 24-hours.
While these treatments work effectively for many, research supports the need for novel and faster-acting treatments. Studies show that for patients with severe depression, only 30% achieve a reduction in symptoms after their
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Declan McLoughlin, Research Professor of Psychiatry at Trinity College Dublin and Consultant Psychiatrist at St Patrick’s Mental Health Services, said, “Years of
research has shown that ketamine can be a powerful and quick acting antidepressant. In the KARMA-Dep-2 trial, we aim to see whether it’s possible to harness the powerful antidepressant action of ketamine as part of routine care for hospital inpatients experiencing severe depression. This has never been done in Ireland before on a scale this size.” The research aims to test the hypothesis or possibility that repeated ketamine infusions (twiceweekly, maximum 8 infusions) as an add-on to current inpatient care will improve depression outcomes. A secondary hypothesis, in collaboration with research at Queen’s University Belfast led by Prof Ciaran O’Neill, predicts that ketamine treatment could lead to a reduction in healthcare costs, and an improved quality of life for those living with the condition. Statistical support to the trial is being provided by Prof Ricardo Segurado at University College Dublin.
Break the cycle of chronic pain PALEXIA® SR Tablets are indicated for the management of severe chronic pain in adults, which can be adequately managed only with opioid analgesics1
PALEXIA® SR was associated with significant improvements in quality of life and function as measured by the Short Form-12 (SF-12) health survey and the EuroQol-5 Dimension (EQ-5D) health status questionnaire in patients with severe chronic low back pain with a neuropathic component2
PALEXIA SR® Prolonged Release Tablets Prescribing Information. Refer to the Summary of Product Characteristics (SmPC) before prescribing. Presentation: 50 mg (white), 100 mg (pale yellow), 150 mg (pale pink), 200 mg (pale orange) and 250 mg (brownish red) prolonged-release tablets contain 50 mg, 100 mg, 150 mg, 200 mg and 250 mg of tapentadol (as hydrochloride) respectively. Indication: Palexia SR is indicated for the management of severe chronic pain in adults, which can be adequately managed only with opioid analgesics. Dosage and method of administration: Individualise according to severity of pain, the previous treatment experience and the ability to monitor the patient. Swallowed whole with sufficient liquid, not divided or chewed, with or without food. The tablet shell may not be completely digested and eliminated / seen in the patient’s stool which has no clinical significance as the active substance will have already been absorbed. Initial dose 50 mg twice a day. Switching from other opioids may require higher initial doses. Titrate in increments of 50 mg twice a day every 3 days for adequate pain control. Total daily doses greater than 500 mg not recommended. Discontinuation of treatment: Taper dose gradually to prevent withdrawal symptoms. Renal/hepatic impairment: Not recommended in patients with severe cases. Caution and dose adjustments with moderate hepatic impairment. Elderly: May need dose adjustments. Children below 18 years: Not recommended. Contraindications: Hypersensitivity to ingredients, suspected or having paralytic ileus, acute intoxication with alcohol, hypnotics, centrally acting analgesics or psychotropics. Not for use when mu-opioid receptor agonists are contraindicated (e.g. significant respiratory depression, acute or severe bronchial asthma or hypercapnia). Special warnings and precautions: Abuse and addiction potential of Palexia should be considered where there is increased risk of misuse, abuse, addiction or diversion. All patients should be carefully monitored for signs of abuse and addiction. Concomitant use with sedating medicinal products such as benzodiazepines or related substances may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedating medicinal products should be reserved for patients for whom alternative treatment options are not possible. If used concomitantly, reduction of dose of one or both agents should be considered and the duration of the concomitant treatment should be as short as possible. The patients should be followed closely for signs and symptoms of respiratory depression and sedation. It is strongly recommended to inform patients and caregivers to be aware of these symptoms. At high doses or in mu-opioid receptor agonist sensitive patients, dose-related respiratory depression may occur. Caution and monitoring required with impaired respiratory function. Should not use in patients susceptible to intracranial effects of carbon dioxide retention (e.g. increased intracranial pressure, impaired consciousness or coma). Use with caution with head injury, brain tumors, moderate hepatic impairment, biliary tract disease including acute pancreatitis. Not recommended if history of or at risk of seizures. May increase the seizure risk in patients taking medicinal products that lower the seizure threshold. Not recommended in severe renal or hepatic impairment. Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage. Care should be taken when combining with mixed mu-opioid agonists/antagonists (e.g. pentazocine, nalbuphine) or partial mu-opioid agonists (e.g. buprenorphine). Should not use with hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption. Interactions: The concomitant use with sedating medicinal products such as benzodiazepines or other respiratory or CNS depressants (other opioids, antitussives or substitution treatments, barbiturates, antipsychotics, H1-antihistamines, alcohol) increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. When combined therapy with a respiratory or CNS depressant is contemplated, the reduction of dose of one or both agents should be considered and the duration of the concomitant use should be limited. Can induce convulsions and increase the potential for selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, antipsychotics and other medicinal products that lower the seizure threshold to cause convulsions. There have been reports of serotonin syndrome in a temporal connection with the therapeutic use of tapentadol in combination with serotoninergic medicinal products (e.g. SSIRs, SNRIs and tricyclic antidepressants). Use with strong inhibitors of uridine diphosphate transferase isoenzymes (involved in glucuronidation) may increase systemic exposure of Palexia SR. Caution if concomitant administration of strong enzyme inducing drugs (e.g. rifampicin, phenobarbital, St John’s Wort) starts or stops as this may lead to decreased efficacy or risk for adverse events, respectively. Avoid use in patients who have taken monoamine oxidase inhibitors (MAOIs) within the last 14 days, due to cardiovascular events. Pregnancy and lactation: Use in pregnancy only if the potential benefit justifies the potential risk to the foetus. Not recommended during and immediately before labour and delivery. Do not use during breast feeding. Driving and using machines: May have major effect on ability to drive and use machines, especially at the beginning or change in dosage, in connection with alcohol or tranquilisers. Undesirable effects: Very common (≥1/10): dizziness, somnolence, headache, nausea, constipation. Common (≥1/100, <1/10): decreased appetite, anxiety, depressed mood, sleep disorder, nervousness, restlessness, disturbance in attention, tremor, involuntary muscle contractions, flushing, dyspnoea, vomiting, diarrhoea, dyspepsia, pruritus, hyperhidrosis, rash, asthenia, fatigue, feeling of body temperature change, mucosal dryness, oedema. Other important undesirable effects observed in clinical trials and/or postmarketing: drug hypersensitivity, depressed level of consciousness, mental impairment, syncope (uncommon ≥1/1000, <1/100), impaired gastric emptying, respiratory depression, convulsion, angioedema, anaphylaxis and anaphylactic shock, drug dependence (rare ≥1/10,000, <1/1000), delirium (unknown). No evidence of increased risk of suicidal ideation or suicide with Palexia SR. Additional information is available on request. Overdose: Seek specialist treatment (see SmPC). Legal classification: POM, CD (Schedule II). Marketing Authorisation numbers and pack sizes: 50 mg: PA 2242/12/4, 28 and 56 packs; 100 mg: PA 2242/12/5, 56 pack; 150 mg: PA 2242/12/6, 56 pack; 200 mg: PA 2242/12/7, 56 pack and 250 mg: PA 2242/12/8, 56 pack. Marketing Authorisation Holder: Grünenthal Pharma Ltd, 4045 Kingswood Road, Citywest Business Park, Citywest, Co. Dublin, Ireland. M-PLX-IE-03-20-0004. Date of Preparation: March 2020. References: 1. Palexia SR Summary of Product Characteristics. 2. Baron R, et al. Tolerability, Safety, and Quality of Life with Tapentadol Prolonged Release (PR) Compared with Oxycodone/Naloxone PR in Patients with Severe Chronic Low Back Pain with a Neuropathic Component: A Randomized, Controlled, Open-label, Phase 3b/4 Trial. Pain Practice. 2016;16(5):600-619. M-PLX-IE-11-20-0008 – November 2020
82 HOSPITAL REVIEW: PAIN
The Future of Non-Invasive Technology in Chronic Pain Management Written by Dr Dominic A. Hegarty, Consultant in Pain Management & Neuromodulation, Mater Private Hospital, Cork Clinical director Pain Relief Ireland President-Elect World Institute of Pain Affiliations: 1. Consultant in Pain Management and Neuromodulation, Mater Private Hospital, Cork, Ireland. 2. School of Medicine, University College, Cork, Ireland.
Pain and the efforts to control chronic pain is the most common reason an individual attends their doctor. In fact, 1 in 8 Europeans report pain on a daily basis. The former Irish MEP Marian Harkin (TD) initially raised this issue and Pain Alliance Europe (PAE) was formed. PAE now represents over 400,000 individuals in 19 different countries with chronic pain (1). The most recent document published by PAE Brain, Mind and Pain (BMP) 2019, which was updated in February (2021), identifies that awareness is the biggest challenge that the European community is facing when it comes to chronic pain. PAE also highlighted that improving education and awareness of across all domains of society including employers, younger generations, policymakers, and healthcare professionals will be required to “reframe the economic and societal impact” of BMP disorders and are “essential steps towards ensuring greater social inclusion of people” with chronic pain. Neurostimulation The clinical application of electrical current (neurostimulation) in the PNS was first considered in the 1960’s. By the 1990’s, percutaneous leads, originally designed for spinal cord stimulation, were being used to treat occipital neuralgia.
Unfortunately, the adverse events received more attention than the positive endpoints, but the seeds of innovation were sown. The advent of smaller implantable leads to provide an electrical field near a nerve or group of nerves to activate local inhibitory interneurons to inhibit nerve fibres carrying afferent pain signals is an important step forward. The method of action continues to be based on the ‘gate control theory’, a concept proposed by Doctors Wall and Melzack (2). Peripheral nerve system as a target The peripheral nervous system (PNS) has offered clinicians the opportunity to treat both acute and chronic pain for generations. This is because the PNS offers an accessible window into an integral pathway of communication between the body and the environment. Touch, proprioception, temperature, and nociception all influence our perception of the world. Peripheral nerve blockade with chemical agents (e.g., local anaesthesia) eliminates these signals and has led to the global success of ambulatory surgery (day-case surgery). Peripheral nerve dysfunction or pathological persistence of nociception from the PNS can alter the way peripheral tissues drive and amplify the pain pathway. This is known as
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peripheral sensitisation (3,4). Biochemical mediators that cause changes in the cell bodies of somatosensory neurons drive these pathophysiological sequences, in turn potentially leading to central changes. Clinically these changes result in ongoing pain, allodynia, hypersensitivity or loss of function (5). Treatment options for chronic pain in the PNS require a long-term treatment plan and may include physical therapy (e.g. acupuncture, massage, desensitisation etc. (6)), oral medication (7), ablative therapy (e.g. thermal or chemical (6)) and/ or neurostimulation (e.g. spinal cord (8) or dorsal root ganglion stimulation (9)). More recently the term bioelectronic medicine has been used to describe the use of neurostimulation to modify the response of nerve tissue (10). Overcoming limitations Two issues have limited the expansion of traditional modulation of the PNS. Firstly, the primary target in PNS stimulation is a nerve. To be successful, electronic leads are required to lie near the nerve branch or nerve trunk before they can reliably influence nerve transmission. This requirement brings with it other issues, such as ensuring the accurate placement of the lead, the need for direct vision or ultrasound guidance to improve safety, and the possibility of migration. Secondly, to provide adequate pain relief, energy consumption, waveform and electrical frequency requirements need to be understood and appropriately applied to each patient to optimise treatment efficacy and safety. If the pain distribution does not neatly fit into the dermatomal distribution of the nerve, the ability to provide crosstalk is vital. Bioelectronic medicine bypasses these issues as it can employ electrical, magnetic, optical or ultrasound technology to deliver targeted, personalized therapies which eliminate drug-centred treatments and improve clinical and economical outcomes
(11–13). A key advantage is its ability to provide energy delivered by an externally positioned device. This therefore allows these therapies to focus on several painful regions simultaneously, to provide pain relief to areas that would extend beyond the expected anatomical parameters. What are current treatment options? Several physical options to manage these pain patterns have been proposed; massage, acupuncture, dry needling, and direct injection are some examples. Electroceuticals is the term used to describe the use of energy to provide relief (14). Transcutaneous electrical nerve stimulation (TENS, (15,16)), photobiomodulation (PBMT, (17,18)) and electromagnetic field (EMF, (19)) have been used in pain medicine to date. a) Transcutaneous Electrical nerve stimulation (TENS) Applying electrical currents through adhesive electrodes placed on the skin surface over the painful area may help pain. This is known as transcutaneous electrical nerve stimulation (TENS). The mechanism of action is to deliver pulsed electrical currents with balanced asymmetrical or symmetrical biphasic rectangular waveforms in which frequency, pulse duration, and amplitude can be adjusted. It is used in both acute (20) and chronic pain conditions (21,22). TENS devices deliver pulsed low-frequency signals across the surface of the skin, typically between two surface electrodes placed on either side of the painful area. The energy is dispatched laterally over the surface, not deep into where the pain is focused. The sensation produced by TENS may act as a distraction from the pain while the device is on, however, there is little residual benefit or functional improvement once the therapy session is over. The inability of TENS devices to penetrate deep into the tissue limits their success. This can be potentially compounded
83 by paraesthesia sensations becoming less tolerable and the skin increasingly irritated. b) Photobiomodulation Photobiomodulation therapy (PBMT) is a non-pharmacologic resource used in the treatment of patients with neck pain (23). It uses laser-based light therapy (light amplification by stimulated emission of radiation) or light emitting diodes (LEDs) from the visible to the infrared spectrum. This includes a portion of the spectrum where light interacts with chromophores leading to photophysical and photochemical reactions in tissues (24). Low-level laser therapy is nonthermal and it may have a stimulating effect on target tissues (30). It is used in several musculoskeletal conditions to decrease pain and inflammation as well as stimulate collagen metabolism and wound healing (25). It is therefore important to investigate the efficacy of PBMT when incorporated into a multimodal treatment plan. Such multimodal treatment plans should also test whether PBMT is superior to other analgesic agents, including electrical currents. c) Electromagnetic Fields (EMF) Electromagnetic fields (EMF) can also be used to treat chronic pain (14). Classic bioelectromagnetic theory suggests that radiofrequency (RF) fields beyond 10 MHz are not capable of producing biological effects other than simple heating (26). However, when low-power RF transmitters are operated adjacent to biological tissue and at maximum output (saturation), it is possible to modulate peripheral nerve activity (27). This therefore suggests that RF EMF electroceuticals may facilitate neuromodulation.
and includes follow-up visits over the medium- to long-term to provide a record of the overall outcomes is required. d) High frequency peripheral nerve stimulation: a new technique for chronic pain management Two factors impact the ability to provide a meaningful sustained influence on the PNS using a non-invasive bioelectronic device. Firstly, the device must be able to overcome the impedance offered by the skin using a high frequency electric field. Secondly it must also be able to provide a low frequency electric field (1-180 Hz) in order to halt action potentials propagating along fibres that ultimately lead to hyperpolarization. It has emerged that adding together two high frequency sine wave signals can form a new spectrum of signals in a 5-6 cm diameter hemisphere beneath electrodes (BioWaveHome (BioWave Inc., Connecticut, USA). The resulting multiplication of the two sine waves can result in the hyperpolarization of nociceptive pain fibres. This therefore means that it is possible to bypass the impedance generated by the skin and modulate the activity of the nerve fibres that provide the sensory information. The clinical impact of this high-frequency summation has
uncovered some interesting preliminary outcomes (35). In a patient survey of 463 individuals (372 males; 91 females), pain intensity (visual analogue scale [VAS]) and Activity of Daily living (ADL) scores significantly improved after two weeks of using this stimulation compared to baseline (pain mean difference: 3.05; 95% CI: 2.86, 3.24; ADL mean difference: 1.82; 95% CI: 1.60, 2.04; (35)). Corresponding improvements in Quality of life (QoL), sleep, mood, functional outcomes and satisfaction scores were also noted. On average 8.0 ± 11.1 hours of pain relief were reported with 54% experiencing reductions in pain medication consumption (47). This open label pilot study is the first to highlight the potential role for a novel bioelectronic technique to manage pain and having meaningful clinical outcomes. With further research comparing the longer-term effects of this stimulation with a control arm/group in specific pain cohorts, he efficacy of non-invasive high frequency neuromodulation in pain will become more established. Summary The application of technology as a treatment solution in pain medicine is ideal. Bioelectronic
energy can modify the function of pain pathways in real-time. The extensive nature of the PNS offers an accessible window into an integral pathway of communication between the body and the environment. Bioelectronic Engineering can address these aspects, so that there is an opportunity to provide neuromodulation that generates comfortable analgesia, without muscle twitching or noxious sensation, which are commonly associated with other electrotherapy devices. The future of non-invasive technology lies in its ability to provide effective, affordable and practical treatment options that can be applied to an enormous number of pain conditions. References available on request Conflict of interest In the past, DH has received speaker honorarium from Platform 14 to participate in cadaver workshops in peripheral nerve stimulation techniques. At present DH acts as a clinical advisory to BioWave Devices, Capri Medical and Tyndall National Institute UCC. DH has not received any funding from industry to prepare this overview.
Pulsed shortwave therapy (PSWT) is a low-power RF electroceutical technology that operates at saturation and relies on tissue absorption of EMF to achieve neuromodulation of peripheral nerves (27,38). A wearable version of PSWT is available for non-prescription use in the United States for treating knee osteoarthritis (29) and plantar fasciitis (30), both of which have been proposed to be linked to central sensitization (31). There is also preliminary evidence suggesting this therapy may be able to reduce acute postoperative pain (32-34). While PSWT may be an interesting therapy at present, research that clarifies the mechanism of action
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84 HOSPITAL REVIEW: DIGITAL SURGERY
Digitalisation in Surgical Training Written by Dr Daniel Galvin & Professor Barry O’Reilly and continues to form the basis for an apprenticeship style model of surgical training. This individualised trainer/trainee relationship is key for successful training but could be augmented by innovative ways of improving learning performance and skills acquisition. Unique and evolving challenges face surgical educators globally as they attempt to maintain standards of surgical education. Access to a platform which easily allows trainees to record their training progress, review cases and identify areas for improvement is lacking. The operative training time. In other high performance fields, such aschallenges aviation, simulation There are significant training has intensified during the pandemic to account for this shortfall. Manychallenges trainees in modern surgical trainees Dr Daniel Galvin, Specialist Registrar Professor Barryforced O’Reilly,to Clinical advanced or subspecialty training have been extendfacing their training to Obstetrics and Gynaecology, Professor in Obstetrics and and trainers. The number of accommodate this. CUMH/RCPI Gynaecology at Cork University surgical trainees has risen
well-being, has had an impact on the time spent operating prior to independent practice as a consultant. Although most surgical training posts do not comply with EWTD regulations and many surgical trainees continue to work onerous shift patterns, working hours have reduced when assessed globally. While trainees are generally able to adapt their work schedules to accommodate elective operating lists the global reduction in working hours further dilutes potential for training opportunities.
In the last 18 months, we have also seen the unique challenges that the Coronavirus pandemic imposed on surgical training. The almost complete cessation of elective surgical procedures Maternity Hospital and the Mater significantly. This has long been Research Fellow, ASSERT Centre, in many areas for much of this Private Hospital recommended by many workforce UCC Outcome time has a huge impact on planning reports and is required Professor and Director of The to meet a growing population’s surgical training. The pandemic The inevitable result of the combination of these challenges shifted surgical skill ASSERT centre and UCC has has exposed a weakness in our need for expert surgical care. It acquisition to later in a trainees’ career. This is particularly evident with respect major training models which do not allow does however, dilute theto potential training opportunities to The volumeprocedures. and complexityAofsurvey we, rapidin digitalisation in all areas surgical collaboration with Ms Orfhlaith O Sullivan,available undertook offor rapid access to high fidelity simulation as a means of offsetting surgical trainees. This expansion surgical procedures performed has of life. The development and gynaecological surgical traineesintegration showedofathe significant fall off inin the number of demands trainees who the reduced access to hands-on training numbers developed dramatically globally internet and innovative Trainees solutions towere provide over last 30 years. care asmart technology into all aspects of are the currently ableWe to now perform variety of gynaecological procedures. asked operative training time. In other high performance fields, such as equivalent training outcomes for for sicker, more complex patients daily life continues at a rapid pace. about their current and what expected tothese be able to do byhas thebeen end of aviation, simulation training has trainees which than at any other point in surgical surgical ability The impact of this they digitalisation difficult achieve level to date. practice. The rapidTrainees expansion were surveyed on surgicalin training practice their training. 2014,and 2017 and 2021. The to average of trainingintensified during the pandemic to account for this shortfall. and variety of surgical procedures has not been as exponential as The European Working Time attained mandates by time that of the wasmay equivalent in all groups. Many trainees in advanced or performed we survey one have expected given the Directive (EWTD) has also had an subspecialty training have been continue to train expert surgeons dramatic change in most other impact on the training of surgical forced to extend their training to to a high standard. areas of our lives. trainees. The reduction in working Notably laparoscopic salpingectomy, laparoscopic ovarian cystectomy and oophorectomy accommodate this. hours, while very welcome in Alongside this, our society has The Halstedian model of ‘See one, form some of the core skills required to provide emergency gynaecology care. Outcome terms of patient safety and doctor been dramatically changed by Do one, Teach one’ still persists The inevitable result of the combination of these challenges has shifted surgical skill acquisition to later in a trainees’ career. This is particularly evident with respect to major surgical procedures. A survey we, in collaboration with Ms Orfhlaith O Sullivan, undertook of gynaecological surgical trainees showed a significant fall off in the number of trainees who are currently able to perform a variety of gynaecological procedures. Trainees were asked about their current surgical ability and what they expected to be able to do by the end of their training. Trainees were surveyed in 2014, 2017 and 2021. The average level of training attained by time of the survey was equivalent in all groups.
Current ability to perform gyanecological procedures 100 90 80 70 60 50 40 30 20 10 0
LCO % 2014
TAH % 2017
Legend: LS=Laparoscopic salpingectomy, LCO=Laparoscopic ovarian cystectomy/oophorectomy, TAH=Total Legend: LS=Laparoscopic salpingectomy, LCO=Laparoscopic ovarian cystectomy/oophorectomy, TAH=Total Abdominal Hysterectomy, VH=Vaginal Hysterectomy
Abdominal Hysterectomy, VH=Vaginal Hysterectomy
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Notably laparoscopic salpingectomy, laparoscopic ovarian cystectomy and oophorectomy form some of the core skills required to provide emergency gynaecology care.
This survey also showed a fall off in trainees’ expectation to be competent to independently
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
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
86 HOSPITAL REVIEW: DIGITAL SURGERY surgical steps. It can also allow identification of bleeding events and other complications.
Expected ability at end of training
A number of commercially available platforms have adopted these techniques for a limited number of surgical procedures and it is possible to generate a surgical performance reports for trainees within these platforms.
100 90 80 70 60 50 40 30 20 10 0
LCO % 2014
TAH % 2017
Legend: LS=Laparoscopic salpingectomy, LCO=Laparoscopic ovarian cystectomy/oophorectomy, TAH=Total Legend: LS=Laparoscopic salpingectomy, LCO=Laparoscopic ovarian cystectomy/oophorectomy, TAH=Total Abdominal Hysterectomy, VH=Vaginal Hysterectomy
Abdominal Hysterectomy, VH=Vaginal Hysterectomy
Real time integration of AI techniques into laparoscopic and robotic surgery has not yet been achieved. AI interpretation of live surgical video for the purposes of identifying anatomical structures and improving safety has been proposed. A number of proof-ofconcept papers have examined this with successful procedural step identification and this has the potential for future development. A further limitation of these AI techniques is that they cannot be applied globally to any surgical technique. The algorithm must be developed specifically to assess a particular surgical procedure and without easy access to large volumes of surgical video and a standardised recording technique its application to open or vaginal surgery is limited at present.
we review and assess surgical universities both nationally and This survey also showed a fall performance. A number of the off in trainees’ expectation to providedwho access This has a knock on impact on internationally more juniorhas trainees would previously have had studies have shown the potential be competent to independently to this type of training. National opportunity to perform these procedures the supervision of senior application of AI trainees to surgical who in perform the majority of training bodiesunder and individual gynaecological procedures practice. A recent review by surgical training schemes shouldmigration turn would also have by developed mentorship skills. This of independent surgical the end of their training. The Garrow et al. examined the various provide frequent access to this Digital platforms practice to later in a trainees’ career has therefore impacted on the ability of junior acquisition of these skills has applications of machine learning type of training for their trainees. secure purpose built digital shifted towards to fellowship level techniques for phase segmentation the outset majority of simulation consultants provide trainingCurrently from the their consultant careers. This cycle has Aplatform for sharing surgical video training whereas previously of surgical videos. It is possible training takes place during a limited the would potential to have long lasting impact on the courses surgicalfortraining landscape they have been expected to teach a machineintoIreland interpret and and techniques between surgeons number of mandatory and trainees which is widely of general obstetrics and surgical video and break it down senior trainees. Early and frequent globally. utilised and secure has yet to be gynaecology consultants. into predefined surgical steps. access to surgical simulation could developed. This would allow for improve trainees learning from This has a knock on impact This allows surgical trainees trainees to see and learn from a early in their careers. on more junior trainees who to easily review their surgical wide variety of surgical techniques would previously have had the performance and identify In May 2021 the Royal College of Potential solutions and encounter rare complications opportunity to perform these anomalies or difficult steps. These Obstetricians and Gynaecologists and pathologies which they procedures under the supervision techniques have predominantly released a “Training Recovery may not otherwise see during of senior trainees who in turn been applied to laparoscopic Simulation Plan” for gynaecological surgical their training. This would also would also have developed cholecystectomy procedures the United Kingdom. have the potential to incorporate Simulation hasThis themigration potential totraining bridgein the gap of the many challenges facing modern mentorship skills. as large publicly available video This plan heavily stresses the training logs and assessment of independent surgicalHigh practice databases exist forinthis procedure. surgical trainees. fidelity simulation has been widely adopted many importance oftraining formal simulation tools. Many platforms which to later in a trainees’ career has These were created with the training programs for trainees currently exist go part of the way industries. The on ability to rehearse surgical techniques in a risk free environment is invaluable therefore impacted the ability intention of allowing deep machine that are integrated on a local and to achieving that but have yet to be of consultants to provide access learning techniques to analyse tojunior trainees. Unfortunately to surgical simulation remains limited for many widely adopted or recommended national level. It discussed the facilities training from the outset of their surgical video. importance of hands -on simulation surgical trainees. Lack standardisation of simulation techniques, methods and equipmentby training bodies. consultant careers. This cycleofhas training days but also of at-home This segmentation has been the potential to have long lasting also impacts on this. Conclusion access to laparoscopic simulation achieved using a number of impact on the surgical training outside of formal simulation techniques including Instrument In conclusion despite the many landscape in Ireland and globally. training days. recognition. The AI algorithm can challenges that modern surgical The welcome formation of surgical simulation centres in many universities both nationally Potential solutions identify specific laparoscopic training presents there are many We recently surveyed gynaecology and internationally has provided access this in type of training. National training bodies andevolving and potential digital surgical instruments which are trainers and to trainees Ireland Simulation used for particular steps in the regarding their preferred individual surgical training schemes should providemethods frequent access to this type of training solutions which will help to improve procedure. The algorithm can Simulation has the potential surgical training. These attempt to of surgical simulation. 100% of forbridge theirthetrainees. thetrainers majority simulation training takes place during a limited then segment video based on the to gap of theCurrently many overcome the challenges faced by and trainees reported that presence of these instruments. For challenges facing modern surgical surgical trainees and streamline simulation training had a positive number of mandatory courses for senior trainees. Early and frequent access to surgical example, the presence of a clip trainees. High fidelity simulation the training process to maximise impact on their surgical practice. simulation could improve learning fromwere early in theirapplicator careers.during a laparoscopic training has been widely adopted trainees Cadaveric workshops ranked all training opportunities. This cholecystectomy may indicate that in many industries. The ability to as most useful by both trainers and is an area of research that the the surgical step being performed rehearse surgical techniques in a trainees. This was followed by ‘dry’ authors are actively pursuing in is the clipping of the cystic duct. risk free environment is invaluable simulation workshops and then collaboration with academia and to trainees. Unfortunately access animal workshops. the Medtech sector. Surgical video can also be to surgical simulation facilities analysed by artificial neural Artificial intelligence (AI) However, there needs to be a remains limited for many surgical networks which identify changes concerted effort from surgical trainees. Lack of standardisation Artificial intelligence (AI) or machine in colour, texture and environment educators, national training bodies of simulation techniques, methods learning is having impacts in many to identify structures and and equipment also impacts and government to ensure we areas of our lives. It allows for intraoperative events. With a on this. continue to produce high quality automation and in depth analysis large enough dataset this allows surgeons now and into the future. for interpretation of surgical on large volumes of data. It has The welcome formation of surgical video and segmentation of the potential to influence how simulation centres in many References on request
AUGUST - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE
BE PREPARED WHEN SEIZURES STRIKE BUCCOLAM (R) is indicated for the for treatment of prolonged, convulsive seizures infants, toddlers, childreninand adolescents (from 3 children months to and <18 years). BUCCOLAM is indicated the treatment ofacute, prolonged, acute, inconvulsive seizures infants, toddlers, adolescents (from 3 months to <18 years). BUCCOLAM® must only be used by parents/carers where the patient has been diagnosed to have epilepsy. For infants between 3–6 months of age, treatment should be in a hospital setting where BUCCOLAM (R) must only be used by parents/carers where the patient has been diagnosed to have epilepsy. For infants between 3-6 months of age, treatment should be in a hospital setting where monitoring is monitoring is possible and resuscitation equipment is available. 1 Please consult the Buccolam® Summary of Product Characteristics (SmPC) before prescribing. ® possible and resuscitation equipment is available. References: 1. Buccolam . Summary of Product Characteristics. Further prescribing information is available on request from Neuraxpharm or the Summary of Product Characteristics - eMail: email@example.com or Tel.: +353 (1) 4688 202 Marketing Authorisation Holder: Laboratories Lesvi S.L. Avinguda Joan Despi, 08970 Barcelona, Spain. Marketing Authorisation Number: EU/1/11/709/001-004 Legal Classification: POM CD. Pricing Information: POA Adverse events should be reported to: medinfo@Neuraxpharm.com - Tel: +353 (1) 4688202 or the Health Products Regulatory Authority - www.hpra.ie – e: firstname.lastname@example.org Tel +353 (1) 676 4971 Fax: +353 1 6767836 ®
Neuraxpharm is delighted to commence operations in Ireland Many of us will suffer mental or neurological disorders at some point in our lives. The wellbeing of those suffering from these disorders is at the heart of what we do. This is why we investigate and develop new solutions. Our commitment has led us to become a European leader in developing medicines for Central Nervous System disorders. We strive to support our doctors, pharmacists, nurses and the families affected. Now that we have located in Ireland, we look forward to working as part of the Irish Healthcare System, supporting patients and healthcare professionals in reducing the impact of Central Nervous System disorders in the lives of patients.
88 HOSPITAL REVIEW: UROLOGY
A Primer on Disorders of Sex Development Written by Mr Fardod O’Kelly MD MA FFSEM FRCS(Urol) Consultant Paediatric and Adolescent Urological Surgeon Division of Paediatric Urology; Beacon Kids; Beacon Hospital, Sandyford, Dublin D18AK68
Introduction: The daily office for a general urologist encompasses an assortment of conditions. Let’s be honest, when it comes to Disorders of Sex Development (DSD), most urologists prefer not to think about it if they don’t have to. This is likely due to several factors, least of all the distant memories of paediatric pearls of wisdom in medical school and postgraduate training. In addition to this, the complexities of DSD
AUGUST - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE
are compounded by the numerous classifications used to identify conditions. The clinical picture may vary from distal hypospadias to ambiguous genitalia, complex gonadal anomalies, or complete sex reversal. What is clear is that all urologists, primary care physicians, paediatricians, gynaecologists, and endocrinologists should have a working knowledge of DSDs, in terms of understanding life-threatening metabolic issues, being able to handle intraoperative consults regarding unexpected findings of gonads, and being cognoscente of the signs of DSDs presenting later in life. From a practical perspective, it may be more useful to classify DSDs based on the typical age of presentation and clinical picture, than classifications based on etiology, genetics, karyotypes, or hormones.
Basic clinically relevant embryology and genetics: The short arm of the Y chromosome contains Sexdeterminant Region Y gene (SRY). Presence of this gene will initiate pathways in primordial germ cells of the embryo at 6-7 weeks gestation. The initiation of this pathway triggers Sertoli cells to produce Anti-Müllerian Hormone (AMH), also known as MIS, prompting the regression of Mullerian ducts. Meanwhile, SRY protein upregulates SOX-9 transcription. This combination, in addition to Steroidogenesis Factor (SF-1), creates a key triangle in male development. When SOX-9 reaches a particular threshold level, the bipotential gonad will switch to the testicle (Figure 1). Figure 1: Biochemical pathways leading to sexual determination from the bipotential gonad
50mgs once daily
50mgs once daily
Her 10th shopping trip since the day she started BETMIGA1
Prescribing Information: Please read the Summary of Product Characteristics (SPC) before prescribing. Presentation: Prolonged-release tablet, containing mirabegron 25mg/50mg. Indication: Symptomatic treatment of urgency, increased micturition frequency and/or urgency incontinence as may occur in adult patients with overactive bladder (OAB) syndrome. Posology and method of administration: The recommended dose is 50 mg once daily. A lower dose of 25mg is recommended for specific patient populations (renal and hepatic impairment) as well as in specific patient populations in combination with strong CYP3A inhibitors such as itraconazole, ketoconazole, ritonavir and clarithromycin. Renal impairment: End stage renal disease (GFR < 15 mL/min/1.73 m2 or patients requiring haemodialysis): Not recommended. Severe renal impairment (GFR 15 to 29 mL/min/1.73 m2): Reduce dose to 25 mg. Severe renal impairment and concomitant strong CYP3A inhibitors: Not recommended. Moderate renal impairment (GFR 30 to 59 mL/min/1.73 m2): 50 mg. Moderate renal impairment and concomitant strong CYP3A inhibitors: Reduce dose to 25 mg. Mild renal impairment (GFR 60 to 89 mL/min/1.73 m2): 50 mg. Mild renal impairment and concomitant strong CYP3A inhibitors: Reduce dose to 25 mg. Hepatic impairment: Severe hepatic impairment (Child-Pugh Class C): Not recommended. Moderate hepatic impairment (Child-Pugh B): Reduce dose to 25 mg. Moderate hepatic impairment and concomitant strong CYP3A inhibitors: Not recommended. Mild hepatic impairment (Child-Pugh A): 50 mg. Mild hepatic impairment and concomitant strong CYP3A inhibitors: Reduce dose to 25 mg. The tablet is to be taken once daily, with liquids, swallowed whole and is not to be chewed, divided, or crushed. It may be taken with or without food Contraindications: Hypersensitivity to the active substance or to any of the excipients (see the SPC for a list of excipients). Severe uncontrolled hypertension defined as systolic blood pressure ≥180 mm Hg and/or diastolic blood pressure ≥110 mm Hg. Special warnings and precautions for use: Renal impairment: Betmiga has not been studied in patients with end stage renal disease (GFR < 15 mL/min/1.73 m2 or patients requiring haemodialysis) and, therefore, it is not recommended for use in this patient population. Data are limited in patients with severe renal impairment (GFR 15 to 29 mL/min/1.73 m2); based on a pharmacokinetic study a dose reduction to 25 mg is recommended in this population. This medicinal product is not recommended for use in patients with severe renal impairment (GFR 15 to 29 mL/min/1.73 m2) concomitantly receiving strong CYP3A inhibitors. Hepatic impairment: Betmiga has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) and, therefore, it is not recommended for use in this patient population. This medicinal product is not recommended for use in patients with moderate hepatic impairment (Child-Pugh B) concomitantly receiving
Date of preparation: June 2019
strong CYP3A inhibitors. Hypertension: Mirabegron can increase blood pressure. Blood pressure should be measured at baseline and periodically during treatment with mirabegron, especially in hypertensive patients. Data are limited in patients with stage 2 hypertension (systolic blood pressure ≥ 160 mm Hg or diastolic blood pressure ≥ 100 mm Hg). Patients with congenital or acquired QT prolongation: Betmiga, at therapeutic doses, has not demonstrated clinically relevant QT prolongation in clinical studies. However, since patients with a known history of QT prolongation or patients who are taking medicinal products known to prolong the QT interval were not included in these studies, the effects of mirabegron in these patients is unknown. Caution should be exercised when administering mirabegron in these patients. Patients with bladder outlet obstruction and patients taking antimuscarinic medicinal products for OAB: Urinary retention in patients with bladder outlet obstruction (BOO) and in patients taking antimuscarinic medicinal products for the treatment of OAB has been reported in postmarketing experience in patients taking mirabegron. A controlled clinical safety study in patients with BOO did not demonstrate increased urinary retention in patients treated with Betmiga; however, Betmiga should be administered with caution to patients with clinically significant BOO. Betmiga should also be administered with caution to patients taking antimuscarinic medicinal products for the treatment of OAB. Interactions: Pharmacokinetic interactions: Mirabegron is a substrate for CYP3A4, CYP2D6, butyrylcholinesterase, uridine diphosphoglucuronosyltransferases (UGT), the efflux transporter P-glycoprotein (P-gp) and the influx organic cation transporters (OCT) OCT1, OCT2, and OCT3. Pharmacokinetic interactions involving the potential for other medicinal products to affect mirabegron exposures: Increases in mirabegron exposure due to drug-drug interactions may be associated with increases in pulse rate. Strong CYP3A inhibitors See Posology and administration above for dose adjustments recommended during concomitant use of strong CYP3A inhibitors in patients with renal or hepatic impairment. Mirabegron exposure (AUC) was increased 1.8-fold in the presence of the strong inhibitor of CYP3A/P-gp ketoconazole. CYP2D6 inhibitors: No dose adjustment is needed for mirabegron when administered with CYP2D6 inhibitors (or in patients who are CYP2D6 poor metabolisers). Inducers: Inducers of CYP3A (such as rifampicin) or P-gp may decrease the plasma concentrations of mirabegron. No dose adjustment of mirabegron is required as this effect is not expected to be clinically relevant. Pharmacokinetic interactions involving the potential for mirabegron to affect exposures to other medicinal products: Inhibition of CYP2D6: Moderate and time dependent inhibition of CYP2D6 by mirabegron may result in clinically relevant drug interactions. CYP2D6 activity recovers within 15 days after discontinuation of mirabegron. Caution is advised if mirabegron is co-administered with medicinal
products metabolized by CYP2D6 with a narrow therapeutic index such as thioridazine, Type 1C antiarrhythmics (e.g.flecainide, propafenone) and tricyclic antidepressants (e.g., imipramine, desipramine). Caution is also advised if mirabegron is co-administered with CYP2D6 substrates that are individually dose titrated. Inhibition of P-gp: Mirabegron is a weak inhibitor of P-gp. For patients who are initiating a combination of Betmiga and digoxin, the lowest dose for digoxin should be prescribed initially. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect. The potential for inhibition of P-gp by mirabegron should be considered when Betmiga is combined with sensitive P-gp substrates e.g. dabigatran. Fertility, pregnancy and lactation: The effect of mirabegron on human fertility has not been established. Betmiga is not recommended during pregnancy and in women of child-bearing potential not using contraception. Mirabegron should not be administered during breast feeding. Refer to SPC for full guidance. Driving and use of machines: Betmiga has no or negligible influence on the ability to drive and use machines. Undesirable effects: Summary of the Safety Profile: the safety of Betmiga was evaluated in 8433 patients with OAB, of which 5648 received at least one dose of mirabegron in the phase 2/3 clinical program, and 622 patients received Betmiga for at least 1 year (365 days). In the three 12-week phase 3 double blind, placebo controlled studies, 88% of the patients completed treatment with this medicinal product, and 4% of the patients discontinued due to adverse events. Most adverse reactions were mild to moderate in severity. The most common adverse reactions reported for patients treated with Betmiga 50 mg during the three 12-week phase 3 double blind, placebo controlled studies are tachycardia and urinary tract infections. The frequency of tachycardia was 1.2% in patients receiving Betmiga 50 mg. Tachycardia led to discontinuation in 0.1% patients receiving Betmiga 50 mg. The frequency of urinary tract infections was 2.9% in patients receiving Betmiga 50 mg. Urinary tract infections led to discontinuation in none of the patients receiving Betmiga 50 mg. Serious adverse reactions included atrial fibrillation (0.2%). Adverse reactions observed during the 1-year (long term) active controlled (muscarinic antagonist) study were similar in type and severity to those observed in the three 12-week phase 3 double blind, placebo controlled studies. The following adverse reactions were observed with mirabegron in the three 12-week phase 3 double blind, placebo controlled studies. The frequency of adverse reactions is defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be established from the available data) Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The adverse events
References: 1. Freeman R, et al. Current Medical Research and Opinion 2017. https://doi.org/10.1080/03007995.2017.1419170.
are grouped by MedDRA system organ class. Infections and infestations: Common: urinary tract infection Uncommon: vaginal infection, cystitis Psychiatric disorders: Not known: Insomnia*, confusional state* Nervous system disorders: Common: headache* dizziness* Eye disorders: Rare: eyelid oedema Cardiac disorders: Common: tachycardia Uncommon: palpitation, atrial fibrillation Vascular disorders: Very rare: Hypertensive crisis* Gastrointestinal disorders: Common: nausea*, constipation*, diarrhoea* Uncommon: dyspepsia, gastritis Rare: lip oedema Skin and subcutaneous tissue disorders: Uncommon: urticaria, rash, rash macular, rash papular, pruritus Rare: leukocytoclastic vasculitis, purpura, angioedema* Musculoskeletal and connective tissue disorders: Uncommon: joint swelling Renal and urinary disorders: Rare: urinary retention* Reproductive system and breast disorders: Uncommon: vulvovaginal pruritus Investigations Uncommon: blood pressure increased, GGT increased, AST increased, ALT increased (*observed during post-marketing experience). Reporting of suspected adverse reactions: see below. Legal category: POM (S1B) Marketing Authorisation number: EU/1/12/809/003 - 25mg EU/1/12/809/010 - 50mg. Marketing Authorisation holder: Astellas Pharma Europe B.V. Sylviusweg 62, 2333 BE Leiden, The Netherlands. Further information is available from: Astellas Pharma Co., Ltd, 5 Waterside, Citywest Business Campus, Dublin 24. Phone: +3531 467 1555. Summary of Product Characteristics with full prescribing information available upon request. Job number: BET_2019_0002_IE Date of preparation of API: 27 May 2019. Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via: HPRA Pharmacovigilance Astellas Pharma Co. Ltd Earlsfort Terrace, IRL - Dublin 2 Tel: + 353 1 467 1555 Tel: +353 1 6764971 E-mail: Irishdrugsafety@astellas.com Fax: +353 1 6762517 Website: www.hpra.ie E-mail: email@example.com.
Approval code: BET_2019_0004_IE
90 HOSPITAL REVIEW: UROLOGY
Around 8-9 weeks, Leydig cells begin to produce testosterone autonomously which peaks at 13 weeks. Testosterone is the main hormone for spermatogenesis, gonadotropin regulation, Wolffian ducts stimulation and sexual differentiation. Dihydrotestosterone (DHT) acts on development of prostate, external genitalia, and is responsible for sexual maturation later in life. External genitalia develop around 10 weeks and will be completed at 12-13 weeks of age. Presentation in the infantile period: The typical presentation of DSD in the infantile period is ambiguous genitalia. This is a clinical term used to describe the appearance of external genitalia which lends to difficulties in assigning gender. In a newborn female this includes an enlarged clitoris and varying degrees of labial fusion. This can be semi-quantified using the Prader Scale (Figure 2). In a male, the presence of hypospadias and a palpable but undescended testicle, either unilateral or bilateral, has almost a 15% chance of having DSD. Hypospadias and a unilateral non-palpable testis increase that risk to 30%, whereas bilateral nonpalpable testes can reach 47%. Isolated proximal hypospadias may also warrant investigation of a possible DSD. DSD in this age group may represent a medical and psychological emergency, requiring an experienced team to handle the situation. The team should include paediatric endocrinology, urology, psychiatry, social work, and genetics. An extended panel including gynecology, neonatology, and bioethics may
Figure 3: Typical appearance of ambiguous genitalia in the newborn period: There appears Establishing a diagnosis in a newborn with ambiguous genitalia: Figure 3: Typical appearance of ambiguous genitalia in the newborn
Scenario 1: Non-Palpable Gonads (Testes) gonad the right, with period: on There appears to be a a left labioscrotal fold and the presence of proximal hypospadias palpable gonad on the right, with a left labioscrotal fold and the presence of proximal hypospadias
1. 46 XX DSD (*Mullerian structures are present*)
• Congenital Adrenal Hyperplasia (CAH) - Error in cortisol synthesis from cholesterol. CAH is the most common cause of DSD overall. 95% of cases the error is in 21-hydroxylase enzyme, 5% is due to 11-βeta hydroxylase. In terms of clinical presentation, 75 % of patients be required. The goals of this team present with with salt wasting and electrolytes abnormalities. The degree of Establishing a diagnosis ambiguous genitalia: are to ensure metabolic stability, in a newborn ambiguity is more severe in salt wasters. These patients are at risk of establish a diagnosis, and help adrenal(Testes) crisis in the first 10 to 21 days assign gender. Scenario 1: Non-Palpable Gonads
Initial assessment should include Karyotype Mullerian Structures Testosterone 17-OH progesterone history and physical examination. 46 XX Present High High History should include similar issues in the family, history of • Excess of Testosterone-ingestion/tumor - Excess of testosterone 1. 46 XX DSD (*Mullerian structures are present*) infant death, infertility in either exposure during pregnancy (medication vs. maternal androgen parent, amenorrhea, virilisation, producing tumor) • Congenital Hyperplasia (CAH) - Error in cortisol synthesis from cholest or hirsutism in the mother.Adrenal A Karyotype Mullerian Structures Testosterone 17-OH progesterone thorough pregnancy history is likewise important, including cause of DSD overall. 95% of cases the error is in 21-hydroxylase most common 46 XX Present High Low maternal use of medications
such as oral contraceptive pills • Aromatase in synthesis of oestrogen,75 or % of patients p due to 11-βeta hydroxylase. In deficiency terms of- Error clinical presentation, or steroids, and if the baby inborn error in cortisol synthesis pathway resulting in low 17-OH was born at term. On physical progesterone, low testosterone, but elevated 17-OH pregnenolone and wasting electrolytes abnormalities. The degree of ambiguity is more severe examination, general and appearance Dehydroepiandrosterone (DHEA) (looking for dysmorphic features, Karyotype Mullerian Structures skeletal malformation, anatomic These patients are at risk of adrenal crisis in the Testosterone first 10 to 2117-OH daysprogesterone malformation, cloacal exstrophy, 46 XX Present Low Low hyperpigmentation), presence of
palpable gonads, penile length, 2. 46 XY DSD (*Mullerian structures are absent*) urethral meatus position. One • Vanishing testes - Bilateral non-palpable UDT in a normal male. Mullerian Structures Testosterone 17-OH Karyotype should consider that having two When the karyotype is 46 XY and Mullerian structures are absent the palpable scrotal gonads almost diagnosis is limited to a normal male with bilateral non-palpable UDT, always indicated the presence embryonic testicular regression or bilateral vanishing testes syndrome. of testicles, since ovaries cannot 46 XX Ovotesticles may bePresent In this situation, obtaining AMHHigh or MIS lab work may be diagnostic High in descend. that a negative result indicates lack of testicular tissue. Alternatively, palpated in the inguinal area but never in the scrotum. (Figure 3). diagnostic laparoscopy may be performed to identify testes.
Excess of Testosterone-ingestion/tumor - Excess of testosterone exposure du (medication vs. maternal androgen producing tumor)
Aromatase deficiency - Error in synthesis of oestrogen, or inborn error in cortisol sy
resulting in low 17-OH progesterone, low testosterone, but elevated 17-OH pr Dehydroepiandrosterone (DHEA) Figure 2: Prader Scale of Female Genital Virilization
AUGUST - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE
91 3. Gonadal differentiation/sex chromosome disorder (*Asymmetrical findings on US and/or chromosomal abnormality*) • Gonadal dysgenesis: Mixed or Partial – When there is asymmetric finding of male or female organs on ultrasound and/or chromosomal abnormality, one should consider gonadal dysgenesis. Diagnostic testing may show low testosterone, elevated LH & FSH , low 17-OHProgesterone, and detectable but low MIS. Overall, when asymmetrical anatomical findings are found on exam or ultrasound, consider gonadal dysgenesis when the karyotype is 46 XY, and ovotesticular DSD when it is 46 XX. Remember, due to the local effects of testosterone and MIS, Mullerian structures may be found only on one side. Mixed gonadal dysgenesis is the second most common cause of ambiguous genitalia, and typically presents with a unilateral intra-abdominal testicle, contralateral streak ovary, evidence of persistent Mullerian structures, and inadequate masculinization. Partial gonadal dysgenesis presents with two dysgenetic testes, and various degrees of Mullerian remnants. Karyotype is usually 46 XY or 45XO/46XY. Two syndromes are important to link with gonadal dysgenesis in that they may have significant impacts later in life. Denys-Drash Syndrome encompasses genital ambiguity, nephropathy, and Wilm’s tumor. Meanwhile, Frasier Syndrome, presents with genital ambiguity and nephropathy. 4. Ovotesticular DSD (*Asymmetrical findings on US and/or chromosomal abnormality*) – Patients with ovotesticular DSD typically have a uterus, left ovary, right testicle or ovotestis. Phenotypically, they are male in 75% and female in 25 %. Karyotype results are 46 XX (60%); 46 XY (7%); 33% mosaicism. Ovotesticular DSD patients may have fallopian tubes, vas deferens, or both. They may have gonadal tissue of both ovary and testis in different pattern of distributions; admixed, compartmentalized, or bipolar. It is important to understand the architecture of the gonad when discussing fertility and gonadectomy. Scenario 2: Palpable Gonads (Testes) 1. 46 XY DSD • Testosterone production disorder - Differential diagnoses include Leydig cell aplasia/agenesis or disorder of testosterone production. The latter could be any errors in 5 enzymes of testosterone synthesis pathways. The earlier enzymes in the pathway are more likely to present with electrolytes abnormalities Karyotype
46 XY Absent
Testosterone receptor disorder - Partial Androgen Insensitivity Syndrome (PAIS) or 5-alpha reductase deficiency. Of note, Complete Androgen Insensitivity Syndrome (CAIS) does not present as ambiguous genitalia. Diagnosis of PAIS is difficult as gonadotropin, testosterone, DHT could be normal. To differentiate this from 5-alpha reductase deficiency, a hCG stimulation test and PCR for androgen receptor are indicated Karyotype
2. 46 XX males - SRY negative version of 46 XX is the main diagnosis at this age Karyotype
3. Gonadal differentiation/ Sex chromosome disorder • Gonadal dysgenesis (Mixed or partial) - Asymmetric finding of male or female organs on US and/or chromosomal abnormality, should prompt discussion of gonadal dysgenesis 4. Ovotesticular DSD Presentation as a Toddler: Scenario 1: Males Phenotypic males present either with precocious puberty or findings of Mullerian structures at the time of inguinal surgeries: 1. Congenital Adrenal Hyperplasia (“Little Hercules”) - In phenotypic males with CAH and XY karyotype, clinical picture is typically of precocious puberty; An over-virilised young boy with normal size testicles, enlarged penis, voice deepening, and acne. Males with CAH should be followed with annual scrotal ultrasound for testicular adrenal rest tumours
2. Persistent Mullerian duct syndrome (Hernia uteri inguinalis) - Present at the time of inguinal surgeries such as hydrocele/hernia repair or orchiopexy with an unexpected finding of Mullerian structures. These patients have 46 XY karyotype with problems in MIS or its receptors. In 10% of these patients, both testicles are located on one side within a hernia sac. This condition is known as transverse testicular ectopia, and 40-50% of these patients have an underlying diagnosis of persistent Mullerian duct syndrome. Given the potential injury to vas deferens at the time of dissection, removal of Mullerian structures at the time of diagnosis is not recommended. Scenario 2: Females Phenotypic females present with finding of a testicle at the time of inguinal surgeries: 1. Complete Androgen insensitivity Syndrome (CAIS) - 1-2% of female infants with inguinal hernia have 46 XY karyotype in the setting of CAIS. One option for female toddlers with an inguinal hernia is to obtain a karyotype. CAIS results when there is an insensitivity of the androgen receptor. These patients have female external genitalia with a short vagina and no evidence of Mullerian structures. Up to 50% of these patients have an inguinal hernia. Gonadectomy can be postponed until puberty to benefit from peripheral conversion of testosterone to oestrogen unless there are palpable testicles on exam or at the time of hernia repair. In this case gonadectomy at the time of surgery may be reasonable given that the youngest reported case of seminoma in CAIS was at age 14 years 2. 17 Oxidoreductase deficiency (17 β HSD) - Presents in a manner similar to CAIS. This is the last enzyme in the testosterone biosynthesis chain and converts androstenedione to testosterone, and estrone to estradiol. Typically, these patients are raised as female. Gonadectomy in patients may require oestrogen replacement and plastic surgery later in life. Presentation at puberty: Scenario 1: Males Presenting with Delayed Puberty or Infertility 1. Klinefelter syndrome (XXY) - The most common disorder of gonadal differentiation. Patients presents with infertility and azoospermia, tall height, broad arm span gynecomastia, small firm testicles (“peanuts”), sparse facial hair, and normal axillary or pubic hair. Need to be aware of breast cancer and extragonadal germ cell tumor risk 2. XX Male - SRY positive, present similar to Klinefelter syndrome except they are shorter 3. Mixed/Partial Gonadal Dysgenesis – May present as a normal infertile male with normal testosterone production and response in puberty. Karyotype will come back 45XO/46XY and future investigation reveals uterus, vagina, and fallopian tube structures. However, partial gonadal dysgenesis may present as a normal infertile male with normal testosterone production and response in puberty and karyotype will come back 46XY or 45XO/46XY 4. Testosterone Production Disorders or Response – These include Leydig cell aplasia/agenesis, 17,20-Lyase deficiency, or 17-hydroxylase deficiency (*Consider this diagnosis for and under-virilised male with hypertension*) 5. Partial Androgen Insensitivity Syndrome (PAIS) – This disorder androgen receptors function can present in different scenarios including in the assessment of infertility. Family history is a clue, but hormonal assessment may be completely normal. hCG stimulation test and PCR for androgen receptor will help establish he diagnosis. These patients are at risk for development of both gonadal and breast cancer 6. Male Congenital Adrenal Hyperplasia (CAH) - Fertility may decrease to 50% in males with CAH compared to the normal population, and this may be related to testicular adrenal rest nodules (TART), which are usually asymptomatic. If exposed to excessive ACTH, such as what happens in CAH, they can enlarge to form masses seen on ultrasound as multiple, bilateral, hypoechoic, heterogeneous mediastinal masses with shadowing Scenario 2: Females masculinizing at Puberty 1. 5-alpha reductase deficiency – 46XY and the issue is in conversion of testosterone to DHT. This disease was crucial to our understanding that the development of external genitalia is DHT rather than testosteronedependant. Throughout puberty these patients will experience onset of erections and increases in phallic size, but no change in hairline.
HOSPITALPROFESSIONALNEWS.IE | HPN • AUGUST - 2021
A combined force against LUTS and BPH
49% of men with LUTS report bladder and prostate symptoms1 VESOMNI treats the symptoms of both the bladder and prostate2 Abbreviated Prescribing Information - Vesomni 6 mg/0.4 mg modified release tablets. Please read the Summary of Product Characteristics (SPC) before prescribing. Presentation: Each tablet contains a layer of 6 mg solifenacin succinate, corresponding to 4.5 mg solifenacin free base and a layer of 0.4 mg tamsulosin hydrochloride, corresponding to 0.37 mg of tamsulosin free base. Indication: Treatment of moderate to severe storage symptoms (urgency, increased micturition frequency) and voiding symptoms associated with benign prostatic hyperplasia (BPH) in men who are not adequately responding to treatment with monotherapy. Posology and method of administration: Adult males, including older people: One Vesomni tablet (6 mg/0.4 mg) once daily taken orally with or without food. The maximum daily dose is one Vesomni tablet. The tablet must be swallowed whole, intact without biting or chewing. Do not crush the tablet. Special populations (see also contraindications below): Renal impairment: Severe renal impairment (creatinine clearance ≤ 30 mL/min): Treat with caution, maximum daily dose in these patients is one Vesomni tablet. Hepatic impairment: Moderate hepatic impairment (Child-Pugh score of 7-9): Treat with caution, maximum daily dose in these patients is one Vesomni tablet. In patients with severe hepatic impairment (Child-Pugh score > 9), the use of Vesomni is contraindicated. Concomitant treatment with moderate and strong inhibitors of CYP450 3A4: e.g. verapamil, ketoconazole, ritonavir, nelfinavir, itraconazole: Treat with caution, maximum daily dose should be limited to one Vesomni tablet. Paediatric population: There is no relevant indication for use of Vesomni in children and adolescents. Contraindications: Patients with hypersensitivy to the active substance(s) or to any of the excipients (see SPC). Patients undergoing haemodialysis. Patients with severe hepatic impairment. Patients with severe renal impairment who are also treated with a strong cytochrome P450 (CYP)3A4 inhibitor e.g. ketoconazole. Patients with moderate hepatic impairment who are also treated with a strong CYP3A4 inhibitor e.g. ketoconazole. Patients with severe gastrointestinal conditions (including toxic megacolon), myasthenia gravis or narrow-angle glaucoma and patients at risk for these conditions. Patients with a history of orthostatic hypotension. Special Warnings and Precautions for Use: Vesomni should be used with caution in patients with: severe renal impairment; risk of urinary retention; gastrointestinal obstructive disorders; risk of decreased gastrointestinal motility; hiatus hernia/ gastroesophageal reflux and/or who are concurrently taking medicinal products (such as bisphosphonates) that can cause or exacerbate oesophagitis; autonomic neuropathy. The patient should be examined in order to exclude the presence of other conditions, which can cause similar symptoms to benign prostatic hyperplasia. Other causes of frequent urination (heart failure or renal disease) should be assessed before treatment with Vesomni is initiated. If a urinary tract infection is present, appropriate antibacterial therapy should be started. QT prolongation and Torsade de Pointes have been observed in patients with risk factors, such as pre-existing long QT syndrome and hypokalaemia, who are treated with solifenacin succinate. Angioedema with airway obstruction has been reported in some patients on solifenacin succinate and tamsulosin. If angioedema occurs, Vesomni should be discontinued and not restarted. Appropriate therapy and/or measures should be taken. Anaphylactic reaction has been reported in some patients treated with solifenacin succinate. In patients who develop anaphylactic reactions, Vesomni should be discontinued and appropriate therapy and/or measures should be taken. As with other alpha1-adrenoceptor antagonists, a reduction in blood pressure can occur in individual cases during treatment with tamsulosin, as a result of which, rarely, syncope can occur. Patients starting treatment with Vesomni should be cautioned to sit or lie down at the first signs of orthostatic hypotension (dizziness, weakness) until the symptoms have disappeared. The ‘Intraoperative Floppy Iris Syndrome’ (IFIS, a variant of small pupil syndrome) has been observed during cataract and glaucoma surgery in some patients on or previously treated with tamsulosin hydrochloride. IFIS may increase the risk of eye complications during and after the operation. Therefore, the initiation of therapy with Vesomni in patients for whom cataract or glaucoma surgery is scheduled is not recommended. Discontinuing treatment with Vesomni 1-2 weeks prior to cataract or glaucoma surgery is anecdotally considered helpful, but the benefit of treatment discontinuation has not been established. During pre-operative assessment, surgeons and ophthalmic teams should consider whether patients scheduled for cataract or glaucoma surgery are being or have been treated with Vesomni in order to ensure that appropriate measures will be in place to manage IFIS during surgery. Vesomni should be used with caution in combination with moderate and strong inhibitors of CYP3A4 and it should not be used in combination with strong inhibitors of CYP3A4, e.g., ketoconazole, in patients who are of the CYP2D6 poor metaboliser phenotype or who are using strong inhibitors of CYP2D6, e.g., paroxetine.
Interactions: Pharmacological interactions: Concomitant medication with other anticholinergic medicinal products may result in more pronounced therapeutic and undesirable effects. Allow approximately one week after stopping treatment with Vesomni before commencing any anticholinergic therapy. The therapeutic effect of solifenacin may be reduced by concomitant administration of cholinergic receptor agonists. Pharmacokinetic interactions: Pharmacokinetic interactions involving the potential for other medicinal products to affect Vesomni exposures: Interactions with CYP3A4 and CYP2D6 inhibitors: See Contraindications, Posology and administration and Special warnings and precautions above. Concomitant administration may lead to increased exposure to both solifenacin (ketoconazole 400 mg/day resulted in a 1.5-fold increase in Cmax and a 2.8-fold increase in AUC). and tamsulosin (ketoconazole 400 mg/day resulted in a 2.2-fold increase in Cmax and a 2.8-fold increase in AUC). Vesomni should be used with caution in combination with strong CYP3A4 inhibitors. Vesomni should not be given together with strong CYP3A4 inhibitors in patients who are also CYP2D6 poor metabolizer phenotype or who are using strong CYP2D6 inhibitors. See SPC for details of the effects of other CYP3A4 and CYP2D6 inhibitors. Inducers: Inducers of CYP3A4 (e.g. rifampicin) may decrease the plasma concentrations of solifenacin and tamsulosin. Information available for the individual active substances: Solifenacin can reduce the effect of medicinal products that stimulate the motility of the gastrointestinal tract, such as metoclopramide and cisapride. Solifenacin did not affect the pharmacokinetics of digoxin, or the pharmacokinetics or effect on prothrombin time of R- or S-warfarin. Co-administration of tamsulosin and other alpha1-adrenoreceptor antagonists could lead to hypotensive effects. Diclofenac and warfarin may increase the elimination rate of tamsulosin. No interactions have been seen when tamsulosin was given concurrently with atenolol, enalapril or theophylline. Fertility, pregnancy and lactation: The effect of Vesomni on fertility has not been established. Ejaculation disorders have been observed in short and long term clinical studies with tamsulosin. Events of ejaculation disorder, retrograde ejaculation and ejaculation failure have been reported in the post authorization phase. Vesomni is not indicated for use in women. Driving and use of machines: No studies have been performed, however patients should be informed about the possible occurrence of dizziness, blurred vision, fatigue and uncommonly somnolence, which may negatively affect the ability to drive or use machines. Undesirable Effects: Summary of the safety profile: Vesomni may cause anticholinergic undesirable effects of, in general, mild to moderate severity. The most frequently reported adverse reactions during the clinical studies performed for the development of Vesomni were dry mouth (9.5%), followed by constipation (3.2%) and dyspepsia (including abdominal pain; 2.4%). Other common undesirable effects are dizziness (including vertigo; 1.4%), vision blurred (1.2%), fatigue (1.2%), and ejaculation disorder (including retrograde ejaculation; 1.5%). Acute urinary retention (0.3%, uncommon) is the most serious adverse drug reaction that has been observed during treatment with Vesomni in clinical studies. List of adverse reactions: the ‘Vesomni frequency’ below reflects adverse drug reactions that have been observed during the double-blind clinical studies performed for the development of Vesomni (based on reports of treatment-related adverse events, which have been reported by at least two patients and occurred with a frequency higher than for placebo in the double-blind studies). The ‘solifenacin frequency’ and ‘tamsulosin frequency’ below reflect adverse drug reactions (ADRs) previously reported with one of the individual components (as presented in the Summary of Product Characteristics (SmPCs) of solifenacin 5 and 10 mg and tamsulosin 0.4 mg respectively that may also occur when receiving Vesomni (some of these have not been observed during the clinical development program of Vesomni). The frequency of adverse reactions is defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data). The adverse events are grouped by MedDRA system organ class preferred term (PT). Vesomni frequency: Nervous system disorders: Common: dizziness Eye disorders: Common: vision blurred Gastrointestinal disorders: Common: dry mouth, dyspepsia, constipation Skin and subcutaneous tissue disorders: Uncommon: pruritus Renal and urinary disorders: Uncommon: Urinary retention*** Reproductive system and breast disorders: Common: ejaculation disorders including retrograde ejaculation and ejaculation failure General disorders and administration site conditions: Common: fatigue Solifenacin 5mg & 10mg frequency#: Infections and infestations: Uncommon: urinary tract infection, cystitis Immune system disorders: Not known: anaphylactic reaction* Metabolism and nutrition disorders: Not known: decreased appetite*, hyperkalemia* Psychiatric disorders: Very rare: hallucination*, confusional state* Not known:
References: 1. Sexton CC, et al. BJU Int 2009; 103(Suppl 3): 12-23. 2. VESOMNI Summary of Product Characteristics. Date of preparation: July 2019 Job code: VESOM_2019_0003_IE
delirium* Nervous system disorders: Uncommon: somnolence, dysgeusia Rare: dizziness*, headache* Eye disorders: Common: vision blurred Uncommon: dry eyes Not known: glaucoma* Cardiac disorders: Not known: palpitations*, Torsade de Pointes*, electrocardiogram QT prolongation*, atrial fibrillation*, tachycardia* Respiratory, thoracic and mediastinal disorders: Uncommon: nasal dryness Not known: dysphonia* Gastrointestinal disorders: Very common: dry mouth Common: dyspepsia, constipation, nausea, abdominal pain Uncommon: gastro-oesophageal reflux disease, dry throat Rare: vomiting*, colonic obstruction, faecal impaction, Not known: ileus*, abdominal discomfort* Hepatobiliary disorders: Not known: liver disorder*, liver function test abnormal* Skin and subcutaneous tissue disorders: Uncommon: dry skin Rare: pruritus*, rash* Very rare: urticaria*, angioedema*, erythema multiforme* Not known: exfoliative dermatitis* Musculoskeletal and connective tissue disorders: Not known: muscular weakness* Renal and urinary disorders: Uncommon: difficulty in micturition Rare: urinary retention***Not known: renal impairment* General disorders and administration site conditions: Uncommon: fatigue, perhiperal oedema Tamsulosin 0.4mg frequency#: Nervous system disorders: Common: dizziness Uncommon: headache Rare: syncope Eye disorders: Not known: vision blurred*, Intraoperative Floppy Iris Syndrome (IFIS)**, visual impairment* Cardiac disorders: Uncommon: palpitations Not known: atrial fibrillation*, arrhythmia*, tachycardia* Vascular disorders: Uncommon: orthostatic hypotension Respiratory, thoracic and mediastinal disorders: Uncommon: rhinitis Not known: dyspnoea*, epistaxis* Gastrointestinal disorders: Uncommon: constipation, nausea, diarrhea, vomiting Skin and subcutaneous tissue disorders: Uncommon: pruritus, rash, urticaria Rare: angioedema Very Rare: Stevens-Johnson syndrome Not known: erythema multiforme*, exfoliative dermatitis* Reproductive system and breast disorders: Common: ejaculation disorders including retrograde ejaculation and ejaculation failure Very rare: priapism General disorders and administration site conditions: Uncommon: asthenia. #: The ADRs from solifenacin and tamsulosin included are the ADRs listed in the summary of product characteristics of both products. *: from post-marketing reporting. Because these spontaneously reported events are from the worldwide post-marketing experience, the frequency of events and the role of solifenacin or tamsulosin and their causation cannot be reliably determined. **: from post-marketing reporting, observed during cataract and glaucoma surgery. ***: see Special warnings and precautions for use. Long-term safety of Vesomni: The profile of undesirable effects seen with treatment up to 1 year was similar to that observed in the 12-week studies. The product is well-tolerated and no specific adverse reactions have been associated with long-term use. Description of selected adverse reactions: For urinary retention see Special warnings and precautions for use. Older people: The therapeutic indication of Vesomni, moderate to severe storage symptoms (urgency, increased micturition frequency) and voiding symptoms associated with BPH, is a disease affecting elderly men. The clinical development of Vesomni has been performed in patients 45 to 91 years of age, with an average age of 65 years. Adverse reactions in the elderly population were similar to the younger population. Reporting of suspected adverse reactions: see below. Overdose: Overdosage with the combination of solifenacin and tamsulosin can potentially result in severe anticholinergic effects plus acute hypotension. Refer to SPC for details of treatment of overdose. Legal Category: Prescription Only Medicine (SIB). Nature and contents of container: Aluminium blister packs containing 30 tablets. Product Authorisation Number: PA1241/016/001. Marketing Authorisation holder: Astellas Pharma Co. Ltd. Further information is available from: Astellas Pharma Co. Ltd, 5 Waterside, Citywest Business Campus, Naas Road, Dublin 24. Phone: +3531 467 1555. Summary of Product Characteristics with full prescribing information available upon request. Job number: VESOM_2019_0001_IE Date of preparation of API: 24 May 2019 Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via: HPRA Pharmacovigilance Astellas Pharma Co. Ltd Earlsfort Terrace, IRL - Dublin 2 Tel: + 353 1 467 1555 Tel: +353 1 6764971 E-mail: Irishdrugsafety@astellas.com Fax: +353 1 6762517 Website: www.hpra.ie E-mail: firstname.lastname@example.org.
HOSPITAL REVIEW: UROLOGY
Lab work demonstrates elevated testosterone, low DHT, and a high testosterone/DHT ratio 2. 17 oxidoreductase (17-β HSD) deficiency - The last enzyme in testosterone biosynthesis chain, may be similar to 5-alpha reductase deficiency in puberty. At puberty, the gonadotropin surge will somewhat overcome the defect in testosterone biosynthesis and patients with experience phallic length growth and other testosterone related characteristics such as muscle mass, change in hairline, gynecomastia and palpable testicles. Male patients will be infertile Risk of malignancies in DSD DSD patients are at increased risk for certain malignancies. For these patients, a higher location of the gonad and the presence of Y chromosome increases malignancy risk. Concern in these patients typically focuses around gonadoblastoma, which is non-malignant but
has the potential for malignant transformation into dysgerminomas or seminomas. These tumors have a relatively good prognosis and respond well to chemotherapy. Conclusion DSD is a difficult topic requiring a team-based approach for diagnosis and management. As a urologist, it is important to be able to recognize patients presenting with DSD and manage unexpected findings intraoperatively. Surgical management in this population may be delayed until testing such as karyotype and lab work are completed. It is easy to get lost in the workup and nomenclature of such a complex diagnosis. It is crucial, that as clinicians, we handle both the patient and their family with the sensitivity these diagnoses require.
Hospital Review News Doctors Urged to Avail of Training Opportunities The President of the Medical Council, Dr Suzanne Crowe has, on the eve of the Dublin Pride Virtual Parade and Pride Day, called on doctors to avail of training opportunities to help them better understand the identities and needs of their LGBTI+ patients. Medical Council President, Dr Suzanne Crowe, said, “As doctors we treat members of the LGBTI+ community and as patients we are treated and cared for by members of the LGBTI+ community. Mutual trust and respect are central to the doctor-patient relationship.”
“As a health service there have been many important improvements in addressing the healthcare needs of the LGBTI+ community in recent years, but more can be done.” “As doctors, we must continue to work for our patients’ needs and fulfil our ethical role as advocates for patient needs. “Doctors should avail of training programmes, courses and workshops to ensure they are aware of the healthcare needs of the LGBTI+ community, while also making themselves aware of the
needs of the various groups in the LGBTI+ community such as the trans community, older LGBTI+ people, LGBTI+ migrants and refugees, LGBTI+ members of the travelling community and the young LGBTI+ community. “There are some excellent courses and workshops available for doctors and healthcare professionals provided by the HSE, postgraduate training bodies, universities, advocacy groups and charities. “Good communication skills are key in caring for and treating
patients and these skills must be developed throughout a doctor’s career. By continuing to build on their communication skills and attending courses and webinars, doctors can learn how to better care for patients and their loved ones and to communicate in a meaningful way. It is essential that doctors respect their patients and use the correct terminology and pronouns which the patient identifies with. “I strongly encourage doctors to participate in these courses when they can,” concluded Dr Crowe.
Cutting Edge ROSA Knee System Patients undergoing total knee replacement at Mater Private Network in Cork could benefit from quicker recovery times and a more customised overall experience, thanks to the introduction of the new ROSA Knee System. This robotic surgical assistant for total knee replacement supports surgeons during the procedure, helping them to tailor the surgical plan and accurate placement of the knee implant to each individual patient. Mater Private Network in Cork is the first hospital in the country to employ this state-of-the-art technology, developed by Zimmer Biomet. A market leader that prioritises adaptable workflow, the ROSA Knee System possesses features to assist with the bone resections, as well as assessing the state of the soft tissues to facilitate implant positioning during surgery. Surgeons at Mater Private Network in Cork are using the new ROSA Knee system to combine accurate data and a robotic arm with their
skill and experience, to target better fit and function of knee replacements compared with traditional methods. The hospital carries out approximately 1,000 joint replacements a year and has an earned reputation of constant innovation in orthopaedics. The ROSA Knee System will help Mater Private Cork surgeons continue their record of good clinical outcomes for their patients. Having already performed a number of knee replacements using the system, Mr. Karuppiah Mahalingam, lead orthopaedic surgeon at Mater Private Cork, commented: “Everyone’s knee is different, and the ROSA system is an excellent tool to help personalise every knee replacement to reflect this. Over the last number of months, I have successfully completed several procedures using this new technology that assists me and my surgical team with live data and guidance throughout the surgery. This can result in an implant
Mater Private Network Cork Mr Maha Mr Davarinos and Surgical Team with Rosa Robot 7 position more accurately placed than by traditional methods, and allows my patients knees to heal faster, regain motion quicker, and feel more natural.”
Robotic surgery has also been linked to shorter hospital stays and lower rates of hospital readmission compared to traditional surgical techniques.
Robotic-assisted knee surgery has been associated with reduced pain, lower usage of pain relief medication, fewer physiotherapy sessions and overall improved knee function following surgery.
As one of Ireland’s major centres for joint replacements, Mater Private Network Cork will continue to make innovative orthopaedic treatment available to patients throughout the Munster region.
HOSPITALPROFESSIONALNEWS.IE | HPN • AUGUST - 2021
94 News NUI Galway Sponsors Major Clinical Trial Professor Patrick Serruys and ProfessorYoshi Onuma examine Quantitative Flow Ratio (QFR) before and after stent implantation of the Healing Targeted Supreme stent and inspect device histopathology
NUI Galway and leading international medical device company SINOMED have teamed up to conduct a clinical trial of a special stent which has the potential to break new ground in the treatment of patients with heart disease.
potentially reducing reliance on some long-term medications such as blood thinners.
The PIONEER-IV trial will take place over several years in 30 hospital centres across Europe and involve 2,540 patients.
The trial is sponsored by NUI Galway and centrally coordinated by the University’s CORRIB Research Centre for Advanced Imaging and Core Laboratory. University Hospital Galway (UHG) is the first European site to enrol patients.
The trial will use the newly patented Healing-Targeted Supreme Stent (HT Supreme™) from SINOMED. The novel drug-eluting stent is designed to encourage rapid healing of the treated blood vessel, thereby
Professor Faisal Sharif, Professor of Translational Cardiovascular Medicine and Innovation at NUI Galway and Consultant Interventional Cardiologist at UHG, is Principal Investigator on the trial in Ireland.
Professor Sharif said, “We are delighted to translate novel devices such as HT Supreme stents for Irish patients. The trial will also allow us to perform assessment on blood vessel narrowing with new and safer software that establishes the absolute necessity to treat that coronary artery stenosis. New devices and technologies, like offered in this trial, allow us to constantly improve the standard of care for our patients by making interventions safer with better clinical outcomes.” Patients will be considered f or the trial if they suffer any type of coronary heart disease, including acute heart attack, chronic complaints or blood vessel narrowing. Eligible patients will undergo a refined physiological blood vessel selection process in order to determine which blood vessel has to be stented and which one could be treated with pharmacological therapy, without the use of a
permanent implant. This strategy is the best guarantee of a safer and more cost-effective treatment. NUI Galway’s CORRIB Core Lab is led by Professor Patrick W Serruys, Established Professor of Interventional Medicine and Innovation, and Professor William Wijns, Science Foundation Ireland Professor of Interventional Cardiology, both of whom are internationally renowned experts in interventional cardiology. Co-chair of the PIONEER-IV trial, Professor Serruys said: “SINOMED has an international reputation for state-of-the-art stents with a healing-targeted mechanism that may help overcome the longstanding problem of traditional stent implantation, allowing for safer long-term results.” Deputy chairman of the trial, Yoshi Onuma, Professor of Interventional Cardiology and medical director of CORRIB Research Centre, said: “The hope is that this trial will simplify the treatment for patients undergoing stent implantation of diseased blood vessels, and could offer benefits to patients when coupled with a shorter duration of blood-thinning medications.” Professor Andreas Baumbach (London), Professor Javier Escaned (Madrid), Professor Faisal Sharif (Galway) and Professor Peter Smits (Rotterdam) will act as global Principle Investigators.
Blood Clots Can Be Mitigated With Early Detection Dr Michelle Lavin, Lead Author, Researcher at the Irish Centre for Vascular Biology and the RCSI School of Pharmacy and Biomolecular Science
The work, led by researchers from RCSI University of Medicine and Health Sciences and the National Coagulation Centre at St James’s Hospital, is published in the British Journal of Haematology. New research has shown that early testing for blood clots in patients who had received the AstraZeneca/ Oxford vaccine led to them being treated successfully, highlighting the need for heightened awareness of the risk among doctors.
Unusual blood clots with low blood platelets have been recognised as a very rare complication of the AstraZeneca vaccine. However, with increased awareness, patients may not have all of these symptoms when they initially present to medical services.
AUGUST - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE
The researchers highlighted four patients who had clotting complications induced by the vaccine (Vaccine Induced Thrombotic Thrombocytopenia, VITT). Based on the current guidance, each patient could have been classified as a low likelihood for this syndrome when they presented to doctors, but due to the increased awareness and clinical vigilance from the medical teams involved, all were sent for testing early, diagnosed and treated successfully. “The risk of developing a blood clot from the vaccine is still far lower than the risk of developing clots from Covid-19, but it is imperative that clinicians are vigilant in detecting symptoms among vaccinated patients,” said Dr Michelle Lavin, the lead author of the paper and researcher at the Irish Centre for Vascular Biology
and the RCSI School of Pharmacy and Biomolecular Science. “Our research has shown that current guidelines lack the sensitivity to detect early cases of vaccine-induced clotting, which could risk missing or delaying diagnoses. As our understanding of this novel condition evolves, heightening our clinical awareness can improve outcomes for patients through early testing and treatment.” This work is part of the Irish COVID-19 Vasculopathy Study (ICVS), supported by a Health Research Board COVID-19 Rapid Response award and also by a philanthropic grant from the 3M Foundation to RCSI University of Medicine and Health Sciences in support of Covid-19 research. The work was carried out in hospitals in both the Republic of Ireland and Northern Ireland.
Clinical R&D 95 ACHILLES THERAPEUTICS ENROLLS FIRST US PATIENT IN ONGOING PHASE I/IIA STUDY IN ADVANCED NON-SMALL CELL LUNG CANCER Achilles Therapeutics plc (NASDAQ: ACHL), a clinical-stage biopharmaceutical company developing precision T cell therapies to treat solid tumors, has announced that the first patient in the United States (US) has been enrolled in the Company's ongoing Phase I/IIa CHIRON clinical trial. CHIRON is an open-label, multicenter Phase I/IIa trial evaluating the safety, tolerability, and activity of clonal neoantigen T cell (cNeT) therapy as a single dose in adult patients with advanced metastatic non-small cell lung cancer (NSCLC). cNeT are selectively expanded T cells that target a patient's own clonal neoantigens which are present on all tumor cells but absent from healthy tissue. This first US patient was enrolled at the Moffitt Cancer Center in Tampa, FL where Dr. Benjamin Creelan is the Principal Investigator. CHIRON is now open at 10 sites in the UK, EU and the US. "We are delighted to have taken our cutting-edge, cNeT platform into the US with the successful enrollment of the first patient at the Moffitt Cancer Center in our ongoing CHIRON study," said Dr Iraj Ali, CEO of Achilles Therapeutics. "With our cNeT platform we prospectively target patient-specific clonal neoantigens and are able to generate comprehensive characterization including the dose of the active cNeT component for each product. We look forward to providing an update from 10 patients across our CHIRON and THETIS studies in NSCLC and melanoma, respectively, in the fourth quarter of this year where we will present data highlighting a basis for our proposed potency assay." CHIRON is expected to recruit approximately 40 patients with advanced unresectable or metastatic NSCLC. The primary objective of the trial is to assess the safety and tolerability of cNeT. Clinical efficacy will be evaluated as a secondary measure. Additional data evaluating cNeT persistence, phenotype, and functionality will be reviewed while also exploring potential biomarkers of clinical activity and factors affecting response. This will include analysis of patient samples using a bespoke plasma ctDNA assay.
"There is still a large unmet need in NSCLC where there are very limited options for relapsed patients. We at the Moffitt are pleased to be the first US-based site for the CHIRON study to evaluate this important, precision tumor-infiltrating lymphocyte therapy," said Dr Benjamin C Creelan, Principal Investigator of the CHIRON study and thoracic oncologist at Moffitt Cancer Center. "This is the first US patient to be enrolled to receive a precision T cell therapy specifically targeting clonal neoantigens and we are pleased to be working with the team at Achilles."
ethical, legal and social implications must be taken into account; these include the perspectives of a broad range of stakeholders, such as, the child, their family, scientists, healthcare professionals, and public health professionals. Furthermore, the resources required to expand the programme should be considered at an early stage.
HIQA ADVISES ON APPROACHES FOR CONSIDERING THE EXPANSION OF THE NEWBORN BLOODSPOT
Dr Máirín Ryan, HIQA’s Deputy CEO and Director of Health Technology Assessment, said, “The current newborn screening programme is highly successful with consistently high uptake rates, estimated at around 99.9%. In considering further expansion of the programme, it is vital that the existing processes are protected and maintained and that any expansion of the programme is preceded by clearly defined and transparent decision-making to ensure ongoing trust and confidence in the programme.”
The Health Information and Quality Authority (HIQA) has published a report on approaches for considering the expansion of newborn bloodspot screening programmes. This report was provided to the National Screening Advisory Committee (NSAC) to help inform the development of their processes for the assessment of conditions being considered for inclusion in Ireland’s National Newborn Bloodspot Screening Programme (NNBSP). The NNBSP provides newborn bloodspot screening (the 'heel prick test'), within the first 72 to 120 hours of life. The current NNBSP screens for eight conditions and each year the NNBSP identifies approximately 110 babies in Ireland with one of these conditions. In 2020, the NSAC recommended the addition of a ninth condition to the programme, and, following the approval of this recommendation by the Minister for Health, the HSE has been making arrangements for its inclusion. HIQA undertook a review of nine countries recognised as having described policy-making processes in place for their newborn bloodspot screening programmes. The review of the academic literature and relevant policy documents examined how and why these countries decide on conditions to screen for. The review also included an examination of the range of conditions currently screened for, as well as the role of emerging technology in NBS programme expansion internationally.
HIQA has recommended that an explicit, structured approach to each aspect of policy-making on this topic should be prepared to ensure consistency and transparency into the future.
Dr Ryan continued: “International screening advisory groups are increasingly recognising the importance of a ‘lifecycle’ approach to making recommendations on newborn bloodspot screening. This includes taking a thorough look at the practicalities of adding a new condition to the programme, and making sure there is a longterm plan for the success of the programme, including its evaluation.” °MEQU WINS A PUBLIC TENDER TO SUPPLY °M WARMER SYSTEM – PORTABLE BLOOD AND IV WARMING DEVICE TO UK MOD It has been announced that °MEQU, in co-operation with UK
partner Fenton Pharmaceuticals, has won a public tender to provide portable blood and IV fluid warming devices (˚M Warmer System) to The Ministry of Defence (MOD) of the United Kingdom. The Ministry of Defence is the government department responsible for implementing the defence policy set by Her Majesty's Government. The UK regular forces consist of the Royal Navy, British Army, Royal Air Force, and Strategic Command. The ˚M Warmer System was chosen by the UK MOD as it has been proven to satisfy all the criteria set for their blood and IV warming needs. The system is not only small, light and robust, but also offers easy and fast setup. Most importantly, it delivers warm blood or IV fluids to patients within a few seconds. Ulrik Krogh Andersen (CEO) commented, “Fluid resuscitation before arriving at a hospital is shown to significantly reduce mortality among severely injured patients. We are glad that the UK MOD chose our ˚M Warmer System to treat their service people. With their choice, we at °MEQU keep up with our mission to improve the survival and recovery rate of patients regardless of where the injury occurs.” Graham Hill (MD Fenton Pharmaceuticals) commented, “We are very happy that the UK MOD has chosen the °M Warmer System as the blood and fluid warmer for British troops. We have for quite some time supplied the system to an increasing number of civilian HEMS units, but this confirms that the system is ideal for both civilian and military use. ˚M Warmer System is currently used both in pre-hospital and in-hospital environments, and ˚MEQU is continuously developing its technology to bring warm blood and IV fluids to more patients.”
The report notes that, when considering expansion of a screening programme, important
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96 Clinical R&D ROCHE OBTAINS CE MARK FOR THE SARS-COV-2 ANTIGEN SELF-TEST NASAL ALLOWING FOR RAPID SELF-TESTING OF COVID-19 AT HOME Roche (SIX: RO, ROG; OTCQX: RHHBY) has received CE mark for its SARS-CoV-2 Antigen Self-Test Nasal for at-home testing. The test will be available in countries accepting the CE mark, including Ireland, through pharmacies and other locations, in packs of five tests. Finbarr Kenny, Director of Ireland, Roche Diagnostics said, "Our new nasal antigen self-test provides results in 15 minutes and has the added advantage of only requiring a sample from the lower part of both nostrils - making it relatively easy and less uncomfortable to perform. The clinical performance of the test was measured by headto-head comparison with our PCR test. With sensitivity between 86 and 91%, the self-test provides a quick and reliable result indicating if a person is currently infectious with Covid-19. "As we navigate the careful road to recovery from this pandemic, PCR and rapid antigen (lateral flow) testing for COVID-19 can both play a critical role in helping to allow normal activities to resume safely and with confidence." An early version of the test has already been available as a home-test in a number of European markets under local special approval pathways since February 2021. With the CE Mark, the SARS-CoV-2 Antigen SelfTest Nasal for rapid self-testing of COVID-19 test has received official approval following the traditional registration pathway and can now also be used in markets that have not established regulatory exemption pathways. By following simple instructions, individuals can perform the test at home using a nasal swab without special training or the supervision of a healthcare worker. The test provides results in as little as 15 minutes and can help people to conveniently check if they are likely to be infectious from the comfort of their home. In the case of children under 18 years of age, the test must be performed by an adult or under close adult supervision. As societies begin to reopen, and in line with local health regulations, the convenient test allows individuals planning to attend an event or gathering to use the test as a tool to confirm that they are not likely to be carriers of a substantial amount of the virus
thus helping them make informed decisions and reduce the risk of transmission to others. This test is part of a partnership with SD Biosensor Inc., with whom Roche has also launched a SARSCoV-2 Rapid Antibody Test in July 2020 and two SARS-CoV-2 Rapid Antigen Tests for professional use in September 2020 and February 2021. These tests will continue to play an important role in fighting this pandemic and remain available for healthcare professional testing. In addition to diagnostic testing, preventive measures remain key to protecting yourself and others against SARS-CoV-2. It is recommended to continue wearing masks, socially distance and practice good hygiene, especially if you have symptoms or known contact with others who have tested positive for the virus. Roche continues to expand its comprehensive COVID-19 portfolio to support healthcare systems in diagnosing SARS-CoV-2 infection. SANOFI LAUNCHES DEDICATED VACCINES MRNA CENTER OF EXCELLENCE Sanofi will invest approximately ¤400 million annually in a first-ofits kind vaccines mRNA Center of Excellence. The Center will work to accelerate the development and delivery of next-generation vaccines by bringing together approximately 400 dedicated employees integrating end-toend mRNA vaccine capabilities with dedicated R&D, digital, and chemistry, manufacturing and controls (CMC) teams across sites at Cambridge, MA (US) and Marcy l'Etoile, Lyon (France). "During the COVID-19 pandemic, mRNA technologies demonstrated potential to deliver new vaccines faster than ever before. However, key areas of innovation such as thermostability and tolerability improvements will be critical to unlock the applications of mRNA in routine vaccination against a broader set of infectious diseases and across all ages. The Sanofi mRNA vaccines Center of Excellence aims to lead the field in this next chapter of vaccine innovation," said JeanFrancois Toussaint, Global Head of Research and Development, Sanofi Pasteur. The Center of Excellence will enable acceleration of the vaccines mRNA portfolio developed through the Translate Bio collaboration established in 2018 and expanded in 2020. "This massive new investment clearly puts us in the race to develop next-generation vaccines
AUGUST - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE
where mRNA technologies can have greatest impact." said Thomas Triomphe, Executive Vice President, Global Head of Sanofi Pasteur. "While mRNA won't be the solution for every infectious disease, its translation into routine prevention could have immense impact for many unmet public health needs. It now becomes a critical new technology in our comprehensive vaccines toolbox, one which could help reinvent health protection in the future." Sanofi is committed to rapidly establishing an industrycompetitive mRNA platform and is working with our partners and all relevant stakeholders, internally and externally, to achieve this objective. TAKEDA, RCPE, INSILICOTRIALS AND THE UNIVERSITY OF GRAZ PARTNER UP Biopharmaceuticals are large and complex drugs that mimic the action of the molecular mechanisms in living organisms. In the past decade, the number of deaths due to cancer and HIV/ AIDS have been significantly reduced and the treatment of several chronic diseases, such as diabetes and cardiovascular diseases, has been enhanced due to the emergence of biopharmaceuticals. Biopharmaceuticals represent one of the fastest growing segments in current drug pipelines, but their large-scale manufacturing and processing pose specific challenges to the drug formulation scientist, as these large and complex molecules are rather sensitive to variations of environmental conditions and process-induced stress. Filling is the final step of the manufacturing process for liquid protein formulations and the focus of this project. A 36-month joint project between the manufacturing site in Vienna of Takeda, one of the world's largest pharmaceutical
companies, the Research Center Pharmaceutical Engineering (RCPE), the technology company InSilicoTrials, and the University of Graz has been initiated to establish the mechanistic basis of the relationship between process parameters and the effect of the resulting stresses on the characteristics of protein based drugs. Takeda and RCPE are in the process of building an ongoing partnership which has been and is currently being used to increase the scientific knowledge for biopharmaceutical products and processes. This project will enhance the understanding of the processinduced mechanisms for proteinbased biopharmaceuticals. Participation in collaborative programs of this kind will also be supportive to product and process development of protein-based drugs in the future, resulting in reduced material requirements and drug development timelines. This collaboration will adopt an innovative approach between Takeda and the partner companies where a lab scale version of one of Takeda's filling line will be designed and assembled. The line will be used to simulate the Takeda filling process on a smaller scale, comparing the effect of various settings of process parameters (filling speed, vial shape, protein concentration etc.). In addition, computational fluid dynamics simulations will be performed to estimate the shear forces, as well as size and dynamics of interfaces the concentrated protein solution is exposed to during the filling process. The generated experimental and simulation data will then be used to train and test algorithms based on state of the art machine learning models, to predict the potential impact of these parameters on the properties of the protein molecule. The final goal is a set of in-silico tools that can be used to guide the design and parameterization of the filling process.
97 BREAKTHROUGH FOR TRACKING RNA WITH FLUORESCENCE
real time, seeing how they are taken up into cells with the help of a microscope.
Researchers at Chalmers University of Technology, Sweden, have succeeded in developing a method to label mRNA molecules, and thereby follow, in real time, their path through cells, using a microscope – without affecting their properties or subsequent activity. The breakthrough could be of great importance in facilitating the development of new RNA-based medicines.
A challenge when working with mRNA is that the molecules are very large and charged, but at the same time fragile. They cannot get into cells directly and must therefore be packaged. The method that has proven most successful to date uses very small droplets known as lipid nanoparticles to encapsulate the mRNA. There is still a great need to develop new and more efficient lipid nanoparticles – something which the Chalmers researchers are also working on. To be able to do that, it is necessary to understand how mRNA is taken up into cells. The ability to monitor, in real time, how the lipid nanoparticles and mRNA are distributed through the cell is therefore an important tool.
RNA-based therapeutics offer a range of new opportunities to prevent, treat and potentially cure diseases. But currently, the delivery of RNA therapeutics into the cell is inefficient. For new therapeutics to fulfil their potential, the delivery methods need to be optimised. Now, a new method, recently presented in the highly regarded Journal of the American Chemical Society, can provide an important piece of the puzzle of overcoming these challenges and take the development a major step forward. "Since our method can help solve one of the biggest problems for drug discovery and development, we see that this research can facilitate a paradigm shift from traditional drugs to RNA-based therapeutics," says Marcus Wilhelmsson, Professor at the Department of Chemistry and Chemical Engineering at Chalmers University of Technology, and one of the main authors of the article. Making mRNA fluorescent without affecting its natural activity The research behind the method has been done in collaboration with chemists and biologists at Chalmers and the biopharmaceuticals company AstraZeneca, through their joint research centre, FoRmulaEx, as well as a research group at the Pasteur Institute, Paris. The method involves replacing one of the building blocks of RNA with a fluorescent variant, which, apart from that feature, maintains the natural properties of the original base. The fluorescent units have been developed with the help of a special chemistry, and the researchers have shown that it can then be used to produce messenger RNA (mRNA), without affecting the mRNA's ability to be translated into a protein at natural speed. This represents a breakthrough which has never before been done successfully. The fluorescence furthermore allows the researchers to follow functional mRNA molecules in
"The great benefit of this method is that we can now easily see where in the cell the delivered mRNA goes, and in which cells the protein is formed, without losing RNA's natural protein-translating ability," says Elin Esbjörner, Associate Professor at the Department for Biology and Biotechnology and the second lead author of the article. Crucial information for optimising drug discovery Researchers in this area can use the method to gain greater knowledge of how the uptake process works, thus accelerating and streamlining the new medicines' discovery process. The new method provides more accurate and detailed knowledge than current methods for studying RNA under a microscope.
to crises. To ensure useful commercialisation of the method, the researchers have submitted a patent application and are planning for a spin-off company, with the support of the business incubator Chalmers Ventures and the Chalmers Innovation Office.
Hospital in London. In 2021, Ms Helen Mohan FRCSI began her Fellowship in colorectal surgery at Peter MacCallum Cancer centre in Melbourne, Australia. These two Fellowships were supported by Johnson & Johnson Medical Devices.
RCSI PARTNERS WITH OLYMPUS TO SUPPORT WOMEN IN SURGERY
Professor P. Ronan O'Connell, RCSI President, said: "We are delighted to welcome Olympus as a partner on the 'PROGRESS Women in Surgery Fellowship'. Through this Fellowship, we are committed to taking the necessary steps to remove the barriers that are preventing women from progressing further in surgery, promote a better understanding of the challenges faced by women in surgery and encourage women medical graduates to strive for a career in surgery."
RCSI has announced that the third PROGRESS Fellowship for Women in Surgery will be supported by Olympus. The prestigious Fellowship gives female surgeons the opportunity to gain exceptional experience and exposure to their chosen field, supporting their progression to consultant. RCSI published the 'PROGRESS: Promoting Gender Equality in Surgery' report in 2017, identifying the complex barriers to female progression in surgery. The report called for the provision of a fellowship for female surgeons to inspire exceptional trainees by providing the opportunity to avail of career-defining international fellowship training. Launched in 2019, the Fellowship enhances the expertise and skill base of Irish female surgeons by supporting their opportunities to gain international exposure in their chosen fields, acquire additional surgical skills, have access to new technologies and contribute to the advancement of surgical science and practice on the island of Ireland. Ms Ailín Rogers FRCSI received the inaugural Fellowship in robotic colorectal surgery and multivisceral resection for advanced pelvic malignancy at Royal Marsden
Alison Harvey, Country Manager of Olympus, said: "Olympus are excited to partner with the RCSI on this fellowship and further demonstrate our commitment to improve patient outcomes through supporting the development of Irish female surgeons. By supporting the PROGRESS Women in Surgery Fellowship, Olympus will help promote gender diversity as well as provide opportunities for the recipient of this fellowship to gain essential experience at world leading institutions." The successful candidate will be awarded a Fellowship up to an amount of ¤45,000, and the RCSI PROGRESS Fellowship Medal which will be presented at the annual RCSI Charter Day Meeting. The closing date for applications is Monday, 1 November.
"Until now, it has not been possible to measure the natural rate and efficiency with which RNA acts in the cell. This means that you get the wrong answers to the questions you ask when trying to develop a new drug. For example, if you want an answer to what rate a process takes place at, and your method gives you an answer that is a fifth of the correct, drug discovery becomes difficult," explains Marcus Wilhelmsson. On the way to utilisation – directly into IVA's top 100 list When the researchers realised what a difference their method could make and how important the new knowledge is for the field, they made their results available as quickly as possible. Recently, the Royal Swedish Academy of Engineering Sciences (IVA) included the project in its annual 100 list and also highlighted it as particularly important for increasing societal resilience
HOSPITALPROFESSIONALNEWS.IE | HPN • AUGUST - 2021
98 Clinical R&D EMPAGLIFLOZIN (JARDIANCE®) APPROVED IN IRELAND FOR THE TREATMENT OF HEART FAILURE WITH REDUCED EJECTION FRACTION The European Commission has granted marketing authorisation for Empagliflozin (Jardiance®) as a treatment for adults with symptomatic chronic heart failure with reduced ejection fraction (systolic heart failure) in Ireland, Boehringer Ingelheim and Eli Lilly and Company have announced. The extension of the indication follows a positive recommendation by the Committee for Medicinal Products for Human Use (CHMP) on 20 May 2021. Marketing authorisation is based on results from the EMPEROR-Reduced trial in which empagliflozin showed a significant 25 percent reduction (ARR 5.2%) in the combined relative risk versus placebo of cardiovascular death or hospitalisation due to heart failure. The findings from the primary endpoint were consistent in subgroups with or without type 2 diabetes. Key secondary endpoint analyses from the trial demonstrated that empagliflozin reduced the relative risk of first and recurrent hospitalisation for heart failure by 30 percent (ARR 8.7%) and significantly slowed kidney function decline. “Empagliflozin was the first SGLT2 inhibitor to demonstrate cardiovascular protective effects and improve cardiovascular outcomes in patients with type 2 diabetes,” said Dr Douglas Clark, Head of Medical Affairs for UK and Ireland at Boehringer Ingelheim. “We are delighted to now be able to offer empagliflozin to people with heart failure with reduced ejection fraction, regardless of diabetes status, and to provide an additional treatment option for the thousands of people who live with heart failure and important metabolic conditions. We look forward to collaborating with NCPE to ensure access to this trusted therapy.” Heart failure is often associated with other diseases of the cardio-renal-metabolic systems such as type 2 diabetes and kidney disease. Due to the interconnected nature of these systems, improvement in one system can lead to positive effects throughout the others. Heart failure is a very common and severe complication of a heart attack and occurs when the heart cannot pump sufficient blood to the rest of the body. There are two forms of the condition; heart failure with reduced ejection
fraction means the heart cannot contract normally, while preserved ejection fraction means the heart cannot properly fill with blood. People with heart failure often experience breathlessness and fatigue, which can severely impact their quality of life. The EMPEROR-Reduced trial is part of the EMPOWER clinical programme, exploring the impact of empagliflozin on the lives of people across the spectrum of cardio-renal-metabolic conditions. The safety profile was similar to the established safety profile of empagliflozin. HSE REIMBURSES NEW SUBCUTANEOUS FORMULATION OF TYSABRITM (NATALIZUMAB) TO TREAT ADULTS LIVING WITH HIGHLY ACTIVE RELAPSING REMITTING-MULTIPLE SCLEROSIS Biogen Ireland have announced that the HSE has agreed to reimburse a subcutaneous (SC) injection of TYSABRITM (natalizumab) for adults living with highly active relapsing-remitting multiple sclerosis (MS). The announcement follows the European Commission’s (EC) decision on the 30th March 2021 meaning that the new route of administration is now approved in Ireland. Natalizumab SC offers comparable efficacy and safety and builds on the long-term data and established clinical benefits of the natalizumab intravenous (IV) formulation. Natalizumab is the only high-efficacy disease modifying therapy for RRMS that offers two routes of administration providing patients and healthcare professionals (HCPs) with the flexibility to choose the one that best fits their individual needs. The SC and IV formulations of natalizumab 300 mg, are administered once every four weeks by a HCP in a clinical setting. The new SC formulation expands the clinical setting beyond infusion centres, potentially bringing care closer to home, e.g., via community healthcare centres, offering patients treatment convenience whilst still providing medical oversight of treatment administration. The administration by a HCP allows for ongoing disease monitoring, including screening for progressive multifocal leukoencephalopathy (PML), identifying and treating potential
AUGUST - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE
hypersensitivity reactions and ensuring adherence to treatment. As well as the shorter SC administration time, compared to the IV formulation, the SC injections also provide the option for HCPs to reduce or remove the 1-hour post-dose observation period, after the first six doses, based on clinical judgement. “This is an important treatment option for people living with MS, as it provides individuals with more flexibility around how they would like to receive their treatment. It still provides people with the opportunity to access their MS Care team but will minimise the time spent receiving treatment and can potentially be administered in more convenient locations, closer to home” said Ava Battles, CEO, MS Ireland. The approval of the SC route of administration for natalizumab is based on data from the DELIVER (Phase 1) and REFINE (Phase 2) studies. The SC formulation of natalizumab 300 mg has shown comparability to the Q4W IV administration of 300mg natalizumab in efficacy, pharmacokinetic (PK) and pharmacodynamic (PD) profiles. The safety of natalizumab SC in both the DELIVER and REFINE studies was generally consistent with the well-established benefit-risk profile of natalizumab IV in other clinical studies and the post-marketing setting, with the exception of injection site pain which can occur with SC injections. “This unprecedented year has put the HSE under significant resource pressures and created new challenges for those living with long-term conditions, like MS, when accessing vital, life impacting treatments,” said Dr Bronagh Hayden, Head of Medical Affairs Biogen Ireland. “As our healthcare and everyday environment evolves, we must continue to provide solutions to address capacity and resource concerns within the health service, whilst addressing patient needs. Reinforced by nearly 15 years of real-world evidence and post marketing experience with natalizumab IV, SC offers a new method of delivery that can help to reduce patient time in a hospital setting and increase convenience in clinical practice.” LEO PHARMA ANNOUNCES MHRA AND EC APPROVAL OF ADTRALZA (TRALOKINUMAB) LEO Pharma UK and Ireland, a leader in medical dermatology, has announced that the Medicines
and Healthcare products Regulatory Agency (MHRA) and the European Commission (EC) has approved tralokinumab for the treatment of moderate-tosevere atopic dermatitis in adult patients who are candidates for systemic therapy. The MHRA and EC approvals make tralokinumab the first and only approved biologic that specifically targets the IL-13 cytokine alone, a key driver of atopic dermatitis signs and symptoms. Tralokinumab is the first high affinity, human monoclonal antibody developed to specifically bind to and inhibit the IL-13 cytokine in adult patients with uncontrolled moderate-to-severe atopic dermatitis. Tralokinumab will be available in a 150 mg/mL prefilled syringe for subcutaneous injection with an initial dose of 600 mg followed by 300 mg every other week. Tralokinumab can be used with or without topical corticosteroids (TCS). “Atopic dermatitis can be an intensely itchy, challenging and unpredictable skin condition for some. As clinicians, we always want more options for patients and the approval of tralokinumab means that clinicians across the UK and Ireland now have an important new treatment option for patients with moderate-tosevere atopic dermatitis in adult patients” said Professor Anthony Bewley, Consultant Dermatologist at Barts Health NHS Trust. PEMETREXED CLONMEL Clonmel Healthcare is delighted to announce the launch of Pemetrexed Clonmel 25mg/ml concentrate for solution for infusion. Pemetrexed Clonmel 25mg/ ml concentrate for solution for infusion is indicated for malignant pleural mesothelioma and non-small cell lung cancer. Full prescribing information is available on request or alternatively please go to www.clonmel-health.ie. Medicinal product subject to medical prescription. Please contact Clonmel Healthcare on 01-6204000 if you require any additional information. PA 126/270/001. PA Holder: Clonmel Healthcare Ltd., Clonmel, Co. Tipperary. Date prepared: May 2021. 2021/ADV/PEM/060H.
Astellas’ XTANDITM (enzalutamide) Approved by European
Astellas’ XTANDITM (enzalutamide) Approved Commission by European Commission Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., “Astellas”) has announced that the European Commission (EC) has approved an additional indication for the
TM oral once-daily (enzalutamide) for adult men Kenji with metastatic hormoneAstellas Pharma Inc.therapy (TSE:XTANDI 4503, President and CEO: Yasukawa, sensitive prostate cancer (mHSPC, also known as metastatic castration-sensitive prostate Ph.D., cancer “Astellas”) hasMen announced that thetend European Commission or mCSPC). diagnosed with mHSPC to have a poor prognosis, with a median survival ofan approximately 3-4 indication years, 1 underscoring the oral need for new treatment options. (EC) has approved additional for the once-daily therapy XTANDITM (enzalutamide) for adult men with metastatic With this indication, enzalutamide is now the only oral treatment approved by the EC to treat hormone-sensitive prostate cancer (mHSPC, knownand asmetastatic metastatic three distinct types of advanced prostate cancer — also non-metastatic castrationresistant prostate cancer (CRPC) and mHSPC. 2 The EC approval is based on results from the castration-sensitive prostate cancer or mCSPC). Men diagnosed with pivotal Phase 3 ARCHES trial which evaluated enzalutamide in men with mHSPC. 3 mHSPC tend to have a poor prognosis, with a median survival Data from the ARCHES showedunderscoring enzalutamide plus the androgen deprivation therapy (ADT) of approximately 3-4 trial years, need for new significantly reduced the risk of radiographic progression or death by 61% versus placebo plus treatment options. ADT in men with mHSPC (n=1,150; hazard ratio [HR]=0.39 [95% confidence interval (CI):
With this indication, enzalutamide is now the only oral treatment The safety analyses of the ARCHES trial appear consistent with the safety profile of approvedenzalutamide by the EC to treat three distinct of advanced prostate in previous clinical trials in CRPC. types In ARCHES, Grade 3 or greater adverse events (defined as severe/disabling or life-threatening) were similar for patients receiving both cancer —(AEs) non-metastatic and metastatic castration-resistant prostate enzalutamide plus ADT and those who received placebo plus ADT (24.3% vs. 25.6%).3 cancer (CRPC) and mHSPC. The EC approval is based on results from The EC marketing authorizationtrial for enzalutamide in men with mHSPC is applicableinto the pivotal Phase 3 ARCHES which evaluated enzalutamide European Union (EU) member countries, and is also valid in Iceland, Norway and men with mHSPC. Liechtenstein. 4 This approval will have no impact on the financial forecasts of the current fiscal year ending Data from the ARCHES trial showed enzalutamide plus androgen March 31, 2022. deprivation therapy (ADT) significantly reduced the risk of radiographic progression or death by 61% versus placebo plus ADT in men with mHSPC (n=1,150; hazard ratio [HR]=0.39 [95% confidence interval (CI): 0.30-0.50]; P<0.0001).3
The safety analyses of the ARCHES trial appear consistent with the safety profile of enzalutamide in previous clinical trials in CRPC. In ARCHES, Grade 3 or greater adverse events (AEs) (defined as severe/ disabling or life-threatening) were similar for patients receiving both enzalutamide plus ADT and those who received placebo plus ADT (24.3% vs. 25.6%).3
Vimovo® is indicated in adults for the symptomatic treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis, in patients who are at risk for developing non-steroidal anti-inflammatory drug (NSAID) -associated gastric and/or duodenal ulcers and where treatment with lower doses of naproxen or of other NSAIDs is not considered sufficient.1
The EC marketing authorization for enzalutamide in men with mHSPC 1 is applicable to European Union (EU) member countries, and is also Certification No.in XTD_2021_0073_IE Date of Preparation: May 2021 valid Iceland, Norway and Liechtenstein. This approval will have no impact on the financial forecasts of the current fiscal year ending March 31, 2022.
Reference: 1. Vimovo Summary of Product Characteristics. Legal classification: POM. Marketing Authorisation number, pack sizes: PA 1019/024/001, 60 packs. Marketing Authorisation Holder: AstraZeneca AB, SE-151 85 Södertälje, Sweden. Further information is available upon request from Grünenthal Pharma Ltd, 4045 Kingswood Road, Citywest Business Park, Citywest, Co Dublin. M-VMO-IE-10-20-0002 – October 2020
New Irish Health and Market Access Landscape Report AXIS Consulting’s recently published Irish Health and Market Access Landscape Report 2021 is a comprehensive overview of the Irish health ecosystem, with critical insights on how the various bodies involved in decision making in Ireland connect and interlink. The inaugural 42 page report provides a deep understanding of the processes involved in reimbursement and the actual timelines for companies from when they make a submission to the authorities to a final reimbursement decision by the HSE. The report finds that the average time taken between the final NCPE recommendation on a Health Technology Assessment (HTA) to
HSE reimbursement approval is on average 13.7 months and notes, that this is considerably longer than the time frame for a reimbursement decision when no HTA has been conducted. Commenting on the findings, Brenda Dooley, AXIS CEO said “While Ireland has a particularly lengthy timeline to reimbursement decision making, this may be due to HSE funding challenges but is, perhaps, more reflective of the lack of an agreed timeline for pricing discussions”. “At the moment we are awaiting the outcome of the negotiations for a new industry state framework agreement. We are hopeful that an important
Brenda Dooley, AXIS CEO
outcome of the negotiations will be the introduction of a process that expedites the timelines for decision making with regards to the introduction of new medicines in Ireland.” The Irish Health and Market Access Landscape Report is available to purchase at www.axisconsulting.ie
HOSPITALPROFESSIONALNEWS.IE | HPN • AUGUST - 2021
When it comes to your patients’ psoriasis treatment goals
What means everything to the patient? The potential for nothing left on their skin.* High skin clearance matters to patients: Patients who achieve and maintain high levels of skin clearance (PASI 9099 or PASI 100) have significantly better HRQoL than those with lower levels of skin clearance (PASI 75-89). 2
* Nothing on the skin: Defined as 75% achievement of PASI90 at Week 16 and ≥50% achievement of PASI 100 at Week 52 in UltIMMa-1 and UltIMMa-2.1
Sustaining high skin clearance or complete skin clearance is associated with incremental and durable benefits in HRQoL and mental health of psoriasis patients. 2
PRESCRIBING INFORMATION (PI) SKYRIZI®▼ (risankizumab) 75 mg solution for injection in pre-filled syringe. Refer to Summary of Product Characteristics (SmPC) for full information before prescribing. PRESENTATION: Each pre-filled syringe contains 75 mg risankizumab in 0.83 ml solution. INDICATION: For treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy. DOSAGE AND ADMINISTRATION: Intended for use under guidance and supervision of a physician experienced in diagnosis and treatment of psoriasis. Dosage: The recommended dose of Skyrizi is 150 mg (two 75 mg injections) by subcutaneous injection at weeks 0, 4, and every 12 weeks thereafter. Consider discontinuation of treatment in patients showing no response after 16 weeks of treatment. Some patients with initial partial response may subsequently improve with continued treatment beyond 16 weeks. Special Populations: Elderly: No dose adjustment required. Renal or hepatic impairment: No dose adjustment required. Paediatric Population: No data available. Overweight patients: No dose adjustment required. CONTRAINDICATIONS: Hypersensitivity to any of the active substances or excipients. Clinically important active infections (e.g. active tuberculosis). SPECIAL WARNINGS AND PRECAUTIONS: See SmPC for full details. In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Skyrizi may increase the risk of infections. In patients with a chronic infection or history of recurrent infections, or known risk factors for infection, Skyrizi should be used with caution. Treatment with Skyrizi should not be initiated in patients with any clinically important active infection until the infection resolves or is adequately treated. Patients should be evaluated for tuberculosis infection prior to initiating treatment. Anti-TB therapy should be considered prior to initiating Skyrizi in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Completion of all appropriate immunisations should be considered prior to initiating therapy. If a patient has received live vaccination (viral or bacterial), it is recommended to wait at least 4 weeks prior to starting treatment with Skyrizi. Patients treated with Skyrizi should not receive live vaccines during treatment and for at least 21 weeks after treatment. If a serious hypersensivity reaction occurs, administration of Skyrizi should be discontinued immediately and appropriate therapy initiated. Skyrizi contains 68.0 mg sorbitol and less than 1 mmol sodium (23 mg) per 150 mg dose. INTERACTIONS: The safety and efficacy of Skyrizi in combination with immunosuppressants, including biologics or phototherapy have not been evaluated. PREGNANCY AND LACTATION: Women of Childbearing potential: An effective method of contraception during treatment
and for at least 21 weeks after treatment should be used. Pregnancy: Limited data available. It is preferable to avoid the use of Skyrizi during pregnancy as a precautionary measure. Lactation: It is not known whether Skyrizi is excreted in breast milk. Human IgGs are known to be excreted in breast milk during the first few days after birth, which decreases to low concentrations soon afterwards; consequently, a risk to the breast-fed infant cannot be excluded during this short period. A decision should be made whether to discontinue/abstain from Skyrizi therapy, taking into account the benefit of breast-feeding to the child and the benefit of Skyrizi therapy to the woman. Fertility: The effect of Skyrizi on human fertility has not been evaluated. ADVERSE REACTIONS: See SmPC for full details on adverse reactions. Very common adverse reactions (≥1/10): Upper respiratory infections. Common adverse reactions (≥1/100 to <1/10): Tinea infections, headache, pruritus, fatigue and injection site reactions. ▼ This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance; Website: www.hpra.ie. Suspected adverse events should also be reported to AbbVie Limited on 01-4287900. LEGAL CLASSIFICATION: POM (S1A). MARKETING AUTHORISATION NUMBERS/PRESENTATIONS: EU/1/19/1361/001: Skyrizi 75 mg solution for injection in pre-filled syringe (Pack of 2 pre-filled syringes). Further information is available from: AbbVie Ltd., 14 Riverwalk, Citywest Business Campus, Dublin 24. DATE OF REVISION: March 2020. PI/1361/002 HRQoL, Health-Related Quality of Life; PASI, Psoriasis Area Severity Index. REFERENCES: 1. Gordon KB, et al. Lancet 2018; 392: 650-661. 2. Ryan C et al. Poster presented at the 27th European Academy of Dermatology & Venerology (EADV) Congress 2018; September 12–16; Paris, France. Skyrizi® Summary of Product Characteristics, available on www.medicines.ie. Date of preparation: September 2020 | IE-RISN-190074