HPN 2022 January by IPN Communications LTD

HOSPITAL PROFESSIONAL NEWS IRELAND

HPN January 2022 Issue 92 HOSPITALPROFESSIONALNEWS.IE

Ireland’s Dedicated Hospital Professional Publication

IN THIS ISSUE: NEWS: Strategy for Specialist Doctor Training Page 7

Therapeutic Indications

CRESEMBA® is indicated in adults for the treatment of:1 Invasive Aspergillosis Mucormycosis in patients for whom amphotericin B is inappropriate

Consideration should be given to official guidance on the appropriate use of antifungal agents.1 Early targeted therapy (pre-emptive or diagnostic-driven therapy) may be instituted pending confirmation of the disease from specific diagnostic tests. However, once these results become available, antifungal therapy should be adjusted accordingly.1 Formulations and strengths1

200 mg powder for concentrate for solution for infusion

Oral

100 mg hard capsules

Scan QR code to visit: www.pfizerhcpconnect.ie

References 1. CRESEMBA Summary of Product Characteristics. 2021 CRESEMBA™ (isavuconazole) PRESCRIBING INFORMATION CRESEMBA™ [isavuconazole] 200 mg powder for concentrate for solution for infusion and 100 mg hard capsules. Please refer to the Summary of Product Characteristics (SmPC) before prescribing CRESEMBA. Presentation: Each vial of CRESEMBA powder for concentrate for solution for infusion contains 200 mg isavuconazole. Each CRESEMBA hard capsule contains 100 mg isavuconazole. Indications: Indicated in adults for the treatment of invasive aspergillosis; mucormycosis in patients for whom amphotericin B is inappropriate. Administration & dosage: Early targeted therapy (pre-emptive or diagnosticdriven therapy) may be instituted pending confirmation of the disease from specific diagnostic tests. However, once these results become available, antifungal therapy should be adjusted accordingly. Loading dose. Loading dose (IV): 200 mg CRESEMBA every 8 hours for the first 48 hours followed by a maintenance dose of 200 mg once daily 12 to24 hours after the last loading dose. The infusion must be administered via an infusion set with an in-line filter with a microporous membrane made of polyethersulfone (PES) and with a pore size of 0.2 μm to 1.2 μm. Switching between intravenous and oral administration is appropriate when clinically indicated. Loading dose (ORAL): two capsules (equivalent to 200 mg of isavuconazole) every 8 hours for the first 48 hours (6 administrations in total) followed by a maintenance dose of two capsules (equivalent to 200 mg of isavuconazole) once daily, starting 12 to 24 hours after the last loading dose. Duration of therapy according to clinical response. The safety and efficacy of CRESEMBA in children aged below 18 years have not been established. Contra-indications: Hypersensitivity to the active substance or to any of the excipients; co-administration with ketoconazole, highdose ritonavir, strong and moderate CYP3A4/5 inducers; patients with familial short QT syndrome. Warnings and precautions: CCaution in patients hypersensitive to azole antifungal agents or taking medicinal products known to decrease the QT interval. CRESEMBA infusion should be stopped if infusion-related reactions or severe cutaneous adverse reactions occur. Monitoring of hepatic enzymes should be considered as clinically indicated. Treatment with isavuconazole is not recommended in patients with severe hepatic impairment (Child-Pugh Class C), unless the potential benefit outweighs the risks. Hepatitis has been reported. Drug interactions: Isavuconazole is a substrate of cytochrome P450 isoenzyme CYP3A4/5; inducers and strong inhibitors of this enzyme may change its plasma levels. Isavuconazole is a moderate inhibitor of CYP3A4/5, a mild inducer of CYP2B6, and a mild inhibitor of

P-glycoprotein (P-gp), organic cation transporter 2 (OCT2), and uridine diphosphateglucuronosyltransferases (UGT) and in vitro, inhibitor of BCRP. Co-administration of CRESEMBA with drugs that are substrates for these enzymes or transporters may change their plasma levels. Monitoring the plasma levels or biological effects of these drugs and appropriate dose adjustment may be required. See SmPC for interaction tables and further information. Pregnancy and lactation: Not be used except in severe or potentially life-threatening fungal infections, if the anticipated benefits outweigh the possible risks to the foetus. Discontinue breastfeeding during treatment. Side-effects: Common (incidence ≥1/100 to <1/10): neutropenia, thrombocytopenia, pancytopenia, leukopenia, anaemia, hypokalaemia, decreased appetite, delirium, headache, somnolence, thrombophlebitis, dyspnoea, acute respiratory failure, vomiting, diarrhoea, nausea, abdominal pain, elevated liver chemistry tests, rash, pruritus, renal failure, chest pain, fatigue, injection site reaction. Uncommon (incidence ≥1/1,000 to <1/100): hypersensitivity, hypomagnesaemia, hypoglycaemia, hypoalbuminaemia, malnutrition, depression, insomnia, convulsion, syncope, dizziness, paraesthesia, encephalopathy, presyncope, neuropathy peripheral, dysgeusia, vertigo, atrial fibrillation, tachycardia, bradycardia, palpitations, atrial flutter, electrocardiogram QT shortened, supraventricular tachycardia, ventricular extrasystoles, supraventricular extrasystoles, circulatory collapse, hypotension, bronchospasm, tachypnoea, haemoptysis, epistaxis, dyspepsia, constipation, abdominal distension, hepatomegaly, hepatitis petechiae, alopecia, drug eruption, dermatitis, back pain, oedema peripheral, malaise, asthenia. Legal Category: S1A. Marketing Authorisation Number (s): EU/1/15/1036/001 (IV); EU/1/15/1036/002 (oral). Marketing Authorisation Holder: Basilea Pharmaceutica Deutschland GmbH, Marie-Curie-Strasse 8, 79539 Lörrach, Germany. Local Representative: Pfizer Healthcare Ireland, Pfizer Building 9, Riverwalk, National Digital Park, Citywest Business Campus, Dublin, 24, Ireland. For further information on this medicine please contact: Pfizer Medical Information on 1800 633 363 or at EUMEDINFO@pfizer.com. For queries regarding product availability please contact: Pfizer Healthcare Ireland, Pfizer Building 9, Riverwalk, National Digital Park, Citywest Business Campus, Dublin 24 + 353 1 467 6500. Last revised: 01/2021. Ref: CM 5_0

For further information on this medicine please contact: Pfizer Medical Information on 1800 633 363 or at medical.information@pfizer.com. For queries regarding product availability please contact: Pfizer Healthcare Ireland, Pfizer Building 9, Riverwalk, National Digital Park, Citywest Business Campus, Dublin 24 + 353 1 467 6500.

Pfizer Healthcare Ireland, 9 Riverwalk, National Digital Park, CityWest Business Campus, Dublin 24, Ireland.

Legal category: S1A. Further information available at www.medicines.ie

This Publication is for Healthcare Professionals Only

PP-CRB-IRL-0146 Date of Preparation December 2021

CONFERENCE: Private Hospitals Association talk Partnerships Page 11 HOSPITAL PHARMACY: Physician Implementation & Pharmacy Recommendations Page 12 VACCINES: Medicines Management and Vaccine Stewardship Page 26 CPD: New onset seizure and Epilepsy Page 31 RESPIRATORY FOCUS: Idiopathic Pulmonary Fibrosis Page 36 FEATURE: Depression and Anxiety in Ireland Page 62

Strength of Balance Introducing JYSELECA – 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

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, VTEs 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 † JAK inhibitor-associated adverse events defined as VTEs, Herpes Zoster reactivation and serious infections.4

Visit strengthofbalance.co.uk to learn more 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 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 film-coated tablets/ bottle Price: Ireland: POA Marketing authorisation number(s): 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. ukmedinfo@gilead.com. Jyseleca® is a trade mark. Date of Preparation: July 2021 UK-RA-JY-202107-00014 Additional monitoring required 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: August 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: August 2021 Job code: UK-RA-JY-202107-00017

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: medsafety@hpra.ie.

January Issue Issue 92

Contents

Foreword

Researcher of the Year Award for Professor William Gallagher P7

Editor As Hospital Professional News’ first issue of 2022 was going to press, the ongoing issue of consultant shortages rattled on. The Irish Hospital Consultants Association (IHCA) has warned that the ongoing shortage across many specialties in the North-East is restricting patients from accessing timely, high-quality medical and surgical care and is contributing massively to growing waiting lists.

Ireland ‘far from where it should be’ in Diabetes care P8 Partnership is key to growth hears Private Hospitals Association Annual Conference P11

More than 5,000 additional people in the North-East are waiting for an outpatient appointment with a hospital Consultant in four specialties, an increase of 49% since 2015, new analysis has revealed.

Three decades of the Irish National Liver Transplant Program P22 Medicines Management and Vaccine Stewardship P26 Calls for Increased Use of Off-Patent Medicines P72

Ambitious new Research Strategy from Trinity College Dublin P79

These lists have also seen the largest increases since 2015 - an average increase of 49%.

REGULARS

In other news this issue, Ireland is "very far from where it should be" in the treatment of children with Type 1 diabetes, an expert in the disease has claimed. A co-ordinated national strategy is vital to confronting the chronic condition, said Consultant Dr Colin Hawkes. Turn to page 8 to read the full story.

Feature: Glucocorticoid Induced Osteoporosis P14 CPD: Epilepsy P31

What are the main factors affecting physician implementation of hospital pharmacist recommendations to optimise medication appropriateness?

Respiratory Focus: Phenotyping and Endotyping in COPD P39 Respiratory Focus: Mild Asthma P45 Respiratory Focus: Cystic Fibrosis P50 22

Clinical R&D: P80 Hospital Professional News is a publication for Hospital Professionals and Professional educational bodies only. Subscription rate for Hospital Professional News ¤60 plus vat per year. All rights reserved by Hospital Professional News. All material published in Hospital Professional News is copyright and no part of this magazine may be reproduced, stored in a retrieval system of transmitted in any form without written permission. IPN Communications Ltd have taken every care in compiling the magazine to ensure that it is correct at the time of going to press, however the publishers assume no responsibility for any effects from omissions or errors.

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

The four specialties of Orthopaedics, Dermatology, Gynaecology and Rheumatology have some of the largest waiting lists and combined they account for half of all those waiting to be assessed by a hospital Consultant in the region. These patients run the risk of either a delayed diagnosis of skin and other cancers or may be living with increased pain while awaiting hip or knee surgery or treatment for arthritis.

ACCOUNTS Rachel Wilson cs.ipn@btconnect.com DIGITAL MARKETING & EDITORIAL EXECUTIVE Danielle Norton danielle@hospitalprofessionalnews.ie CPD Lead Sibongile Swan Mude swan@ipn.ie CONTRIBUTORS Mr Robert Callaghan | Dr Kieran Dalton Dr Richard Conway | Mary E Walsh Tom Fahey | Frank Moriarty Dr Gráinne Sheill | Muriel Pate Dr Gerard Mullane | Dr Albi Chalissery Dr Padraig Ridge | Dr Sinead Walsh Dr Emma McNally | Dr Aoife O’Reilly Professor Eddie Moloney | Clare Foley Professor Eleanor Dunican Ruth Morrow | Philip Watt | Philip Hyland Mark Shevlinc | Jamie Murphy Orla McBridec | Robert Foxa Kristina Bondjersd | Thanos Karatziase Richard P. Bentallf | Anton Martinezf Frédérique Vallières | Dr Chris O’Connell Dr Julia Sopena Falco Professor Aidan McCormick

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That is the question posed by Mr Robert Callaghan and Dr Kieran Dalton, Pharmaceutical Care Research Group, School of Pharmacy, University College Cork, Cork and on page 12 they provide an overview of a peer-reviewed research paper conducted by Dr Kieran Dalton, Dr Aoife Fleming, Professor Stephen Byrne and Professor Denis O’Mahony. As the principal phase of the Covid-19 vaccination programme in Ireland comes to an end, it is a good time to reflect on the important role that pharmacists and their teams have played in the Centralised Vaccination Centres (CVCs). In a special report, Muriel Pate, Medication Safety Specialist Pharmacist in the HSE Quality and Safety Directorate talks about medicines management and vaccine stewardship. Turn to page 26 to read more. January brings our Respiratory Special Focus, carrying a huge range of clinically authored and contributed articles across this therapeutic field. On page 36 we have an update on Idiopathic Pulmonary Fibrosis written by Dr Sinead Walsh and Dr Padraig Ridge whilst on page 45 Dr Aoife O’Reilly and Professor Eleanor Dunican question if it is time to change how mild asthma is managed. I hope you enjoy the issue.

HOSPITAL PROFESSIONAL NEWS IRELAND Ireland’s Dedicated Hospital Professional Publication

HOSPITALPROFESSIONALNEWS.IE | HPN • JANUARY 2022

News

Hospital Pharmacy Annual Congress

In around three months, the European Association of Hospital Pharmacists (EAHP) will be hosting the largest European gathering of hospital pharmacists in Vienna, Austria. The 26th Congress of EAHP, which will take place between the 23rd and the 25th of March 2022 will bring together

healthcare professionals from all over the globe that are seeking to improve their level of training. EAHP’s Scientific Committee, under the lead of Thomas De Rijdt, has prepared an interesting and innovative Congress programme that caters to the educational needs of the profession and

takes into account the latest developments in hospital pharmacy. The 26th edition of EAHP’s Congress – which will also celebrate our association’s 50th anniversary – centres around theme "Hospital pharmacists – changing roles in a changing world".

The Student Programme will explore contemporary ethical challenges in hospital pharmacy practice, while the Pharmacotherapy Session will be looking at advances in heart failure pharmacotherapy. Different seminars will be hosted that will provide attendees with up-todate information on for example working with limited resources, the role of the hospital pharmacist in disaster management, waste reduction, gene and cell therapies, compounding for paediatrics and medication safety. Hands-on workshops will focus on teamwork in the hospital, pharmacoeconomics, quality improvement and quality assurance, the prescribing cascade and patient-centred medication reviews. Registration is possible via EAHP’s website: www.eahp.eu

Pharmacy Commitment to Equity Pharmacists from around the world along with the International Pharmaceutical Federation (FIP) have made a new global commitment to action on accelerating vaccination equity, access and sustainability through pharmacy. The commitment is based on the outcomes of FIP’s 2021 Transforming Vaccination programme, which culminated in a leadership summit on pharmacy-based vaccination policy and advocacy. Building on the outcomes of FIP’s 2020 Transforming Vaccination programme, the 2021 programme, “Accelerating equity, access and sustainability through policy development and implementation”, has explored equity in vaccinations across different angles of age, gender, literacy and education, and interprofessional unity and collaboration in addition to identifying regional priorities across the globe.

Winter Plan Risks HSE ‘Slide Back’ Commenting on the publication of the HSE Winter Plan 202122, Professor Alan Irvine, President of the Irish Hospital Consultants Association (IHCA) said the provision of an additional ¤77 million announced is indeed ‘welcome’, but that the association fears ‘it will not adequately address the serious challenges we are now facing.’ He said, “This is the second winter of Covid-19 and is unlikely to be the last. Without the strategic, empathetic leadership needed to bring forward multiannual plans that are delivered through devolved, local decision making and implementation, we risk slipping back into prepandemic stagnation and not

learning from the challenges faced during the pandemic. “The continued trend of sluggish, centralised and politically driven decisions is losing precious time for those of us on the ground and for our patients. “The very fact that the Winter Plan has been published in midNovember, whilst the service is already bearing the brunt of increased pressures and winter illnesses, does not invoke confidence or trust in our health service management. “In fact, it only shortens the time period that we have to put in place effective measures to address the winter surge in hospital admissions resulting from the circulation of

JANUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

Covid-19, influenza and other respiratory viruses at the same time. The equally slow pace of decision and action on Covid-19 booster jabs is also playing out in hospitals, with many healthcare staff at risk of being or currently out with the virus. “The Winter Plan cannot now deliver on the beds promised in the time given. The numbers are evident as we now see a gap of around 350 desperately needed acute hospital beds – and we are already feeling the effects of that shortfall. Incredibly, after 20 months of the pandemic and many additional billions of euro allocated to the HSE budget, we have fewer ICU beds on a population basis than in 2009.* “Nor does this Winter Plan provide

clear investment or actions to recruit the professionals required to fill beds with patients and treat them with the timely care they need. “Additional Consultants need to be appointed, on terms to be agreed with their representative bodies, together with more facilities and better infrastructure to take Ireland’s acute public hospitals and patients through the difficult months - and years – ahead. “In an already overstretched public hospital service, these shortfalls will make addressing the continuing increases in demand for care in our public hospitals even more challenging, at a time when our staff and patients are exhausted by stress, delays and Covid-19.”

News

Researcher of the Year Accolade for Professor Gallagher Science Foundation Ireland (SFI) has named Professor William Gallagher its Researcher of the Year, in honour of his many outstanding achievements in the field of cancer research. The UCD researcher was awarded the prestigious prize at this year’s SFI Science Summit, held digitally for a second time, an annual event where members of Ireland’s research community come together to celebrate and discuss significant contributions made to science, technology, engineering, and maths. “I am indebted to the various members of my research group, both past and present, along with other colleagues in academia and

industry across the world that I have had the great pleasure to collaborate with,” said Professor Gallagher on receiving the award. “One in two people in Ireland will be diagnosed with cancer at some point in their lifetime. Indeed, practically every family in the country is being or has been affected in some way by this complex collection of diseases, including my own. Our cancer research work has been focused on taking new discoveries from the laboratory bench and bringing them closer to clinical implementation.” The Conway Fellow was not the only UCD researcher to be recognised at the 2021 SFI

Professor William Gallagher

Science Summit, as Dr Dara Stanley was named ‘Early Career Researcher of the Year’, Professor Helen Roche won ‘SFI Mentorship Award’, and ‘Science Image of the Year’ was awarded to Dr Aileen Doran.

Professor Lambe Recognised for Vaccine Innovation Pictured with Pat Kenny is Associate Professor Teresa Lambe, who has recognised at the 2021 UCD Alumni Awards. Professor Lambe, a graduate from University College Dublin played a pivotal role in the fight against Covid-19, as the Principal Investigator at the Jenner Institute, which oversaw the University of Oxford's development of OxfordAstraZeneca – a vaccine that has been administered to nearly half a billion people worldwide. The Kildare native worked for 10 months to co-develop the vaccine, leading the pre-clinical studies required to allow clinical trials to commence in April 2020. Professor Lambe, who completed her graduate studies at UCD in 2002 as well as studied pharmacology and molecular genetics at the University in 1997, is an Associate Professor and Principal Investigator in the Medical Sciences Division at the University of Oxford.

New Strategy to Strengthen Specialist Doctor Training The Forum of Irish Postgraduate Medical Training Bodies has developed a Strategic Framework to guide the further development of postgraduate medical education and training in the decade to 2030. The Framework is designed to provide leadership and direction while identifying the key areas for immediate and longer-term action, delivered by targeted collaborative initiatives and programs. It will align with identified workforce planning needs and major policy initiatives across the health system in Ireland. This represents the culmination of over two years of consultation and consensus seeking,

involving representatives of the Postgraduate Training Bodies and Training Managers, the National Doctors Training & Planning programme of the HSE (NDTP), The Medical Council, The Department of Health, Sláintecare Programme and others in the Healthcare Provider and Academic sectors. It expresses renewed commitment to work collectively and in partnership with all major stakeholders to assure continued excellence in training in Ireland. The vision for future medical training is both patient-focused and trainee-centred. It aligns with the needs of our future health service and acknowledges

an ethical commitment to our global health responsibilities. This will yield clear benefits in patient outcomes and justify the continued public investment and expenditure. It is mindful of the lessons of patient experience and recognises the fundamental obligation to earn and sustain trust and confidence in medical expertise. The strategy recognises that doctors of the future will need a skill set which differs from those held by previous generations. The Strategic framework contains five primary initiatives focused on delivering the following:

2) Greater collaboration to support more effective teamwork and use of technology to serve patient needs. 3) Collection and use of data to measure training & develop actionable insights to improve training and patient safety. 4) Greater alignment between future healthcare planning and developments within postgraduate training in Ireland. 5) Provide oversight to a programme of strategic investment in Postgraduate Education and Training.

1) Accelerated, targeted improvements in training for trainees and trainers.

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News

Ireland – ‘Far from Where it Should be’ in Diabetes Dr Colin Hawkes, Consultant Paediatric Endocrinologist, Cork University Hospital

Advances in technology, however, have largely replaced the fingerstick glucose checks with glucose monitors and insulin injections with insulin pumps. Possible signs of diabetes in children include increased thirst, frequent urination, bed wetting, reduced energy, unexplained weight loss, extreme hunger (possibly with craving for sugary foods) and vaginal thrush.

of this disease," said Dr Hawkes, a paediatric endocrinologist at CUH. “We are very far from where we should be, there is a lot more that we need to be doing to meet the needs of these children and their families. “In CUH alone, we have an exceptional team but we should have six diabetes nurses for the number of children we care for and we only have three. We have submitted a business case requesting three more. It is extremely difficult to provide the care these children deserve at such low staffing levels.

Ireland is "very far from where it should be" in the treatment of children with Type 1 diabetes, an expert in the disease has claimed. A co-ordinated national strategy is vital to confronting the chronic condition, said Consultant Dr Colin Hawkes ahead of World Diabetes Day held in November past.

He and the team at Cork University Hospital treats almost 500 children with Type 1 diabetes, but insufficient resources mean it is not possible to see children every three months, as recommended - with some waiting six-eight months between appointments. “We are also totally unequipped to address the psychological burden

“We also should be at the forefront of research in this condition and are working to generate energy and funding to build a research team and programme. This will help change the future of this condition.” In Type 1 diabetes, the immune system attacks the pancreas, destroying cells that make insulin crucial for sending glucose (sugars) to the body's cells for energy. When a child is diagnosed, they must learn to detect glucose levels and administer insulin throughout the day and night.

“We know that if it is not properly controlled, it increases the risk of heart disease, blindness and kidney failure in adulthood. It is extremely important to get it right. This is critical in childhood, where we are setting the child on a life-long journey in managing this condition. “The aspiration should be that every child should have access to the same and the best standard of care, regardless of where they live. There is not equity in Ireland in access to a full diabetes multidisciplinary team. “Cork is the largest centre in Ireland without a dedicated psychologist to support these families. “CUH is a regional centre of excellence for children with type 1 diabetes in the South/Southwest Hospital Group. In addition to our local children, we provide diabetes expertise for children in Kerry and as far as Clonmel (Tipperary). “Rather than bringing children long distances to us, appropriate staffing of the diabetes programme at Cork would allow our diabetes team to perform regional outreach clinics. In my view, that should be the model.”

Body Clock and Inflammatory Disease Link New research from RCSI has demonstrated the significant role that an irregular body clock plays in driving inflammation in the body’s immune cells, with implications for the most serious and prevalent diseases in humans. The research was led by the School of Pharmacy and Biomolecular Sciences at RCSI University of Medicine and Health Sciences. The circadian body clock generates 24-hour rhythms that keep humans healthy and in time

with the day/night cycle. This includes regulating the rhythm of the body's own (innate) immune cells called macrophages. When these cell rhythms are disrupted (due to things like erratic eating/ sleeping patterns or shift work), the cells produce molecules which drive inflammation. This can lead to chronic inflammatory diseases such as heart disease, obesity, arthritis, diabetes and cancer, and also impact our ability to fight infection. In this study, the researchers looked at these key immune

JANUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

cells called macrophages with and without a body clock under laboratory conditions. They were interested to understand if macrophages without a body clock might use or 'metabolise' fuel differently, and if that might be the reason these cells produce more inflammatory products. The researchers found that macrophages without a body clock took up far more glucose and broke it down more quickly than normal cells. They also found that, in the mitochondria (the cells energy powerhouse), the pathways

by which glucose was further broken down to produce energy were very different in macrophages without a clock. This led to the production of reactive oxygen species (ROS) which further fuelled inflammation. Dr George Timmons, lead author on the study, said, “Our results add to the growing body of work showing why disruption of our body clock leads to inflammatory and infectious disease, and one of the aspects is fuel usage at the level of key immune cells such as macrophages.”

▼ The Next Line Is Clear¹

LORVIQUA as monotherapy is indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) whose disease has progressed after: •

lectinib or ceritinib as the first ALK tyrosine kinase a inhibitor (TKI) therapy; or

•

crizotinib and at least one other ALK TKI.1

References: 1. Lorviqua® Summary of Product Characteristics. PRESCRIBING INFORMATION ▼This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. Refer to section 4.8 of the SPC for how to report adverse reactions. Lorviqua®▼ 25 mg and 100 mg film-coated tablets IE Prescribing Information: Before prescribing Lorviqua (lorlatinib) please refer to the full Summary of Product Characteristics (SmPC). Presentation: Each 25 mg film-coated tablet contains 25 mg lorlatinib; Each 100 mg film-coated tablet contains 100 mg lorlatinib. Indications: Lorviqua as monotherapy is indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK) positive advanced non small cell lung cancer (NSCLC) whose disease has progressed after alectinib or ceritinib as the first ALK tyrosine kinase inhibitor (TKI) therapy, or crizotinib and at least one other ALK TKI. Dosage and Administration: Treatment should be initiated and supervised by a physician experienced in the use of anticancer medicinal products. The recommended dose is 100 mg lorlatinib taken orally once daily. Treatment is recommended as long as the patient is deriving clinical benefit from therapy without unacceptable toxicity. If a dose is missed, then it should be taken as soon as the patient remembers unless it is less than 4 hours before the next dose. Patients should not take 2 doses at the same time to make up for a missed dose. To manage adverse reaction, dose interruption or dose reduction see SmPC section 4.2. Concurrent use of lorlatinib with medicinal products that are strong CYP3A4/5 inhibitors and grapefruit juice products may increase lorlatinib plasma concentrations, see SmPC section 4.2 for further information. Special populations: Elderly (≥ 65 years): There are limited data on this population, no dose recommendation can be made for patients aged 65 years and older (see section 5.2). Renal impairment: See SmPC section 4.2. No dose adjustment is required for patients with mild or moderate renal impairment. A reduced dose of lorlatinib is recommended in patients with severe renal impairment (absolute eGFR < 30 mL/min), e.g. a once daily starting dose of 75 mg taken orally (see SmPC section 5.2). No information is available for patients on renal dialysis. Hepatic impairment: See SmPC section 4.2. No dose adjustment is required for patients with mild hepatic impairment. No information is available for lorlatinib in patients with moderate or severe hepatic impairment. Therefore, lorlatinib is not recommended in patients with moderate to severe hepatic impairment (see section 5.2). Paediatric population: The safety and efficacy of lorlatinib in children and adolescents < 18 years of age have not been established. Method of administration: Lorlatinib is for oral use. Patients should be encouraged to take their dose of lorlatinib at approximately the same time each day with or without food (see SmPC section 5.2). The tablets should be swallowed whole (tablets should not be chewed, crushed or split prior to swallowing). No tablet should be ingested if it is broken, cracked, or otherwise not intact. Contra-indications: Hypersensitivity to the active substance or to any of the excipients. Concomitant use of strong CYP3A4/5 inducers (see SmPC sections 4.4 and 4.5). Special Warnings and Precautions: Hyperlipidaemia: The use of lorlatinib has been associated with increases in serum cholesterol and triglycerides (see SmPC section 4.8). Serum cholesterol and triglycerides should be monitored before initiation of lorlatinib; 2, 4 and 8 weeks after initiating lorlatinib and regularly thereafter. Initiate or increase the dose of lipid lowering medicinal products, if indicated (see SmPC section 4.2). Central nervous system (CNS) effects: CNS effects have been observed in patients receiving lorlatinib, including psychotic effects and changes in cognitive function, mood, mental status or speech (see SmPC section 4.8). Dose modification or discontinuation may be required for those patients who develop CNS effects (see SmPC section 4.2). Atrioventricular block: Lorlatinib was studied in a population of patients that excluded those with second degree or third degree AV block (unless paced) or any AV block with PR interval > 220 msec. PR interval

prolongation and AV block have been reported in patients receiving lorlatinib (see SmpC section 5.2). Monitor electrocardiogram (ECG) prior to initiating lorlatinib and monthly thereafter, particularly in patients with predisposing conditions to the occurrence of clinically significant cardiac events. Dose modification may be required for those patients who develop AV block (see SmPC section 4.2). Left ventricular ejection fraction decrease: Left ventricular ejection fraction (LVEF) decrease has been reported in patients receiving lorlatinib who had baseline and at least one follow-up LVEF assessment. In patients with cardiac risk factors and those with conditions that can affect LVEF, cardiac monitoring, including LVEF assessment at baseline and during treatment, should be considered. In patients who develop relevant cardiac signs/symptoms during treatment, cardiac monitoring, including LVEF assessment, should be considered. Lipase and amylase increase: Elevations of lipase and/or amylase have occurred in patients receiving lorlatinib (see SmPC section 4.8). Risk of pancreatitis should be considered in patients receiving lorlatinib due to concomitant hypertriglyceridemia and/or a potential intrinsic mechanism. Patients should be monitored for lipase and amylase elevations prior to the start of lorlatinib treatment and regularly thereafter as clinically indicated (see SmPC section 4.2). Interstitial lung disease/Pneumonitis: Severe or life threatening pulmonary adverse reactions consistent with ILD/pneumonitis have occurred with lorlatinib (see SmPC section 4.8). Any patient who presents with worsening of respiratory symptoms indicative of ILD/ pneumonitis (e.g. dyspnoea, cough and fever) should be promptly evaluated for ILD/pneumonitis. Lorlatinib should be withheld and/or permanently discontinued based on severity (see SmPC section 4.2). Hypertension: Hypertension has been reported in patients receiving lorlatinib (see SmPC section 4.8). Blood pressure should be controlled prior to initiation of lorlatinib. Blood pressure should be monitored after 2 weeks and at least monthly thereafter during treatment with lorlatinib. Lorlatinib should be withheld and resumed at a reduced dose or permanently discontinued based on severity (see SmPC section 4.2). Hyperglycaemia: Hyperglycaemia has occurred in patients receiving lorlatinib (see SmPC section 4.8). Fasting serum glucose should be assessed prior to initiation of lorlatinib and monitored periodically thereafter according to national guidelines. Lorlatinib should be withheld and resumed at a reduced dose or permanently discontinued based on severity (see SmPC section 4.2). Interactions: Concomitant use of a strong CYP3A4/5 inducer is contraindicated (see SmPC sections 4.3 and 4.5). No clinically meaningful changes in liver function tests were seen in healthy subjects after receiving a combination of lorlatinib with the moderate CYP3A4/5 inducer modafinil (see section 4.5). Concurrent administration of lorlatinib with CYP3A4/5 substrates with narrow therapeutic indices, including but not limited to alfentanil, ciclosporin, dihydroergotamine, ergotamine, fentanyl, hormonal contraceptives, pimozide, quinidine, sirolimus and tacrolimus, should be avoided since the concentration of these medicinal products may be reduced by lorlatinib (see SmPC section 4.5). Lorlatinib is a weak inducer of CYP2B6, no dose adjustment is necessary when lorlatinib is used in combination with medicinal products that are mainly metabolised by CYP2B6 (see SmPC section 4.5). Lorlatinib is a weak inducer of CYP2C9, no dose adjustment is required for medicinal products that are mainly metabolised by CYP2C9. Patients should be monitored in case of concomitant treatment with medicinal products with narrow therapeutic indices metabolised by CYP2C9 (e.g. coumarin anticoagulants) (see SmPC section 4.5). Lorlatinib is a weak inducer of UGT, no dose adjustment is required for medicinal products that are mainly metabolised by UGT. Patients should be monitored in case of concomitant treatment with medicinal products with narrow therapeutic indices metabolised by UGT (see SmPC Section 4.5). Lorlatinib is a moderate inducer of P gp. Medicinal products that are P gp substrates with narrow therapeutic indices (e.g. digoxin, dabigatran etexilate) should be used with caution in combination with lorlatinib due to the likelihood of reduced

PP-LQA-IRL-0068

Preparation Date: September 2021

plasma concentrations of these substrates. Lorlatinib should be used with caution in combination with substrates of BCRP, OATP1B1, OATP1B3, OCT1, MATE1 and OAT3 as clinically relevant changes in the plasma exposure of these substrates cannot be ruled out (see SmPC section 4.5). Fertility, pregnancy and Breast-feeding: Fertility: Male fertility may be compromised during treatment with lorlatinib (see SmPC section 5.3). Men should seek advice on effective fertility preservation before treatment. It is not known whether lorlatinib affects female fertility. Pregnancy: Lorlatinib is not recommended during pregnancy or for women of childbearing potential not using contraception. Women of childbearing potential should be advised to avoid becoming pregnant while receiving lorlatinib. A highly effective non hormonal method of contraception is required for female patients during treatment because lorlatinib can render hormonal contraceptives ineffective (see SmPC sections 4.5 and 4.6). If a hormonal method of contraception is unavoidable, then a condom must be used in combination with the hormonal method. Effective contraception must be continued for at least 35 days after completing therapy (see SmPC section 4.6). During treatment and for at least 14 weeks after the final dose, male patients with female partners of childbearing potential must use effective contraception, including a condom, and male patients with pregnant partners must use condoms (see SmPC section 4.6). Breast-feeding: Lorlatinib should not be used during breast feeding. Breast feeding should be discontinued during treatment and for 7 days after the final dose. Lactose intolerance: This medicinal product contains lactose as an excipient. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose galactose malabsorption should not take this medicinal product. Effects on ability to drive and use machines: Lorlatinib has moderate influence on the ability to drive and use machines. Caution should be exercised when driving or operating machines as patients may experience CNS effects (see SmPC section 4.8). Undesirable Effects: See SmPC section 4.8. The overall safety profile of lorlatinib is presented from data from 295 adults treated with lorlatinib 100 mg once daily with advanced NSCLC from Study A (Phase II 1001 (n=275), Phase I (n=17), Japanese Cohort (n=3)). The most common (≥2%) Grade ≥3 adverse reactions of lorlatinib were Anaemia, Hypercholesterolaemia, Hypertriglyceridaemia, Cognitive effects, Peripheral neuropathy, Oedema, Weight increased, Lipase increased, Amylase increased. Commonly reported adverse events (≥ 1/100 to < 1/10) were Hyperglycaemia, Psychotic effects, Mental status changes, Speech effects, Pneumonitis. Dose reductions due to adverse reactions occurred in 23.4% of patients receiving lorlatinib. Very common (≥ 1/10) adverse reactions in patients receiving lorlatinib in this study were Anaemia, Hypertension, Hypercholesterolaemia, Hypertriglyceridaemia, Mood effects, Cognitive effects, Peripheral neuropathy, Headache, Vision disorder, Diarrhoea, Nausea, Constipation, rash, Arthralgia, Myalgia, Oedema, Fatigue, Weight increased, Lipase increased, Amylase increased. Common (≥ 1/100 to < 1/10) adverse effects were Speech effects, Pneumonitis. Legal Category: S1A. Package quantities and Marketing Authorisation Numbers: Lorviqua 25 mg film-coated tablets EU/1/19/1355/003, 90 tablets. Lorviqua 100 mg film-coated tablets EU/1/19/1355/002, 30 tablets. For further information on this medicine please contact: Pfizer Medical Information on 1800 633 363 or at EUMEDINFO@pfizer.com For queries regarding product availability please contact: Pfizer Healthcare Ireland, Pfizer Building 9, Riverwalk, National Digital Park, Citywest Business Campus, Dublin 24 + 353 1 4676500. Marketing Authorisation Holder: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium. Date of Preparation: 07/2021 Ref: LQ 5_0

10 News

First in Prostate Cancer at Blackrock Blackrock Clinic CEO James O'Donoghue

the development saying, “At the Blackrock Clinic we strive to provide the most advanced care to all of our patients. The PSMA PET/CT scan using the Fluorine-18 radioisotope is the latest technology we have introduced specifically to improve men’s health and wellbeing.”

Blackrock Clinic is now providing a new type of scan for prostate cancer. The PSMA (Protein Specific Membrane Antigen) is labelled with F-18 and the PET/ CT scan is used to detect the F-18 PSMA within the body for the first time in Ireland. PSMA provides the most accurate staging evaluation for men with prostate cancer. The scan is most popular for patients who have previously had prostate cancer and are now representing with concern of disease recurrence, most frequently with elevated prostate-specific antigen (PSA). PSMA can also be used as a staging tool to more accurately detect the spread of prostate cancer in a newly diagnosed patient. Due to difficulties accessing this scan in Ireland,

many Irish patients currently have to go overseas to the UK or Europe for these scans.

Blackrock Clinic is the only private hospital in the country offering such a scan and agreement has been reached with the VHI to fund this diagnostic test for members

on certain plans. If a patient’s insurer does not cover the cost of this scan, it is available on a selfpay basis. Internationally, these scans are widespread in the evaluation of prostate cancer. PSMA PET/CT is now considered the best staging tool for the most common cancer affecting men, representing a new standard of care. However, in Ireland, only one public hospital is currently providing PSMA PET/CT scanning which means that there are long delays in accessing this important diagnostic tool. Being the first hospital to provide PET/CT in Ireland in 2000, Blackrock Clinic is delighted with this development as it will significantly improve access to these valuable scans for patients and consultants.

The PSMA PET/CT Scan uses nuclear isotopes in Fluorine-18 to detect certain proteins in the body by attaching to and “lighting up” on a scan when they come into contact with cancerous growths. Professor Stephen Connolly, a Consultant Urologist at the Blackrock Clinic said, “This is very good news for men with prostate cancer. This simple and effective scan will help to quickly and accurately evaluate prostate cancer, which in turn will lead to better precision in treatment and improvements in outcome.” CEO of the Blackrock Clinic, James O’Donoghue welcomed

'Normal PSMA' scan - Citation: R.W. Foley, S.L. Redman, R.N. Graham, W.W. Loughborough, D. Little, Fluorine-18 labelled prostate-specific membrane antigen (PSMA)-1007 positron-emission tomography–computed tomography: normal patterns, pearls, and pitfalls, Clinical Radiology, Volume 75, Issue 12, 2020, Pages 903-913, ISSN 0009-9260, https://doi. org/10.1016/j.crad.2020.06.031. (https://www.sciencedirect.com/science/ article/pii/S0009926020302737)

HIQA Advises NSAC on Ethics Frameworks The Health Information and Quality Authority (HIQA) has published a review of international ethics frameworks to help inform the work of the National Screening Advisory Committee (NSAC). NSAC is developing an ethics framework to support its evaluations and deliberations in relation to population-based screening programmes in Ireland. The development of this framework follows the

recommendations of the Scoping Inquiry into the CervicalCheck Screening Programme by Dr Gabriel Scally ('the Scally Report'), which emphasised the role of ethics in the consideration of programmes. HIQA’s review identified and described ethics frameworks used internationally for policy-making in the context of screening. Sources for the review included bodies with responsibility for screening policy-making, public health

JANUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

agencies, national ethics bodies, and international agencies. While considerable variation was found in the content and structure of the frameworks identified, consistencies were noted in the ethical principles and procedural values that are considered. Several frameworks highlighted the need to consider the relevance and relative importance of values or principles within different contexts of screening (for example, adult versus child programmes), and

the possibility that some values and principles may conflict with each other. Furthermore, as public health decisions related to screening are taken at the population or community level, the values and principles that guide these decisions differ from those that guide traditional clinical decision-making. Therefore, it is important to balance the consideration of the benefits and harms of screening as they relate to the overall population and for the individual.

Conference 11

Private Hospitals Association Committed to New Era of Partnership Bill Maher speaking at the Private Hospitals Association annual conference

Key Research Findings • 62% of people believe private care should be removed from the public hospital system.

between our sectors arising from our shared experiences since March 2018. This, in my view, paves the way for new pathways of working and collaborating together that will achieve improved outcomes for all patients.”

A sizable majority of Irish people believe healthcare in Ireland should be planned and delivered by the public and private healthcare sectors both working in partnership to help address the country’s key acute hospital problems. The finding contained in research published by the Private Hospitals Association also highlights a fall in public support and understanding of Sláintecare, with 46% of those surveyed considering that the key aims of Sláintecare are achievable. The research results were presented at a special conference hosted by the Private Hospitals Association in Dublin, and revealed that amongst 1000 people recently surveyed, 65% admitted to having a poor understanding of Sláintecare and its goals. While 62% of those surveyed believe that private care should be removed from the public hospital system, almost 7 out of 10 surveyed (69%) believe healthcare in Ireland should be planned and delivered by both the private and public sectors working in partnership rather than on a separate basis. An even more sizable 83% of people say both sectors should work jointly to clear the large backlog that exists in hospital waiting lists. Private Hospitals Association member hospitals operate almost one-third of the acute hospitals in Ireland. PHA members treat over 400,000 patients annually in 18 hospitals located throughout Ireland. The half-day conference event which was addressed by Minister for Health, Stephen Donnelly, focussed on the changing

• 69% believed healthcare in Ireland should be planned and delivered by both sectors working together in partnership rather than on a standalone basis – 31% say it should be standalone.

A special focus of the conference was on current and future trends in private health care – how patient care will evolve over the next five to ten years and the priorities for investment to ensure provision of the most up-to-date and appropriate treatments. The Conference also looked at the partnership role with health insurers going forward and the global trend of focusing on keeping people in good health, as well as making them better.

relationship between private hospitals and the wider health sector in Ireland; the key lessons being learned from the COVID-19 pandemic; and the potential for new partnership models aimed at addressing the pressing health needs of our population. In his keynote address to the Conference, incoming Chairman Bill Maher, highlighted the potential for a new era of engagement, collaboration and partnership between the private and public healthcare systems in Ireland following on from the experiences gathered over the extraordinary 20 month period since the Covid-19 pandemic took hold here. He said, “While there can be few silver linings arising from a global pandemic, one significant positive we can point to is the greater level of understanding that now exists

• The public is divided on whether Sláintecare is achievable - 46% deemed it achievable, 54% said not. • 62% say it will take at least 15-20 years to implement Sláintecare if at all. • 69% also believe that both sectors should also work in partnership to deliver the extra 2,600 new hospital beds promised under Sláintecare over the next 15 years.

The event came at an important juncture as the fallout continues from the impact of the Covid-19 pandemic on Irish healthcare delivery; as outpatient waiting lists in Ireland approach record highs and significant questions are being asked about the national strategy on the future of health care, Sláintecare.

• 83% say hospital waiting lists should be tackled in partnership with the private system rather than the public system seeking to resolve the problem alone. • 58% of those surveyed had private health insurance.

The Private Hospitals Association Conference which took place online and came live from the Herbert Park Hotel, featuring a range of speakers including the Minister for Health, private healthcare providers, insurers, health economists, pharma and med-tech leaders and the HSE.

• Of the 50% of those who had recently sought to access private healthcare, 67% of those described their experience as either very good or good, 21% as okay and 12% as poor.

67% rate their experience of accessing private hospital treatment good or very good, down 5%. 12% rate the experience as poor or very poor.

Experience of Accessing Private Hospital Treatment

Very Good

Good

Okay

Poor

Very Poor

31%

36%

21%

12%

67%

Q: Please rate your experience based on the following categories: My experience was... (Single select, n=496).

www.ireachhq.com

HOSPITALPROFESSIONALNEWS.IE | HPN • JANUARY 2022

Hospital Pharmacy

Physician implementation of hospital pharmacist recommendations What are the main factors affecting physician implementation of hospital pharmacist recommendations to optimise medication appropriateness? attributed to implementation rates, very little research had been conducted to explore in depth the main factors affecting physicians’ implementation of hospital pharmacist recommendations. Therefore, researchers from University College Cork decided to investigate this by conducting oneon-one semi-structured interviews with hospital pharmacists and physicians from two Irish teaching hospitals. In total, 14 interviews were performed, including six pharmacists (sampled based on experience) and two physicians from each of the following grades: intern, senior house officer, registrar, and consultant. At the time of the interviews, pharmacists did not have prescribing authority within either hospital, and primarily worked according to a wardbased clinical pharmacy model. Outlined below are the five major themes that were generated from the interviews, which describe the main factors affecting physicians’ implementation of hospital pharmacist recommendations. 1. Clinical relevance and complexity of the recommendation

Written by Mr Robert Callaghan (top) and Dr Kieran Dalton, Pharmaceutical Care Research Group, School of Pharmacy, University College Cork, Cork, Ireland Hospital pharmacists play a key role in identifying and resolving instances of potentially inappropriate prescribing, particularly in multimorbid older patients with polypharmacy. This has been backed up by evidence from many randomised controlled trials showing that pharmacists reduce the incidence of adverse drug reactions, emergency department visits, and medicationrelated readmissions. Importantly, pharmacist interventions with a high proportion of medication recommendations implemented by physicians are more likely to achieve significant improvements in patient outcomes compared to those with lower implementation rates, which generally result in non-significant patient outcomes. However, despite the importance

Clinical relevance and priority: Put simply, recommendations that are of high clinical relevance and clearly provide patient benefit or prevent patient harm will be implemented. Physicians are more likely to prioritise the implementation of recommendations on patients’ acute issues, as that is their focus in hospital. The urgency with which the recommendation must be addressed affects its prioritisation relative to physicians’ other work commitments. “…it's probably something that might not be deemed particularly important or it's not going to cause any adverse effect, at least in the short term. You know, those kinds of things would be slower to be acted upon, maybe because people would have graded it in their head as to how important that particular intervention is based on other jobs that they have to do that day” [Pharmacist 3] Recommendations related to issues that are less clear-cut – the “grey areas”, as one pharmacist described – are less likely to be implemented as they may not be

JANUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

as straightforward or not supported by evidence-based guidelines. These recommendations therefore require greater knowledge and decision-making, and less likely to be implemented by junior doctors practising in the hospital. 2. Interprofessional communication Route of communication: Recommendations provided verbally, especially when communicated face to face, are significantly more likely to be implemented than those in written format. This is likely because a synchronous verbal discussion allows the pharmacist to best explain their rationale, and thereafter the physician can clarify their choice for implementation or not. Pharmacist manner and language: Pharmacist recommendations delivered in a clear, confident, and assertive way are much more likely to be implemented. However, it was pointed out that there is a fine balance between assertiveness and arrogance; with pharmacists often playing a ‘corrective role’, it is important that this is not misconstrued. Therefore, one way that pharmacists can facilitate implementation is by adjusting their language to minimise causing offence. “…we do not want to be arrogant either by coming in and saying ‘you are wrong’. My recommendations are always ‘consider doing this’, because the recommendations I have made are based on this guideline” [Pharmacist 2] 3. Prescriber role and identity Physician grade and experience: The physician’s level of experience was emphasised as important. Most interviewees acknowledged that junior doctors would be more likely to implement pharmacists’ recommendations. However, it was noted that this may in some cases be a blind trust, either due to a lack of knowledge or due to hierarchical influences. “I remember back when I was an intern and I would have trusted everybody more senior than me, which would have been everyone. So, I might have just done it without thinking about it too much…” [Physician 6]

In other scenarios, particularly for more complex decisions, junior doctors may be less likely to implement pharmacist recommendations, as they may not have the authority to act upon them – deferring responsibility to their seniors. “I feel like I do not have the power to make the pharmacy decisions really. So, really, I would have to talk to the registrar or the consultant on the service…” [Physician 7] It was highlighted that senior doctors may be more resistant to pharmacists’ recommendations, and that their views can have an important “trickle-down effect” that influences their junior colleagues to either be welcoming or dismissive of pharmacist recommendations. Specialty: Typically, when a pharmacist recommendation concerns a medication in a physician’s specialty, it is likely that a physician will readily accept any appropriate recommendations. However, an interesting contrast appeared regarding recommendations that are less explicitly aligned to the specialty of physicians. Some implement more recommendations as they welcome pharmacists’ advice in areas beyond the physicians’ expertise. Conversely, other specialists may be slower to implement pharmacist recommendations beyond their perceived scope of practice, especially when it may encroach on other specialists’ areas of expertise. Personality: Interviewees explained that the physician’s personality can be another factor affecting implementation, with some physicians being open-minded and willing to take recommendations on board, whilst others are less receptive to pharmacists’ advice – which may be viewed as a challenge to physicians’ judgement or encroachment on their role. “We have very supportive physicians, they are very supportive of pharmacy and are very happy to take your recommendations on board and would always thank us for flagging things. And then we would have physicians who do not like to be questioned on their treatment decisions.” [Pharmacist 2]

13 4. Knowing each other and developing trusting relationships Knowing each other: Although not essential, interviewees indicated that a physician knowing the pharmacist facilitates implementation. Familiarity enhances pharmacistphysician interactions, supports the development of collaborative relationships, and contributes to regular uptake of recommendations. However, it was evident from the interviews that pharmacists placed a greater importance on knowing each other than the physicians. “…it's definitely important that… they know you I suppose, that they have seen you around, they know who you are… they have had positive interactions with you before definitely I think improves the likelihood that they'll take on board what you have to say.” [Pharmacist 5] Relationship-building: Sharing a greater rapport and interpersonal connection increases the likelihood of implementation. However, frequent staff changeovers hinder pharmacists’ formation of these relationships, particularly with junior doctors, and therefore “starting from scratch again” with the need to recurrently develop new pharmacist-physician relationships. Trusting pharmacists’ recommendations: It was found that physicians may not be aware of pharmacists’ training, skills, or roles in medication optimisation, which can influence their trust in pharmacists’ recommendation. Building trust usually takes time; one way this can be achieved is by pharmacists consistently providing high-quality recommendations to the physician. “I think once you prove yourself to them a bit, they warm to you a bit. I suppose it would be the same as any new doctor. They'd be slow to trust you until there's trust there.” [Pharmacist 1]. When trust has been established, this may be manifested as physicians seeking out and approaching pharmacists for advice, and subsequently implementing their recommendations. 5. The hospital environment Timing and opportunity: Despite the preference for face-to-face discussions, it is not always possible for pharmacists to have a clear opportunity to meet with physicians in the busy hospital environment, thus often relying

on impromptu opportunistic encounters on wards and corridors. It was indicated that implementation would be facilitated by pharmacists having a prescheduled time to discuss their recommendations, such as a ward round or multidisciplinary team meeting. “…unless you are on a round with them, it's difficult to find [an opportunity to meet] afterwards. You're running around bleeping people, nosing into doctors' rooms to see if someone is in there…so it can be…it can make it difficult” [Pharmacist 4] Documentation in health records: When there is insufficient information about the physicians' plan for the patient documented in health records, this can contribute to pharmacists making recommendations that are of lower relevance or not in line with the physicians' plan, therefore meaning recommendations are less likely to be implemented.

may be communicated more often in written form, and therefore may not be implemented as readily. However, even with face-to-face communication, this research demonstrates that implementation may be hampered if the recommendation recipient is not a decision-maker on the medical team. It would therefore be prudent, where possible, to have more scheduled discussions between pharmacists and senior physicians, rather than solely relying on spontaneous interactions. Pharmacist involvement with ward rounds has been shown to significantly reduce preventable adverse drug events as it provides pharmacists the opportunity to proactively prevent inappropriate prescribing, rather than the more traditional reactive role of retrospectively reviewing patients’ prescriptions.

With interviewees emphasising the importance of pharmacists and physicians working as part of a team, consideration should be given to the clinical pharmacy models used in hospitals. Previous research from Tallaght University Hospital has shown that a team-based pharmacist approach resulted in significantly more recommendations being implemented compared to standard ward-based care (95.9 versus 69.3%), with only the team-based approach resulting in a significant improvement in medication appropriateness. Moreover, the team-based recommendations were implemented earlier, which may be vital in the prevention of adverse drug reactions. However, with team-based models, pharmacists may not be able to review the same number of patients, therefore necessitating increased staffing levels.

“You know it's so much better to work with the physicians as a team rather than work with them in isolation on the ward. They do not get to know you. They do not build a relationship” [Pharmacist 6]

With recurrent hospital staff changeover, it is important that pharmacists develop strong relationships with senior physicians; this modelling of trust with pharmacists should have the “trickle-down effect” described to encourage junior physicians to trust pharmacists and implement their recommendations. However, what was clear from the interviews, and which may hinder the formation of such relationships, was the hierarchical culture in hospitals. It was described how pharmacists often utilise indirect communication methods to facilitate implementation (e.g. gentle reminders, suggestions, questions) to minimise embarrassment or defensive behaviour from physicians. This type of culture impedes teamwork in healthcare; whilst greater interprofessional education has been suggested as a strategy to increase collaboration between healthcare professionals, further evidence is required to explicitly show its impact on patient outcomes.

Implications of this research

What is already known about this subject

This study supports previous research which showed that synchronous two-way discussion and face-to-face contact not only help with the implementation of pharmacist recommendations, but are also key components in developing collaborative pharmacist-physician working relationships. It additionally reiterates that pharmacists’ written recommendations are less likely to be implemented by physicians. Although, this may be confounded by the fact that less urgent recommendations or those of lower clinical relevance

• Some pharmacist interventions have a lower proportion of recommendations implemented by physicians, which are more likely to result in non-significant patient outcomes compared to pharmacist interventions with high implementation rates.

Staffing levels and pharmacist presence: Insufficient levels of hospital pharmacists were found to be an issue. With a greater pharmacist presence, this would increase accessibility to physicians and face-to-face discussions, and allow more time for collaborative teamwork – all contributing to more recommendations being implemented. Working as a team: Interviewees on both sides indicated that the hospital pharmacist may often be perceived as an “outsider”, and affirmed that pharmacists who work closely with physicians as part of a team are more likely to have their recommendations implemented.

Conclusion This study has generated a greater understanding of the key factors affecting physician implementation of pharmacist recommendations. It is therefore important to consider these facilitators and barriers in order to enhance the implementation of pharmacists’ recommendations, and ultimately to optimise both medication appropriateness and patient safety going forward. The article above was Written by Mr Robert Callaghan (4th year pharmacy student) and Dr Kieran Dalton, and is based on a peer-reviewed research paper conducted by Dr Kieran Dalton, Dr Aoife Fleming, Professor Stephen Byrne (School of Pharmacy, University College Cork), and Professor Denis O’Mahony (Cork University Hospital). For more information on this study, please review the open access paper at: https://bpspubs. onlinelibrary.wiley.com/doi/ full/10.1111/bcp.14987

• There is a paucity of qualitative research that has explored the underlying behavioural determinants of physician nonimplementation of pharmacist recommendations. What this study adds • This study reveals the key factors affecting physician implementation of hospital pharmacist recommendations: the clinical relevance and complexity of recommendations; the method of interprofessional communication; the physician role and identity; the nature of the pharmacist–physician relationship; and the hospital environment. These factors must be considered in designing future pharmacist interventions.

HOSPITALPROFESSIONALNEWS.IE | HPN • JANUARY 2022

Osteoporosis

Management of Glucocorticoid Induced Osteoporosis Written by Dr Richard Conway, Consultant Physician & Rheumatologist, St James's Hospital

DXA

Introduction Glucocorticoids are currently an indispensable part of the treatment approach to a wide variety of medical conditions. While generally extremely effective, at least temporarily, the multitude of attendant adverse events associated with glucocorticoid use should see them viewed as “our best of drugs, our worst of drugs”. These adverse events included hypertension, diabetes mellitus, infection, weight gain, muscle weakness, and of particular relevance to the current conversation, osteoporosis and increased fracture risk.1 Glucocorticoid effect on bone Glucocorticoids are an essential part of the physiology of the normally functioning human body. Conceptually many glucocorticoid induced adverse events can be thought of as an amplification of the normal physiologic roles of glucocorticoids. Glucocorticoids induce an early high bone turnover state. The consequences of this can be rapid and profound with increased fracture risk evident within three months of glucocorticoid initiation. If glucocorticoids are continued over a prolonged timeframe this switches to a low bone turnover state with a net loss of bone strength due to a more marked effect on synthesis than resorption. The highest rate of bone loss occurs within the first 3-6 months of glucocorticoid use however bone density continues to progressively decline at a slower rate with ongoing treatment.2 Both higher daily glucocorticoid dose and higher cumulative glucocorticoid dose are associated with a progressive increase in fracture risk.

While glucocorticoids will reduce bone mineral density as measured by DXA, they also increase fracture risk independent of bone mineral density. Therefore, at any given bone mineral density, the fracture risk is increased in individuals receiving glucocorticoids. This is reflected in the incorporation of glucocorticoids in the FRAX fracture risk prediction model. While the majority of individuals receiving long-term glucocorticoids should have a DXA scan performed, it is of greater importance to perform a clinical fracture risk assessment, using a formalised tool such as FRAX or using clinician gestalt. Those identified as being at moderate or high risk of fracture should be treated as osteoporosis irrespective of DXA results. Minimising Fracture Risk A key concept that must not be forgotten is that the clinical end point we care about in osteoporosis care is fracture. Osteoporosis does not cause symptoms in the absence of fracture and while it may be slightly disingenuous to suggest, the perfect osteoporosis treatment would reduce fracture risk to zero and its effect on bone mineral density would be irrelevant. The management of osteoporosis frequently focuses on medication strategies to increase bone mineral density, while these are important, they are only one component of the approach to minimising fracture risk. While osteoporotic fragility fractures can occur with minimal or no trauma, falls remain an important and neglected aetiologic factor in many fractures, particularly non-vertebral fractures. Strategies to reduce falls in terms of muscle and balance strengthening exercise as well as minimisation of environmental and other risk factors for falls have the most immediate impact in terms of fracture reduction. Smoking cessation, alcohol moderation, and the appropriate management of other active contributory medical conditions are all important elements to osteoporosis management.

JANUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

Improving Bone Mineral Density Getting the Building Blocks Right Bone is a complex biomechanical structure, and as with the construction of any structure, it is necessary to have the correct building materials for the job. The importance of calcium and vitamin D to bone health has long been appreciated. What is less well recognised is that the importance is in having adequate amounts of these, and that more is not necessarily better and may even be harmful. Excess calcium has been associated with increased cardiovascular disease and excess vitamin D with ureteric stones.3 This leads to the fundamental concept that calcium supplementation is for individuals with calcium deficiency and that vitamin D supplementation is for individuals with vitamin D deficiency. Thankfully we have a reliable method of measuring vitamin D sufficiency, using serum vitamin D levels. Calcium is more complex, in that serum calcium does not reflect total body calcium. Our physiology requires serum calcium to be tightly regulated, and therefore the body will sacrifice all other reserves of calcium, particularly the bones, in order to maintain serum calcium in the normal range. Adequate calcium intake is best assessed by performing a calcium intake questionnaire with patients. If dietary calcium intake is insufficient it requires supplementation. By far the best source of supplementation is by increasing dietary intake through increased calcium rich foods. If this is not possible or practical then calcium supplements can be utilised. Vitamin D insufficiency is slightly trickier as the best source is from sunlight, something which is both conspicuously absent in Ireland and which carries risks with increased exposure, namely skin cancer. Therefore, serum vitamin D deficiency is usually best managed by supplements. There are two approaches to this, one is to start a standard dose supplement and increase the vitamin D slowly to sufficiency. Another approach is a loading dose approach, with an initial high dose for the first 6 weeks and then a standard dose. There is little evidence that either approach is superior, and aside from the setting of severe deficiency, the standard dose

approach is usually more practical. Whichever approach is used, a subsequent recheck of serum vitamin D to ensure the success of supplementation leading to repletion is essential. Adequate dietary protein intake is also crucial in maintaining bone health, with recent data emphasising the importance of sufficient protein consumption in preventing falls and fractures.4 Affecting Bone Remodelling A basic tenet of the approach to glucocorticoid use is that it is far easier to prevent bone loss than to reverse it. While not every patient on glucocorticoids requires pharmacologic treatment, many do, Figure 1. This is particularly true for those who have other risk factors for fracture including increasing age. This risk stratification is complex and individualised. In terms of treatment choices there is one important consideration in terms of which medication to choose when selecting a preventative treatment for glucocorticoid induced osteoporosis. This resolves around the anticipated duration of glucocorticoid exposure. There are three main groups of pharmacologic treatments used in this setting, the anti-resorptive agents of bisphosphonates and denosumab, and the bone formation stimulating teriparatide. Bisphosphonates are favoured in the setting of expected temporary use for a number of reasons, especially due to their prolonged beneficial effects after stopping the agent due to their incorporation in bone. Essentially this means, that in individuals who do not have co-existent osteoporosis for other reasons, that the majority of the time, the bisphosphonate can be stopped when the glucocorticoids are. Similarly, as the duration of steroid use will often be 1 year or less, an oral bisphosphonate rather than an annual intravenous infusion is more pragmatic. Denosumab, which inhibits RANKligand has a particular concern with its use, in that it has a rapid off effect once ceased with an associated precipitous drop in bone mineral density. This is the reason that drug holidays are not appropriate in individuals receiving denosumab, and is also a concern around the potential short term prophylactic use in the setting of glucocorticoids. Teriparatide, is a daily injection for 2 years, and

rheumatology (Hoboken, NJ). 2017;69(8):1521-37. 15 Figure 1

Long-term glucocorticoids

Ensure calcium and vitamin D sufficiency

Address other fracture risk factors

Rheumatology guidelines.5 However, glucocorticoid-induced osteoporosis is a variable and complicated condition and every patient requires individualised assessment and management. It is also a condition where we are operating with very significant limitations in data. Due to this the existing guidelines can be difficult to interpret with large amounts of information and discussion. In clinical practice we see vastly more patients undertreated than overtreated. The default position should be that each individual on long-term glucocorticoids aged 40 years or older requires treatment, including a bisphosphonate, and reasons should be found to justify not doing this. As this is a complex area, if there is any doubt, specialised referral to a bone health service is encouraged. Summary

Low risk

Monitor BMD

Moderate/High Risk

Age ≥ 40

Age < 40

Glucocorticoid-induced osteoporosis is a significant health problem with high rates of the negative consequence of fracture. Many of these fractures are preventable with appropriate management. All individuals receiving long-term glucocorticoids require fracture risk assessment and nonmedication strategies to improve bone health. The majority of those aged 40 years or older receiving long-term glucocorticoids will also require a bisphosphonate. References

History of Fragility fracture OR Z-score <-3 OR >10% year BMD drop OR High dose glucocorticoid and ≥ 30

Bisphosphonate (or alternative)

must be followed by an antiresorptive, again in the setting of non-permanent glucocorticoid use, this is a less attractive option. Determining the Need for Continuing Treatment As a general rule, most individuals need to continue their bone prophylaxis as long as they remain on glucocorticoids, and certainly as long as they are >5mg/

day prednisolone equivalent dose. Osteoporosis is incredibly common with half of women and one quarter of men suffering an osteoporotic fracture during their lifetime. Osteoporosis is also very much a hidden disease with the majority of individuals undiagnosed until they suffer the end consequence of a fracture. Many individuals undergoing glucocorticoid treatment meet

Fragility fracture OR Age ≥ 50/Post-menopausal and Tscore ≤ -2.5 OR FRAX ≥ 10% major fracture or ≥ 1% hip fracture OR high dose glucocorticoids

Bisphosphonate (or alternative)

screening criteria for DXA, but even in the absence of this should undergo bone density assessment prior to consideration of cessation of bone prophylaxis. Guidelines Excellent guidelines exist for the prevention and management of glucocorticoid-induced osteoporosis, for example the American College of

1. Proven A, Gabriel SE, Orces C, O'Fallon WM, Hunder GG. Glucocorticoid therapy in giant cell arteritis: duration and adverse outcomes. Arthritis and rheumatism. 2003;49(5):703-8. 2. Laan RF, van Riel PL, van de Putte LB, van Erning LJ, van't Hof MA, Lemmens JA. Low-dose prednisone induces rapid reversible axial bone loss in patients with rheumatoid arthritis. A randomized, controlled study. Annals of internal medicine. 1993;119(10):963-8. 3. Bolland MJ, Avenell A, Baron JA, Grey A, MacLennan GS, Gamble GD, et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: metaanalysis. BMJ (Clinical research ed). 2010;341:c3691. 4. Iuliano S, Poon S, Robbins J, Bui M, Wang X, De Groot L, et al. Effect of dietary sources of calcium and protein on hip fractures and falls in older adults in residential care: cluster randomised controlled trial. BMJ (Clinical research ed). 2021;375:n2364. 5. Buckley L, Guyatt G, Fink HA, Cannon M, Grossman J, Hansen KE, et al. 2017 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis. Arthritis & rheumatology (Hoboken, NJ). 2017;69(8):1521-37.

HOSPITALPROFESSIONALNEWS.IE | HPN • JANUARY 2022

Osteoporosis

Persistence with oral bisphosphonates and denosumab among older adults in primary care in Ireland Authors: Mary E. Walsh1 http://orcid.org/0000-0001-8920-7419 | Tom Fahey1 http://orcid.org/0000-0002-5896-5783 Frank Moriarty1,2 https://orcid.org/0000-0001-9838-3625 Affiliations: 1HRB Centre for Primary Care Research, Department of General Practice, Royal College of Surgeons in Ireland, Dublin, Ireland | 2School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland Osteoporosis and associated fragility fractures can result in significant disability, morbidity and mortality with 20% of individuals who experience a hip fracture dying in the first year.1, 2 It is estimated that one in five women and one in twenty men over the age of 60 have osteoporosis and 3% of older adults are expected to experience fragility fractures annually.3, 4 Adults at high fracture risk, including those with osteoporosis, previous fractures or those who take medication that reduces bone quality, should be offered pharmacological treatment where no contraindication exists.5-8 Oral bisphosphonates have been shown to prevent fractures in men and women and they are the most cost-effective initial therapy for osteoporosis.6, 8, 9 Denosumab, a newer antiresorptive treatment, involves six-monthly administration by subcutaneous injection, usually administered by a healthcare professional. It is recommended in patients with high fracture-risk where they are unable to take oral bisphosphonates due to difficulties with administration or intolerance caused by upper gastrointestinal symptoms.6-8 Denosumab has been shown to prevent fractures in women.7 While research in men remains

limited, it improves bone mineral density (BMD) and has shown an effect on fracture incidence in particular cohorts.7, 9, 10 To be cost-effective and result in optimal fracture reduction, it is important that oral bisphosphonates and denosumab are prescribed and taken/administered correctly, at the appropriate time intervals, without unwarranted gaps in treatment or early cessation.11, 12 Adherence (the extent to which a patient acts in accordance with the prescribed interval and dose regimen) and persistence (the accumulation of time from initiation to discontinuation of therapy) have both been found to be suboptimal in oral bisphosphonate and denosumab use.13, 14 Clinical guidelines recommend that bisphosphonates are continued without a break for a period of at least three years and for up to ten years in those deemed to be at high risk of fracture.6,15-17 However, a large recently published systematic review found that 2-year persistence for oral bisphosphonates was less than 30% in most studies and that only 35% to 48% of patients are adherent at 2 years [13]. Persistence in denosumab treatment is particularly important, as the suppression of bone

Figure 1. Flow-diagram of patient selection

JANUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

resorption rapidly reverses where treatment is delayed by as little as three months.18, 19 There is some evidence that this could result in rebound vertebral fractures.20 A recent systematic review including 16 studies of denosumab showed that average 2-year persistence was only 55%.14 Treatment with oral bisphosphonates after stopping denosumab is protective against negative effects in most patients after one year of treatment, however stronger replacement treatments may be required for patients taking denosumab for longer periods.21, 22 Internationally, General Practitioners (GPs) have reported uncertainty about prescription breaks in bisphosphonate treatment and cessation of denosumab.23 Recent estimates of persistence for these medications are not available in primary care in Ireland and so the extent of the problem in the Irish setting is unknown. Furthermore, identification of factors associated with early discontinuation of these medications in a large representative primary care database could reveal circumstances in which education or input from specialists would be warranted.

Study objectives The aim of this study is to estimate persistence rates for oral bisphosphonates and denosumab in a cohort of older primary care patients in Ireland who are newly prescribed these medications and to identify factors associated with time to discontinuation. METHODS Study Design The REporting of studies Conducted using Observational Routinely-collected health Data (RECORD) statement was used in the conduct and reporting of this retrospective cohort study.24 Setting and data source Data were collected as part of a larger study from 44 general practices in the Republic of Ireland in the areas of Dublin (n=30), Galway (n=11), and Cork (n=3) using the patient management software Socrates (www.socrates. ie) between January 2011 and 2017 [25, 26]. Data, anonymised at the time of extraction, included demographic, clinical, prescribing and hospitalisation records of patients who were 65 years and older at the date of data extraction (2017). Ethical approval was

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

MOVYMIA®: THE NEW TERIPARATIDE BIOSIMILAR FROM CLONMEL HEALTHCARE

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

October 2019. 2019/ADV/TER/122H

Osteoporosis

obtained from the Irish College of General Practitioners. Participants Patients were eligible for inclusion in analysis if they were newly prescribed oral bisphosphonates or denosumab during the study period (see Figure 1). Cohorts of patients initiated on oral bisphosphonates and denosumab were defined and analysed separately, resulting in potential overlap between these groups. Prescriptions for bone-health medications were identified from two sources: GP prescription records (WHO Anatomical Therapeutic Chemical classification codes) and discharge summaries of hospitalisation records (based on free-text trade and generic names). See Online Resource 1 for detailed search terms and codes. The start of the observation period for each individual was defined as their first recorded GP consultation, prescription or hospitalisation within the dataset. For the oral bisphosphonate cohort, as it is a first-line treatment, they were defined as “newly prescribed” if they received a first prescription for a bisphosphonate and had at least 12 months of observation before this without receiving any bonehealth medication prescription (see Online Resource 1 for definition and codes). For the denosumab cohort, they were defined as “newly prescribed” if they received

a first denosumab prescription and had at least 12 months of observation before this without a denosumab prescription. Estimate of persistence Persistence was defined as the time from initiation to discontinuation of therapy.13 Discontinuation was considered to have occurred if there was a gap in coverage of prescriptions of more than 90 days. This grace period ensured patients with short periods of discontinuation (e.g. due to dental procedures) or delaying in obtaining a new prescription were not classified as having discontinued. The coverage of prescriptions for oral bisphosphonates was calculated based on specified duration and number of issues detailed in GP prescription records, while each prescription of denosumab covered a six-month period (168 days). For the small proportion of prescriptions that were based on hospital discharge summaries, a six-month prescription (168 days) was assumed. All patients were observed for as long as data allowed after initiation of medication. For calculation of two-year persistence, patients were excluded if the initiation of medication occurred less than two-years before the end of the data-collection period. The number of patients who switched to an alternative bone-health medication within 90 days of the end of coverage period of the initial medication was calculated.

These patients were subsequently excluded from the estimate of 2-year persistence. A sensitivity analysis was conducted to include those who switched in estimating 2-year persistence, adding persistence to their new medication to persistence to their initial medication. Statistical analysis Demographic and clinical variables were described for bisphosphonate and denosumab cohorts. Two-year persistence for bisphosphonates and denosumab was calculated with 95% confidence intervals. Factors associated with time to discontinuation Time to discontinuation of medication was calculated in days for oral bisphosphonates and for denosumab for each patient who had at least 12 months of data after medication initiation. Patients who were found to switch to an alternative bone-health medication were excluded from time to discontinuation analysis. Exposures Exposures were defined during the time-period prior to medication initiation. These included age at the point of medication initiation, a record of osteoporosis, fragility fracture or calcium/ vitamin prescription in GP or hospitalisation records (Online Resource 1), number of unique prescribed medications in the 12 months prior to initiation

and health cover type. Number of medications was analysed categorically (0-5, 6-10, 11-15 and >15 medications). Health cover type was grouped into three categories relevant to the Irish healthcare system based on whether patients are required to pay at the point of care: “General Medical Services scheme” (GMS, covering GP care, hospital care and medications), Doctor Visit Card (DVC, covering GP care only), and Private.27 For oral bisphosphonates, dosing frequency of medication (weekly or monthly) was also included as an exposure. For the denosumab cohort, whether the patient had been on previous bone-health medication was included in the analysis. Statistical analysis Separate Kaplan Meier curves were generated to explore time to discontinuation of oral bisphosphonates (by dosing frequency) and denosumab. Factors associated with time to discontinuation were explored using univariable and multivariable Cox regression for oral bisphosphonates and denosumab. Unadjusted and adjusted Hazard Ratios (HRs) were calculated with 95% confidence intervals (CIs). Confidence intervals were adjusted for clustering of patients within GP practices. Stata 16 (StataCorp. 2019) was used for analyses and statistical significance was assumed at p<0.05. RESULTS Participants Figure 1 shows a flow-diagram of selected patients. From 41,901 patients, n=1,569 newly initiated on oral bisphosphonates and n=1,615 on denosumab. The majority of prescriptions were identified from GP records rather than hospital discharge summaries. In the bisphosphonate cohort, 89% (n=1,391) were prescribed a medication with a weekly regimen, while 11% (n=178) were prescribed monthly dosing frequencies. In the denosumab cohort, n=689 individuals (43% of those who initiated) had been prescribed a different bone-health medication previously, while n=926 (57%)

Figure 2. Kaplan Meier graph of time to discontinuation of bisphosphonates by dosing frequency

JANUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

Lead your patients to stronger bones with Prolia®

1-4

10 YEAR DATA 5S

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

* Prolia® should not be stopped without considering alternative treatment in order to prevent rapid bone mineral density loss and a potential rebound in vertebral fracture risk.6 PROLIA® (denosumab) Brief Prescribing Information

Please refer to the Summary of Product Characteristics (SmPC) before prescribing Prolia. Pharmaceutical Form: Pre-filled syringe with automatic needle guard containing 60 mg of denosumab in 1 ml solution for injection for single use only. Contains sorbitol (E420). Indication: Treatment of osteoporosis in postmenopausal women at increased risk of fractures. Dosage and Administration: 60 mg Prolia administered as a subcutaneous injection once every 6 months. Patients must be supplemented with calcium and vitamin D. No dosage adjustment required in patients with renal impairment. Not recommended in paediatric patients under 18 years of age. Give Prolia patients the package leaflet and patient reminder card. Re-evaluate the need for continued treatment periodically based on the benefits and potential risks of denosumab on an individual patient basis, particularly after 5 or more years of use. Contraindications: Hypocalcaemia or hypersensitivity to the active substance or to any of the product excipients. Special Warnings and Precautions: Traceability: Clearly record the name and batch number of administered product to improve traceability of biological products. Hypocalcaemia: Identify patients at risk for hypocalcaemia. Hypocalcaemia must be corrected by adequate intake of calcium and vitamin D before initiation of therapy. Clinical monitoring of calcium levels is recommended before each dose and, in patients predisposed to hypocalcaemia, within 2 weeks after the initial dose. Measure calcium levels if suspected symptoms of hypocalcaemia occur. Renal Impairment: Patients with severe renal impairment (creatinine clearance < 30 ml/ min) or receiving dialysis are at greater risk of developing hypocalcaemia. Skin infections: Patients receiving Prolia may develop skin infections (predominantly cellulitis) requiring hospitalisation and if symptoms develop then they should contact a health care professional immediately. Osteonecrosis of the jaw (ONJ): ONJ has been reported rarely with Prolia 60 mg every 6 months. Delay treatment in patients with unhealed open soft tissue lesions in the mouth. A dental examination with preventative dentistry and an individual benefit:risk assessment is recommended prior to treatment with Prolia in patients with concomitant risk factors. Refer to the SmPC for risk factors for ONJ. Patients should be encouraged to maintain good oral hygiene, receive routine dental check-ups and immediately report oral symptoms during treatment with Prolia. While on treatment, invasive dental procedures should be performed only after careful consideration and avoided in close proximity to Prolia administration. The management plan of patients who develop ONJ should be set up in close collaboration between the treating physician and a dentist or oral surgeon with expertise in ONJ. Osteonecrosis of the external auditory canal: Osteonecrosis of the external auditory canal has been reported with Prolia. Refer to the SmPC for risk factors. Atypical femoral fracture (AFF): AFF has been reported in patients receiving Prolia. Discontinuation of Prolia therapy in patients suspected to have AFF should be considered pending evaluation of the patient based on an individual benefit risk assessment. Longterm antiresorptive treatment: Long-term antiresorptive treatment may contribute to an increased risk for adverse outcomes such as ONJ and AFF due to significant suppression of bone remodelling. Concomitant medication: Patients being treated with Prolia should not be treated concomitantly with other denosumab containing medicinal products. Warnings for Excipients: Patients with rare hereditary problems of fructose intolerance should not use Prolia. Interactions: Prolia did not affect the pharmacokinetics of midazolam, which is metabolized by cytochrome P450 3A4 (CYP3A4). There are no clinical data on the co-administration of denosumab and hormone replacement

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

therapy (HRT), however the potential for pharmacodynamic interactions would be considered low. Pharmacokinetics and pharmacodynamics of Prolia were not altered by previous alendronate therapy. Fertility, pregnancy and lactation: There are no adequate data on the use of Prolia in pregnant women and it is not recommended for use in these patients. It is unknown whether denosumab is excreted in human milk. A risk/benefit decision should be made in patients who are breast feeding. Animal studies have indicated that the absence of RANKL during pregnancy may interfere with maturation of the mammary gland leading to impaired lactation post-partum. No data are available on the effect of Prolia on human fertility. Undesirable Effects: The following adverse reactions have been reported: Very common (≥ 1/10) pain in extremity, musculoskeletal pain (including severe cases). Common (≥ 1/100 to < 1/10) urinary tract infection, upper respiratory tract infection, sciatica, constipation, abdominal discomfort, rash, alopecia and eczema. Uncommon (≥ 1/1000 to < 1/100): Cellulitis, ear infection and lichenoid drug eruptions. Rare (≥ 1/10,000 to < 1/1,000): Osteonecrosis of the jaw, hypocalcaemia (including severe symptomatic hypocalcaemia and fatal cases), atypical femoral fractures, and hypersensitivity (including rash, urticaria, facial swelling, erythema and anaphylactic reactions). Very rare (< 1/10,000): Hypersensitivity vasculitis. Please consult the Summary of Product Characteristics for a full description of undesirable effects. Pharmaceutical Precautions: Prolia must not be mixed with other medicinal products. Store at 2°C to 8°C (in a refrigerator). Prolia may be exposed to room temperature (up to 25°C) for a maximum single period of up to 30 days in its original container. Once removed from the refrigerator Prolia must be used within this 30 day period. Do not freeze. Keep in outer carton to protect from light. Legal Category: POM. Presentation and Marketing Authorisation Number: Prolia 60 mg: Pack of 1 pre-filled syringe with automatic needle guard; EU/1/10/618/003. Price in Republic of Ireland is available on request. Marketing Authorisation Holder: Amgen Europe B.V., Minervum 7061, NL-4817 ZK Breda, The Netherlands. Further information is available from Amgen Ireland Limited, 21 Northwood Court, Santry, Dublin DO9 TX31. Prolia is a registered trademark of Amgen Inc. Date of PI preparation: July 2021 (Ref: IE-PRO-0721-00001) Adverse reactions/events should be reported to the Health Products Regulatory Authority (HPRA) using the available methods via www.hpra.ie. Adverse reactions/events should also be reported to Amgen Limited on +44 (0)1223 436441 or Freephone 1800 535 160. References: 1. Prolia® [denosumab], Summary of Product Characteristics. 2. Cummings SR et al, N. Eng. J Med 2009;361:756-765. 3. Holzer G et al, J Bone Miner Res 2009;24(3):468-74. 4. Poole K et al; J Bone Miner Res 012; 27 (suppl1):S44 abstract 1122. 5. Bone HG, et al; Lancet Diabetes Endocrinol. 2017;5:513-23;3-23. 6. Tsourdi E, et al. Bone. 2017;105:11–7. 7. Hernlund E, et al. Arch Osteoporos. 2013;8:136; 8. Kanis JA, et al. Osteoporos Int. 2019;30:3–44; 9. Brown JBMR 2013 Vol28 pp746-752.

Osteoporosis Figure 3. Kaplan Meier graph of time to discontinuation of denosumab

Findings in the context of previous research

were observed to initiate directly onto denosumab. In total, 56% and 51% of the bisphosphonate and denosumab cohorts were observed to discontinue the medication. Only 9% and 6% of those who discontinued bisphosphonates and denosumab respectively were switched to a different bone-health medication within 90 days of the end of the coverage period. Estimate of persistence For oral bisphosphonates and denosumab, n=1,212 and n=1,146 patients respectively had at least 2 years between medication initiation and the end of data collection and did not switch to an alternative bone-health medication. Among these groups, two-year persistence was 49.4% (95% CI 46.5% to 52.2%) for bisphosphonates, and 53.8% (95% CI 50.9% to 56.8%) for denosumab. Sensitivity analysis including those who switched to an alternative medication resulted in estimates of 50.9% (95% CI 48.2% to 53.7%) for bisphosphonates and 53.6% (95% CI 50.7% to 56.4%) for denosumab. Factors associated with time to discontinuation of oral bisphosphonates A total of n=1,487 patients were included in the time to discontinuation of oral bisphosphonates analysis. In the n=801 patients who

discontinued bisphosphonates without switching onto another bone-health medication, mean time to discontinuation was 295 days (SD=332 days). Figure 2 shows a Kaplan Meier graph of time to discontinuation of bisphosphonates by dosing frequency. Those on monthly regimens had a higher risk of discontinuation (log-rank test, p=0.02). On multivariable analysis, being 80 years or older (HR=1.26, 95% CI=1.04 to 1.52, p=0.02) was associated with a higher hazard of discontinuation of oral bisphosphonates. GMS health cover (HR=0.49, 95% CI=0.36 to 0.66, p<0.01), prescription of calcium or vitamin D (HR= 0.79 95% CI= 0.66 to 0.93, p<0.01) and being on 6-10 medications rather than 0-5 medications (HR= 0.82 95% CI= 0.69 to 0.98, p=0.03) was associated with a lower hazard of discontinuation of oral bisphosphonates. The relationship between time to discontinuation and oral bisphosphonate dosing frequency did not remain statistically significant on multivariable analysis. Factors associated with time to discontinuation of denosumab A total of n=1,568 patients were included in the time to discontinuation of denosumab analysis. In the n=782 patients who discontinued denosumab without switching onto another bone-

JANUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

health medication, mean time to discontinuation was 401 days (SD=321 days). Figure 3 shows a Kaplan Meier graph of time to discontinuation of denosumab. On multivariable analysis, no factors were found to be associated with a higher hazard of discontinuation of denosumab. GMS health cover (HR=0.71 95% CI= 0.57 to 0.89, p<0.01), and having a diagnosis of osteoporosis (HR= 0.76 95% CI= 0.69 to 0.84, p<0.01) were associated with a lower hazard of discontinuation of denosumab. DISCUSSION Summary of findings This study includes a large and representative cohort of older adults in the primary care setting with a long period of follow-up between 2012 and 2017. To our knowledge, it is the first estimate of persistence in bone-health medication in a general older population in the Republic of Ireland since 2009 and the wide-spread introduction of denosumab.11, 28 Findings of suboptimal two-year persistence (49% for oral bisphosphonates and 54% for denosumab) in the current study are in line with previous research.13, 14 Having state-funded health cover was the only factor found to be protective against discontinuation of both medications.

For over half of patients in this study who were started on denosumab, it was the first bone-health medication they were observed to take, despite it not being recommended as a first-line treatment in most cases.6-8, 21 This recommendation is due in part to the cost of the medication but also due to the need to pre-screen for hypocalcaemia and co-morbidities and due to complications that arise with cessation of the drug.7, 21, 29 This pattern of prescribing reflects findings from a large primary care study in Australia where denosumab went from making up a small percentage of bone-health prescriptions in 2012 to being the most frequently prescribed in 2017.23 The denosumab cohort in this study included a higher proportion of female patients and more patients with a diagnosis of osteoporosis in comparison to the bisphosphonate cohort. This aligns with the strength of evidence for denosumab among women at highest risk of fracture.5, 7, 9 The rate of contraindication to oral bisphosphonates among this group is not known, however it is unlikely to explain the rate of denosumab prescribing as firstline therapy. Due the increased popularity of the medication among GPs in recent years, further investigation of the reasoning behind these treatment decisions is warranted. A particularly concerning finding is that only 6% of those who discontinued on denosumab were switched to an alternative bone-health medication despite this being strongly recommended by current evidence.22 For those not switched to another medication, only 55% continued taking denosumab without a gap in treatment for two-years, which is similar to findings of a recent systematic review including 16 studies from the USA, Canada and sixteen European countries.14 Where denosumab injections are received 9-12 months apart as opposed to 6-monthly, bone turnover markers increase significantly while increases in BMD drop by over half.18, 19 A post-hoc analysis of a randomised controlled trial of 1,001

21 participants, also found the rate of vertebral fractures increases five-fold on discontinuation of denosumab, quickly approaching the fracture rate observed on placebo.20 While switching to oral bisphosphonates can protect against these changes in most patients, recently published results of a randomised controlled trial of 61 patients on longerterm therapy found that a single dose of zoledronate infusion was not sufficient to maintain benefits.21, 22 GPs in Australia have expressed an awareness of the quick reversal of BMD gains after stopping denosumab but also uncertainty about how and when to stop denosumab or the risks of doing so.23 It is likely that GPs in Ireland have similar concerns and education and support in this area appears to be urgently required. Poor persistence on oral bisphosphonates is also a concern. A 2011 meta-analysis of five studies and over 100,000 patients indicated that fracture risk increased by up to 40% with nonpersistence of bisphosphonates.12 In the oral bisphosphonate cohort in the current study, two-year persistence was estimated at 49% between 2012 and 2017, showing no improvement on older work.11, 28 Two previous Irish studies of bisphosphonate persistence between 2005 and 2009 showed a 1-year rate of less than 50% in patients hospitalised with a fragility fracture28 and a 2-year rate of 50% in the general older population.11 In five studies from the USA, Canada, Hungary and Sweden that were included in a recent systematic review and that measured two-year persistence using similar treatment gaps as the current analysis, estimates ranged from 19% to 46%.13, 30-34 While there is some clinical uncertainty about whether particular patients should be given a break or “bisphosphonate holiday” after 3-5 years to avoid increasing the risk of adverse events, this should not influence persistence after only two years on medication.15-17, 23 Furthermore, this cohort would be considered at relatively higher risk of fragility fracture as they have an average age of 77, a fracture history prevalence of 10% and a diagnosis of osteoporosis in 30% of the group. Guidelines suggest that among patients at high fracture risk, alendronic acid may be safely continued for up to 10 years and risedronate for up to seven years.6 It should be noted that our estimate of persistence could be optimistic

as we used a conservative acceptable treatment gap of 90 days and excluded switchers onto alternative medications.13, 35 In addition, in contrast to previous research, our study did not find more frequent dosing regimens of oral bisphosphonates to be associated with discontinuation.28, 31-33, 36 In fact, on univariable analysis, monthly regimens had a higher Hazard Ratio than weekly formulations. This may reflect monthly formulations being targeted towards patients likely to have challenges persisting to the prescribed regimen. Having state-funded health cover (GMS) was the only factor found to be protective against discontinuation of both oral bisphosphonates and denosumab in this study. This relationship remained strong even after adjusting for age. This is important, as the GMS scheme in Ireland is means-tested but a higher income threshold applies to those aged 70 and over.27 For this reason, 50-55% patients in this study aged under 70 years were covered by DVC/GMS in comparison to 90% of patients 70 years and older. Such patients who have free access to GPs, practice nurses and medications may be more likely to return for repeat prescriptions, support and administration of medication (in the case of denosumab). Older age group (80 years and older) showed some association with discontinuation of oral bisphosphonates on multivariable analysis, independent of health cover, but this was not observed in the denosumab cohort. In previous literature, age has shown an inconsistent relationship with persistence of these medications with both the oldest (>75 years) and youngest (<65 years) most likely to discontinue.13, 35, 37, 38 This may be related to an increased likelihood of adverse effects at older ages or patients or physicians not prioritising treatment of fracture risk in younger patients.35 As this study included only patients who were aged over 65 by 2017, this could have resulted in higher persistence overall. In our study, prescription of calcium or vitamin D was associated with a lower hazard of discontinuation of oral bisphosphonates and having a recorded diagnosis of osteoporosis was associated with a lower hazard of discontinuation of denosumab. This could potentially be explained by ongoing osteoporosis

management being reflective of the patient and physician prioritising the need for therapy, which is suggested to be an important determinant of adherence to these medications.35 Prior BMD testing, using other drugs for osteoporosis and calcium or vitamin D supplementation have been associated with better persistence in previous research.13, 36, 39 In contrast to several other studies however, a history of fragility fracture was not found to be associated with improved persistence in our analysis.13, 39 This is surprising, as one would expect a fracture experience to highlight the need for treatment and improve the management pathway. Studies in Australia and Canada have found that for secondary fracture prevention, while specialist-led programmes can facilitate better initiation of therapy, primary care physician follow-up is as effective at improving persistence.40, 41 This suggests that GPs could be supported to provide long-term management of osteoporosis in patients with fragility fracture but that once-off reviews with geriatricians could be beneficial. This requires further investigation in the Irish setting. Strengths and limitations A strength of this study is that we ascertained prescribing from multiple sources (i.e. GP prescription records and hospitalisation discharge summaries). We included a washout period to look at those newly initiated on medication as patients have been found to be more persistent if evaluated from their first exposure to osteoporosis therapy.42 Using routinely collected data, we were unable to assess reasons for discontinuation of medication that may have been clinically appropriate and do not know if it resulted from a risk-benefit discussion with patients. Therefore some cases of non-persistence may have been discontinuations for a clinically appropriate reason. We were also unable to determine if patients received prescriptions/ treatment (including denosumab or bisphosphonate infusion) solely from outpatient appointments with hospital-based specialists or during hospital admissions. Regardless, the very high rate of non-persistence to denosumab without observed replacement by bisphosphonates or other therapies within the primary care setting is a major concern, due to risk of rebound vertebral

fractures.20 As data related to prescribing, it is not possible to determine whether prescriptions were dispensed, or if patients took their medication as prescribed. This may have resulted in an optimistic persistence rate. Finally, it is unknown, whether those “initiated” could have been finishing a “bisphosphonate holiday” or those discontinuing could have re-initiated later on. Discontinuing denosumab however has significant risks in the short-term and so looking for delayed re-initiations was not an objective of our analysis. Clinical implications Non-persistence/ adherence to osteoporosis medications is wasteful and can pose significant patient risks, especially in the case of denosumab treatment. Further research is required in the Irish primary care setting, given the mixed public-private health system, to explore the reasons for prescribing choices and patterns and to evaluate interventions targeted at both patients and physicians. A recent systematic review found that multi-component education programmes that included patients in the decision-making process around osteoporosis treatment and specific regimens improved medication persistence.43 A 2012 Irish analysis suggested that investing ¤120 annually per patient into interventions would remain cost-effective if they improved adherence and persistence to osteoporosis medication by just 10%.11 This warrants further testing. CONCLUSION This study has identified a number of areas where fracture preventive prescribing among older adults in primary care could be improved. This includes the common use of denosumab as a first-line treatment, sub-optimal rates of persistence with bisphosphonates and denosumab at two years and low rates of switching to other preventative treatments among those stopping denosumab. Free access to primary care services and medications may facilitate persistence, however other interventions targeting patients and prescribing in primary care to optimise prescribing warrant evaluation. References available on request

Originally published in Archives of Osteoporosis 2021, doi: 10.1007/ s11657-021-00932-7.

HOSPITALPROFESSIONALNEWS.IE | HPN • JANUARY 2022

Liver Disease

Three decades of the Irish National Liver Transplant Program

Written by Dr Julia Sopena Falco, Liver Unit, St Vincent's University Hospital, Elm Park, Dublin 4

Written by Professor P Aiden McCormick, Liver Unit, St Vincent's University Hospital, Elm Park, Dublin 4

Summary

with primary biliary cholangitis or massive hepatomegaly causing pressure symptoms and malnutrition in polycystic liver disease. In general patients would not be considered for liver transplant if they are over 70 years of age or have significant co-morbid disease with a related mortality risk of greater than 50% at 5 years.

The Irish national liver transplant program was established in St Vincent's University Hospital in 1993. Since then over 1,000 patients have received a transplant. Currently the program is staffed by five liver transplant surgeons and five hepatologists. The hospital also hosts the national pancreas transplant program and is the national referral centre for primary cancers of the liver and pancreas and for neuroendocrine tumours (NET). Survival figures are excellent with > 92% survivals at one year for elective patients. The program is limited to adult transplant only. The numbers of patients requiring paediatric liver transplant are small and these patients are currently referred to King's College Hospital in the United Kingdom. Over the past three decades there have been significant changes in the indications for transplant. Autoimmune liver disease, with the exception of primary sclerosing cholangitis, is less common. Transplants for hepatocellular carcinoma and alcoholic liver disease have increased. Medical therapy for hepatitis B, C and Budd-Chiari syndrome has improved with reduced requirement for liver transplantation. New indications

such as cystic fibrosis liver disease, multi-visceral transplant and cholangiocarcinoma have become accepted. it is hoped the introduction of normothermic machine perfusion for donor organs will help to increase transplant availability. Assessment for liver transplant Patients are considered for transplant if they have a primary liver disease with a significant risk of mortality in the short to medium term. This includes patients with both chronic liver disease and fulminant hepatic failure. The mortality risk related to elective liver transplant is approximately 7-8% at one year and the mortality related to liver transplant for fulminant hepatic failure is approximately 20% at one year. Thus the mortality rate for the underlying condition has to exceed these figure to justify the risk. A number of risk scores have been developed to help with decision making for both acute and chronic liver disease. These include the MELD score (Model for End stage Liver Disease) and the King's College criteria for fulminant hepatic failure. Occasionally patients may be considered for liver transplant on quality of life indications, but this is rare. Examples would be severe, intractable pruritus in patients

JANUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

Allocating donor organs When patients are placed on the waiting list the timing of transplant depends on the availability of a suitable liver and the number of patients on the waiting list. The donor organ is matched by blood group and size. For example an O liver can be given to any patient, an AB recipient can receive any liver but an O recipient can only receive an O liver. The liver needs to be reasonably matched in size with donor/recipient weights varying by less than 10Kgs in general. A donor liver may be reduced in size but this adds to the complexity of the surgical procedure. Allocation depends on the severity of the liver disease rather than on waiting list time. The MELD score is used to select the recipient who requires the transplant most urgently. For patients with fulminant hepatic failure there is a formal liver sharing system with the United

Kingdom. There are very strict criteria for allocating these donor grafts and patients with chronic liver disease are precluded. Complications post-transplant Over the past 28 years the field of liver transplantation has changed markedly. In the early days of the program rejection, both acute and chronic, and infection were major problems. It is now unusual to lose a liver due to rejection. We tend to favour relatively light immunosuppression early posttransplant. This helps to prevent infection and preserve renal function. Episodes of acute cellular rejection are relatively common (30%-40%) in the early weeks following surgery but are managed with steroid therapy if required. Chronic rejection used to be a cause of graft loss, particularly in young females with autoimmune liver disease. With modern immunosuppressive regimens this has become very rare. The liver is a relatively immuno-tolerant organ, compared to heart, kidney or lungs. Viral and fungal infections, CMV, candida and aspergillus, were also a major problem, in the past. Current antiviral and antifungal prophylaxis regimes are very effective at preventing these infections. Recurrent disease is a problem for a minority of patients with primary sclerosing cholangitis

23 may also down-stage some patients to within Milan criteria and allow consideration of liver transplantation. A minority of patients with cholangiocarcinoma are suitable for liver transplant. These include patients with small hilar tumours after radiation and chemotherapy treatment. This is a demanding treatment regimen but patients who respond have acceptable 5 year survival rates.4 Budd-Chiari syndrome.

and hepatocellular carcinoma and this still presents a challenge. Changing indications for liver transplantation The type of liver disease in patients referred for and undergoing liver transplant has changed markedly over the past 3 decades. In table 1 are summarised the aetiologies from the start of the program compared to the years 2018-2019. The most striking changes are the increase in the numbers of patients transplant for alcoholic liver disease and hepatocellular carcinoma and the decrease in the number transplanted for autoimmune hepatitis and primary biliary cholangitis. In contrast to the other autoimmune liver diseases the number of patients transplanted for primary sclerosing cholangitis has increased. This is possibly explained by the fact that there is now effective medical therapy for both autoimmune hepatitis and primary biliary cholangitis. It is well known that steroids, azathioprine, budesonide and other immunosuppressive drugs can improve prognosis in autoimmune hepatitis. Ursodeoxycholic acid improves survival in primary biliary cholangitis. Bezafibrate and obeticholic acid are now available for non-responders. The widespread and effective use of these various medications is probably reflected in the reduced numbers coming to liver transplant. Unfortunately, that is not the case for primary sclerosing

cholangitis. There is no effective medical therapy and the number of patients suffering from this condition is rising. In addition these patients are at increased risk of a range of malignancies including cholangiocarcinoms, gall bladder carcinoma, colon cancer and lymphoma. Effective medical treatment for primary sclerosing cholangitis is one of the great unmet needs in hepatology.

rule disadvantages patients who present for the first time with liver failure due to alcoholic hepatitis and who may not survive 6 months without transplant. Pilot studies in France and Belgium have demonstrated acceptable medium term results for this patients group.2 A pilot study has been approved in the United Kingdom and it likely that we will hear a lot more on this topic.

Alcohol related liver disease

Hepatocellular carcinoma.

One of the striking features in table 1 is the increase in the number of transplants for alcoholic liver disease. Unfortunately the prevalence of alcoholic liver disease in Ireland continues to increase.1 Currently patients with alcoholic liver disease are required to have at least 6 months abstinence, insight into any addiction issues and reasonable social support before listing is considered. The PEth (phosphatidylethanol) test is very useful to confirm abstinence. Phosphatidyethanol is a direct alcohol biomarker with an average half-life of 4-5 days. It can detect significant alcohol intake up to 4 weeks previously. There is a lot of debate about the 6 month rule. It is certainly true that 6 months abstinence is not predictive of long term abstinence. The alternative view is that failure to maintain abstinence for 6 months while being assessed for liver transplant is predictive of failure to abstain post-transplant. A counter argument is that the 6 month

There has been a significant increase in the number of liver transplants for hepatocellular carcinoma in recent years. The Milan criteria, published in 19963, established that patients with a small tumour burden could be transplanted successfully with a low risk of tumour recurrence. The criteria have subsequently been expanded somewhat, while maintaining excellent results. The numbers coming to transplant are increasing because 6 monthly ultrasound screening in cirrhotic patients is detecting small tumours earlier. The risk of hepatoma development is 1-2% per year in cirrhotic patients. With improved medical management of cirrhosis related complications, patients are living longer and developing hepatomas. For patients not suitable for liver transplant, due to age, co-morbidity or other factors, locoregional therapy with transarterial chemoembolization (TACE) or radiofrequency ablation are improving prognosis also. These therapies

Budd-Chiari syndrome or hepatic venous out-flow obstruction can present as fulminant or sub-fulminant hepatic failure. Liver transplant was one of the principal treatments. It has since been discovered that early anticoagulation and/ or TIPS shunting are effective treatments to alter the natural history and prevent liver failure. The mortality rates from BuddChiari syndrome have fallen over the past two decades, probably due to improvements in treatment. In an national inpatient sample from the United States 8,435 hospitalizations related to Budd-Chiari syndrome, overall in-hospital mortality for decreased significantly from 18% in 1998 to 8% in 2017.5 Liver transplantation is now rarely required for Budd-Chiari syndrome. Hepatitis B Transplantation for hepatitis B has undergone a number of changes over the years. In the early days of liver transplantation rapid re-infection of the graft with fibrosing cholestatic hepatitis was associated with high mortality. Transplant was limited to patients with fulminant hepatitis B or delta co-infection. With the advent of hepatitis B immune globulin and oral antiviral agents this all changed and many patients with hepatitis B were successfully transplanted. Universal vaccination and long term antiviral treatment mean that relatively few hepatitis B patients now come to transplant. The exception are patients with combined hepatitis B and delta infection as there are no currently available, effective treatment for hepatitis Delta to prevent progression to cirrhosis and hepatocellular carcinoma. With the recent development of effective oral treatment for delta infected patients it is hoped that liver transplant for hepatitis B will rarely be required. Cystic Fibrosis Ireland has a high prevalence of cystic fibrosis. After lung disease, liver disease is the second

HOSPITALPROFESSIONALNEWS.IE | HPN • JANUARY 2022

Liver Disease

Aetiology % of transplants

1993-98

2019-21

Autoimmune hepatitis Primary biliary cholangitis Alcoholic cirrhosis Primary sclerosing cholangitis Hepatocellular carcinoma NASH/Cryptogenic cirrhosis Viral hepatitis Budd Chiari syndrome Fulminant hepatic failure Cystic fibrosis Others

16 18 14 13 1 5 5 3 15 0 10

3 4 23 16 15 7 6 0 11 2 13

commonest cause of mortality. With improving medical therapy and life expectancy increasing numbers of these patients are presenting with complications of cirrhosis. Portal hypertensive related complications including bleeding varices, ascites and malnutrition are common presenting problems. Timely liver transplant can improve quality of life, lung function and prognosis in these patients. Lung function and colonisation with resistant organisms are limiting issues. To date one patient has received a combined lung- liver transplant in the program. It is hoped that the new CFTR modulators will help to prevent the progression of liver disease as well as lung disease and render liver transplantation unnecessary for this condition. The future The major limitation in liver transplantation is the shortage of

donor livers, which is a worldwide phenomenon. Approaches to increasing the supply of donor organs include developing the organ donation infrastructure, introducing presumed consent, organs procured following cardiac death (DCD), living related partial liver donation and normothermic machine perfusion. There has been significant investment in the organ donation network in recent years and the debate and publicity around presumed consent is very welcome. A small number of additional organs may be procured following cardiac death. In areas of the world where brain death criteria are not widely accepted, living related partial liver donation is the most common technique for liver transplantation. Results are excellent but high volumes are necessary to minimise risk to the donor and it is unlikely to be appropriate for a medium volume program such as ours. The

most exciting new approach to optimising donor organ availability is the use of normothermic machine perfusion. A significant proportion of donor livers are not used, usually because of concerns about excess fatty infiltration. This is associated with a major risk of primary non-function and graft failure. Normothermic machine perfusion means the liver is perfused at normal temperature and its function analysed prior to transplantation. Using this techniques, investigators in the United Kingdom transplanted 71% of organs which previously would have been discarded.6 They reported 100% 90 day survival. There are still problems with this approach as biliary strictures developed in 18%. Nevertheless it represents a significant advance. Funding has been made available and it is hoped to introduce this technique to our program in the near future.

References 1. Mongan D, McCormick PA, O'Hara S, Smyth B, Long J. Can Ireland's increased rates of alcoholic liver disease morbidity and mortality be explained by per capita alcohol consumption? Alcohol Alcohol. 2011;46(4):500. 2. Mathurin P, Moreno C, Samuel D, Dumortier J, Salleron J, Durand F, et al. Early liver transplantation for severe alcoholic hepatitis. N Engl J Med. 2011;365(19):1790-800. 3. Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334(11):693-9. 4. Duignan S, Maguire D, Ravichand CS, Geoghegan J, Hoti E, Fennelly D, et al. Neoadjuvant chemoradiotherapy followed by liver transplantation for unresectable cholangiocarcinoma: a singlecentre national experience. HPB (Oxford). 2014;16(1):91-8. 5. Alukal JJ, Zhang T, Thuluvath PJ. Mortality and health care burden of Budd Chiari syndrome in the United States: A nationwide analysis (1998-2017). World J Hepatol. 2021;13(6):686-98. 6. Mergental H, Laing RW, Kirkham AJ, Perera M, Boteon YL, Attard J, et al. Transplantation of discarded livers following viability testing with normothermic machine perfusion. Nat Commun. 2020;11(1):2939.

News Providing Regulatory Support: HPRA Annual Report The Health Products Regulatory Authority (HPRA) has published its 2020 annual report, detailing its activities to regulate medicines, devices and other health products for the benefit of people and animals. The report outlines the HPRA’s programme of work in each of the health product areas it regulates, as well as highlighting how the national regulator responded effectively and rapidly to significant developments, including COVID-19. During 2020, the HPRA’s key activities included:

• The authorisation of 251 (2019: 300) new human medicines for the Irish market through the national, mutual recognition and decentralised procedures. An additional 155 medicines were authorised through the centralised route – co-ordinated by the European Medicines Agency (EMA) – with the HPRA serving as rapporteur and co-rapporteur for 12 and six applications, respectively. • The authorisation of 57 new veterinary medicines for the Irish market through the national, mutual recognition

JANUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

and decentralised procedures contributing to the record figure of approximately 1,880 veterinary medicines now authorised for the Irish market. • Approval for 73 clinical trials of human medicines, including seven COVID-19 related trials. • The receipt of 7,752 adverse reaction reports in relation to human medicines, as well as 391 suspected adverse reactions and events reported in relation to veterinary medicines. • Lead member state for monitoring the safety of 70

nationally authorised active substances in addition to 56 centrally authorised human medicines as part of its contribution to the work of the Pharmacovigilance Risk Assessment Committee at the EMA. • The detention of 1,610,295 dosage units of fake and other illegal medicines (2019: 1,018,678). Products detained included sedatives, erectile dysfunction medicines, analgesics and anabolic steroids.

Metastatic Cancer 25 Physiotherapy and Cancer Care: Providing Rehabilitation across the Cancer Continuum Written by Dr Gráinne Sheill, Chartered Physiotherapist /Post-doctoral Research Fellow, Discipline of Physiotherapy, Trinity College Dublin/University of Dublin

Providing rehabilitation for patients living with cancer is of the utmost importance. Oncology patients go through therapies such as surgery, chemotherapy and radiation, which may damage healthy cells in addition to those that are malignant. This can lead to physical and psychological problems, such as muscle weakness, lymphedema, physical disability and cognitive issues. Irish cancer survivors have reported unmet needs across multiple cancer types, in particular: physical needs (specifically, pain, fatigue, and sleep disturbances); psychological needs such as the fear of recurrence; need for greater access to support services; sexuality related needs and information deficits. Cancer rehabilitation focusses on recovery from both cancer and any associated treatments. Rehabilitation, including exercise based rehabilitation, has the potential to limit and manage the side-effects of cancer and its associated treatments, improving the quality of life of anyone living with cancer. Rehabilitation also appears to be cost-effective and may reduce both direct and indirect health care costs, thereby reducing the financial burden of cancer. The physiotherapy cancer rehabilitation team in St James’s Hospital provides rehabilitation to patients during all stages of cancer treatment. From the point of diagnosis, our prehabilitation physiotherapist works with oncology patients to prepare them for surgery, often during neo-adjuvant treatment.

There is evidence that increasing physical activity levels before cancer treatment can lessen the complications experienced by patients during and after treatment. Each patient is assessed and given an exercise programme to maximise their physical function. Since it was established in 2019, the SJH prehabilitation service ‘OpFit’ has seen approximately 600 patients annually. During the COVID-19 pandemic the service converted to an online service, providing daily exercise classes for patients around Ireland. Our lymphoedema physiotherapists provide a service to detect and treat lymphoedema at the earliest point possible. Patients receiving cancer treatment may experience lymphoedema as a result of the accumulation of fluid and other elements (eg protein) in the tissue spaces due to an imbalance between interstitial fluid production and transport. Early detection is key to optimal management of lymphoedema, and to monitor and treat lymphoedema in the

long term. The management of lymphoedema involves education, lymphatic drainage, the provision of compression garments and prescription of exercise. Our surveillance lymphoedema therapist work with patients to ensure they can self-manage their lymphoedema which can often be a life-long condition. Our acute Haematology/Oncology rehabilitation team provides inpatient physiotherapy treatment to all Oncology, Haematology and post-operative breast surgery (including reconstruction) patients in St James’s Hospital. All patients will be seen on the wards postoperatively to review exercises and to provide advice on physical activity once discharged home. This team also sees patients with breast cancer one month after they leave the hospital to assess patient’s strength and movement and ensure patients get back to their normal daily activities.

The newest initiative undertaken by the physiotherapy team is a cancer rehabilitation service. This service provides an exercise based rehabilitation service to patients during and after cancer treatment. Strong evidence from high quality clinical trials now exists to support specific exercise prescriptions to optimise several psychosocial outcomes including anxiety, depression, fatigue and health related quality of life, while multiple trials report improvements in measures of health-related fitness including cardiorespiratory fitness, muscle strength and physical activity in populations living with cancer. Patients can now access individual assessments, treatment sessions and group exercise programmes with our cancer rehabilitation physiotherapist online and in-person. If you would like to learn more about these services please contact grasheill@stjames.ie

Pictured left to right: Yvonne Doherty (Lymphoedema), Gráinne Sheill (Cancer Rehabilitation), Claire Murtagh (Early Detection Lymphoedema), Ruth McMenamin (Acute Rehabilitation), Sarah Moore (Prehabilitation)

HOSPITALPROFESSIONALNEWS.IE | HPN • JANUARY 2022

26 Medicines Management

Medicines Management and Vaccine Stewardship Medicines Management and Vaccine Stewardship in the Centralised Vaccination Centres in the Covid-19 Vaccination Programme in Ireland

Written by Muriel Pate, Medication Safety Specialist Pharmacist in the HSE Quality and Safety Directorate

As the principal phase of the Covid-19 vaccination programme in Ireland comes to an end, it is a good time to reflect on the important role that pharmacists and their teams have played in the Centralised Vaccination Centres (CVCs). At the peak of this once in a lifetime vaccination campaign, there were 48 CVCs in operation across Ireland, with at least one CVC in each county. They have been responsible for delivering almost 4million doses of Covid-19 vaccines up to the end of October 2021, as part of the largest vaccination effort in modern history. Within each CVC was a designated ‘Responsible person for Medicines Management’, who led a team of pharmacist(s), pharmacy technician(s), other healthcare professional(s) and / or student(s).

The number of staff and skill mix varied depending on the size of the CVC and availability of staff in each location. The pharmacy team typically commenced work 30-60 minutes before the first vaccination, finishing after the return of the last vial. Pharmacy teams have been drawn from all sectors of the profession, with community and hospital pharmacists working together and many also joining from academia and industry. Some pharmacists returned from career breaks or retirement while many pharmacy students and pharmaceutical technician students also joined the programme. Despite the varied previous career paths, these teams came together, pooling their knowledge and expertise, in a time where the country most needed a co-ordinated healthcare team. In the larger vaccination centres, the Defence Forces played an important role supporting medicines management, as

Marie Ronan/ Defence Forces Mayo

Portlaoise Pharmacy Team well as a wider logistics role, in particular managing preparation of trays of syringes and other consumables in appropriate quantities for vaccinators. The broad range of staff has also been reflected in those employed more widely in the CVCs. There have been nine different professions working as vaccinators, all with a range of experience, together with those working in management, administrative roles, stewards and volunteers. The range and number of staff involved warranted an increased focus on the importance of standardised procedures to support safe practice.

Vaccine Stewardship The HSE objective for the vaccination programme is “to ensure equitable access to a safe and effective vaccine with the goals of limiting mortality and morbidity from COVID-19, protecting healthcare capacity and enabling social and economic activity.” This has required robust processes to be in place for vaccine stewardship and medicines management so that the quality attributes of COVID-19 vaccines are maintained and vaccinations are administered safely, effectively and efficiently. Stewardship can be defined as the “careful management of something entrusted to one’s care” and typically refers to items which have high value or are particularly precious. Due to the small quantities available in the early stages of the programme, Covid-19 vaccines were highly sought after and the appropriate care and management of them was crucial. Indeed, there was significant potential for misuse to emerge as anything which is seen as lifesaving, life preserving and in short supply will create a black market. To ensure equitable access, the Irish Government developed priority classification groups for scheduling vaccinations according to risk factors such as age and co-morbidities. It was thus important to maintain good vaccine stewardship in order

JANUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

27 to support the programme and maximise the number of doses which were available. Interpol highlighted a wide range of crimes and scams which exploit the fear and uncertainty surrounding Covid-19 and have recommended vigilance for counterfeit medical products, fraud and cybercrime. Internationally there have been multiple reports of theft of vials or in some cases the final doses from a vial of Covid-19 vaccine and even empty Covid-19 vaccine vials which can subsequently be filled with another liquid (e.g. water). In some countries, particularly early in 2021, there were reports of people purporting to be healthcare workers calling to people’s homes and offering Covid-19 vaccines for a fee. Hence, the secure disposal of empty vials and defacing of labels were identified as being important components of vaccine stewardship. Pharmacists may not typically form part of the vaccination team for other vaccination programmes in Ireland however there are a number of factors which made delivery of the Covid-19 programme more complex and thus led to increased involvement of pharmacists in key roles. Specific Handling Requirements of Covid-19 Vaccines The Covid-19 vaccines and in particular, the mRNA vaccines, have very specific storage requirements and expiry times. This required processes to support receipt and secure storage of vaccines together with cold chain preservation. The additional pressure of the existence of four different Covid-19 vaccines, all with specific requirements, made it vital to label vaccines with updated expiry and discard times. The mRNA vaccines also have additional limits on handling which outlines maximum travel durations and movement restrictions. With some of the larger CVCs delivering over 4,000 vaccines per day, any deviations could have an impact on a very large quantity of vaccines.

the vicinity of the patient. All vaccinators are trained to dispose of the used needle and syringe immediately after administration and never to re-enter a vial a second time. Nevertheless, there is still potential for this to happen in error with potentially catastrophic consequences. This risk led to the development and approval of centralised syringe preparation. This was a pharmacy-led process which was employed in some of the CVCs so that vaccinators were presented with labelled syringes with a pre-prepared dose of the vaccine. It also offered efficiencies for the vaccinators and as part of the end of the day process. There is also an additional dilution step with Comirnaty (Pfizer BioNTech Covid-19 Vaccine). In the CVCs, a decision was made that this step had to take place in a central area separate to the vaccination booths and that only a diluted vial would be labelled and released to the booths for use. This was to reduce the risk of an error such as an undiluted vial being mistaken for a diluted vial. This dilution process was undertaken in the pharmacy area and was led by the pharmacy team, with support from vaccinators. Traceability and Efficiency Software called TrackVax has been developed in partnership with GS1 Ireland, specifically to support medicines management processes and traceability of the vaccines in the CVCs. This has included barcode scanning on receipt at the CVC. When dispensing, TrackVax facilitated labelling of the vials with the appropriate discard time and a further barcode scan was used to reconcile used vials and record the number of doses achieved. TrackVax also allowed national oversight of the quantities of the vaccines in each of the CVCs, permitting easy tracking of the supply levels needed in each centre. With some variation in the number of doses achieved from

the different Covid-19 vaccines, there was a focus on evaluating factors which affected the yield. One of the key factors was the type of syringe and needle used. Low dead volume syringes were purchased by HSE procurement for the vaccination programme however some variation between different brands of syringes emerged, which often impacted on whether a final dose could be achieved from a multi-dose vial. The experience of staff also played a role in the dose yield achieved and staff were supported with additional training as required. Reports from TrackVax allowed early identification if there were any changes in yield. This data helped to support an early evidence based decision with HSE procurement to recall one type of syringe following reports of a drop in average yield below 6 doses of Comirnaty per vial when those syringes started to be used. It has been estimated that this early switch helped to achieve an additional 75,000 doses in the subsequent months. The end of the day process required intensive collaboration with Clinical Leads to ensure all doses were used and minimise the requirement for standby lists. The HSE implemented a no waste

Aviva Pharmacy Team

policy for the Covid-19 vaccines therefore the removal of vials from the fridge was aligned with the number of remaining confirmed appointments for the session, but with specific focus on the number of people checked-in and present on site. The live data from TrackVax facilitates both the end of day vaccine reconciliation as sites can keep very close track of opened vials vs remaining appointments and the reporting process as automated reports are generated. Muriel Pate is Medication Safety Specialist Pharmacist in the HSE Quality and Safety Directorate. She joined the medicines management subgroup of the HSE centralised vaccination centres (CVCs) planning group in January, taking over as chair of the group in April. The group prepared guidance which was implemented in all HSE CVCs. With thanks to Muireann Counihan & Ahmed Tamu (4th year pharmacy placement students) and Siobhain Duggan (GS1 Ireland) for their assistance with this article.

Managing risks associated with Multi-dose vials Pre-filled syringes are a preferred method of delivery for a vaccination programme, however due to the time pressures of the pandemic, this type of preparation is not yet available for the Covid-19 vaccines. Consequently, the requirement to use multi-dose vials containing 5-12 doses per vial poses particular risks which are internationally recognised. One such risk is biological contamination when a vial is being pierced multiple times in

HOSPITALPROFESSIONALNEWS.IE | HPN • JANUARY 2022

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 06 May 2021 available on www.medicines.ie. 3. TECENTRIQ 840 mg concentrate for solution for infusion Summary of Product Characteristics 06 May 2021, available on www.medicines.ie. Date of item: July 2021. M-IE-00000762. ABRIDGED PRESCRIBING INFORMATION (API). For full prescribing information refer to the Summary of Product Characteristics [SmPC]. Tecentriq® (atezolizumab)

▼ 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 ▼

This medicinal product is subject to additional monitoring. This will allow quick identification of new infusion (One 14 ml vial of concentrate contains 840mg of atezolizumab). 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 platinum-containing 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 nonsmall 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 ALKpositive 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. Immunerelated 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 Stevens-Johnson 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 nab-paclitaxel 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 infection (for non-HCC patients), 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 t o 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: July 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, Or alternatively, report to: The Drug Surveillance Centre HPRA Pharmacovigilance Roche Products (Ireland) Limited Website: www.hpra.ie Telephone: (01) 4690700 Email: ireland.drug_surveillance_centre@roche.com Tecentriq® Summary of Product Characteristics [SmPC] is available on www.medicines.ie. API M-IE-M-IE-00000725 based on Tecentriq 840mg and 1,200mg SmPCs dated 06 May 2021

▼

For adults. Not actual patients.

SLOW DOWN SPMS WITH ACTIVE DISEASE.1

IT’S TIME FOR MAYZENT® MAYZENT® is the first and only oral treatment specifically indicated for SPMS with active disease1,2*† Mayzent ▼ (Siponimod) 0.25mg and 2mg film-coated tablets ▼ This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 of the SmPC for how to report adverse reactions.Important note: Before prescribing, consult Summary of Product Characteristics (SmPC). Presentation: Tablets: 0.25 mg film-coated tablets corresponding to 0.25 mg siponimod. 2 mg filmcoated tablets corresponding to 2 mg siponimod. ♦Excipient with known effect: Each tablet of 0.25 mg contains 59.1 mg lactose (as monohydrate) and 0.092 mg soya lecithin. Each tablet of 2 mg contains 57.3 mg lactose (as monohydrate) and 0.092 mg soya lecithin. Indications: Treatment of adult patients with secondary progressive multiple sclerosis (SPMS) with active disease evidenced by relapses or imaging features of inflammatory activity. Dosage and administration (D&A): Treatment with Mayzent should be initiated and supervised by a physician experienced in the management of multiple sclerosis. CYP2C9 genotype should be determined before initiation of treatment. Mayzent should not be used in patients with a CYP2C9*3*3 genotype. Treatment initiation with a titration pack that lasts for 5 days. Once daily intake in the morning. On day 1 and 2: 0.25 mg. On day 3: 0.5 mg. On day 4: 0.75 mg. On day 5: 1.25 mg. Maintenance dose starts on day 6. Adults: Maintenance dose: 2 mg once daily. Maintenance dose for CYP2C9 *2*3 or *1*3 genotype: 1 mg once daily. No dose adjustments are needed in patients with renal impairment. Caution should be exercised when initiating treatment in patients with mild or moderate hepatic impairment (see section CI). Mayzent should be used with caution in the elderly patients (65 years or above) due to insufficient data on safety and efficacy. ♦Missed dose and re-initiation: If a dose is missed on one day in the first 6 days of treatment or if 4 or more consecutive daily doses are missed during maintenance therapy, the same initial dose titration and monitoring recommendations should apply. Contraindications (CI): Hypersensitivity to the active substance, or to peanut, soya or any of the excipients listed. ♦Immunodeficiency syndrome. ♦History of progressive multifocal leukoencephalopathy (PML) or cryptococcal meningitis (CM). ♦Active malignancies. ♦Severe liver impairment (Child Pugh class C). ♦Patients who in the previous 6 months had a myocardial infarction (MI), unstable angina pectoris, stroke/transient ischaemic attack (TIA), decompensated heart failure (requiring inpatient treatment), or New York Heart Association (NYHA) class III/IV heart failure. ♦Patients with a history of second degree Mobitz type II atrioventricular (AV) block, third degree AV block, sino atrial heart block or sick sinus syndrome, if they do not wear a pacemaker. ♦Patients homozygous for CYP2C9*3 (CYP2C9*3*3) genotype (poor metaboliser). ♦During pregnancy and in women of childbearing potential not using effective contraception. Warnings and precautions (W&P): ♦Infections: Before initiating treatment with Mayzent, a recent complete blood count (CBC) (i.e. within last 6 months or after discontinuation of prior therapy) should be available. Assessments of CBC are also recommended periodically during treatment. Absolute lymphocyte counts <0.2 x 109/l, if confirmed, should lead to dose reduction to 1 mg. Confirmed absolute lymphocyte counts <0.2 x 109/l in such a patient (already receiving 1 mg) should lead to interruption of Mayzent until the level reaches 0.6 x 109/l when re initiation of Mayzent can be considered. In patients with severe active infection, wait for resolution before initiating treatment. Patients should be instructed to report symptoms of infection to their physician promptly. Effective diagnostic and therapeutic strategies should be used in patients with symptoms of infection while on therapy and up to 3 to 4 weeks after discontinuation. Consider discontinuing therapy if a serious infection develops. Vigilance is advised for clinical symptoms or magnetic resonance imaging (MRI) findings suggestive of PML or for clinical symptoms of CM and, if suspected, Mayzent treatment should be suspended until PML or CM can be excluded. If diagnosed, appropriate treatment should be initiated. Patients without a healthcare professional confirmed history of varicella or without vaccination against varicella zoster virus (VZV) should be tested for antibodies to VZV prior to treatment initiation. ♦Vaccination: VZV vaccination is recommended in antibody-negative patients and initiation of treatment should be postponed for 1 month to allow the full effect of vaccination to occur. Concomitant use is not recommended with live attenuated vaccines and for 4 weeks after stopping Mayzent therapy. Vaccines may be less effective if administered during Mayzent treatment. Treatment discontinuation 1 week prior to planned vaccination until 4 weeks after is recommended. ♦Anti-neoplastic, immune-modulating or immunosuppressive therapies (including corticosteroids): Caution is required when used concomitantly with Mayzent and in the weeks after administration of any of these medicinal products is stopped. ♦Macular edema: Siponimod therapy should not be initiated in patients with macular oedema until resolution. An ophthalmic examination is recommended 3 to 4 months after Mayzent therapy initiation in all patients. In patients with history of diabetes mellitus, uveitis or underlying/co-existing retinal disease Mayzent should be used with caution due to potential increase of risk of macular oedema and an opthalmic examination is recommended prior to and regularly during therapy. Discontinuing therapy is recommended if macular edema develops. After resolution, reinitiation of treatment after discontinuation should be based on the potential benefits and risks for the individual patient. ♦Bradyarrhythmia and Treatment initiation with certain pre existing cardiac conditions: See section CI. ♦Patients with the following cardiac conditions should be observed for a period of 6 hours after the first dose of Mayzent for signs and symptoms of bradycardia: sinus bradycardia (heart rate <55 bpm), history of first- or second- degree (Mobitz type I) AV block, history of myocardial infarction, or history of heart failure (patients with NYHA class I and II). In these patients, it is recommended that an electrocardiogram (ECG) is obtained prior to dosing and at the end of the observation period. If post dose bradyarrhythmia or conduction related symptoms occur or if ECG 6 hours post dose shows new onset second degree or higher AV block or QTc ≥500 msec, appropriate management should be initiated and observation continued until the symptoms/findings have resolved. If pharmacological treatment is required, monitoring should be continued overnight and 6 hour monitoring should be repeated after the second dose. ♦Due to the risk of serious cardiac rhythm disturbances or significant bradycardia Mayzent should not be used in patients with: history of symptomatic bradycardia or recurrent syncope, uncontrolled hypertension, or severe untreated sleep apnoea. In such patients, treatment with siponimod should be considered only if the anticipated benefits outweigh the potential risks, and advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring strategy. ♦Mayzent should not be used in patients with significant QT prolongation (QTc >500 msec) or who were treated with QT prolonging medicinal products with known arrhythmogenic properties. ♦Mayzent should not be used in patients with arrhythmias requiring treatment with class Ia (e.g. quinidine, procainamide) or class III (e.g. amiodarone, sotalol) antiarrhythmic medicinal products (risk of torsades de pointes). ♦Mayzent should not be used in patients receiving concurrent therapy with heart-rate-lowering calcium channel blockers (such as verapamil or diltiazem) or other substances that may decrease heart rate (e.g. ivabradine or digoxin) (risk of severe bradycardia and heart block). ♦If concomitant treatment with one of the above substances is being considered during initiation of treatment with Mayzent, advice from a cardiologist should be sought regarding the switch to a nonheart-rate-lowering medicinal product or appropriate monitoring for treatment initiation. ♦At treatment initiation, use with caution in patients receiving

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

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

August 2021 | IE_145831

CPD 83: EPILEPSY Continuing Professional Development

CPD

Written by Dr Gerard Mullane and Dr Albi Chalissery Dr Gerard Mullane MB MCh BAO MRCPI is a Neurology Registrar in Beaumont Hospital in the RCSI hospital group. Dr Albi Chalissery MBBS MRCPI MD is a Consultant Neurologist at Beaumont Hospital Dublin and Connolly Hospital, Blanchardstown in RCSI hospital group. Her specialty interest includes Epilepsy, and she recently established a “New seizure” clinic at Beaumont hospital.

Dr Gerard Mullane

60 Second Summary Epilepsy is “a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures. Older terms such as “simple partial” and “complex partial” seizures have now largely been replaced by terms “focal aware seizures” or “focal seizures with impaired awareness” in the most recent ILAE classification. The correct identification and classification of seizures and epilepsy syndromes is important as it can have major effects on treatment decisions. The core investigations remain EEG and dedicated epilepsy protocol MRI brain but more extensive investigations such as genomic analysis and autoantibody screening are being increasingly used due to a greater understanding and becoming more cost effective. Despite the availability of investigations, it is important to recognise that epilepsy is primarily diagnosed on careful clinical history and often all investigations can be normal. The treatment options available to clinicians in seizures has become broader and it is important to recognise the side effects of the more common anti-seizure drugs, as well as their mechanism of action. Many other medications can affect the metabolism of ASMs and it is important to check for drug interaction prior to the commencement of new medications. The driving regulations regarding seizures is clearly laid out in the RSA guidelines. The general restriction is 1 year for patients with known seizure disorder and 6 months for first unprovoked seizure or seizures in the context of alcohol. The restrictions regarding group 2 vehicles (buses and trucks) are much more restrictive and requires 10 years of seizure freedom with no medications for patients with known seizures and 5 years of medicine free seizure freedom after a single unprovoked seizure.

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

knowledge gap - will this article satisfy those needs - or will more reading be required?

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

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

3. PLAN - If I have identified a

5. WHAT NEXT - At this time you may like to record your learning for future use or assessment. Follow the

Dr Albi Chalissery

4 previous steps, log and record your findings. Published by HPN. Copies can be downloaded from www.irishpharmacytraining.ie Disclaimer: All material published is copyright, no part of this can be used in any other publication without permission of the publishers and author. Novartis has no editorial oversight of the CPD programmes included in these modules.

New onset seizure and Epilepsy: Diagnosis and Management Introduction In accordance with the International League Against Epilepsy (ILAE) 2005 definition, epilepsy is “a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures and by the neurobiologic, cognitive, psychological, and social consequences of this condition”. It affects approximately 50 million people worldwide1 and 37,000 in Ireland.2 The term epilepsy encompasses a broad range of seizure semiologies, as well as the increasingly recognised epilepsy syndromes. The classification published by the ILAE in 2017 has empowered clinicians to better understand and differentiate between different subtypes of seizures and epilepsy within this heterogenous disease.3 Classification The updated 2017 classification of seizures acknowledges the limitations of previous classifications, while attempting to simplify the process of diagnostic differentiation. The updated guidelines have advocated a threetier approach: seizure type, epilepsy type and epilepsy syndrome. Seizure Type Seizures are due to the altered

electrical activity from different parts of the brain and generally classified as being either focal or generalised in onset.4 Focal seizures originate within the neuronal network in one hemisphere, whereas generalised seizures rapidly engage both cerebral hemispheres. Focal seizures are further subdivided into those with ‘intact awareness’ and those with ‘reduced awareness’. Reduced awareness is generally defined as lack of understanding regarding a patient’s sense of self or their surroundings. Importantly, it does not necessarily refer to lack of awareness that a seizure is occurring. Impaired awareness is believed to be secondary to depressed subcortical arousal systems. The terms “focal aware seizure” and “focal seizure with impaired awareness” have largely replaced the previous terms of “simple partial seizure” and “complex partial seizure” respectively. Focal seizures can be further classified based on the specific motor or non-motor manifestations they exhibit. These include automatisms (purposeless, repetitive motor activities such as lip smacking or patting), focal atonic seizures (loss of tone of one body part), focal clonic seizures (repeated, regular stereotypical

jerking movements) and focal myoclonic seizures (repeated, irregular, non-rhythmic jerking). Non-motor focal seizures present with a variety of symptoms including alterations in blood pressure and heart rate, sweating, piloerection, rising epigastric sensation, déjà vu, emotional disturbance or changes in sensory phenomena. Finally focal seizures can be classified as to whether or not they progress to a bilateral tonic clonic seizure. In this article the localization of focal seizures based on location of epileptogenic foci are not discussed. Generalised seizures are similarly classified by motor or non-motor manifestations. Tonic-clonic seizures are the most commonly described type of generalised motor seizures, however it is important to recognise that this term also encompasses tonic, clonic, atonic and myotonic seizures as well as the significant overlap in these subtypes. Nonmotor generalised seizures (also still known as absence seizures) generally present with sudden cessation of activity, occasionally with associated automatisms and followed by an immediate recovery. These seizures generally show evidence of generalised spike- wave activity on Electroencephalograph (EEG).

seizures as well as the significant overlap in these subtypes. Non-motor generalised seizures (also still known as absence seizures) generally present with sudden cessation of activity, occasionally with associated automatisms and followed by an immediate recovery. These seizures generally show evidence of generalised spike- wave activity on Electroencephalograph CPD 83: EPILEPSY (EEG).

Focal Onset

Generalised Onset

Motor Onset

Motor

•Automatisms •Focal atonic seizures •Focal clonic seizures •Focal Myoclonic seizures

•Tonic-Clonic •Pure Tonic •Pure Clonic •Atonic •Myotonic

Unknown Onset Motor/Nonmotor Manifestations

Nonmotor Onset •Autonomic dysfunction •Deja Vu •Rising epigastric sensation •Sensory disturbance

Intact awareness

Nonmotor/Abscence

Vs Impaired awarenes

+/- progression to bilateral tonic clonic

Figure 1. Updated approach to seizure type classification, based on 2017 ILAE guidelines

Figure 1. Updated approach to seizure type classification, based on 2017 ILAE guidelines Epilepsy Type

Epilepsy Syndrome

types, EEG and imaging features that tend to occur together.” These include childhood absence epilepsy, juvenile absence epilepsy and juvenile myoclonic epilepsy. Reflex epilepsy syndromes are also described, the most commonly known being photosensitive epilepsy, but reflex reading epilepsy and startle epilepsy have also been described.

The second tier of classification The description of several concerns epilepsy type. This distinct epilepsy syndromes is assumes the patient has a a new addition to the current diagnosis of epilepsy. The epilepsy classification syndrome and type is largely determined clinically is being increasingly used and supported by EEG findings. due to greater availability of Epilepsies are classified as investigations, including genetic generalised or focal. Patients with testing. It is defined as “a cluster generalised epilepsy, for example of features incorporating seizure have generalised seizure types with evidence of generalised spike and wave activity on EEG. Patients Table 1 shows a summary of some of the most with one or more focal seizure important risk factors for developing epilepsy types are considered to have focal epilepsy. EEG findings in focal Table Table 1: Risk 1: Risk factors factors epilepsy include focal slowing, Birth/ Birth/ pregnancy pregnancy (hypoxic (hypoxic brain brain injury, injury, asphyxia) asphyxia) or focal epileptiform discharges, however the EEG can often be Febrile Febrile convulsion convulsion (increase (increase the the riskrisk of hippocampal of hippocampal normal. The newly described sclerosis) sclerosis) “combined generalised and focal epilepsy” is used to describe Traumatic Traumatic head head injury/ injury/ Brain Brain tumour/surgery tumour/surgery patients with both generalised and Family Hx of Hxseizure/epilepsy of seizure/epilepsy focal seizures, such as in patients Family with Dravet Syndrome or LennoxInfection Infection (meningitis/encephalitis) (meningitis/encephalitis) Gastaut Syndrome. When there is insufficient evidence to classify Vascular Vascular disorder/ disorder/ Neurodegenerative Neurodegenerative disorder disorder epilepsy as focal or generalised, the term “unknown ” is used.

A practical approach to the patient with new seizures5 The evaluation of a possible new seizure disorder starts with careful history taking and the diagnosis is mostly clinical, supported by ancillary investigations. The next question that needs to be asked is whether the episode in question is a true epileptic seizure or a seizure mimic. If the event is an epileptic seizure one has to identify whether or not the event was likely an unprovoked event. Consideration must be given to known provoking factors such as sleep deprivation, alcohol or drug use, hypoglycaemia or other metabolic derangements. An extensive assessment of risk factors and provocative factors (Table 1 and 2) can also offer valuable information about relative risk of developing epilepsy. Thorough questioning can reveal a remote history of previously unidentified clinical events, which can be present in approximately 20% of cases. In cases of suspected temporal lobe epilepsy (which is the most common focal epilepsy), these events can be quite subtle, ranging from acute emotional disturbance to transient sensory abnormalities, which the patient themselves may not have remarked on unless questioned directly. Seizures accompanied by acute change in mental status, fever or focal neurological deficit warrant urgent assessment for intracerebral infection or inflammation with laboratory work up, neuroimaging and lumbar puncture. Investigations The cornerstone of investigation for patients presenting with a new diagnosis of seizure remains a dedicated high quality MRI brain and EEG. MRI can be

Table 2 shows some of the most encountered provoking factors for seizures Table Table 2: Common 2: Common provocative provocative factors: factors: Sleep Sleep deprivation deprivation Alcohol Alcohol withdrawal withdrawal Metabolic Metabolic (hypoNa, (hypoNa, HypoCa, HypoCa, hypo/hyper hypo/hyper glycaemia) glycaemia) Barbiturate Barbiturate or benzodiazepine or benzodiazepine withdrawal withdrawal Illicit Illicit drugdrug use use (cocaine, (cocaine, amphetamines, amphetamines, opioids, opioids, phencyclidine) phencyclidine) Medications Medications (tramadol, (tramadol, imipenem) imipenem)

Table Table 1 shows 1 shows a summary a summary of some of some of the of the most most important important riskrisk factors factors for for developing developing epilepsy epilepsy Table Table 2 shows 2 shows some some of the of the most most encountered encountered provoking provoking factors factors for for seizures seizures Investigations Investigations TheThe cornerstone cornerstone of investigation of investigation for for patients patients presenting presenting withwith a new a new diagnosis diagnosis of seizure of seizure remains remains a a dedicated dedicated highhigh quality quality MRIMRI brain brain andand EEG. EEG. MRIMRI cancan be preceded be preceded by CT by in CTcertain in certain clinical clinical circumstances, circumstances,

33 Figure 2: Neuroimaging showing epileptogenic lesions (A) CT brain axial view (noncontrast) showing bifrontal encephalomalacia secondary to head injury; (B) MRI brain T2 axial showing cavernoma in R frontal lobe; (C) MRI T1 axial, post contrast sequence showing subependymal grey matter heterotopia at the left ventricular atrium; (D) MRI brain FLAIR Coronal sequence showing hippocampal sclerosis (right)

classified as: structural, genetic, metabolic, infectious, immune and unknown.

Figure 2: Neuroimaging showing epileptogenic lesions (A) CT brain axial view (noncontrast) showing bifrontal encephalomalacia secondary to head injury; (B) MRI brain T2 axial showing cavernomaclinical in R frontal lobe;as (C)these MRI T1 axial, post contrast patients tend sequence to have a preceded by CT in certain showing subependymalsuch grey matter heterotopia at the higher left ventricular atrium; (D) brain FLAIR frequency ofMRI epileptiform circumstances, as acutely Coronal sequence showing hippocampal sclerosis (right) discharges when compared to altered mental state or focal focal seizures. It is important to neurological deficit and is easily recognise that routine in available compared in up of a patient EEG remains an essential parttoofMRI the work with new seizures. It can offerEEG a confirmation the hospital setting can often be urgent scenarios. of suspected diagnosis in The some preferred cases, as well as vital information regarding epileptogenic focus and even when theinclinical neuroradiological underlying epilepsy type. investigation EEG after a new onset seizurenormal, can show epileptiform activity approximately suspicion of an underlying seizure for new onset seizures is 3 Tesla disorder is high. EEG provides MRI brain with specific epilepsy a relatively short snapshot of an protocol however many institutions individual patient, and the yield have 1.5 T MRI imaging which increases with the length of EEG, would be sufficient in the initial rising to greater than 90% with work up. The images should be prolonged (24-36 hour) EEG reviewed by a neuroradiologist monitoring, however this is not provided with detailed clinical generally practicable in the clinical information including the setting. It is also important to note suspected clinical epileptic focus. that a number of confounding Figure 2 below shows some of the factors can affect EEG known epileptogenic lesions that interpretation. Prolonged video can detected on neuroimaging. EEG, where patients are admitted EEG remains an essential part of to a dedicated monitoring unit for the work up of a patient with new usually 3-4 days for continuous seizures. It can offer a confirmation EEG recording and video of suspected diagnosis in some monitoring) remains an invaluable cases, as well as vital information tool, particularly in assessing regarding epileptogenic focus refractory cases for epilepsy and underlying epilepsy type. surgery or in cases where non EEG after a new onset seizure epileptic attack disorder (NEAD) can show epileptiform activity in is suspected. Approximately 25% approximately 29% of patients, of patients considered to have however the cumulative rates of refractory epilepsy are found to detecting epileptiform increases have non epileptic seizures on with repeated EEG. The usage prolonged video EEG monitoring. of sleep deprived EEG also Underlying aetiology: The increases the rates of detecting aetiology of a suspected epilepsy clinically relevant abnormalities. should be elucidated where EEG has greater utility in the possible. These can be broadly evaluation of generalised seizures

• Structural epilepsies can be detected on dedicated epilepsy protocol MRI and can therefore be considered for surgical evaluation for potential resection. In patients with persistent focal epilepsy and normal MRI, FDG PET can be useful in looking for hypometabolic regions . • Genetic epilepsies: The majority of epilepsies are considered to have a genetic basis and the mechanism of inheritance is likely polygenic. Advances in genomic sequencing have become increasingly used in the investigation of epilepsy and specific genetic panels can usually be requested based on the predominant seizure semiology and other clinical features. Whole exome sequencing is also being used increasingly due to improvements in turnaround time and reducing financial costs. • Metabolic epilepsies usually present at an early age and are associated with cognitive and motor impairment. Careful clinical examination and history can offer clues to the underlying pathology and can guide investigations for specific errors of metabolism. • Infectious epilepsies may result both from acute cerebral insults, such as acute Herpes Simplex Virus encephalitis or bacterial meningitis, and delayed seizure presentations as seen in fungal infections, tuberculosis, toxoplasmosis, malaria, HIV and neurocysticercosis. • Immune or inflammatory related epilepsy is associated with

autoantibodies directed at either neuronal cell surface proteins or intracellular antigens. These can often be associated with underlying malignancy. These patients often also present with behavioural or cognitive disturbance, neuropsychiatric symptoms or autonomic dysfunction. Certain specific seizure semiologies have been linked with specific underlying pathogenic antibodies, such as faciobrachial dystonic seizures seen in LGI1 associated encephalitis or orofacial dyskinesia associated with NMDA encephalitis. The evaluation for possible immune mediated seizures includes lumbar puncture for evidence of active inflammatory CSF, testing for autoimmune and paraneoplastic antibodies in serum and CSF, MRI with particular attention paid to temporal lobes and brainstem as well as thorough investigation for possible underlying tumours such as ovarian teratomas in NMDA encephalitis. Management6 First ever seizure: When considering the patient presenting with first presentation of a seizure, after it had been established that it was likely a clinical seizure event without provoking factors, the clinical decision regarding drug treatment is raised. After the first seizure, the risk of another seizure is greatest within the first two years and can range from 21-45%. The initiation of an antiseizure medication (ASM) would be quite reasonable if there is a clear epileptiform abnormality in EEG and or epileptogenic focus in neuroimaging. In the case of an isolated seizure with no clear evidence of predisposition to further events, ASM is generally not indicated due to potential side effects associated with these medications, as well as the financial burden on the patient, which can be quite significant. “Breakthrough seizures in patients with known epilepsy.” These patients require careful questioning to determine whether or not this represents a true treatment failure. One of the most common causes of “breakthrough seizures” is issues with medication compliance. Medication non-compliance is at approximately 50% worldwide and leads to higher economic costs associated with increased

Figure 3. Timeline of increasing availability of anti-seizure medications over time. 8

CPD 83: EPILEPSY

Type of seizures

Commonly used anti-seizure medications (Discuss contraception in women and Valproate should not be used in women of childbearing age).

Focal

Carbamazepine (CBZ)/CBZ derivatives, Lamotrigine*

Generalized

Lamotrigine*, Levetiracetam, Sodium Valproate

Myoclonic

Levetiracetam, Topiramate, Sodium Valproate

healthcare usage. ASM nonto prevent prolonged seizures and use of showers instead and Risk of Rash/Hypersensitivity Table 3: Commonly ASMs in different types of seizures compliance can haveused significant or status epilepticus. It is also avoiding*climbing unguarded negative effects including an important to educate family heights are also essential to increased risk of “Sudden members about the use of buccal reduce risk of seizure related unexpected death in epilepsy” midazolam in the event of seizures injury. Epilepsy Ireland, a national (SUDEP). Risk and factors for nonthe of hospital Counselling Management ofoutside the risks Livingsetting. with This Epilepsy:organisation established in 1966 adherence include polypharmacy drug can be easily administered providing support to improve in older patients, patients in by a prefilled oral syringe to quality of life of people with There is an increased risk for mood disorders and anxiety in people with epilepsy which could negatively their late adolescence and early buccal cavity by family members epilepsy in Ireland. They offer a impact their quality of life. Mortality is also increased for people suffering fromofepilepsy most and adulthood, as well as concurrent or carers. range services and to patients psychiatric as their families and can be a helpful commonly comorbidities from sudden such unexpected death in epilepsy (SUDEP). The risk is higher with uncontrolled Counselling and Management of low mood an anxiety. As previously resource in providing education generalisedknown tonic-clonic seizures andthe hence about drug compliance the diagnosis of riskseducation of Living with Epilepsy mentioned, provoking after a from new diagnosis. epilepsysuch is essential. With increasingThere duration ASMs, the increases compared to factors as sleep deprivation, is anof increased riskrisk for for fracture Driving Regulations post Seizure excess alcohol consumption mood disorders and anxiety in and illicit drug use may increase people with epilepsy which could The regulations regarding driving the risk of seizure and may not negatively impact their quality of and epilepsy are laid out in the represent a true treatment failure. life. Mortality is also increased for “Sláinte agus Tiomáint Medical people suffering from epilepsy Fitness to Drive Guidelines”.8 Anti-seizure medications: The The guideline makes an important and most commonly from sudden general principle in management distinction between patients unexpected death in epilepsy of epilepsy is treating with an driving group 1 (i.e motorcycles, (SUDEP). The risk is higher appropriate ASM based on the cars and tractors) and group 2 with uncontrolled generalised suspected underlying seizure type (Trucks and buses) vehicles. tonic-clonic seizures and hence and epilepsy syndrome. There education about drug compliance has been a dramatic increase in A number of factors influence from the diagnosis of epilepsy is the number of ASMs available for the duration of driving restriction; essential. With increasing duration use in the last 20 years. Whereas including whether or not the of ASMs, the risk for fracture previously clinicians would be seizure was a first time event increases compared to general limited to use of a small number or an event in the context of a population (2-6 times higher in of agents with significant side known seizure disorder, as well people with epilepsy) and requires effects, there are now over 30 as whether alcohol or illicit drug monitoring by DEXA scan and agents in use, with a generally use was related to the event. The management of osteopenia more favourable side effect restrictions are summarised in and osteoporosis. profile. ASMs are broadly divided Figure 4 but the general rule is that into narrow and broad-spectrum the driving restriction is doubled Advice about unsupervised drugs. Narrow spectrum drugs for those driving group 2 vehicles. swimming, avoid using bathtub are generally chosen in clear focal epilepsies but may result in a paradoxical worsening if used in generalised seizures. The number Seizure with a diagnosis of ASMs continues to increase. Unprovoked First Other ASMs approved in more (or high probability) of Seizure recent years includes perampanel, epilpesy brivaracetam, cannabidiol, cenobamate and fenfluramine. The ASMs listed below in Table 3 are commonly used in different types of seizures in clinical practice. Emergency rescue medications such as buccal midazolam (Buccolam 10 mg in 2 ml) is prescribed for patients who had generalized seizure. The aim is

Figure 4. Summary of driving restrictions for patients with seizures

Table 3: Commonly used ASMs in different types of seizures * Risk of Rash/Hypersensitivity

There are a number of special circumstances that must be considered also. For example: patients who are having ASMs withdrawn entirely are generally advised not to drive during the duration of reduction and for 3 months after. For patients who have very clear provoking factors for a seizure, such as eclampsia or convulsive syncope, sometimes a driving restriction is not required, if the provoking cause is treated but this is decided on a case by case basis at the discretion the the treating clinician. It is important to recognise that seizures in the context of alcohol excess or illicit drug use do not qualify as clear provoked seizures for licencing purposes. For seizures associated with alcohol or illicit drug use, a 6-month restriction is imposed for group 1 vehicles, and 5 years for group 2. Restriction for driving could also influence their ability to work, maintain relationship and to live independently. Health professionals managing and promoting health of the patients with epilepsy should be committed to improve quality of life of the person and their family. References available on request

Seizure related to alcohol/ drug use

Group 1

• 6 months

• 1 year

• 6 months

Group 2

• 5 years (with no ASM use)

• 10 years (with no ASM use)

• 5 years (with no ASM use)

Figure 4. Summary of driving restrictions for patients with seizures

Restriction for driving could also influence their ability to work, maintain relationship and to live independently. Health professionals managing and promoting health of the patients with epilepsy should be committed to improve quality of life of the person and their family.

News 35

New Study on Epilepsy A new study which monitored the outcome and uptake of Covid-19 vaccines in people with epilepsy has recently been published in epilepsy medical journal, Epilepsia. The study assessed data collected from three medical centres across China from July 24th – August 31st 2021. In total, 981 people were recruited for this study and were interviewed using questionnaires to collect & assess data surrounding their reasons for taking or not taking the vaccine and to assess the outcome of the vaccine on those taking part. Of the 981 people recruited, 491 people had epilepsy; 217 had other neuropsychiatric conditions and 273 had no underlying conditions.

The questionnaire presented to participants with epilepsy sought to learn more about their condition, seizure control and reasons for hesitation around vaccination. This way their condition pre & post vaccination could be monitored and assessed. Data was collected from healthy controls to compare this with the data with those with epilepsy to see whether there was an increased report of side-effects amongst people with epilepsy and to learn more about hesitancy around vaccination. When this data was collected and assessed, the authors of the research have made two key conclusions: 1. The data collected from people with epilepsy has found no evidence suggesting worsening seizure control

post-vaccination; with less than 10% reporting an increase in seizures post vaccination. However, for this cohort of people who reported an increase in seizures, the study’s authors speculate that this may have been coincidental and owing to the fluctuating nature of epilepsy rather than any post-vaccination side-effects. 2. Vaccination rates amongst people with epilepsy were much lower than their “healthy” controls. At the time of the study, 93% of healthy controls had been administered with a first dose of a vaccine, compared to 42% of those with epilepsy. People with epilepsy cited hesitance around vaccination due to potential loss of seizure control/increase in seizure frequency and concerns around

potential adverse side-effects of vaccination. Alongside the above two key findings, no incidences of status epilepticus amongst those with epilepsy was recorded while reports of adverse side-effects (pain at injection site, fatigue, headache, fever etc) were not increased in people with epilepsy when compared with “healthy” controls. The findings of this study are very welcome as this represents the first wide-scale study on the use of COVID-19 vaccines in people with epilepsy. You can read this study in full by visiting the Epilepsia website at the link below: https://onlinelibrary.wiley.com/ doi/10.1111/epi.17138

BE PREPARED WHEN SEIZURES STRIKE BUCCOLAM (R) is indicated for the treatment of prolonged, acute, convulsive seizures in infants, toddlers, children and adolescents (from 3 months to <18 years). 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 possible and resuscitation equipment is available. Further prescribing information is available on request from Neuraxpharm or the Summary of Product Characteristics - eMail: medinfo@neuraxpharm.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: medsafety@hpra.ie Tel +353 (1) 676 4971 Fax: +353 1 6767836

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PULMONARY FIBROSIS

Idiopathic Pulmonary Fibrosis: An Update

Written by, Dr Padraig Ridge; MRCPI - Respiratory Specialist Registrar, Galway University Hospital

Written by, Dr Sinead Walsh; MRCPI, PhD - Consultant Respiratory and Sleep Physician, Galway University Hospital, Lecturer in Medical Education, NUI Galway

Introduction

an underlying connective tissue disorder that was sub-clinical at time of first presentation. The condition is more common in males than females.

Interstitial lung disease (ILD) refers to a broad spectrum of lung conditions that affect the interstitial rather than the airway compartment of the lung. It spans a large number of distinct entities, but can be viewed broadly as those with an identifiable cause, those with granulomatous pathology and those considered idiopathic interstitial pneumonias. The age of onset varies considerably. The most common chronic progressive-fibrosing idiopathic interstitial pneumonia is idiopathic pulmonary fibrosis (IPF)(Lederer and Martinez, 2018). Significant progress has been made in the understanding and management of IPF in recent years. This article will outline an update on IPF. Epidemiology Epidemiological data for IPF varies due to differing methods of data collection worldwide. Throughout Europe and North America, the estimated incidence of IPF ranges from 2.8 to 19 cases per 100,000 people per year (Olson et al., 2018). Prevalence of IPF increases with age, with the majority of patients age over 50 years at diagnosis. Patients are typically in the sixth and seventh decades of life at presentation. Patients with IPF who are younger than 50 at diagnosis are rare. Such patients may have familial IPF or may subsequently manifest features of

Pathogenesis The pathogenesis of IPF is unclear but likely results from the dynamic interaction of genetic, epigenetic, and environmental risk factors. Genetic predisposition results from gene mutations (e.g. MUC5B polymorphism) or a combination of common gene variants. Known environmental exposure includes cigarette smoke and viruses. Micro-aspiration of gastric contents in to the lung is another potential cause of injury, with the prevalence of gastro-oesophageal reflux being elevated in IPF (Raghu et al., 2006). A number of aging-associated mechanisms have been implicated, including genetic instability, abnormal shortening of telomeres, mitochondrial dysfunction and cellular senescence. This results in abnormal phenotypic and functional changes in the airway and alveolar epithelium. The activated dysfunctional epithelium releases mediators, leading to the migration, proliferation and activation of hyperactive mesenchymal cells. These organise in clusters of fibroblasts and myofibroblasts, which are responsible for the secretion of excessive extracellular matrix materials, including collagens

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and fibronectin. This leads to profibrotic macrophages arriving and progressive matrix stiffness, ultimately resulting in lung destruction (Pardo and Selman, 2021).

IPF. As IPF progresses, the hallmark chest x-ray findings are reduced inspiratory lung volumes, bilateral reticular opacification, with a basilar and peripheral predilection/predominance.

Clinical presentation of IPF

In IPF, pulmonary function tests will demonstrate a restrictive abnormality. This is evident by reduced lung volumes, as identified by a total lung capacity (TLC) measurement of less than 80% predicted. The forced vital capacity (FVC) is typically reduced, along with reduced diffusing capacity of the lung for carbon monoxide (DLCO), indicating impaired gas exchange. However, it is important to remember that spirometry and lung volume measurements can be normal, particularly during the early stages of disease or when there is concurrent emphysema (Cottin et al., 2017).

Shortness of breath on exertion is typically the first presenting feature of IPF. It presents insidiously, with gradual progression over a period of months to years. Patients can notice reduced exercise tolerance. A persistent dry cough is another presenting feature, along with weight loss and fatigue. Initial symptoms are often attributed to ageing, deconditioning or other co-morbidities, which may lead to a delayed diagnosis for patients. IPF patients may have nonspecific symptoms for up to five years before a diagnosis is made. Common mis-diagnoses include chronic obstructive pulmonary disease (COPD) and congestive cardiac failure (CCF) (Hewson et al., 2018). Fine end-inspiratory crepitations on clinical examination are a common finding in IPF patients. These ‘velcro-like’ crepitations are predominantly audible in the lower posterior lung zones and in the axillae. Crepitations are the most specific among the chest physical signs at first presentation (Martinez et al., 2017). Finger clubbing is also found in 30-50% of patients. . As the disease progresses and respiratory failure develops, central cyanosis may be evident. The lack of specific clinical features and co-existence of other conditions can delay the diagnosis of IPF, which has a negative impact on patient survival in IPF (Lamas et al., 2011). Increased awareness and knowledge of interstitial lung diseases will be required to improve early diagnosis and earlier access to treatments. Investigations A chest x-ray is a very useful first radiological test when a patient presents with symptoms of dyspnoea and cough. It is important to note that the chest x-ray lacks diagnostic specificity for IPF but is useful to exclude other causes of dyspnoea. The appearances may be normal or demonstrate non-specific findings early in the disease course of

If an interstitial lung disease is suspected from the history, physical examination and initial investigations, a high-resolution CT (HRCT) thorax should be performed. The HRCT thorax will determine if ILD is present and can identify specific radiological patterns that will help the clinician in narrowing the differential diagnosis (Raghu et al., 2018). The finding of honeycombing with or without peripheral traction bronchiectasis in a subpleural and basal distribution is consistent with definite ‘usual interstitial pneumonia’ (UIP), considered the hallmark radiological pattern of IPF. The positive predictive value of a radiologic diagnosis of UIP on a HRCT scan for a pathological diagnosis of UIP is between 90 – 100% (Raghu et al., 2018). Mediastinal lymphadenopathy may be present in patients with UP and asymmetric disease can occur in up to 25% of cases. Making a diagnosis A major challenge in making a diagnosis of IPF is the exclusion of other known causes of ILD, such as environmental exposures, connective tissue disorders and drug toxicity. A detailed history of both medication use and exposures at home, work and other places the patient frequently visits is required. Clinicians are required to make judgements regarding the aetiological significance of a patients exposures. Careful attention to a thorough physical examination excluding other

IMAGE TWO:

Taken from: https:// irishthoracicsociety.com/wpcontent/uploads/2018/08/ ITS-Pulmonary-Fibrosis-PositionStatement.pdf

clinical signs of connective tissue

disorders Taken from:is also required.

or used with extreme caution if the patient is also using other CYP12A inhibitors (e.g. ciprofloxacin) or inducers (e.g. omeprazole).

(Lederer and Martinez, 2018)

Pulmonary rehabilitation is a To establish a diagnosis of IPF comprehensive intervention https://irishthoracicsociety.com/wp-content/uploads/2018/08/ITS-Pulmonary-Fibrosis-Positionand to rule out other ILD’s or designed to improve the physical Nintedanib (Ofev™) is a tyrosine overlapping conditions, cases and psychological status of Statement.pdf kinase inhibitor, with inhibition require multi-disciplinary team patients with chronic advanced of platelet-derived growth factor (MDT) discussion, ideally at ILD lung disease through respiratory (PDGF) receptor, fibroblast specialist centres. A diagnosis muscle and exercise training. It also growth factor (FGF) receptor, of IPF is achieved through an promotes long-term adherence and vascular endothelial growth iterative discussion within the to health-enhancing behaviours. factor (VEGF) receptor. It MDT, a practice that is endorsed Pulmonary rehabilitation for reduces the rate of decline in by international guidelines (Raghu IPF patients increases exercise FVC and reduces the time to the et al., 2018). tolerance and quality of life first acute exacerbation of IPF (Gomes-Neto et al., 2018). Management (Richeldi et al., 2014). It has also The evidence base for longdemonstrated efficacy across As with other chronic lung term oxygen therapy (LTOT) in a broad range of progressive IMAGE THREE: conditions, management of IPF is lacking. Patients with fibrosing ILD’s, in addition to IPF patients involves improving significant resting hypoxemia IPF (Flaherty et al., 2019). The symptoms, preserving lung An idea for image three would be adose HRCT scan showing features of (oxygen IPF. Please let us know saturation <88% or if you of nintedanib is 150mg function, improving health quality, PaO2 < 7.3 kPa) should be orally twice daily. Liver function would like usadverse to get effects these images. minimising of treated with LTOT. Many patients tests are required at baseline and treatment and ideally, improving with IPF have normal oxygen regularly thereafter. Side effects survival. (Martinez et al., 2017). saturations at rest but rapidly include diarrhoea and nausea. desaturation upon exertion. The Due to the mechanism of action Pharmacological management use of ambulatory oxygen when of nintedanib, patients on oral Two anti-fibrotic drugs were mobilising may improve exercise anti coagulation should be treated approved for IPF treatment in capacity and relieve dyspnoea with nintedanib if the anticipated 2014, namely pirfenidone and in these patients. However, benefit outweighs the risk and nintedanib, based on wellthe burden of therapy and the they should be closely monitored conducted randomised controlled potential to generate anxiety for bleeding risk. trial, which demonstrated that both about running out of oxygen must Choosing one anti-fibrotic over drugs slowed disease progression. be considered. More studies another can be difficult for the regarding the role of oxygen Pirfenidone (Esbriet™) is an anticlinician, due to the absence therapy in IPF are required. fibrotic drug that decreases the of head to head clinical trials. proliferation of fibroblasts and Decisions about anti-fibrotics Whilst micro-aspiration of gastric the accumulation of collagen. should be based on what is most contents into the lung has been It reduces the rate of decline suitable for the individual patient. implicated in the aetiology of in the FVC, with improved IPF, antacid therapy has failed A number of trials have provided progression-free survival (King to demonstrate any benefit and evidence that the combination Jr et al., 2014). It should be in fact, may be associated with of pirfenidone and nintedanib taken three times daily with food increased respiratory infections is safe and tolerable to patients at a target dose of 801mg that (Kreuter et al., 2016). Thus, (Flaherty et al., 2018). Future is titrated upwards over a 14 reflux-directed therapy should be randomised controlled trials to day period. Liver function tests considered on an individual basis if evaluate whether combining the are required at baseline and the patient has symptoms of reflux. two anti-fibrotic drugs increases regularly thereafter. Side effects effectiveness remains to be Patient support and education are include photosensitivity, rash, determined. At present, the drugs essential when a patient receives and gastrointestinal discomfort. are not given in combination. a diagnosis of IPF. The Irish Lung Patients are advised to avoid Fibrosis Association (ILFA) is the sun exposure and to wear sun Non-pharmacologic national patient organisation for protection. If side effects and/or lung fibrosis, providing support hepatotoxicity develops, the dose Non-pharmacologic management to patients and their families. of pirfenidone can be reduced, or is essential. This includes Exercise DVD’s, ‘2000 steps temporarily held and reintroduced cessation of smoking, maintaining a day’ challenges and regular at a slower dose titration. an up to-date vaccination profile, patient support groups are some Pirfenidone is metabolised by the diagnosis and management of ways that ILFA provides support anxiety and depression, weight cytochrome P450 1A2 (CYP1A2) and nutrition management and education. The National enzymes, and should be avoided

Patient Charter for IPF was developed by ILFA in 2015 (SEE IMAGE TWO). Once a diagnosis of IPF is suspected, there is a need to deliver the key areas of this charter to improve patient care and outcomes. Monitoring a patient over time/ disease response Once a patient is diagnosed and commenced on appropriate therapy, regular review at specialist ILD clinics is necessary. Symptoms are closely monitored. Patients are advised that whilst the anti fibrotic drugs should slow the rate of FVC decline, their symptoms will persist and likely worsen. PFT’s are performed at regular intervals. Longitudinal changes in respiratory physiology is an important predictor of mortality in IPF (Nakamura and Suda, 2015). A decline in FVC over six to twelve months is a reliable predictor of mortality in IPF. DLCO declines are also associated with decreased survival, but demonstrate less consistency than the FVC (Latsi et al., 2003). Assessment for lung transplantation Lung transplantation is recognised as the only effective treatment for IPF. In Ireland over 30% of patients receiving lung transplantation have IPF. Appropriate and timely referral to the National Lung Transplant Centre at the Mater University Hospital is required. All patients should be considered for transplant referral with clear emphasis on prioritising patients with rapidly declining lung function, DLCO below 40%, or respiratory failure. Older patients frequently have co-morbidities that preclude transplantation but decisions should be made on a case by case basis (Walsh and O’Regan, 2018). Concurrent rates of cancer in IPF Patients with IPF have increased rates of lung cancer, with the prevalence of lung cancer in IPF varying from 4.4 to 9.8% (Margaritopoulos et al., 2017). This is particularly in those

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PULMONARY FIBROSIS KING JR, T. E., BRADFORD, W. Z., CASTRO-BERNARDINI, S., FAGAN, E. A., GLASPOLE, I., GLASSBERG, M. K., GORINA, E., HOPKINS, P. M., KARDATZKE, D. & LANCASTER, L. 2014. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. New England Journal of Medicine, 370, 2083-2092. KREUTER, M., WUYTS, W., RENZONI, E., KOSCHEL, D., MAHER, T. M., KOLB, M., WEYCKER, D., SPAGNOLO, P., KIRCHGAESSLER, K.-U. & HERTH, F. J. 2016. Antacid therapy and disease outcomes in idiopathic pulmonary fibrosis: a pooled analysis. The Lancet Respiratory Medicine, 4, 381-389. LAMAS, D. J., KAWUT, S. M., BAGIELLA, E., PHILIP, N., ARCASOY, S. M. & LEDERER, D. J. 2011. Delayed access and survival in idiopathic pulmonary fibrosis: a cohort study. American journal of respiratory and critical care medicine, 184, 842-847. LATSI, P. I., DU BOIS, R. M., NICHOLSON, A. G., COLBY, T. V., BISIRTZOGLOU, D., NIKOLAKOPOULOU, A., VEERARAGHAVAN, S., HANSELL, D. M. & WELLS, A. U. 2003. Fibrotic idiopathic interstitial pneumonia: the prognostic value of longitudinal functional trends. American journal of respiratory and critical care medicine, 168, 531-537. LEDERER, D. J. & MARTINEZ, F. J. 2018. Idiopathic pulmonary fibrosis. New England Journal of Medicine, 378, 1811-1823.

who have a smoking pack year history of at least 35 pack years and those with co-existing emphysema (Kato et al., 2018). Lung cancer commonly develops in the peripheral parts of the lower lobes, adjacent to areas of UIP. Distinction between malignancy and areas of confluent fibrosis can be difficult, especially if prior imaging is unavailable. Clinicians should be mindful of the increased rates of lung cancer in IPF. Palliative care Patients with IPF should receive timely and adequate access to community, general and specialist palliative care services. The major aims of palliative care in IPF are to improve quality of life by addressing the patients symptoms. Their psychological and spiritual needs can also be explored, to ensure that IPF patients live well with their disease. IPF continues to have a poor prognosis. International studies demonstrate a median survival of three to five years from diagnosis. However, the prognosis is variable with some patients experiencing longer survival times dependent on the disease stage. Acute exacerbations (flares) of IPF Whilst the majority of IPF patients demonstrate a gradual worsening in their symptoms over time, a significant minority of patients experience episodes of acute worsening of respiratory symptoms without an identifiable cause, termed an acute exacerbation of IPF (Collard et al., 2016). An acute exacerbation of IPF is most likely triggered by an acute event (e.g. micro-aspiration,

infection, mechanical stretch) on a background of fibrosis, leading to widespread acute lung injury (characterised by hyaline membrane formation and interstitial oedema). The acute exacerbation may also precipitate acceleration of the underlying fibrotic process (Collard et al., 2016). There are no proven effective therapies for acute exacerbations of IPF. Many patients receive systemic steroids without an evidence base to support this intervention. Supplemental oxygen is given to correct hypoxemia. Estimated in-hospital mortality is up to 90% in IPF patients presenting with an acute exacerbation and in respiratory failure. Mechanical ventilation carries a high mortality rate. If there is no clear reversible cause for the respiratory failure outside of the progressive fibrosis, it is not recommended to place a patient on mechanical ventilation (Rush et al., 2016). Non-invasive respiratory support, such as non-invasive ventilation and nasal high flow oxygen therapy can be delivered as the ceiling of care. Conclusion The knowledge around IPF has greatly expanded over the past ten years. Optimal management involves early diagnosis via MDT input and deciding on appropriate treatment. Management decisions involve balancing standardof-care approaches with the patients’ wishes and expectations. Treatment requires consideration of medication side effects, potential drug interactions, consideration of the optimal time for lung transplant assessment and recognising when it may be appropriate to withdraw intervention and introduce palliative

JANUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

care measures. More studies are required to assess the optimal treatments for acute exacerbations of IPF and to develop optimal therapies to halt and even reverse progressive fibrosis. References COLLARD, H. R., RYERSON, C. J., CORTE, T. J., JENKINS, G., KONDOH, Y., LEDERER, D. J., LEE, J. S., MAHER, T. M., WELLS, A. U. & ANTONIOU, K. M. 2016. Acute exacerbation of idiopathic pulmonary fibrosis. An international working group report. American journal of respiratory and critical care medicine, 194, 265-275. COTTIN, V., HANSELL, D. M., SVERZELLATI, N., WEYCKER, D., ANTONIOU, K. M., ATWOOD, M., OSTER, G., KIRCHGAESSLER, K.-U., COLLARD, H. R. & WELLS, A. U. 2017. Effect of emphysema extent on serial lung function in patients with idiopathic pulmonary fibrosis. American journal of respiratory and critical care medicine, 196, 1162-1171. FLAHERTY, K. R., FELL, C. D., HUGGINS, J. T., NUNES, H., SUSSMAN, R., VALENZUELA, C., PETZINGER, U., STAUFFER, J. L., GILBERG, F. & BENGUS, M. 2018. Safety of nintedanib added to pirfenidone treatment for idiopathic pulmonary fibrosis. European Respiratory Journal, 52. FLAHERTY, K. R., WELLS, A. U., COTTIN, V., DEVARAJ, A., WALSH, S. L., INOUE, Y., RICHELDI, L., KOLB, M., TETZLAFF, K. & STOWASSER, S. 2019. Nintedanib in progressive fibrosing interstitial lung diseases. New England Journal of Medicine, 381, 1718-1727. GOMES-NETO, M., SILVA, C. M., EZEQUIEL, D., CONCEIÇÃO, C. S., SAQUETTO, M. & MACHADO, A. S. 2018. Impact of pulmonary rehabilitation on exercise tolerance and quality of life in patients with idiopathic pulmonary fibrosis: a systematic review and meta-analysis. Journal of cardiopulmonary rehabilitation and prevention, 38, 273-278. HEWSON, T., MCKEEVER, T. M., GIBSON, J. E., NAVARATNAM, V., HUBBARD, R. B. & HUTCHINSON, J. P. 2018. Timing of onset of symptoms in people with idiopathic pulmonary fibrosis. Thorax, 73, 683-685. KATO, E., TAKAYANAGI, N., TAKAKU, Y., KAGIYAMA, N., KANAUCHI, T., ISHIGURO, T. & SUGITA, Y. 2018. Incidence and predictive factors of lung cancer in patients with idiopathic pulmonary fibrosis. ERJ open research, 4.

MARGARITOPOULOS, G. A., ANTONIOU, K. M. & WELLS, A. U. 2017. Comorbidities in interstitial lung diseases. European Respiratory Review, 26. MARTINEZ, F. J., COLLARD, H. R., PARDO, A., RAGHU, G., RICHELDI, L., SELMAN, M., SWIGRIS, J. J., TANIGUCHI, H. & WELLS, A. U. 2017. Idiopathic pulmonary fibrosis. Nature Reviews Disease Primers, 3, 1-19. NAKAMURA, Y. & SUDA, T. 2015. Idiopathic pulmonary fibrosis: Diagnosis and clinical manifestations. Clinical Medicine Insights: Circulatory, Respiratory and Pulmonary Medicine, 9, CCRPM. S39897. OLSON, A. L., GIFFORD, A. H., INASE, N., PÉREZ, E. R. F. & SUDA, T. 2018. The epidemiology of idiopathic pulmonary fibrosis and interstitial lung diseases at risk of a progressive-fibrosing phenotype. European Respiratory Review, 27. PARDO, A. & SELMAN, M. 2021. The interplay of the genetic architecture, aging, and environmental factors in the pathogenesis of idiopathic pulmonary fibrosis. American Journal of Respiratory Cell and Molecular Biology, 64, 163-172. RAGHU, G., FREUDENBERGER, T., YANG, S., CURTIS, J., SPADA, C., HAYES, J., SILLERY, J., POPE, C. N. & PELLEGRINI, C. 2006. High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis. European Respiratory Journal, 27, 136-142. RAGHU, G., REMY-JARDIN, M., MYERS, J. L., RICHELDI, L., RYERSON, C. J., LEDERER, D. J., BEHR, J., COTTIN, V., DANOFF, S. K. & MORELL, F. 2018. Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline. American journal of respiratory and critical care medicine, 198, e44-e68. RICHELDI, L., DU BOIS, R. M., RAGHU, G., AZUMA, A., BROWN, K. K., COSTABEL, U., COTTIN, V., FLAHERTY, K. R., HANSELL, D. M. & INOUE, Y. 2014. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. New England Journal of Medicine, 370, 2071-2082. RUSH, B., WISKAR, K., BERGER, L. & GRIESDALE, D. 2016. The use of mechanical ventilation in patients with idiopathic pulmonary fibrosis in the United States: a nationwide retrospective cohort analysis. Respiratory medicine, 111, 72-76. WALSH, S. M. & O’REGAN, A. W. 2018. Diffuse Parenchymal Lung Diseases in the Elderly. Current Geriatrics Reports, 7, 174-180.

COPD

Phenotyping and Endotyping in COPD: The Search for Targeted Therapies Written by Dr Emma McNally, Respiratory SpR and Professor Eddie Moloney, Respiratory Consultant, Tallaght University Hospital Chronic obstructive pulmonary disease (COPD) is a heterogeneous condition, with patients displaying varying pathophysiological and clinical features including chronic predominantly neutrophilic inflammation of the airways and irreversible airflow obstruction. This leads to emphysematous destruction of lung tissue and deterioration of pulmonary function. The most common cause is cigarette smoking. Genetics, childhood lung development and environmental exposures also play a role. The clinical presentation ranges from exertional dyspnea and respiratory tract infections, to progressive severe exacerbations of the disease that may require hospitalisation, reduced exercise tolerance, respiratory failure, and associated co morbidity including pulmonary hypertension, sleep disordered breathing, depression and an increased risk of lung cancer. It remains the third leading cause of death worldwide.1 To date, treatment has focused predominantly on guideline directed therapy primarily concentrated on symptom management and treatment of exacerbations with inhaled bronchodilator and corticosteroid therapy, an often chronic reliance on oral corticosteroids and frequent antibiotics. Adjunctive, non-pharmacological therapies including oxygen prescription, non-invasive ventilation, and pulmonary rehabilitation are also implemented. The identification of COPD endotypes, with distinct underlying disease mechanisms may allow for targeted treatment strategies directed towards specific biological pathways.

COPD Phenotypes COPD phenotypes refers to a single or combination of disease attributes that describe similarities between subgroups of COPD patients based on clinically significant parameters. Ideally individuals grouped within a clinical phenotype should demonstrate a similar clinical trajectory and response to treatment due to a common underlying biological mechanism (i.e. endotype).2 The idea of phenotyping within COPD is well established, with many textbooks traditionally describing the ‘blue bloater’ versus the ‘pink puffer’, of course referring to those with chronic bronchitis and emphysema respectively. In fact, as far back as 1989, Snider classified airflow obstruction into three groups via a non-proportional venn diagram which largely still hold true; asthma, emphysema and bronchitis.3 Despite much analysis, it remains challenging to accurately and consistently define phenotypes among the COPD cohort. Spirometry indices, FEV1/FVC ratio <70%, are used to diagnose, and the decline in FEV1 used to assess the severity of disease. A bronchodilator response of >15% and 200ml increase in FEV1 may indicate an asthma-COPD overlap phenotype.4 Radiological phenotyping with computed tomography (CT) assessment of small airway disease versus emphysema would offer an objective measure of parenchymal disease that correlates well with histopathologic findings and is predictive of the degree of expiratory airflow obstruction,

Dr Emma McNally, Respiratory SpR,

Professor Eddie Moloney, Respiratory Consultant, Tallaght University Hospital

however allocation of resources in most centers will not allow for CT use for categorization of COPD as the primary indication.5 The frequency of pulmonary exacerbations lends itself to a clinical phenotype; the frequent exacerbator. Defined as >2 exacerbations/year, this phenotype is associated with higher mortality and healthcare utilisation.5 Exacerbation predominant COPD is recognized by the global initiative for chronic obstructive lung disease (GOLD) and is used in their classification system (GOLD C/D; >2 exacerbations/yr or 1 exacerbation requiring hospitalization) and hence, influences their treatment algorithm.6

a lack of correlation to specific disease mechanisms underpinning these phenotypes has limited their impact regarding personalized therapies thus far.

While historical phenotypes based on clinical characteristics and newer emerging phenotypes are becoming increasingly recognized,

COPD Endotypes COPD endotypes imply known molecular mechanisms leading to the clinical phenotype of the disease, Often, these are recognized by associated biomarkers that are reflective of the underlying biologic processes. Genetic endotypes The best described endotype in COPD is alpha one antitrypsin (AAT) deficiency. AAT is a protease inhibitor (Pi). In healthy individuals, AAT acts to inhibit destruction by the serine protease neutrophil elastase, an enzyme which attacks lung elastin and damages bronchial and alveolar wall integrity. The gene that encodes AAT is SERPINA1 and is located on the long arm of chromosome 14. The normal allele is referred to as ‘M”. Thus “Pi*MM” indicates homozygosity for the normal allele. “Pi*ZZ” refers to homozygosity for the ‘Z’ allele, the most common mutation in the SERPINA1 gene, associated with very low levels of AAT and a very high risk of developing rapidly progressive

HOSPITALPROFESSIONALNEWS.IE | HPN • JANUARY 2022

COPD

emphysema. Further point mutations include the “S” allele, homozygosity for this infers moderately reduced levels of AAT without increased risk of emphysema, however compound heterozygosity such as ‘Pi*MZ’ or” Pi*SZ” leads to an increased risk of emphysema, particularly in smokers. Individuals with the ‘null’ allele (Pi*Null) have undetectable levels of plasma AAT and therefore are at highest risk of severe pulmonary manifestations. This phenotype is thankfully the least common.7 AAT deficiency is under-recognised and clinicians should consider it as a potential diagnosis in all adults with persistent airflow obstruction but especially in adults who develop emphysema at a young age (<50), emphysema in the absence of smoking history or other environmental exposures, lower lobe predominant emphysema, adult onset asthma and unexplained bronchiectasis. Bear in mind that patients may present with hepatic or cutaneous manifestations of the condition also. Diagnosis is confirmed by testing serum levels of AAT (<11mmol/L = severe deficiency), followed by confirmatory genotyping alongside spirometry and pulmonary imaging. Treatment with intravenous augmentation therapy (pooled human alpha 1 proteinase), aims to elevate the serum and interstitial levels of AAT and has been proven to slow the rate of lung density loss on CT. Treatment is recommended for patients with confirmed deficiency of AAT

with a severe genotype and in whom FEV1 is within 30-65% of predicted.6, 8 Inflammatory Endotypes Eosinophils are innate immune cells which are regulators of the type 2 immune response pathway. Eosinophils usually remain quiescent in blood until exposed to pro inflammatory mediators such as IL3, IL5 and GM-CSF at which point they become activated and migrate to sites of inflammation. Once in the lungs, eosinophils release a range of pro-inflammatory cytokines, chemokines and growth factors which contribute to sustained inflammation and tissue damage.9 Eosinophilic inflammation occurs frequently in COPD and its use as an endotype is surpassing others given its clinical applicability. Airway eosinophilia can be measured via sputum and bronchial mucosa sampling. However, studies show that peripheral blood eosinophilia (>0.3x109/L) correlated with an elevated sputum eosinophil count (>3%) in 70% of cases, hence blood eosinophils are accepted as a surrogate biomarker for airway eosinophilia.10 Eosinophilia in COPD is associated with an increased frequency of exacerbations, readmissions to hospital and accelerated disease progression. The evidence is compelling that this endotype demonstrates an exaggerated response to inhaled corticosteroids (ICS) and systemic steroids. Several post hoc analyses have demonstrated a slower decline in FEV1, reduced exacerbation rates and improved symptoms in

patients with elevated eosinophil counts receiving ICS compared to those with lower eosinophil counts.11 The IMPACT trial (Informing the pathway of COPD treatment) went on to prospectively demonstrate a greater reduction in exacerbation frequency in patients with eosinophilic inflammation (>150cell/uL) with the use of once daily triple therapy (ICS/LAMA/ LABA) compared with LAMA/LABA or ICS/LABA combinations.12 The body of evidence conferring the benefit of ICS in eosinophilic inflammation in COPD was reflected in the updated GOLD guidelines, 2019. Peripheral blood eosinophil count is now taken into account alongside the known ‘ABCD’ classification. An ICS in conjunction with a LABA or LABA/LAMA is recommended for individuals with persistent dyspnea and eosinophils >0.3x109/L, or, those with eosinophils >0.1x109/L plus >2 exacerbations per annum, or one exacerbation requiring hospitalisation. Patients should be monitored for a response to treatment and adverse events such as pneumonia, which may prompt consideration of withdrawal of ICS.13 Several treatments targeting the eosinophilic pathway with monoclonal antibody therapies for eosinophilic COPD are in development. Mepolizumab targets the IL-5 ligand and inhibits IL5 receptor signaling in eosinophils. It was approved as an adjunctive treatment in severe asthma with associated eosinophilia in 2015. In this group it has been shown to reduce exacerbation frequency, improve symptoms, improve FEV1 and reduced oral corticosteroid use. Initial studies on the use of

mepolizumab in the eosinophilic COPD population did not show a statistically significant reduction in exacerbations or improvement in FEV1, however emerging Phase III data indicated an improvement in exacerbation rates in patients with elevated eosinophils and COPD.14 Phase III data collection is ongoing. Benralizumab targets the IL5 receptor and demonstrated similar clinical benefits in severe eosinophilic asthma as mepolizumab with regards exacerbations, FEV1, corticosteroid use and symptoms. Phase II trials in the eosinophilic COPD cohort did not suggest an improvement in exacerbation rates but did demonstrate an improvement in FEV1 in COPD patients with elevated eosinophils allocated to benralizumab.15 Phase III trials are ongoing. There is ongoing research into other pathways of innate and adaptive immunity which undoubtedly contribute to the pathophysiology of COPD. For example, there is emerging evidence of a potential role of the type 17 helper T cells (Th 17) and their pro inflammatory cytokines; IL-17A in the pathogenesis of COPD, more specifically the emphysematous phenotype.16 Similarly, while intermittent respiratory infections with viral and bacterial pathogens are a hallmark of COPD, bacterial colonization in sputum and bronchoscopy derived samples is well described. At a molecular level, this bacterial colonization and frequency of exacerbations may be linked to a defect of phagocytosis of bacteria by macrophages.17 Defects in IL- 22 have been suggested as partly responsible for this lack of infection control and airway colonization.16 These theories are underdeveloped and require further analysis. Conclusion COPD is phenotypically heterogeneous. An improved understanding of the underlying biological mechanisms which drive the chronic inflammation associated with the disease is required to aid the identification of endotypes. In recent years, progress has been made with the recognition of eosinophilic COPD as an endotype and its inclusion in treatment guidelines. Currently, there are number of promising areas of research into the identification of additional endotypes and potential biomarkers which will need refinement and longitudinal assessment of their viability and stability over time as therapeutic targets. References on request

JANUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

NOW AVAILABLE

IND/GLY/MF 114/46/136μg

ONCE DAILY ENERZAIR® BREEZHALER® + SENSOR*

daily

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

MEDICATION REMINDERS3

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

ONCE DAILY

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: drugsafety.dublin@novartis.com 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.

CHEST 2021

Managing the IPF Patient Across the Disease Spectrum Amy Hajari Case, MD, FCCP, Director of the Interstitial Lung Disease Program at Piedmont Healthcare in Atlanta

pulmonary rehabilitation, research opportunities, transplant evaluation, and supportive care, Dr. Case noted, while advocating for a shared decision-making approach to establishing each patient’s plan.

The annual CHEST Conference for 2021 took place recently, providing clinical updates directly from the experts who are furthering innovation, advancing patient care, and educating the next generation of chest medicine professionals. The American College of Chest Physicians is the global leader in advancing best patient outcomes through innovative chest medicine education, clinical research, and team-based care. During the session Managing the IPF Patient Across the Disease Spectrum: An Evidence-Based Update, two pulmonary specialists outlined the challenges in treating idiopathic pulmonary fibrosis (IPF), including key management decisions at the time of diagnosis and approaches to managing acute exacerbation.

If antifibrotic therapy is used, the choice between the two antifibrotic drugs with US Food and Drug Administration approval for the treatment of IPF—pirfenidone and nintedanib—is not clear cut. Both options slow disease progression as measured by forced vital capacity, but neither is expected to change any symptoms of IPF, Dr. Case explained. When selecting which drug to use, she said adverse events reported with each option should be considered. Of patients taking nintedanib in a phase 3 trial, 62% reported experiencing diarrhea, 24% nausea, and 15% abdominal pain. Among patients taking pirfenidone in a separate phase 3 trial, 36% reported nausea, 30% a rash, and 27% an upper respiratory tract infection. At regular intervals following a diagnosis of IPF, the patient should undergo pulmonary function

Amy Hajari Case, MD, FCCP, Director of the Interstitial Lung Disease Program at Piedmont Healthcare in Atlanta, opened the session with a discussion on how to manage a patient with a new IPF diagnosis. “When we think about the patient with idiopathic pulmonary fibrosis, our minds immediately go to antifibrotic therapy,” she said. “But what I want us to think about is comprehensive management of the IPF patient, meaning that the antifibrotic therapies that we have are only part of the management plan for our patients.” A comprehensive management plan might include treatment of comorbidities, smoking cessation, preventive care, education and support groups,

JANUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

testing, a 6-minute walk to assess functional status and the need for supplemental oxygen, liver function testing, and follow-up imaging, Dr. Case said. Tejaswini Kulkarni, MD, MBBS, Assistant Professor and Director of the Interstitial Lung Disease Program at the University of Alabama at Birmingham, outlined current and emerging therapies for managing the acute exacerbation of IPF (AE-IPF), including antimicrobial therapy, bronchoscopy, oxygen therapy, mechanical ventilation, and antifibrotic drugs. “As the most common cause of death in most of the IPF cohorts, the implications of AE are profound, but unfortunately there are no proven or effective treatments,” Dr. Kulkarni said. “The severity of AEs is variable, and these do impact treatment decisions to some extent, but the currently used therapeutic approaches are all based on expert consensus or small uncontrolled or retrospective studies.” Corticosteroids are the most common treatment for patients with AE-IPF. “The idea behind that is that the pathological finding in an acute exacerbation of IPF is diffuse alveolar damage, and the utilization of corticosteroids is

based on the extrapolation of its effects that have been seen on pulmonary inflammation in the acute lung injury models and the ARDSM models,” Dr. Kulkarni said, adding that there are no specific recommendations regarding dose, route of administration, or duration of corticosteroid use in AE-IPF. She cited a prospective study that reported avoiding steroids may reduce adverse events associated with immunosuppression for patients with AE-IPF. A singlecenter retrospective study of 82 patients showed no significant difference in in-hospital mortality among those who were given steroids and those who were not. However, the all-cause mortality of the cohort receiving steroids was increased shortly after hospital discharge, Dr. Kulkarni said. Autoantibody Reduction for Acute Exacerbations of Idiopathic Pulmonary Fibrosis (STRIVE-IPF), which is currently enrolling phase 2 participants, is studying an autoantibody reduction protocol for AE-IPF. “AE-IPF confers a poor prognosis. The revised diagnostic criteria have shifted to more of a pathophysiology basis rather than an etiology basis, but the management of AE-IPF really remains enigmatic, so ultimately, focus on the best supportive care for your patient,” Dr. Kulkarni said.

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

References:

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.

BRONCHOSCOPIC INTERVENTIONS

A Breath of Fresh Air: Bronchoscopic Interventions for Patients with COPD Preclinical human trials have demonstrated the feasibility of targeted lung denervation, he noted. Other emerging treatments include bronchial rheoplasty and metered cryospray. “Bronchoscopic therapies for patients with chronic bronchitis are still in the early phase of clinical research, and larger randomized controlled trials are ongoing to confirm the available data and to evaluate the treatment durability,” Dr. Ghattas said. Christian Ghattas, MD, Assistant Professor of Medicine, The Ohio State University Medical Center

Van K. Holden, MD, FCCP, Assistant Professor, University of Maryland School of Medicine

Vivek Murthy, MD, FCCP, Assistant Professor and Associate Director of Interventional Pulmonology, NYU Langone Health

Bronchoscopic procedures to treat COPD continue to evolve. A panel of experts discussed the dynamics of current, novel, and emerging treatments for COPD during the CHEST 2021 session, A Breath of Fresh Air: Bronchoscopic Interventions for Patients With COPD.

within 1 year, Dr. Holden said. Post-procedure follow-up is recommended at 1 to 2 weeks, 1 month, 3 months, 6 months, 12 months, and yearly thereafter.

“An ideal patient would be someone who has completed pulmonary rehab and remains very symptomatic despite maximal medical therapy for COPD,” Dr. Murthy said.

Van K. Holden, MD, FCCP, Assistant Professor, University of Maryland School of Medicine, began the session with a discussion of bronchoscopic lung volume reduction (BLVR), including an overview of the procedure, associated complications, and outcomes. Pneumothorax is the most commonly reported complication of BLVR, occurring in up to 34% of patients and most often within 3 days of treatment. As a result, Dr. Holden said, post-procedure care for patients undergoing BLVR should include hospitalization for at least 3 days and advanced planning for pneumothorax. “In general, the outcome of pneumothorax after valve placement is resolution with no long-term side effects; however, prolonged air leak is common,” she said. Most complications, including pneumothorax, occur within 90 days of BLVR, although 8% of patients develop pneumonia

A meta-analysis of 10 studies showed significant increases in forced expiratory volume (FEV1) and St. George’s Respiratory Questionnaire (SGRQ) scores in patients who had undergone BLVR with either the Zephyr Endobronchial Valve or the Spiration Valve System, but only the Zephyr valves showed significant improvement in 6-minute walk distance, Dr. Holden explained. In patients with heterogeneous emphysema without collateral ventilation, both valves were equally efficacious in FEV1 and SGRQ improvement. Vivek Murthy, MD, FCCP, Assistant Professor and Associate Director of Interventional Pulmonology, NYU Langone Health, provided an overview of predictors for best outcomes for BLVR. He listed absolute contraindications for BLVR candidacy, including an active infection or recent episode of bronchitis or pneumonia, active smoking, an allergy to any of the components of an endobronchial valve (silicone, nitinol, polyurethane, and nickel), bullae occupying more than one-third of the hemithorax, and incomplete lobar fissures.

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Other suggested inclusion criteria include patients with Global Initiative for Chronic Obstructive Lung Disease stage 3-4 or grade C-D, hyperinflation, a reduced 6-minute walk distance, and a Modified Medical Research Council dyspnea score of ≥2. Computed tomography and single photon emission computed tomography imaging and invasive techniques are used to evaluate patients for BLVR, Dr. Murthy noted. Christian Ghattas, MD, Assistant Professor of Medicine, The Ohio State University Medical Center, addressed the potential of novel bronchoscopic therapies for COPD. Targeted lung denervation is a potentially minimally invasive method of denervating the lungs of pulmonary vagal inputs, Dr. Ghattas explained. This approach targets the peribronchial branches of the vagus nerve while preserving the bronchial epithelium and aims to achieve sustained bronchodilation and reduced mucus secretion, simulating the effect of anticholinergic drugs.

During the CHEST 2021 keynote address, Dr Demondes Haynes, MD, FCCP spoke to persevering amid the COVID-19 pandemic and the importance of identifying the things that keep us motivated. He addressed the importance of empathic communication with patients and the contribution of creating a more diverse and inclusive workforce in medicine. Dr Haynes also discussed ways that today’s health care professionals can encourage enrollment in medical programs and training for more individuals from traditionally underrepresented groups to build the foundation for a more representative and empathetic future of medicine. Dr Haynes, who is a CHEST member, currently serves as the Associate Dean for Admissions for the School of Medicine at the University of Mississippi Medical Center, where he is a Professor of Medicine in the Division of Pulmonary, Critical Care, and Sleep Medicine. The CHEST 2022 event will be held on October 16-19, 2022 in Nashville, Tennessee bringing the most up-to-date education in clinical pulmonary, sleep, and critical care medicine through simulation sessions, original research presentations, interactive gaming, and much more. The American College of Chest Physicians is the global leader in advancing best patient outcomes through innovative chest medicine education, clinical research, and team-based care.

ASTHMA

It is Time to Change How We Manage Mild Asthma Written by Dr Aoife O’Reilly & Professor Eleanor Dunican, St. Vincent’s University Hospital and University College Dublin Management of asthma has traditionally relied on inhaled corticosteroid (ICS) used regularly for asthma control as well as inhaled short-acting beta agonist (SABA) used as needed for symptom relief. In 2019, the Global Initiative for Asthma (GINA) made a fundamental change to its recommendations for the treatment of asthma. GINA no longer recommends regular use of SABA as a reliever without an ICS. All patients diagnosed with asthma should be prescribed an ICS, either regularly or as needed for respiratory symptoms. In patients with mild asthma, ICS/formoterol should be used as a reliever instead of regular ICS, to avoid the risk of patients reverting to SABA monotherapy. This article outlines the rationale and evidence that supports the most radical change to asthma management in the last 50 years. The history of SABAs indicated a problem early in their use SABAs were the first inhaled therapy commonly prescribed for asthma and provide symptomatic relief (within 5 minutes) through rapid-onset bronchodilation but have no anti-inflammatory properties. Therefore, with the sudden rise in SABA use in the late 1950s, there was a calamitous rise in asthma deaths in England and Wales, with an almost 400% increase in deaths from asthma in the 5-34 year age group. This sudden epidemic of asthma deaths was thoroughly investigated, and many theories were proposed to explain it. SABA toxicity was thought to be the most likely explanation. Less traction was given to the alternative theory that over-reliance on the reliever effects of SABAs led to fatal delays in patients seeking medical care. Subsequently, after a warning was issued that excessive use of SABAs was dangerous, the sales of SABAs dropped precipitously and asthma deaths returned to pre-pandemic levels. Authorities concluded that high doses of SABAs are toxic and the direct cause of rise in asthma deaths seen with their introduction. Incidentally, the same year the warning was issued, admissions to hospital for asthma and prescriptions for systemic

corticosteroids increased, both important management steps in treating life-threatening asthma attacks. Since then, many studies over the decades have replicated a dose-dependent association between overuse of SABA and asthma mortality. Pharmacological management of mild asthma relied on SABA monotherapy ICSs were introduced into clinical practice in the early 1970’s and revolutionised the management of asthma. ICSs reduce airway inflammation and airway hyperresponsiveness, improve asthma control and reduce exacerbations, making them the cornerstone of asthma management. ICS and SABA are the most commonly prescribed therapies for asthma, but the way in which they have been traditionally prescribed to those with mild to moderate asthma does not align to the underlying biology of the disease. Before 2019, guidelines internationally recommended SABA monotherapy as first line treatment for mild asthma (symptoms less than twice a month), even though many studies have shown inflammatory airway changes present across the entire spectrum of asthma severity. The rationale for this recommendation was the belief that prescribing regular ICS to patients with infrequent symptoms would be excessive and poorly adhered to. From a patient’s perspective, the most tangible measure of asthma control is day-to-day symptoms. Patients with mild asthma often fail to notice any obvious difference in symptoms while taking regular ICS, but notice rapid improvement with SABA, leading to the belief that the SABAs are more effective at controlling their disease. ICS with SABA for symptom relief is superior to regular ICS in mild asthma Studies have shown that use of regular ICS is superior to as-needed SABA in reducing exacerbation risk in patients with mild asthma, and this benefit persists even when symptoms are very infrequent. To overcome the challenge of convincing

Dr Aoife O’Reilly, St. Vincent’s University Hospital and University College Dublin

Professor Eleanor Dunican, St. Vincent’s University Hospital and University College Dublin

relatively asymptomatic patients to take regular low-dose ICS, one potential approach was investigated: matching ICS inhaler use on a puff-per-puff basis with as-needed SABA. Studies in adult and paediatric populations have shown no difference in time to asthma worsening with symptomdriven use of ICS with SABA compared to regular ICS. However, this approach requires the patients to carry two inhalers for relatively infrequent symptoms, which may be challenging to achieve.

budesonide was shown to be superior to SABA at preventing asthma exacerbations, and was more effective than regular low dose ICS (with as needed SABA) at preventing severe asthma exacerbations in mild to moderate asthma. ICS/LABA used as needed resulted in a 64% reduction in severe exacerbations and a prolonged time to first severe exacerbation compared to SABA.

A study using a single combination inhaler containing ICS and SABA demonstrated that symptomdriven use of beclomethasone (ICS) and albuterol (SABA) in a single inhaler was as effective as regular use of beclomethasone and was associated with a lower 6-month cumulative dose of inhaled corticosteroid. Symptom-driven ICS/formoterol use reduces exacerbations in mild asthma However, since there are no combination ICS/SABA inhalers on the market, investigators have also studied symptom-driven use of formoterol, a long acting beta agonist (LABA) and budesonide (ICS) in a single inhaler. The choice of formoterol over other LABAs is due to its rapid onset (approximately 2-3 minutes) of action, making it suitable as a reliever. In mild asthma, symptom-driven use of formoterol/

Interestingly, the reduction in exacerbations seen with asneeded ICS/LABA is not driven by the anti-inflammatory ICS component alone. In patients using ICS regularly, as-needed LABA is superior to SABA at reducing exacerbations. However, as-needed use of ICS/ LABA is superior to LABA or SABA alone. Conclusion Even patients with infrequent asthma symptoms can suffer severe or fatal asthma attacks. Overuse of SABA is associated with increased asthma mortality due to its lack of anti-inflammatory properties and resultant delay in patients seeking medical care. In patients with asthma symptoms less than twice a month, current recommendations are that they should be prescribed as-needed low-dose ICS-formoterol for symptom relief (preferred), or take low dose ICS whenever SABA is needed for symptom relief.

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ASTHMA IN WINTER

Management of Asthma During Winter grossly under-estimated the number of people with asthma in Ireland. The annual economic burden of asthma is a staggering ¤472million. 2017 saw 2.4 million GP and 625,000 practice nurse asthma consultations respectively, 421,000 specialist visits, 133,000 emergency department visits and 8,000 hospital admissions. One person dies every 5 days from an acute asthma attack and there is one attendance at emergency departments every 4 minutes by a person with asthma.

Written by Ruth Morrow, Respiratory Nurse Specialist, Asthma Society of Ireland

Asthma is a heterogeneous disease, usually characterized by chronic airway inflammation defined by the history of respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough that vary over time and in intensity, together with variable expiratory airflow limitation (GINA, 2021).

The exact cause of asthma remains unknown. There are numerous triggers which can cause symptoms and these differ from person to person. Winter time can be particularly challenging for people with asthma due to cold air and common viruses being common triggers. The clinical features of asthma (wheeze, cough, shortness of breath and chest tightness) result from changes in the airways as a result of abnormal sensitivity called bronchial hyper-reactivity. The muscle of the bronchial walls becomes hypertrophied causing occlusion of the airway resulting in contraction of the muscle causing bronchospasm. Secondly, in the

Asthma affects over 380,000 people in Ireland. 7.1% of Irish adults have asthma with 890,000 likely to experience it sometime in their lifetime. One person continues to die from asthma in Ireland every 6 days despite advances in the knowledge of the mechanisms of asthma and pharmacology. In 2019, the Asthma Society of Ireland published Easing the Economic Burden of Asthma – The Impact of a Universal Asthma SelfManagement Programme. The report, for the first time, publishes confirmation of the enormity of the burden of asthma and contains, up-to-date figures on the number of people affected by asthma in Ireland. Previous estimates

mucosal, submucosa and smooth muscle layers of the bronchi and bronchioles inflammatory cells infiltrate. Eosinophils, neutrophils, macrophages, mast cells and plasma cells are found in varying numbers. All of these cells contain chemical mediators that produce the “asthmatic response”. With the increase in secretions, plugging of the smaller airways result. Asthma is a condition where not only bronchospasm occurs but muscle constriction, mucosal swelling and an increase in secretions in the lumen in the airways (Figure 1). Asthma Phenotypes Other phenotypes include: exercise-induced, neutrophilic, severe, fixed-obstruction, aspirininduced, and occupational Assessing Asthma The Asthma Control Test (ACT) is a useful tool for assessing asthma control. The maximum score is 25. If the patient scores 19 or below, this indicates that the patient’s asthma is not controlled and should be advised to attend their GP for review of their asthma. The ACT can be downloaded from https://www. asthmacontroltest.com/.

Asthma Management Gina (2021) provides a stepwise approach to managing with the emphasis on symptom management and control. Patients can move through the steps based on the level of asthma control. It is not uncommon for some patients to require an increase in their medication during the winter months which can be deescalated in the spring/summer months. Track 1 is the preferred option with low dose ICS-formoterol as the reliever and controller being the medication of choice. Using ICS-formoterol as reliever reduces the risk of exacerbations compared with using a SABA reliever, with similar symptom control and similar lung function. Track 2 offers an alternative option with SABA as the reliever option. Inhaled corticosteroids should be taken when SABA is used. This track should be used if Track 1 is not possible, or is not preferred by a patient with no exacerbations on their current controller therapy. Before considering a regimen with SABA as a reliever, consider whether the patient is likely to be adherent with daily controller – if not, they will be exposed to the risks of SABA-only treatment

Air trapped in alveoli Relaxed smooth muscles

Tightened smooth muscles

Wall inflamed and thicken

Figure 1: Pathology of asthma

Normal airway

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Asthmatic airway

Asthmatic airway during attack

47 Eosinophilic Asthma/T2 asthma/Allergic asthma

Non-eosinophilic asthma/non-T2 asthma/non-allergic asthma

Triggers – House dust mite, pollen, feathers, fluff, animal dander, foods

Triggers- cold air, exercise, smoking, hormones

Atopy

Non-atopic

Usually diagnosed in children

Usually diagnosed in over 40s

Responds well to inhaled corticosteroids

Requires high doses of inhaled corticosteroids to gain control

ie the risk of severe asthma exacerbations and asthma-related death. Both tracks offer additional treatment options to optimise control of symptoms which includes Montelukast, sublingual immunotherapy, Tiotropium and biological therapies. Six Tips for managing Asthma to follow during the colder months: 1. Put an Asthma Action Plan in place (Figure 3). An Asthma Action Plan contains all the information a person with asthma needs to keep their condition in control. Every person with asthma should be offered a plan. It should be reviewed frequently and any time medication is changed. These can be downloaded for free from asthma.ie and should be filled out with the person’s healthcare professional.

Asthma Phenotypes

4. Asthma medication should be taken as prescribed and the reliever inhaler carried at all times. This is especially important during the winter months as respiratory triggers are so prevalent. If the reliever inhaler is being used more than twice a week, this may indicate that the person’s asthma is not controlled and may be at risk of an asthma flare-up. 5. Check inhaler technique: it is extremely important to ensure correct use asthma devices correctly to optimise deposition of medication to the lungs and to reduce the risk of side effects. Inhaler technique for asthma inhalers on the Irish market can be viewed here: https:// www.asthma.ie/about-asthma/ resources/inhaler-techniquevideos

Other phenotypes include: exercise-induced, neutrophilic, severe, fixed-obstruction, aspirininduced, and occupational 2. Immunisation with influenza 6. Cold air can trigger asthma – Figure 2: Asthma Phenotypes and pneumococcal vaccine should be encouraged in people with asthma. Pneumococcal vaccine can be administered at any time throughout the year while influenza vaccine can be administered up until the end of April. Immunisation against COVID 19 should also be encouraged if not already done.

Assessing Asthma

take precautions to reduce the risk of cold air triggering an asthma flare-up. To help reduce symptoms which are triggered by cold air, it can be helpful to cover the mouth with a snood or scarf on colder days. This heats the air before it enters the lungs making it easier to breathe. Another tip is to exercise indoors during bouts of cold weather if at all possible. It’s important to stay warm during the winter months but make sure the home is well ventilated. If wind and rain trigger asthma symptoms, keep windows closed, particularly on bad days. The Asthma Society Winter Wellness Guide can be access here: https://www.asthma.ie/ winter-wellness-guide

The Asthma Control Test (ACT) is a useful tool for assessing asthma control. The maximum score is 25. If the patient scores 19 or below, this indicates that the patient’s asthma is not controlled and should be advised to attend their GP for review of their asthma. The ACT can be downloaded from https://www.asthmacontroltest.com/. 3. Follow the HSE’s advice on preventing the spread of COVID-19. This highly contagious illness can be very problematic for people with asthma, especially those with severe asthma. Information on keeping well with asthma during COVID19 can be found here: https://www.asthma.ie/keepingwell-with-asthma-and-copdduring-covid-19

Asthma Management

Gina (2021) provides a stepwise approach to managing with the emphasis on symptom management People who have questions Society’s HSE-funded Asthma and control. Patients can move through the steps based the level of asthma control. It1800 is not Adviceline on 44 54 64. Both abouton managing their asthma are services are free and allow users encouraged to send a WhatsApp uncommon for some patients to require an increase in their medication during the winter months to communicate directly with an message to the Sláintecare-funded which can be deescalated in the spring/summer months. 1 isservice the on preferred option low asthma nurse with specialist. AsthmaTrack WhatsApp 086 059 0132 or freephone the Asthma dose ICS-formoterol as the reliever and controller being the medication of choice. Using ICSformoterol as reliever reduces the risk of exacerbations compared with using a SABA reliever, with similar symptom control and similar lung function. Track 2 offers an alternative option with SABA as HOSPITALPROFESSIONALNEWS.IE | HPN • JANUARY 2022 the reliever and inhaled corticosteroids as the controller option. This track should be used if Track 1

PRESCRIBING INFORMATION (PI) SKYRIZI®▼ (risankizumab) 75 mg solution for injection in pre-filled syringe; Skyrizi 150 mg solution for injection in pre-filled pen and Skyrizi 150 mg solution for injection in prefilled syringe. Refer to Summary of Product Characteristics (SmPC) for full information before prescribing. PRESENTATION: Skyrizi 150 mg solution for injection in pre-filled pen/syringe: each prefilled pen/syringe contains 150 mg risankizumab in 1 mL solution. Skyrizi 75 mg solution for injection in pre-filled syringe: each pre-filled syringe contains 75 mg risankizumab in 0.83 ml 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 by subcutaneous injection at weeks 0, 4, and every 12 weeks thereafter. Two 75mg pre-filled syringes should be injected for the full 150 mg dose. 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. Excipients with known effect (75 mg solution for injection only): 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: Skyrizi 75 mg solution for injection in pre-filled syringe (Pack of 2 prefilled syringes): EU/1/19/1361/001; Skyrizi 150 mg solution for injection in pre-filled pen: EU/1/19/1361/002; Skyrizi 150 mg solution for injection in pre-filled syringe: EU/1/19/1361/003. Not all presentations may be marketed. Further information is available from: AbbVie Ltd., 14 Riverwalk, Citywest Business Campus, Dublin 24. DATE OF REVISION: May 2021 PI/1361/003 HRQoL, Health-Related Quality of Life; PASI, Psoriasis Area Severity Index. REFERENCES: 1. Gordon KB, et al. Lancet 2018; 392: 650661. 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: August 2021 | IE-RISN-210074

High skin clearance matters to patients: Patients who achieve and maintain high levels of skin clearance (PASI 90-99 or PASI 100) have significantly better HRQoL than those with lower levels of skin clearance (PASI 75-89).2 Sustaining high skin clearance or complete skin clearance is associated with incremental and durable benefits in HRQoL and mental health of psoriasis patients.2

What means everything to the patient? The potential for nothing left on their skin.* * 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

CYSTIC FIBROSIS

Cystic Fibrosis Developments in 2020/21: A Patient Group Perspective Written by Philip Watt, CEO, Cystic Fibrosis Ireland

cover gaps and emerging issues in CF related post-transplant care and fertility. Many will be familiar of the advocacy by patients to secure the innovative CF drug ‘Orkambi’ in 2017. However many will be less aware that the same agreement that brought Orkambi to Ireland also provided access to a suite of related CFTR modulators, the most important of these is Kaftrio (Trikafta in the US). When these drugs are extended to younger age cohorts, more that 90% of people with CF in Ireland will have the potential to benefit from at least 1 of the 4 major Vertex drugs available for CF (known as CFTR Modulators). However concomitantly there will be a percentage of patients with CF who will remain reliant on future therapy discoveries, including the possibilities raised by Gene Therapies.

Due to continued very positive developments in accessing new and innovative medications that tackle the underlying case of cystic fibrosis and steady improvements in specialised hospital centres and care over the past decade, more people with Cystic Fibrosis (CF) are reaching adulthood in Ireland than ever before. Almost 60% of the CF patients in Ireland (circa 1400 in total) are now 18 years or over compared with 54% in 2009. Over the same decade, the percentage of adults with CF aged 40 years or over has increased from 4% to almost 12%. CF is a genetic, chronic and fatal multi organ disease that primarily impacts on the lungs and digestive systems. The indigenous population in Ireland has the highest incidence of CF in the world However the overall incidence in Ireland has declined to UK levels in recent years because of inward migration/ greater diversity in Ireland’s overall population that expanded in the 2000’s. Recent developments related to CF care has given renewed hope that CF is now a more manageable disease and it is anticipated that predicted survival ages will continue to increase.

The encouraging figures on CF patient demography are available because of the existence of the excellent Cystic Fibrosis Registry of Ireland, established by the national patient group, Cystic Fibrosis Ireland (CFI) in 1999 and which became an independent entity, in line with international good practice, in 2003. It is worth noting that many patient groups in Ireland remain without the benefit of an adequate patient registry resulting in major information/data deficits to inform current and future care. It is also known that industry is often reluctant to undertake clinical trials in countries that do not has such patient registries, so other non CF diseases in Ireland may be losing out in helping to develop ground-breaking new therapies as a consequence, especially rare diseases. One of the key developments in CF care over the past decade has been the significant upgrading of CF hospital centres, particularly since the ground-breaking Pollock Report was published by CFI in 2005. Specialised adult CF hospital centres in St Vincent’s; Beaumont; Cork, Limerick and Galway have all received major infrastructural upgrades because of combination of patient group

JANUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

advocacy and direct charitable and state funding. Most of the Paediatric CF centres including the CHI group in Dublin; Limerick; Cork and shared care centres in Drogheda, Cavan, Waterford and Castlebar have similarly benefitted from the advocacy, increased state funding and important part funding from CFI over the past decade. Further progress in improving adults CF facilities in Beaumont Hospital and University Hospital Galway is planned in 2022/2023, but remain dependent on final Government and Hospital decisions. The most important of these is the proposed 20 room in-patient unit for adults with CF in Beaumont Hospital. All being well it is anticipated this facility will be completed by 2023. In recent years the HSE National Clinical Programme for CF has contributed to CF care by providing an updated and more detailed model of care to that set out in the Pollock Report in 2005, informed in large part by the European Standards developed by the European CF Society over the past decade. The establishment of the NCP for CF was again mainly a s a consequence of CFI advocacy. It is anticipated that the model of care will expanded in time to

CFI is currently supporting health research in respect of real world outcomes from medications through the CF Recover research project, led by Professor Paul McNally. Further important research projects are also underway/planned focussing on pregnancy; dental care; transition; telehealth and co-morbidities such as liver disease and CF. All of these involve a Public and Patient Involvement (PPI) dimension and CFI is developing a PPI panel of people with CF to inform such research projects undertaken by our universities and hospital centres and by Phd students, including those students with CF. One of the welcome outcomes of the reimbursement and extension of Kaftrio in 2021 has been a reported increase in pregnancies for women with CF who had previously been too ill to have children or who could not benefit from IVF treatment. It is hoped that the Government will also follow through on its promise to ensure that Ireland provides adequate support for all who need IVF in Ireland. The most significant clouds for CF care in Ireland in 2021 have been the ongoing crisis of COVID -19 and ongoing and new gaps in clinical posts, particularly in the number of CF consultants and Multi-Disciplinary Team posts

51 ‘cocooning’ for almost 2 years with the concomitant impact on wellbeing and depression.

such as psychologists, nurses and social workers. The Covid-19 pandemic remains an on-going concern for people with cystic fibrosis as we approach the end of 2021.

Of particular concern are the immunocompromised, including those waiting for or who have a double lung transplant as a consequence of CF. Many CF patients have been effectively

Momentum towards independent living has been slowed or paused as adults with CF now face additional challenges in accessing a living wage because of understandable additional health fears from the pandemic. A direct consequence of COVID-19 has been the reduction in most transplant programmes in Ireland. All lung transplants in Ireland declined by 58% between 2020 and 2019, with fears for similar reductions in 2021. This is not meant as a criticism of our dedicated hospitals and clinicians, but as a ‘call for action’. Improved post-transplant CF care remains an ongoing priority for CFI. It is hoped that the promised change

from opt-in to opt-out organ donation will be enacted in 2022 as a consequence of the Human Tissue Bill. It is also hoped that the Government will publish an updated National Rare Disease Plan in 2022, though progress remains slow. Cystic Fibrosis Ireland takes this opportunity to thank all the dedicated healthcare workers; our CF hospital centres; the HSE and the Minister for Health, Stephen Donnelly TD for their ongoing support for CF care. We thank our many supporters and friends who have worked so hard to sustain our fundraising over the past 2 years. It is heartening that in a survey undertaken by UCD 80% of those surveyed said they looked to CFI for accurate information and support in 2020.

RESPIRATORY FOCUS: RESEARCH

New Hope for COPD Dr Suzanne Cloonan, Associate Professor in Respiratory Medicine in Trinity’s School of Medicine and Tallaght University Hospital (TUH) describes her laboratory’s research investigating how cellular iron metabolism is regulated in the lungs of patients with COPD, and how dysregulation of iron uptake, release, or turnover contributes to the disease process. The role of iron in COPD Excessive iron build up in the lungs is thought to be a major factor in COPD. Dr Cloonan’s research team believe they have identified the culprit for the excess which is a gene they previously found to increase patients’ susceptibility to the progressive lung disease. This gene, called IRP2 is tasked with regulating iron uptake in cells. The team’s discovery was significant because it validates the results of a 2009 study that implicated IRP2 in the disease’s development and demonstrates how the gene supports COPD. The findings also illustrate that IRP2 may be a powerful therapeutic target. Dr Cloonan described the lab’s focus, “We want to figure out where in the lung this iron accumulates and how this excess of iron affects the development of COPD. We are asking the following questions: Where does this iron

come from given that cigarette smoke contains very little iron? What cells types are important in iron accumulation in the lung? Does having more iron promote the growth of bad bacteria rendering COPD patients more susceptible to infection?” Dr Cloonan’s team also aim to find out how iron is transported into and out of the mitochondrion (mitochondria are the ‘powerhouse’ of the cell). Mitoferrin-2 and mitoferrin 1 are mitochondrial membrane proteins that are thought to be involved in iron transport across the mitochondrial inner membrane into the mitochondrial matrix. The researchers investigate how these transporters contribute to normal mitochondrial function, metabolism and dynamics in the cell and how they co-ordinate with other aspects of cellular iron regulation. The team also investigates how disturbances in iron metabolism underlie and drive alveolar macrophage-associated immune system disarray in COPD. Their research focuses on iron uptake, turnover, metabolism and export in alveolar macrophages and how these normal homeostatic processes are essential for the innate immune response to infection.

Dr Suzanne Cloonan, Associate Professor in Respiratory Medicine in Trinity’s School of Medicine

Research collaborations Dr Cloonan collaborates with TUH’s Professor Seamus Donnelly (Professor of Respiratory and Interstitial Disease) and St James Hospital’s Professor Joseph Keane (Professor of Medicine). She highlights the crucial input from post-doctoral researchers Dr Claire Healy and Dr Niamh Williams in her laboratory. Dr Cloonan is part of a multi-centre study of COPD aiming to better classify patients for clinical trials. She says, “We worked closely with SPIROMICS (Subpopulations and Intermediate Outcomes in COPD Study). SPIROMICS is a USA-based multi-centre longitudinal observational study of chronic COPD. SPIROMICS was designed to guide future development of therapies for COPD by providing robust criteria for subclassifying COPD participants into groups most

likely to benefit from a given therapy during a clinical trial, and identifying biomarkers/ phenotypes that can be used as intermediate outcomes to reliably predict clinical benefit during therapeutic trials.” Patient education on COPD Creating awareness of COPD, along with engagement with patients and clinicians, is a core focus for Dr Cloonan and her team. Key groups include the Irish Thoracic Society and COPD Support Ireland.

HOSPITALPROFESSIONALNEWS.IE | HPN • JANUARY 2022

RESPIRATORY SYNCYTIAL VIRUS INFECTION

Respiratory Syncytial Virus Infection (RSV) With Theresa Lowry Lehnen, GPN, RNP, PhD. Clinical Nurse Specialist and Associate Lecturer at Institute of Technology Carlow

“ Respiratory syncytial virus is primarily a childhood infection, however, it may occur at any age and can be most severe in infants under one year of age, the immunocompromised, and in people aged 65 years and older. It infects 90% of children within the first 2 years of life and frequently re-infects older children and adults,” she says. Respiratory Syncytial Virus infection can present as a variety of clinical syndromes including upper respiratory tract infections, bronchiolitis, pneumonia, exacerbations of asthma and viral-induced wheeze. Presentation in Children

Respiratory syncytial virus (RSV) is a common, ubiquitous and contagious viral pathogen that infects the respiratory tract of most children by 2 years of age. RSV is an RNA pneumovirus of the Paramyxoviridae family, and humans are the only natural host. Worldwide, it is estimated that RSV is responsible for approximately 33 million lower respiratory tract illnesses, three million hospitalisations, and up to 199,000 childhood deaths. We recently spoke to Clinical Nurse Specialist and Associate

Lecturer at Institute of Technology, Carlow, Theresa Lowry Lehnen to understand more about this contagious area. RSV typically spreads via hands, fomites and the airborne aerosol route. Respiratory syncytial virus spreads from person to person by aerosol droplets through coughing or sneezing, and is also spread through direct contact by touch. Theresa notes that RSV can survive on surfaces and objects for 24 hours and spread can occur indirectly through contact with contaminated hands.

Theresa says that for most babies and young children, the infection is mild presenting with cold like symptoms which usually last 1 to 2 weeks. “For a small percentage, however, RSV infection can lead to serious and sometimes lifethreatening problems such as pneumonia or bronchiolitis,” she adds. “The chance of developing severe infection is highest for premature babies, children less than 10 weeks old, children less than 2 years of age with congenital heart or chronic lung disease and infants and young children with

a weak immune system or who are immunocompromised. Adults with weakened immune systems and those aged 65 years and older are also at increased risk of developing severe RSV disease.” Respiratory Syncytial Virus infection has been a notifiable disease in Ireland since January 2012, and RSV activity in Ireland is monitored by the HSE-Health Protection Surveillance Centre (HPSC). Respiratory Syncytial Virus infections occur in a seasonal pattern in temperate climates with epidemics from October to April. Outbreaks typically occur in the winter months with the highest numbers of infections usually reported in December and January every year. The sharp winter peak varies little in timing or size from year to year, in contrast to influenza. Incubation Period and Symptoms Theresa continues, “The incubation period for RSV is usually 4 - 6 days, but ranges from 2 to 8 days depending on host factors such as the age of the patient and whether it is the patient's primary infection with RSV. After inoculation into the nasopharyngeal or conjunctival mucosa, the virus rapidly spreads into the respiratory tract, where it targets its preferred growth medium, apical ciliated epithelial cells. There it binds to cellular receptors using the RSV-G glycoprotein and uses the RSV-F fusion glycoprotein to fuse with host cell membranes and insert its nucleocapsid into the host cell to begin its intracellular replication.” Symptoms include; fever, rhinorrhoea, pharyngitis, nasal congestion, sneezing, coughing which can be croupy or barking in nature, tachypnoea, sore throat, wheeze, decreased appetite and ear infections in children. In very young infants, irritability, decreased activity and breathing difficulties may be the only symptoms of infection. Lower respiratory tract infections, such as pneumonia or pneumonitis, are most likely to occur during a child's first infection with RSV and

JANUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

FOR YOURSELF, WOULD YOU CONSIDER

BOTH EFFICACY AND SAFETY?

Choose both efficacy and safety with ELIQUIS®

ELIQUIS is a factor Xa inhibitor that offers superior risk reduction in stroke and systemic embolism, with significantly less major bleeding vs. warfarin in non-valvular AF patients.1,* • Superiority demonstrated on stroke / systemic embolism vs. warfarin 1 • Superiority demonstrated on major bleeding vs. warfarin 1 ELIQUIS® (apixaban) PRESCRIBING INFORMATION Ireland Consult Summary of Product Characteristics (SmPC) before prescribing PRESENTATION: Film-coated tablets; 5 mg and 2.5 mg apixaban. INDICATION (SPC section 4.1): Prevention of stroke and systemic embolism in adults with non-valvular atrial fibrillation (NVAF) with one or more risk factors, such as prior stroke or transient ischaemic attack (TIA), age ≥ 75 years, hypertension, diabetes mellitus or symptomatic heart failure (NYHA Class ≥ II). Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults (see Special warnings and precautions for information on haemodynamically unstable PE patients). Prevention of venous thromboembolic events (VTE) in adults who have undergone elective hip or knee replacement surgery (2.5 mg only). DOSAGE AND ADMINISTRATION (SPC section 4.2): Oral. Taken with water, with or without food. Prevention of stroke and systemic embolism in patients with NVAF: The recommended dose is 5 mg twice a day. In patients who meet at least two of the following criteria: serum creatinine ≥ 1.5 mg/dL (133 micromole/L), age ≥ 80 years, or body weight ≤ 60 kg the recommended dose is Eliquis, 2.5 mg twice daily. Patients with severe renal impairment (creatinine clearance 15-29 ml/min) should receive Eliquis 2.5 mg twice daily. Therapy should be continued long term. Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt): The recommended dose for the treatment of acute DVT and treatment of PE is 10 mg twice daily for the first 7 days followed by 5 mg twice daily. As per available medical guidelines, short duration of treatment (at least 3 months) should be based on transient risk factors (e.g. recent surgery, trauma, immobilisation). The recommended dose for the prevention of recurrent DVT and PE is 2.5 mg twice daily. When prevention of recurrent DVT and PE is indicated, the 2.5 mg twice daily dose should be initiated following completion of 6 months of treatment with Eliquis 5 mg twice daily or with another anticoagulant. The duration of overall therapy should be individualised after careful assessment of the treatment benefit against the risk for bleeding. Prevention of VTE (VTEp): elective hip or knee replacement surgery: The recommended dose is 2.5 mg twice a day. The initial dose should be taken 12 to 24 hours after surgery. Hip replacement surgery, the recommended duration of treatment is 32 to 38 days. Knee replacement surgery, the recommended duration of treatment is 10 to 14 days. Missed Dose for All Indications: If a dose is missed, Eliquis should be taken immediately and then continue with twice daily dose as before. Switching: Switching treatment from parenteral anticoagulants to Eliquis (and vice versa) can be done at the next scheduled dose. These medicinal products should not be administered simultaneously. Switching treatment from VKA therapy to Eliquis: Warfarin or other VKA therapy should be discontinued and Eliquis started when the international normalized ratio (INR) is < 2. Switching treatment from Eliquis to VKA therapy: Administration of Eliquis should be continued for at least 2 days after beginning VKA therapy. After 2 days of co- administration of Eliquis with VKA therapy, an INR should be obtained prior to next scheduled dose of Eliquis. Co-administration of Eliquis and VKA therapy should be continued until the INR is ≥2. Renal Impairment - mild or moderate renal impairment: For the prevention of VTE in elective hip or knee replacement surgery (VTEp), for the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt), no dose adjustment is necessary. For the prevention of stroke and systemic embolism in patients with NVAF and serum creatinine ≥ 1.5 mg/dL (133 micromole/L) associated with age ≥ 80 years or body weight ≤ 60 kg, a dose reduction is necessary. In the absence of other criteria for dose reduction (age, body weight), no dose adjustment is necessary. Severe renal impairment (creatinine clearance 15-29 mL/min): For the prevention of VTE in elective hip or knee replacement surgery (VTEp), for the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt), Eliquis is to be used with caution. For the prevention of stroke and systemic embolism in patients with NVAF, patients should receive the lower dose of Eliquis 2.5mg twice daily. In patients with creatinine clearance < 15 mL/min, or in patients undergoing dialysis, there is no clinical experience therefore Eliquis is not recommended. See SmPC for further details. Hepatic impairment: Contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk. Not recommended in patients with severe hepatic impairment. Use with caution in patients with mild or moderate hepatic impairment (Child Pugh A or B). No dose adjustment is required in patients with mild or moderate hepatic impairment. Use with caution in patients with elevated liver enzymes (ALT/AST >2 x ULN) or total bilirubin ≥ 1.5 x ULN. Prior to initiating Eliquis, liver function testing should be performed. Catheter ablation (NVAF): Patients can continue Eliquis use while undergoing catheter ablation. Cardioversion (NVAF): Eliquis can be initiated or continued in NVAF patients who may require cardioversion. See SmPC for further details. Patients with NVAF and acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI): There is limited experience of treatment with apixaban at the recommended dose for NVAF patients when used in combination with antiplatelet agents in patients with ACS and/or undergoing PCI after haemostasis is achieved. See SmPC for further details. Paediatric population: Eliquis is not recommended in children and adolescents below the age of 18. CONTRAINDICATIONS (SPC section 4.3): Hypersensitivity to active substance or to excipients, active clinically significant bleeding, hepatic disease associated with coagulopathy and clinically relevant bleeding risk, lesion or condition if considered a significant risk factor for major bleeding, see SmPC for further details. Concomitant treatment with any other anticoagulant agent except under specific circumstances of switching anticoagulant therapy or when unfractionated heparin (UFH) is given at doses necessary to maintain an open central venous or arterial catheter or when UFH is given during catheter ablation for atrial fibrillation, see SmPC for further details. WARNINGS AND PRECAUTIONS (SPC section 4.4): Haemorrhage risk: Carefully observe for signs of bleeding. Use with caution in conditions with increased risk of haemorrhage. Discontinue administration if severe haemorrhage occurs. An agent to reverse the anti-factor Xa activity of apixaban is available. For information on reversal and managing bleeding, see SmPC for further details. Interaction with other medicinal products affecting haemostasis: Concomitant treatment with any other anticoagulant is contraindicated (see contraindications). Concomitant use of Eliquis with antiplatelet agents increases the risk of bleeding. Care with concomitant SSRIs, SNRIs or NSAIDs, including acetylsalicylic acid. Following surgery, other platelet aggregation inhibitors are not recommended concomitantly with Eliquis. In patients with atrial fibrillation and conditions that warrant mono or dual antiplatelet therapy, a careful assessment of the potential benefits against the potential risks should be made before combining this therapy with Eliquis. A clinical trial enrolled patients with atrial fibrillation with ACS and/or undergoing PCI and a planned treatment period with a P2Y12 inhibitor, with or without ASA, and oral anticoagulant (either apixaban or VKA) for 6 months. Concomitant use of ASA increased the risk of ISTH (International Society on Thrombosis and Hemostasis) major or CRNM (Clinically Relevant Non-Major) bleeding in apixaban-treated subjects. See SmPC for further details. Use of thrombolytic agents for the treatment of acute ischemic stroke: Limited experience. Patients with prosthetic heart valves: safety and efficacy of Eliquis have not been studied in patients with prosthetic heart valves, with or without atrial fibrillation. Therefore, the use of Eliquis is not recommended in this setting. Patients with antiphospholipid syndrome: Direct acting Oral Anticoagulants (DOACs), including Eliquis, are not recommended for patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome (see SmPC for further details). Surgery and invasive procedures: Discontinue at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of bleeding. Discontinue at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding. If surgery or invasive procedures cannot be delayed, appropriate caution should be exercised, taking into consideration an increased risk of bleeding. Eliquis should be restarted after the invasive procedure or surgical intervention as soon as possible provided the clinical situation allows and adequate haemostasis has been established. For patients undergoing catheter ablation for atrial fibrillation, Eliquis treatment does not need to be interrupted. Temporary discontinuation: Discontinuing anticoagulants, including Eliquis, for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of thrombosis. Lapses in therapy should be avoided and if anticoagulation with Eliquis must be temporarily discontinued for any reason, therapy should be restarted as soon as possible. Spinal/ epidural anaesthesia or puncture: Patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal haematoma which can result in long- term or permanent paralysis. The risk of these events may be increased by the post- operative use of indwelling epidural catheters or the concomitant use of medicinal products affecting haemostasis. Indwelling epidural or intrathecal catheters must be removed at least 5 hours prior to the first dose of Eliquis. The risk may also be increased by traumatic or repeated epidural or spinal puncture. Patients are to be frequently monitored for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, bowel or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention the physician should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis. There is no clinical experience with the use of Eliquis with indwelling intrathecal or epidural catheters. See SmPC for further details. Haemodynamically unstable PE patients or patients who require thrombolysis or pulmonary embolectomy: Eliquis is not recommended as an alternative to unfractionated heparin in patients with pulmonary embolism who are haemodynamically unstable or may receive thrombolysis or pulmonary embolectomy since the safety and efficacy of Eliquis have not been established. Patients with active cancer: Patients with active cancer can be at high risk of both venous thromboembolism and bleeding events. When apixaban is considered for DVT or PE treatment in cancer patients, a careful assessment of the benefits against the risks should be made. Renal impairment: see dosage and administration section. Elderly patients: Increasing age may increase haemorrhagic risk. Also, the co-administration of Eliquis with ASA in elderly patients should be used cautiously because of a potentially higher bleeding risk. Body weight: Low body weight (< 60 kg) may increase haemorrhagic risk. Hepatic impairment: see dosage and administration section. Interaction with Inhibitors of CYP3A4 and P-gp: Not recommended with strong inhibitors of both CYP3A4 and P-gp. These medicinal products may increase Eliquis exposure by 2-fold or greater in the presence of additional factors that increase Eliquis exposure (e.g. severe renal impairment) see SmPC for further details. Interaction with Inducers of CYP3A4 and P-gp: Eliquis should not be used for the treatment of DVT and PE in patients receiving concomitant systemic treatment with strong inducers of both CYP3A4 and P-gp since efficacy may be compromised. Concomitant systemic treatment with strong inducers of both CYP3A4 and P-gp, Eliquis should be used with caution for the prevention of VTE in elective hip or knee replacement surgery, for the prevention of stroke and systemic embolism in patients with NVAF and for the prevention of recurrent DVT and PE, though no dose adjustment for Eliquis is required during concomitant therapy with such medicinal products. Hip fracture surgery: Eliquis has not been studied in clinical trials in patients undergoing hip fracture surgery. Therefore, it is not recommended in these patients. Laboratory parameters: Clotting tests (PT, INR, and aPTT) are affected by the mechanism of action of apixaban. Changes observed at the expected therapeutic dose are small and subject to a high degree of variability, see SmPC for further details. Information about excipients: Eliquis contains lactose. Patients with galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take Eliquis. DRUG INTERACTIONS (SPC Section 4.5): Eliquis should be used with caution when co-administered with SSRIs/SNRIs, NSAIDs, ASA and/or P2Y12 inhibitors because these medicinal products typically increase the bleeding risk. There is limited experience of co-administration with other platelet aggregation inhibitors (such as GPIIb/IIIa receptor antagonists, dipyridamole, dextran or sulfinpyrazone) or thrombolytic agents. As such agents increase the bleeding risk, co-administration of these products with Eliquis is not recommended. See SmPC for further details.Due to an increased bleeding risk, concomitant treatment with any other anticoagulants is contraindicated, except under specific circumstances of switching anticoagulant therapy, when UFH is given at doses necessary to maintain an open central venous or arterial catheter or when UFH is given during catheter ablation for atrial fibrillation. Administration of activated charcoal reduces Eliquis exposure. Also see contraindications and special warnings and precautions section; Consult SmPC (contraindications, special warnings and precautions and drug interactions) for full details on interactions. PREGNANCY AND LACTATION (SPC section 4.6): Pregnancy: As a precautionary measure, it is preferable to avoid the use of apixaban during pregnancy. Breastfeeding: A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from apixaban therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. UNDESIRABLE EFFECTS (SPC section 4.8): Increased risk of occult or overt bleeding from any tissue or organ, which may result in post haemorrhagic anaemia. The signs, symptoms, and severity will vary according to the location and degree or extent of the bleeding. Frequencies: common (≥ 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). Prevention of VTE in adult patients who have undergone elective hip or knee replacement surgery (VTEp): Common: anaemia; haemorrhage*; haematoma*; nausea; contusion. Uncommon: thrombocytopenia*; epistaxis*; haematochezia*; liver function test abnormal (including blood bilirubin increased*); haematuria*; specific haemorrhage such as gastrointestinal*, abnormal vaginal*, urogenital*, post procedural*, wound secretion*, incision site*, operative*. Rare: hypersensitivity*; anaphylaxis*; haemoptysis*; gingival bleeding*; specific haemorrhage such as eye (including conjunctival)*, rectal*, muscle*. Not known: angioedema*; specific haemorrhage such as brain (encompassing intracranial, intraspinal)*, intra-abdominal*, respiratory tract*, haemorrhoidal*, mouth*, retroperitoneal*, traumatic*, erythema multiforme*. Prevention of stroke and systemic embolism in adult patients with NVAF, with one or more risk factors (NVAF): Common: anaemia; haemorrhage*; haematoma*; hypotension (including procedural hypotension); epistaxis*; nausea; gingival bleeding*; gamma-glutamyltransferase increased; haematuria*; contusion; specific haemorrhage such as eye (including conjunctival)*, gastrointestinal*, rectal*. Uncommon: thrombocytopenia*; hypersensitivity*; anaphylaxis*; haemoptysis*; haematochezia*; liver function test abnormal (including blood bilirubin increased*); specific haemorrhage such as brain (encompassing intracranial, intraspinal)*, intra-abdominal*, haemorrhoidal*, mouth*, abnormal vaginal*, urogenital*, post procedural*, wound secretion*, incision site*, operative*, traumatic*. Rare: specific haemorrhage such as respiratory tract*, retroperitoneal*, muscle*. Very Rare: erythema multiforme*. Not known: angioedema*. Treatment of DVT and PE, and prevention of recurrent DVT and PE (VTEt): Common: anaemia; thrombocytopenia*; haemorrhage*; haematoma*; epistaxis*; nausea; gingival bleeding*; gamma-glutamyltransferase increased; alanine aminotransferase increased; skin rash; haematuria*; contusion; specific haemorrhage such as gastrointestinal*, mouth*, rectal*, abnormal vaginal*, urogenital*. Uncommon: hypersensitivity*; anaphylaxis*; haemoptysis*; haematochezia*; liver function test abnormal (including blood bilirubin increased*); specific haemorrhage such as eye (including conjunctival)*, haemorrhoidal*, muscle*, post procedural*, wound secretion*, incision site*, operative*, traumatic*. Rare: specific haemorrhage such as brain (encompassing intracranial, intraspinal)*, respiratory tract*. Not Known: angioedema*; specific haemorrhage such as intra-abdominal* and retroperitoneal*, erythema multiforme*. *Denotes serious adverse reaction Refer to SmPC for all other adverse events LEGAL CATEGORY: POM. MARKETING AUTHORISATION NUMBER (SPC section 8): EU/1/11/691/002-3, EU/1/11/691/008, EU/1/11/691/014 PACKAGE QUANTITIES: Carton of 20 film-coated tablets 2.5 mg, 60 film-coated tablets 2.5 mg, 56 film-coated tablets 5 mg, 28 film- coated tablets 5 mg. MARKETING AUTHORISATION HOLDER (SPC section 7): Bristol-Myers Squibb/Pfizer EEIG, Plaza 254, Blanchardstown Corporate Park 2, Dublin 15, D15 T867, Ireland FOR FURTHER INFORMATION CONTACT: medical.information@bms.com or 1 800 749 749 (Ireland) DATE OF PREPARATION: April 2021 ADDITIONAL INFORMATION AVAILABLE ON REQUEST Approval Code: 432-IE-2100041

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

*with one or more risk factors, such as prior stroke or transient ischaemic attack (TIA); age≥ 75 years; hypertension; diabetes mellitus; symptomatic heart failure (NYHA Class ≥ II) AF = Atrial Fibrillation. Reference: 1. Granger CB et al. N Engl J Med 2011; 365: 981–992. Date of approval: May 2021 Job code: PP-ELI-IRL-0497 www.eliquis.ie

RESPIRATORY SYNCYTIAL VIRUS INFECTION RSV Research and Outlook

Vaccination

The development of a successful treatment or prophylactic agent has the potential to revolutionise the care and outcome for severe RSV infections in the world’s most vulnerable infant population.” may develop in 30-70% of first infection. Typically, only between 1% and 3% of infected infants require hospitalisation. Bronchiolitis is an inflammatory process in the small airways of the lungs and is the most common clinical syndrome associated with RSV infection. Theresa adds, “This typically presents in infants under 1 year of age but may be diagnosed in children up to 2 years old, and is characterised by a short history of low-grade fever, cough, coryza, dyspnoea and reduced feeding. The symptoms usually peak in clinical severity between day 3 and 5 of the illness. RSV bronchiolitis presents a significant clinical burden. In the UK, infection with RSV is responsible for up to 80% of all cases of bronchiolitis, similar to that of 65–70% in the US. “In older children, Respiratory Syncytial Virus typically presents as an URTI, viral pneumonia, episodic viral-induced wheeze or an acute exacerbation of asthma. Viral pneumonia is a common illness with 5 million cases reported in children annually. A meta-analysis of nine studies involving over 4000 children investigating viruses identified by polymerase chain reaction, found that RSV was the causative organism in 11% of communityacquired pneumonia cases.”

There is currently no vaccine available against RSV infection. She continues, “Palivizumab, which is a humanised mouse monoclonal antibody specific for the F protein of RSV, provides passive immunity against RSV. Palivizumab inhibits RSV binding to host cells and prevents fusion of infected cells with adjacent cells. It is authorised in Ireland for the prevention of serious lower respiratory tract disease requiring hospitalisation caused by RSV in children at high risk for RSV disease. “Differences in epidemiology, practice setting, health care systems and drug cost have resulted in variability in palivizumab recommendations and use nationally and internationally. Palivizumab prophylaxis reduces the absolute risk of RSV hospitalisation from about 10% to 5% for premature babies, infants with chronic lung disease and haemodynamically significant congenital heart disease, particularly when complicated by large left-toright shunts and pulmonary hypertension. It does not reduce mortality or the need for mechanical ventilation.” Treatment and Prevention The mainstay of treatment for the vast majority of RSV infections is supportive including rest, fluids and paracetamol, but passive preventive immunisation is available for at-risk children, including premature infants and infants with a history of cardiac, pulmonary, or neuromuscular diseases. “Those with severe respiratory illness require hospitalisation, oxygen therapy, IV fluids and ventilatory support in the form of a high-flow nasal cannula, CPAP, or intubation, and mechanical ventilation,” she says. “Ribavirin is the only licensed antiviral medication for the specific treatment of RSV infection but due to drug toxicity, including bone marrow suppression and potential carcinogenicity and teratogenicity and minimal clinical benefit, it has not been recommended for routine clinical use. Ribavirin, may be considered for a small number of patients and treatment of RSV with Ribavirin must be done under the supervision of an infection

JANUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

specialist such as a consultant microbiologist or an infectious disease specialist. “Other treatment modalities for bronchiolitis have been tried in the past and have failed to show broad, reproducible efficacy on clinically significant outcomes in RSV and bronchiolitis. These include albuterol, epinephrine, steroids, hypertonic saline, antibiotics, and chest physical therapy, and routine use of these interventions is not recommended. Antibiotics are not effective against RSV and it is important that unnecessary antibiotics are discontinued once a diagnosis is confirmed, to avoid adverse drug reactions and antibiotic resistance. “Although palivizumab may help prevent serious complications of RSV infection, it is not used to treat RSV infection. It has however, been shown to reduce the risk of hospitalisation by 39-78% in various groups of infants predisposed to developing severe RSV disease. Palivizumab is given as an intramuscular injection monthly (up to five doses) during the RSV season. As it is very expensive and has a half-life of 18–21 days, meaning monthly injections are required to maintain protective titres, cost–benefit analyses limit its use to only the most vulnerable infants, those born prematurely with moderate or severe BPD, haemodynamically significant, acyanotic congenital heart disease, severe combined immunodeficiency or infants with other severe chronic lung conditions or requiring long-term ventilation.” Theresa says prevention and patient education is key, and frequent, careful handwashing is the most important measure in preventing the spread of RSV. “In the hospital setting, RSV transmission can be prevented by managing children with RSV together in the same ward, paying strict attention to handwashing guidelines, using barrier precautions and avoiding overcrowding through restriction of visitors. Several studies have shown that strict infection control practices including hand hygiene, the use of personal protective equipment when necessary, timely detection and isolating or cohorting infants with RSV infection can reduce nosocomial RSV infection rates by 39–67%.”

Theresa concludes, “The management of Respiratory Syncytial Virus disease in infants and children is primarily supportive with antiviral medications reserved for the most vulnerable. Palivizumab continues to be the only effective prophylactic medication licensed for use, however, its high cost prevents it from being used in all infants. “The development of a welltolerated, clinically effective and cost-effective RSV vaccine and therapeutic agent remains a global health priority. It is likely that a licensed RSV vaccine is several years away, however, given the burden of RSV infection and the associated costs globally there is much ongoing research into the development of a welltolerated and effective vaccine. The main target populations for vaccination include infants, school age children, pregnant women and older adults. Multiple different vaccine approaches are being considered including live-attenuated chimeric, wholeinactivated, particle-base, subunit, nucleic acid and genebased vectors. There are also ongoing efforts to develop long acting monoclonal antibodies for infants. “Three agents, ribavirin, IVIG and palivizumab have been extensively used and investigated as antiviral treatments for RSV. To date none have proven unequivocally beneficial, and effective treatments and research continues into future therapies. At least 14 anti-RSV treatment products are undergoing phase I and II clinical trials, of which 5 have included paediatric patients. “Novel therapeutic molecules developed to date include, fusion inhibitors, non-fusion inhibitors, polymerase inhibitors, antibodies, nucleoside analogues, small-interfacing RNAs and a benzodiazepine. They have various targets on RSV such as the F protein, RNA polymerase, nucleoprotein and nucleocapsid mRNA. It is hoped that one of these products will become a licensed treatment for RSV infection in children and adults over the coming years. The development of a successful treatment or prophylactic agent has the potential to revolutionise the care and outcome for severe RSV infections in the world’s most vulnerable infant population.” References available on request

KEYTRUDA: helping to redefine overall survival expectations for more patients with mNSCLC1-4 PD-L1 <1% or unknown

PD-L1 1-49%

PD-L1 >50%

NONSQUAMOUS

√

1st line Combination** Therapy3

SQUAMOUS

√

1st line*** Monotherapy4

NON-SQUAMOUS AND SQUAMOUS

√

Line

Histology

1st line Combination* Therapy2

* KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of metastatic non-squamous NSCLC in adults whose tumours have no EGFR or ALK positive mutations. ** KEYTRUDA, in combination with carboplatin and either paclitaxel or nab-paclitaxel, is indicated for the first-line treatment of metastatic squamous NSCLC in adults. *** KEYTRUDA, as monotherapy, is indicated for the first-line treatment of metastatic non-small cell lung carcinoma (NSCLC) in adults whose tumours express PD-L1 with a≥ 50% tumour proportion score (TPS) with no EGFR or ALK positive tumour mutations.

Adverse events should be reported. Reporting forms and information can be found at www.hpra.ie. Adverse events should also be reported to MSD (Tel: 01-2998700) Reference 1. Keytruda Summary of Product Characteristics, September 2021, 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.

Date of Preparation: September 2021

Other clinically significant immune-related adverse reactions: The following additional clinically significant, immune-related adverse reactions, have been reported in clinical studies or in post-marketing experience: uveitis, arthritis, myositis, myocarditis, pancreatitis, Guillain-Barré syndrome, myasthenic syndrome, haemolytic anaemia, sarcoidosis, encephalitis, myelitis, vasculitis, cholangitis sclerosing and gastritis. Refer to SmPC for information on management of significant immune-related adverse reactions. Complications of allogeneic Haematopoietic Stem Cell Transplant (HSCT): Allogeneic HSCT after treatment with pembrolizumab: Cases of graft-versushost-disease (GVHD) and hepatic veno-occlusive disease (VOD) have been observed in patients with classical Hodgkin lymphoma undergoing allogeneic HSCT after previous exposure to pembrolizumab. Allogeneic HSCT prior to treatment with pembrolizumab: In patients with a history of allogeneic HSCT, acute GVHD, including fatal GVHD, has been reported after treatment with pembrolizumab. Infusion-related reactions: For Grades 3 or 4infusion reactions including hypersensitivity and anaphylaxis, stop infusion and permanently discontinue pembrolizumab. With Grades 1 or 2 infusion reactions, infusion may continue with close monitoring. Premedication with antipyretic and antihistamine may be considered. Overdose: There is no information on overdose with pembrolizumab. In case of overdose, monitor closely for signs or symptoms of adverse reactions and treat appropriately. INTERACTIONS No formal pharmacokinetic drug interaction studies have been conducted with pembrolizumab. No metabolic drug drug interactions are expected. The use of systemic corticosteroids or immunosuppressants before starting pembrolizumab should be avoided because of their potential interference with the pharmacodynamic activity and efficacy of pembrolizumab. Corticosteroids can be used as premedication, when pembrolizumab is used in combination with chemotherapy, as antiemetic prophylaxis and/or to alleviate chemotherapy-related adverse reactions. FERTILITY, PREGNANCY AND LACTATION Women of childbearing potential Women of childbearing potential should use effective contraception during treatment with pembrolizumab and for at least 4 months after the last dose of pembrolizumab. Pregnancy No data on use in pregnant women. Do not use during pregnancy unless the clinical condition of the woman requires treatment with pembrolizumab. Breast-feeding It is unknown whether pembrolizumab is secreted in human milk. A risk to newborns/ infants cannot be excluded. Fertility No clinical data available. SIDE EFFECTS Refer to SmPC for complete information on side effects. Pembrolizumab is most commonly associated with immune-related adverse reactions. Most of these reactions resolved with appropriate medical treatment or withdrawal of pembrolizumab. The most serious adverse reactions were immune-and infusion-related adverse reactions. Monotherapy: Very Common: anaemia, hypothyroidism, decreased appetite, headache, dyspnea, cough, abdominal pain, nausea, vomiting, constipation, musculoskeletal pain, arthralgia, asthenia, oedema, pyrexia, diarrhoea, rash, pruritus, fatigue. Common: pneumonia, thrombocytopenia, neutropenia, lymphopenia, hyponatraemia, hypokalaemia, hypocalcaemia, insomnia, neuropathy peripheral, lethargy, dry eye, cardiac arrhythmia (including atrial fibrillation), hypertension, hyperthyroidism, thyroiditis, insomnia, dizziness, dysgeusia, pneumonitis, colitis, dry mouth, severe skin reactions, vitiligo, dry skin, alopecia, eczema, dermatitis acneiform, erythema, dermatitis, myositis, pain in extremity, arthritis, influenza like illness, chills, AST and ALT increases, hypercalcaemia, increase in blood alkaline phosphatase, blood bilirubin increased, blood creatinine increased, infusion related reaction. Combination with chemotherapy: Very Common: pneumonia, anaemia, neutropenia, thrombocytopenia, hypothyroidism, hyponatraemia, hypokalaemia, decreased appetite, insomnia, dizziness, neuropathy peripheral, headache, dyspnoea, cough, alopecia, nausea, diarrhoea, vomiting, abdominal pain, constipation, rash, pruritus, musculoskeletal pain, arthralgia, pyrexia, fatigue, asthenia, oedema, blood creatinine increased. Common: febrile neutropenia, leukopenia, lymphopenia, infusion related reaction, hyperthyroidism, hypocalcaemia, dysgeusia, lethargy, dry eye, cardiac arrhythmia (including atrial fibrillation), vasculitis, hypertension, pneumonitis, colitis, dry mouth, gastritis, hepatitis, severe skin reactions, dry skin, erythema, dermatitis, myositis, pain in extremity, arthritis, acute kidney injury, influenza-like illness, chills, hypercalcaemia, ALT increase, AST increased, blood alkaline phosphatase increased, blood bilirubin increased. Combination with axitinib: Very Common: hyperthyroidism, hypothyroidism, decreased appetite, headache, dysgeusia, hypertension, dyspnoea, cough, dysphonia, diarrhoea, abdominal pain, nausea, vomiting, constipation, palmar-plantar erythrodysaesthesia syndrome, rash, pruritus, musculoskeletal pain, arthralgia, pain in extremity, fatigue, asthenia, pyrexia, alanine aminotransferase increased, aspartate aminotransferase increased, blood creatinine increased. Common: pneumonia, anaemia, neutropenia, leukopenia, thrombocytopenia, infusion related reaction, hypophysitis, thyroiditis, adrenal insufficiency, hypokalaemia, hyponatraemia, hypocalcaemia, insomnia, dizziness, lethargy, neuropathy peripheral, dry eye, cardiac arrhythmia (including atrial fibrillation), pneumonitis, colitis, dry mouth, gastritis, hepatitis, severe skin reactions, dermatitis acneiform, dermatitis, dry skin, alopecia, eczema, erythema, myositis, arthritis, tenosynovitis, acute kidney injury, nephritis, oedema, influenza like illness, chills, blood alkaline phosphatase increased, hypercalcaemia, blood bilirubin increased PACKAGE QUANTITIES KEYTRUDA 25 mg/mL: 4 mL of concentrate in a 10 mL Type I clear glass vial. Legal Category: POM. Marketing Authorisation numbers EU/1/15/1024/002 Marketing Authorisation holder Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands. Date of revision: June 2021. © Merck Sharp & Dohme B.V. 2021. All rights reserved. Further information is available on request from: MSD, Red Oak North, South County Business Park, Leopardstown, Dublin D18 X5K7 or from www.medicines.ie. PSUSA-202009-II-097

IE-KEY-00476

KEYTRUDA® (pembrolizumab) ABRIDGED PRODUCT INFORMATION Refer to Summary of Product Characteristics before prescribing. PRESENTATION KEYTRUDA 25 mg/mL: One vial of 4 mL of concentrate contains 100 mg of pembrolizumab. INDICATIONS KEYTRUDA as monotherapy is indicated for the treatment of advanced (unresectable or metastatic) melanoma in adults. KEYTRUDA as monotherapy is indicated for the adjuvant treatment of adults with Stage III melanoma and lymph node involvement who have undergone complete resection. KEYTRUDA as monotherapy is indicated for the first-line treatment of metastatic non-small cell lung carcinoma (NSCLC) in adults whose tumours express PD-L1 with a ≥50% tumour proportion score (TPS) with no EGFR or ALK positive tumour mutations. KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of metastatic non-squamous NSCLC in adults whose tumours have no EGFR or ALK positive mutations. KEYTRUDA, in combination with carboplatin and either paclitaxel or nab-paclitaxel, is indicated for the first-line treatment of metastatic squamous NSCLC in adults. KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic NSCLC in adults whose tumours express PD-L1 with a ≥1% TPS and who have received at least one prior chemotherapy regimen. Patients with EGFR or ALK positive tumour mutations should also have received targeted therapy before receiving KEYTRUDA. KEYTRUDA as monotherapy is indicated for the treatment of adult and paediatric patients aged 3 years and older with relapsed or refractory classical Hodgkin lymphoma (cHL) who have failed autologous stem cell transplant (ASCT) or following at least two prior therapies when ASCT is not a treatment option. KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic urothelial carcinoma in adults who have received prior platinum-containing chemotherapy. KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic urothelial carcinoma in adults who are not eligible for cisplatin-containing chemotherapy and whose tumours express PD L1 with a combined positive score (CPS) ≥ 10. KEYTRUDA as monotherapy or in combination with platinum and 5-fluorouracil (5-FU) chemotherapy, is indicated for the first-line treatment of metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) in adults whose tumours express PD-L1 with a CPS ≥ 1. KEYTRUDA as monotherapy is indicated for the treatment of recurrent or metastatic HNSCC in adults whose tumours express PD-L1 with a ≥ 50% TPS and progressing on or after platinum-containing chemotherapy. KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of advanced renal cell carcinoma (RCC) in adults. KEYTRUDA as monotherapy is indicated for the first line treatment of metastatic microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer in adults. KEYTRUDA, in combination with platinum and fluoropyrimidine based chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic carcinoma of the oesophagus or HER-2 negative gastroesophageal junction adenocarcinoma in adults whose tumours express PD-L1 with a CPS ≥ 10. DOSAGE AND ADMINISTRATION See SmPC for full details. Therapy must be initiated and supervised by specialist physicians experienced in the treatment of cancer. The recommended dose of KEYTRUDA in adults is either 200 mg every 3 weeks or 400 mg every 6 weeks administered as an intravenous infusion over 30 minutes. The recommended dose of KEYTRUDA as monotherapy in paediatric patients aged 3 years and older with cHL is 2 mg/kg bodyweight (up to a maximum of 200 mg), every 3 weeks administered as an intravenous infusion over 30 minutes. KEYTRUDA must not be administered as an intravenous push or bolus injection. When administering KEYTRUDA as part of a combination with intravenous chemotherapy, KEYTRUDA should be administered first. Treat patients until disease progression or unacceptable toxicity. Atypical responses (i.e., an initial transient increase in tumour size or small new lesions within the first few months followed by tumour shrinkage) have been observed. Recommended to continue treatment for clinically stable patients with initial evidence of disease progression until disease progression is confirmed. For the adjuvant treatment of melanoma, KEYTRUDA should be administered until disease recurrence, unacceptable toxicity, or for a duration of up to one year. KEYTRUDA, as monotherapy or as combination therapy, should be permanently discontinued (a) For Grade 4 toxicity except for: endocrinopathies that are controlled with replacement hormones; or haematological toxicity, only in patients with cHL in which KEYTRUDA should be withheld until adverse reactions recover to Grade 0-1; (b) If corticosteroid dosing cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks; (c) If a treatment-related toxicity does not resolve to Grade 0 1 within 12 weeks after last dose of KEYTRUDA; (d) If any event occurs a second time at Grade ≥ 3 severity. Patients must be given the Patient Alert Card and be informed about the risks of KEYTRUDA. Special populations Elderly: No dose adjustment necessary. Data from patients ≥ 65 years are too limited to draw conclusions on cHL population. Data are limited in patients ≥ 75 years for pembrolizumab monotherapy in patients with resected Stage III melanoma and MSI-H or dMMR CRC; for pembrolizumab in combination with axitinib in patients with advanced RCC; for chemotherapy combination in patients with metastatic NSCLC and oesophageal carcinoma; for pembrolizumab (with or without chemotherapy) in patients receiving first line treatment for metastatic or unresectable recurrent HNSCC. Renal impairment: No dose adjustment needed for mild or moderate renal impairment. No studies in severe renal impairment. Hepatic impairment: No dose adjustment needed for mild hepatic impairment. No studies in moderate or severe hepatic impairment. Paediatric population: Safety and efficacy in children below 18 years of age not established except in paediatric patients with cHL. CONTRAINDICATIONS Hypersensitivity to the active substance or to any excipients. PRECAUTIONS AND WARNINGS Assessment of PD-L1 status When assessing the PD-L1 status of the tumour, it is important that a well-validated and robust methodology is chosen to minimise false negative or false positive determinations. Immune-related adverse reactions Immune-related adverse reactions, including severe and fatal cases, have occurred in patients receiving pembrolizumab. Most immune related adverse reactions occurring during treatment with pembrolizumab were reversible and managed with interruptions of pembrolizumab, administration of corticosteroids and/or supportive care. Immune related adverse reactions have also occurred after the last dose of pembrolizumab. Immune-related adverse reactions affecting more than one body system can occur simultaneously. See SmPC for full details. Immune-related pneumonitis: Patients should be monitored for signs and symptoms of pneumonitis.. Suspected pneumonitis should be confirmed with radiographic imaging and other causes excluded. Refer to SmPC for information on management of immune-related pneumonitis. Immune-related colitis: Patients should be monitored for signs and symptoms of colitis, and other causes excluded. Consider the potential risk of gastrointestinal perforation. Refer to SmPC for information on management of immune-related colitis. Immune-related hepatitis: Patients should be monitored for changes in liver function (at the start of treatment, periodically during treatment and as indicated based on clinical evaluation) and symptoms of hepatitis, and other causes excluded. Refer to SmPC for information on management of Immune-related hepatitis. Immune-related nephritis: Patients should be monitored for changes in renal function, and other causes of renal dysfunction excluded. Refer to SmPC for information on management of immune-related nephritis. Immune-related endocrinopathies: Severe endocrinopathies, including adrenal insufficiency, hypophysitis, type 1 diabetes mellitus, diabetic ketoacidosis, hypothyroidism, and hyperthyroidism have been observed with pembrolizumab treatment and patients should be monitored for these endocrinopathies. Refer to SmPC for information on management of immune-related endocrinopathies. Immune-related skin adverse reactions: Patients should be monitored for suspected severe skin reactions and other causes should be excluded. Cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving pembrolizumab. If SJS or TEN is confirmed, pembrolizumab should be permanently discontinued.

PNEUMONIA

Factors Associated With Treatment Failure in Moderately Severe Community-Acquired Pneumonia A Secondary Analysis of a Randomized Clinical Trial Written by Aurélien Dinh, MD1,2; Clara Duran, MSc1; Jacques Ropers, PharmD3; et al Infectious Diseases Unit, Raymond-Poincaré University Hospital, Assistance Publique–Hôpitaux de Paris (APHP) Paris Saclay University, Garches, France Epidemiology and Modeling of Bacterial Evasion to Antibacterials Unit, Institut Pasteur, Paris, France 3 Clinical Research Unit, Pitié-Salpétrière University Hospital, APHP, Paris, France 1 2

Aurélien Dinh, MD

clinical trial that studied antibiotic treatment duration (3 vs 8 days of β-lactam treatment) among 310 patients hospitalized with moderately severe CAP who reached clinical stability at day 3 of treatment. In this secondary analysis, we aim to evaluate the risk factors for treatment failure among this specific population. Methods Study Design, Sites, and Study Population

Introduction Up to 5.6 million cases of community-acquired pneumonia (CAP) occur annually in the US,1 resulting in 600 000 to 800 000 hospitalizations, with the highest incidence rate in older patients.1-4 Community-acquired pneumonia is a heterogeneous disease that ranges from a mild, self-limiting disease to a severe infection that causes respiratory failure, shock, and death.5,6 Treatment failure is the most serious complication. Failure significantly increases the risk of complications, length of hospital stay, and death, especially

in patients with severe CAP.3,7-13 The incidence of clinical failure in patients with CAP ranges from 6% to 24%3,7-12 and can reach up to 31% in patients with severe CAP.13 Several risk factors for treatment failure have been identified in the literature, such as age, smoking, malnutrition, previous CAP episodes, and comorbidities (chronic pulmonary disease, asthma, and immunosuppression).14 Reaching clinical stability is associated with a high rate of favorable outcomes.15 The Pneumonia Short Treatment (PTC) trial was a placebo-controlled randomized

JANUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

We performed a secondary analysis of a double-blind randomized clinical trial (the PTC trial), which included 310 patients with moderately severe CAP in 16 teaching hospitals in France, from December 19, 2013, to February 1, 2018. Data analysis was performed from July 18, 2019, to February 15, 2020. The primary outcome was treatment failure 15 days after first antibiotic intake, defined as a temperature greater than 37.9 °C and/or absence of resolution or improvement of respiratory symptoms (coughing frequency or severity, sputum production, dyspnea, or crackles) and/or additional antibiotic treatment for any cause. The study design and main results have been published previously.16 In brief, patients who met the following inclusion criteria were studied: age of 18 years or older, hospitalized in a non–critical care ward for CAP, treated with β-lactams, chosen at the discretion of the physician in charge to receive amoxicillin-clavulanate (oral or intravenous) or parenteral third-generation cephalosporin (ceftriaxone or cefotaxime), and presented after 72 hours of treatment with a clinical response defined by the presence of stability criteria.3 Race and ethnicity data

are not allowed to be collected in France for research by law; therefore, these data are not available for analysis. Communityacquired pneumonia was defined as the association of at least 1 acute clinical sign compatible with pneumonia (among dyspnea, cough, purulent sputum, or crackles), temperature greater than 38°C, and a pulmonary infiltrate on chest radiography. Stability criteria were defined, according to the Infectious Diseases Society of America, as apyrexia (temperature ≤37.8 °C), heart rate less than 100 beats/min, respiratory rate less than 24 breaths/min, arterial oxygen saturation of 90% or higher, systolic blood pressure of 90 mm Hg or higher, and normal mental status.3 Main exclusion criteria were signs of severe and/ or complicated CAP, known immunosuppression, health care–associated pneumonia or suspicion of aspiration pneumonia, any other infection that necessitated concomitant antibiotic treatment, and/ or suspected or confirmed legionellosis. The trial was approved by the Versailles/Saint-Germain-en-Laye University Ethics Committee, the French National Agency for Medicines and Health Products Safety, and the French Data Protection Agency. The study was performed in accordance with the ethical principles of the Declaration of Helsinki17 and the Guidelines for Good Clinical Practice. All participants provided written informed consent, which included the conduct of future studies. All data were deidentified. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline. Randomization and Masking After 3 full days (72 hours) of β-lactam treatment, patients with all clinical criteria of stability were randomly assigned in a 1:1 ratio to receive oral amoxicillin-clavulanate (500 mg/62.5 mg) treatment or

57 placebo (2 pills 3 times daily) for 5 extra days. Randomization was performed with stratification according to randomization site and Pneumonia Severity Index (PSI) (score of ≤70 or >70). The PSI is scored from 0 to 395, stratifying patients into classes according to the 30-day risk of death: low risk for classes I and II (scores, 0-70), low risk for class III (scores, 71-90), medium risk for class IV (scores, 91-130), and high risk for class V (scores, 131-395). Patients, treating physicians, investigators, pharmacists, and study coordinators were masked to treatment allocation. Variables We performed this secondary analysis among the per-protocol study population, which included all patients randomly assigned to treatment, patients not erroneously included, patients who received their assigned treatment, and patients who received at least 80% of this treatment, except if discontinuation was attributable to worsening of their condition. Those who withdrew consent after more than 1 dose of study treatment and those lost to follow-up, except if they received additional treatment since day 3, were excluded.

Statistical Analysis Continuous variables are presented as means (SDs) and as tabular descriptions for qualitative characteristics. Normality tests were first performed, and normal (and lognormal) distribution was found for all data. We used χ2 tests to compare the distributions of categorical variables, whereas 2-tailed, unpaired t tests were used to compare the distributions of quantitative continuous variables. All reported P values were based on 2-sided tests, and P ≤ .05 was considered statistically significant. To identify risk factors associated with failure at day 15, a univariate analysis by logistic regression was performed, using demographic and medical characteristics as well as all clinical, biological, and radiological data from day 0 of antibiotic treatment. A multivariable analysis by logistic regression was then performed using all variables from the univariate analysis that had a P ≤ .20, except for variables such as PSI score and urea nitrogen level to avoid multicollinearity with other variables from the regression model (eg, age, sex, and creatinine clearance). Odds ratios (ORs) were calculated from the univariate and multivariable analysis to quantify association with failure at day 15 with 95%

CIs. An OR greater than 1.00 was considered to be associated with failure. Analyses were performed with the use of R software, version 3.6.1 (R Foundation for Statistical Computing). Results Among the 310 patients included in the PTC trail, the per-protocol analysis at day 15 comprised 291 patients (174 [59.8%] male; mean [SD] age, 69.6 [18.5] years), with a failure rate of 26.8% (n = 78). Main comorbidities were chronic lung disease (68 [23.4%]), heart failure (60 [20.7%]), and diabetes (54 [18.6%]). Main causes of failure were no resolution or improvement of symptoms (62 [79.5%]), additional antibiotic treatment (8 [10.2%]), and fever at day 15 (4 [5.1%]). Only 1 patient in the failure group had died before day 15, after experiencing fever and possible pulmonary edema.

dyspnea associated with crackles (1 [1.6%]), cough associated with purulent sputum (1 [1.6%]), and sputum associated with crackles (1 [1.6%]). Similar evolutions of mean (SD) CAP scores were found in all patients at day 0 (43.8 [19.0] vs 45.4 [20.7], P = .61) and at day 3 (58.4 [19.8] vs 62.7 [20.2], P = .14). However, patients with treatment failure at day 15 had lower mean (SD) CAP scores at day 8 (57.8 [22.5] vs 69.0 [18.8], P < .001) and day 15 (51.9 [18.4] vs 75.3 [18.1], P < .001). Furthermore, mean (SD) CAP scores for each respiratory symptom were significantly different between the 2 groups (dyspnea: 0.5 [10.6] vs 4.0 [9.9], P = .01 at day 8 and −1.1 [11.1] vs 5.5 [9.1], P < .001 at day 15; cough: −2.9 [7.5] vs −0.1 [7.9], P = .01 at day 8 and −4.0 [6.9] vs 1.5 [7.6], P < .001 at day 15; and sputum production: 0.4 [23.8] vs 8.9 [20.9], P = .01 at day 8 and −7.3 [22.9] vs 12.7 [18.6], P < .001 at day 15) (Figure 1).

rs Associated With Treatment Failure in Moderately Severe Community The main symptoms present at day Analysis of a Randomized Clinical Trial 15 among patients with treatment failure were purulent sputum alone (15 [24.2%]), dyspnea alone (14 [22.6%]), cough alone (13 [21.0%]), cough and purulent sputum (11 [17.1%]), cough and crackles (3 [4.8%]), crackles alone (2 [3.2%]), dyspnea associated with purulent sputum (2 [3.2%]), dyspnea associated with cough (2 [3.2%]),

Open. 2021;4(10):e2129566. doi:10.1001/jamanetworkopen.2021.29566

The variables included demographic characteristics, clinical and radiological data, and results of usual blood tests from the first day of β-lactam treatment (day 0). Disease severity within the first 24 hours after diagnosis, determined with the PSI,18 antibiotic treatment duration (3 or 8 days), and pneumonia-related symptoms scored using the CAP score19 were also included in the secondary analysis. The CAP score, which is a clinical score used to quantify subjective CAP symptoms, has been described by Moussaoui et al.19 It is a short and reliable questionnaire that evaluates changes in respiratory symptoms and well-being during the treatment of CAP. The CAP score is scored from −5.91 [more severe symptoms] to 101.2 [none or mildest symptoms];) Visits with the physician in charge of the patients were planned 15 days after the start of antibiotic treatment, and clinical data (stability criteria, CAP score, and adverse events) were recorded.

The factors significantly associated with treatment failure at day 15 in univariate analysis were as follows: male sex (OR, 1.74; 95% CI, 1.01-3.07), age per year (OR, 1.03;

Figure 1: Course of Symptom According to Outcome (Community-Acquired Pneumonia [CAP] Score) Error bars indicate standard deviation. A higher CAP score corresponds to fewer pneumonia symptoms.

HOSPITALPROFESSIONALNEWS.IE | HPN • JANUARY 2022

95% CI, 1.01-1.05), chronic lung disease (OR, 1.85; 95% CI, 1.033.30), PSI score at day 0 (OR, 1.01; 95% CI, 1.00-1.02), creatinine clearance at day 0 (OR, 0.99; 95% CI, 0.98-1.00), and urea nitrogen level at day 0 (OR, 1.07; 95% CI, 1.00-1.14). Systolic arterial pressure at day 0 (OR, 1.00; 95% CI, 1.00-1.02) and platelet count at day 0 (OR, 1.00; 95% CI, 1.001.00) had a P < .20 and therefore were not statistically significant in the univariate analysis but were included in the multivariable regression model. When PSI score and urea level at day 0 were excluded to avoid multicollinearity, the factors significantly associated with treatment failure at day 15 in multivariable analysis were male sex (OR, 1.92; 95% CI, 1.08-3.49) and age per year (OR, 1.02; 95% CI, 1.00-1.05). Any collinearity between the 2 variables was also verified by comparing the study population’s characteristics according to their sex: no significant statistical difference was found between male sex and age (mean (SD) age, 69.4 [18.3] vs 70.0 [18.9] years; P = .76). Discussion In this secondary analysis of a randomized clinical trial of patients with CAP who reached clinical stability after 3 days of antibiotic treatment, only male sex and age were associated with higher risk of failure. Our study population is similar to the usual population described in the literature concerning patients hospitalized with CAP, with the exception of patients with immunosuppression, who were excluded from our trial. Indeed, the median age of the population with CAP usually described is between 70 and 74 years, with most being male

PNEUMONIA

and having a high number of comorbidities, such as diabetes, chronic obstructive pulmonary disease, chronic heart failure, and a PSI score of III to IV.20-22 Although approximately half of patients with moderately severe CAP reach clinical stability within 3 days,15,23 which is associated with a shorter hospital stay and a better prognosis,22 the originality of our study is to focus on those patients and observe their clinical outcome. Our study found that risks factors for treatment failure among patients hospitalized for CAP who reached clinical stability at day 3, in univariate analysis, were age and sex, which are well-known risk factors associated with failure in the literature and may be the most influential characteristics24; PSI score, which has been used to evaluate the lethality rate18; chronic lung disease; and kidney failure, which is often associated with failure and therefore could be a marker of severity rather than a proper risk factor. In the multivariable analysis, only male sex and age were significantly associated with treatment failure. Risks factors for failure have been explored in the literature. Despite heterogeneity of failure definition, age and comorbid conditions have also been associated with a higher risk of failure in previous works.9,12,25 In a systematic review of the literature,14 29 studies were selected, with 45% of them focused on individuals 65 years or older to determine risk factors for CAP. Several risk factors were identified: age, smoking, environmental exposures, malnutrition, previous CAP, chronic pulmonary disease, asthma, functional impairment, poor dental health, immunosuppressive therapy, oral corticosteroids,

and treatment with gastric acid– suppressive drugs. Some of these factors could be corrected, which would reduce morbidity and mortality among adult patients with CAP, particularly among the older patients. Regarding nonmodifiable criteria, age and chronic pulmonary disease were also identified in our study. In the current study, only a few of these risk factors were significant, possibly because only patients with CAP who reached clinical stability at day 3 were included. As previously reported, reaching clinical stability is associated with a high rate of favorable outcome.15 In our original study, patients treated with 3 or 8 days of β-lactam therapy reached the same cure rate. Thus, the antibiotic treatment durations used had no association with failure in this analysis. However, rates of failure vary in the literature, depending on the different definitions used and time of assessment. Moreover, failure could be attributable to noninfectious causes. For instance, in a prospective, multicenter cohort study8 performed in hospitalized patients, treatment failure occurred in 15% of patients, with early failure occurring in 62% and late failure in 38%. The causes were infectious in 40%, noninfectious in 16%, and undetermined in 44%. These findings emphasize the difficulty in defining failure and harmonizing criteria to compare study results because risk factors for failure depend on its definition. Overall, the failure rate ranged from 11% to 16%,8,10,11 with a rate of early clinical failure varying from 6% to 9%.8,9 The failure rate in our trial seems higher than previously reported, especially among patients who reached early clinical stability probably because of the stringent definition of cure in our

trial. Indeed, persistence of clinical symptoms (eg, cough) without worsening or additional antibiotic was considered as failure. In fact, our description of failure indicated that the main causes for classification as failure were the persistence or worsening of clinical symptoms. Few patients were classified as having treatment failure for additional antibiotic treatment or death. In addition, the main persistent or worsened symptoms of patients at day 15 were purulent sputum, cough, and dyspnea but not fever. However, these symptoms are usually reported as persistent among patients with pneumonia without indicating treatment failure.26 In our study, all patients had similar evolutions of CAP score from day 0 to day 3. The CAP score at day 0 was not associated with failure. However, patients classified as having treatment failure at day 15 had lower CAP scores at day 8 and day 15 for each respiratory symptom. Therefore, this finding is consistent with the study's definition of failure, which included persistence or worsening of respiratory symptoms. Finally, following biomarker levels was not associated with failure in our study. Indeed, C-reactive protein and procalcitonin levels, which were collected when available, did not seem informative among patients who were stable at day 3. Another study27 also found that neither procalcitonin nor leukocyte count was associated with cure. Procalcitonin is an interesting tool to shorten treatment duration, as demonstrated by 2 metaanalyses.28,29 Nevertheless, a recent trial28 that compared procalcitonin levels and clinical evolution among patients with suspected lower respiratory tract infection found no association with antibiotic prescriptions. Finally, the recent Infectious Diseases Society of America and American Thoracic Society guidelines state that, despite reducing duration of antibiotic therapy, the use of procalcitonin level monitoring does not lead to overall lower durations of treatment compared with recommended durations.29 This finding reinforces the importance of clinical examination on biological data. Conclusions In this study, among patients with CAP who met the criteria for stability after 3 days of antibiotic treatment, age and sex but not comorbidities or severity of disease were associated with an increased risk of failure. Surveillance of clinical signs (ie, stability criteria) is of paramount importance. These results should be taken in account for the treatment of patients with CAP. References on request

JANUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

TUBERCULOSIS

Quality Management - How Ending Tuberculosis in Ireland Could Be Approached - World Tuberculosis Day 2022

Written by James O’Connell, MSc, MD - Specialist Registrar Public Health Medicine, Department of Public Health, Health Service Executive West, Galway

Quality Management−How Ending Tuberculosis in Ireland could be Approached james.oconnell3@hse.ie World Tuberculosis Day 2022

Figure 1. Projected incidence of tuberculosis, Ireland, 2021-2050 Written James O’Connell, MSc,detected MD and treated, 13% less The 2015 by Sustainable treatment is available and free. Figure 1. Projected incidence of Specialist Registrar Public Medicine, of J., Public Health, Health Service Development Goals (SDGs) setHealth out Source Most in Ireland treatedPrioritiestuberculosis, than in 2019. Department Finding the “missing adapted from: O’Connell A Quality ofpatients Care Evaluation toare Identify for Improving Tuberculosis Ireland, 2021-2050 a shared global vision for a better, Care successfully for TB. Despite all millions”, most of whom are inRoyal 16 College in Ireland (Thesis), Dublin, of Surgeons in Ireland. Executive West, Galway

Source adapted from: more sustainable future through 17 this, even Ireland will fail to reduce high-burden countries, is a major O’Connell J., A Quality of Care interlinked goals. Goal three is to challenge to addressing TB. So too the incidence of TB sufficiently Evaluation to Identify Priorities ensure healthy lives and promote toglobal meet the WHOfor End targets by TB, global Although countries are disproportionately affected elimination will The 2015 Sustainable Development Goalslow-income (SDGs)TBset out a shared vision a TB better, are drug-resistant and human for Improving Tuberculosis Care well-being for all and includes (Figure 1).with To stay track, the immunodeficiency virus (HIV)require action bygoals. all countries, consistent theonvision of the SDGs and the principles of more sustainable future through 17 interlinked Goal three is to ensure healthy lives in Ireland (Thesis), Dublin, Royal targets to end tuberculosis (TB). incidence of TB will need to TB co-infection which, although College of Surgeons the End TB only Strategy. High-income countries, more robust in Ireland. and promote well-being for all and includes targets to end (TB). Despite beingpermust develop Despite being preventable and decline from such 5.6 to as 0.6Ireland, cases comprising a minority of tuberculosis treatable, TB is a leading cause of 100,000 between 2019 and 2035. to TBof prevention and control, both nationally preventable and treatable, TB isapproaches a leadingglobally, cause global morbidity and mortality, with 10and internationally. With regard infections can be difficult global morbidity and mortality, with This would be an 89% reduction, toending diagnose and treat. to TB, an approach by Ireland can begin by considering just four questions−what? million infected and 1.5 million TB-related deaths in 2020. To achieve the SDG and World 10 million infected and 1.5 million substantially more than the 46% who? why? and how? Ireland is a high-income Health Organisation End targets (Table 1),country greater progress must made. seen In in TB-related deaths in 2020. ToTB Strategy reduction in TBbe incidence withwere a low detected incidence ofand TB,treated, 13% achieveonly the SDG Health the 16 years prior 2019. This 2020, 59%and of World TB cases globally less than in to 2019. drug-resistant TB, and HIV-TB Organisation End TB Strategy is also assuming no detriment in What is needed to end TB? Finding the “missing millions”, most of whom areare in most 16 high-burden countries, a major co-infection. There targets (Table 1), greater progress TB control duringisthe COVID-19 of TB, such as Italy, Spain and probably few missing cases here human challenge to addressing are drug-resistant TB and immunodeficiency virus must be made. In 2020, only TB. So too pandemic. In other high-income United States of America, annually, and upon diagnosis, drug 59% of TB cases globally were countries with a low incidence Provided health care is aaccessible, TB-related mortality,the transmission, and other (HIV)-TB co-infection which, although comprising only minority of infectionsmorbidity, globally, can there were reports of delays in TB undesirable outcomes should be avoidable for most patients, particularly in high-income be difficult to diagnose and treat. diagnosis, more severe disease at Table 1. Tuberculosis targets diagnosis moreofTB infection countries. However, TB care is complex due to patient-related factors (e.g.,and a lack according to the Sustainable among household contacts during Table 1. Tuberculosis targets according to the Sustainable Development Goals and End awareness of symptoms, vulnerable population groups), disease-related factors (e.g., Development Goals and End the pandemic. Tuberculosis Strategy. prolonged non-specific symptoms, the association between TB treatment outcomes and Tuberculosis Strategy low-income countries depression, TB and cardiovascular disease or chronic lung disease,Although TB and malnutrition), are disproportionately affected health programme-related factors (e.g., lackEnd of knowledge of TB among will Indicator Sustainable TB Strategyand awareness by TB, global elimination require action bytools all countries, health care providers) Development and diagnostic and treatment-related factors (diagnostic are 2035 consistent with the vision of the lacking and prolonged Goals courses of multidrug therapy). For this reason, it is increasingly SDGs and the principles of the recognised that TB care must be of high-quality and accommodateEnd forTB these factors to 2030 Strategy. High-income bridge the gap between accessing care and achieving desirable outcomes countries,(Figure such as2). Ireland, must Reduction in number of TB deaths compared with 90% 95% develop more robust approaches 2015 (%) to TB prevention and control, Reduction in TB incidence rate compared with 80% 90% both nationally and internationally. With regard to ending TB, an 2015 (%) approach by Ireland can begin by TB-affected families facing catastrophic costs due Zero Zero considering just four questionsto TB (%) what? who? why? and how?

Ireland is a high-income country with a low incidence of TB, drug-resistant TB, and HIV-TB | HPN • JANUARY 2022 HOSPITALPROFESSIONALNEWS.IE co-infection. There are most probably few missing cases here annually, and upon diagnosis, drug treatment is available and free. Most patients in Ireland are treated successfully for TB.

What is needed to end TB? Provided health care is accessible, TB-related morbidity, mortality, transmission, and other undesirable outcomes should be avoidable for most patients, particularly in high-income countries. However, TB care is complex due to patient-related factors (e.g., a lack of awareness of symptoms, vulnerable population groups), diseaserelated factors (e.g., prolonged non-specific symptoms, the association between TB treatment outcomes and depression, TB and cardiovascular disease or chronic lung disease, TB and malnutrition), health programme-related factors (e.g., lack of knowledge and awareness of TB among health care providers) and diagnostic and treatment-related factors (diagnostic tools are lacking and prolonged courses of multidrug therapy). For this reason, it is increasingly recognised that TB care must be of high-quality and accommodate for these factors to bridge the gap between accessing care and achieving desirable outcomes (Figure 2). High-quality TB care cannot be assumed. From the prior experiences of New York city and London, where TB had resurged after decades of retreat, it is clear a declining burden of TB

Figure 2. Conceptual model to describe the role of high-quality health care for TB. Source: O’Connell J., A Quality of Care Evaluation to Identify Priorities for Improving Tuberculosis Care in Ireland (Thesis), Dublin, Royal College of Surgeons in Ireland.

TUBERCULOSIS

disease is not confirmatory of high-quality TB care. Instead, as the burden declines, there is a risk of low-quality care emerging because prevention and control activities may become deprioritised, services may become under-funded and health care providers’ knowledge and awareness of TB may decline. To counter this, quality should be defined, measured, monitored, and improved as part of a quality management programme (Table 2). Within the literature, many widely used definitions of quality are derived from the health care providers’ perspective, but quality is in the eye of the beholder. How quality is defined will vary, depending on the perspective of who is defining it and where they are located in the system of care. Ensuring patient perspectives on quality of care are recognised is extremely important if healthy lives and well-being are to be achieved. Where their perspectives are not accommodated with sufficient priority, health care services may fail to provide care that meets patient needs and expectations, despite otherwise trying to improve care. Once defined, quality should be measured to identify low-quality care that must be rectified. Traditional metrics applied in TB care are outcome measures such as incidence, mortality and treatment outcomes and process measures such as drug-susceptibility testing, laboratory confirmation of disease and HIV testing. However, quality measures should be derived from a consensus of stakeholders that have considered patient needs and expectations. Such measures may include quality of life, patient reported outcomes

and user experience. Measures of user experience may be valued by patients and could refer to facility or organisational aspects of their care such as the ease of access, affordability or patient centeredness aspects such as the providers’ respect for privacy, confidentiality, and dignity. Monitoring quality can then identify initiatives that have led to sustained improvement, and if not, identify the need for further action. A quality management programme could help strengthen TB prevention and control in Ireland, where TB care is decentralised. Many deficits in TB care quality in Ireland are a result of systemwide problems that may be better solved at a system level through a quality management programme rather than at a local level alone. Integration of a TB quality management programme into the national quality management structure may allow for the TB programme to engage those whose practice does not directly or frequently involve TB, e.g., general practitioners or pharmacists. This is important because highquality care is necessary across the health programme, not just in TB services. For example, high-quality TB care at first presentation in primary care is equally important as high-quality TB care in dedicated tertiary TB clinics. Quality management programmes can be a means of progressing integration of the care provided between primary and tertiary care services, while ensuring the quality of care does not diminish during the process of integration. Additionally, a quality management programme could enable centralized collection of standardized data that could be analysed and

Figure 2. Conceptual model to describe the role of high-quality health care for TB.

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interpreted to be informative for local as well as national quality improvement initiatives. Within TB care, quality management is not a new concept. Other countries with a low incidence of TB, such as Canada, England and the United States of America, are applying a quality management approach to latent and active TB care. However, internationally, quality management in TB care has not expanded beyond traditional metrics of care quality to form holistic measures that will identify what is needed to end TB. Globally, TB prevention and control programmes are highly dependent on learning from the experiences of other programmes on how best to reduce the burden of TB. By developing a patient-centered TB quality management programme, the national TB programme in Ireland could be a world first and demonstrate its merits and weaknesses. Who is affected by low-quality TB care and why? TB care quality should be equitable, but often it is not. To develop effective quality improvement initiatives, it is not enough only to identify low-quality care, but those who are affected most by it must be characterized and the reasons why understood. For example, delayed presentation among those with symptoms of TB is a problem common in both high and low-incidence settings. Some patients may be affected more than others e.g., those with HIV, co-existing lung disease, low access (geographical or sociopsychological barriers), old age, immigrants or those with alcoholism and substance abuse. Consider cough among people presenting with TB in Ireland. How do people behave when they have a cough and why? How does this behaviour differ according to patient characteristics? Perhaps those with substance abuse chose not to seek health care, and the reasons for this behaviour may be complex, such as a lack of trust in health care providers or previous poor experiences of care. What about economic immigrants in Ireland? Perhaps many engage with a primary care provider, or a pharmacist when they develop a cough, but maybe during initial presentations to health care providers language or cultural differences, or a lack of awareness of TB symptoms among health care providers leads to delays in TB diagnosis. These are only suppositions generalised from the international literature, but demonstrate that where lowquality care is evident, whatever the measure, knowledge of the characteristics of those affected,

61 and the underlying reasons why, must be established if it is to be addressed. To do this, qualitative research that seeks to understand patients’ and health care providers’ experiences and behaviours will be important.

receive appropriate same-day treatment. In high-income, lowincidence settings, improving latent tuberculosis diagnostics will be necessary to eliminate TB. Current latent tuberculosis How will low-quality TB care screening tools (interferon-gamma be improved? release assay and tuberculin skin test) cannot distinguish with When considering medicine in high enough accuracy those the modern era, TB care has not latently infected who will develop advanced as it should have. active TB from those who will Progress in developing new TB not. As a result, where latent vaccines has been slow. There tuberculosis screening is scaled are less than twenty candidate TB programmatically, many patients vaccines in development, none of are treated to achieve a population which have moved beyond phase level benefit in TB control when three trials. Besides the century they personally may accrue no old Bacillus Calmette- Guerin benefit. This is particularly relevant vaccine, other vaccines to help for countries such as Ireland, end TB will not be available in where the population is ageing, the near future. Diagnostic and because the risk-benefit ratio treatment developments are of latent tuberculosis treatment in the pipeline that could fulfil becomes less favourable with patient and health care provider age. Fortunately, the identification expectations of high-quality care. of biosignatures that may reliably Regarding diagnostics, the needs identify those most likely to of high-incidence low-income benefit from treatment is rapidly and low-incidence high-income evolving. Regarding TB treatment, settings differ. In the former, prolonged courses of multidrug finding the missing millions is a therapy are still necessary for priority and decentralised testing active TB, but a recent trial will be key to doing this. This will published in the New England require the replacement of hub Journal of Medicine suggests and spoke models comprising treatment duration for patients with smear microscopy and referralpulmonary TB may be reduced based centralised GeneXpert from 6-months to 4-months using testing with onsite less costly a rifapentine-based regimen. next generation GeneXpert Edge However, the limited availability testing that may be reliably used and high cost of rifapentine in in resource-constrained clinics. some parts of the world will This could reduce missed TB hinder its use. Directly-observed diagnoses, reduce the time taken therapy has been a cornerstone for diagnosis and ensure they treatment support since Table 2. Components of a qualityTBmanagement programme

the 1990s. Although today its relevance is greatest for TB care in high-burden settings, in low burden settings, it still has a role for patients at risk of treatment non-adherence. In recent years, video-observed therapy has been developed to be a more acceptable, effective, and cheaper option than traditional directlyobserved therapy. In addition to video-observed therapy, smart pillboxes and medication labels that enable patients to communicate with their health care provider that they have taken their medication are being evaluated in randomised trials in high burden settings. When implementing new rapid diagnostics and treatment supports, a quality improvement approach should be taken to strengthen supporting processes and maximize benefit. This article has sought to describe how quality management could be a beneficial approach to addressing TB in Ireland, consistent with the vision of the SDGs and the End TB Strategy. According to Dr Tedros Adhanom Ghebreyesus, Director General of the WHO, “Quality is not a given” and takes “vision, planning, investment, compassion, meticulous execution, and rigorous monitoring, from the national level to the smallest, remotest clinic”. However, given the challenge cross-border migration poses to ending TB globally, efforts to

Components Quality programme

Description A characterization of the programme’s leadership, accountability structures, membership, roles and responsibilities of technical working groups and oversight committee, and expectations for communicating program updates and activities. Quality statement A brief mission statement that characterizes the aims of the quality management programme. Performance A description of which performance measures will be tracked as part measurement of the quality management programme, and how, when, and by system whom they will be routinely collected and reported. Goals Stakeholder and patient participation Evaluation

Annual quality improvement work plan

A set of targets around which the programme will seek to prioritize and structure quality initiatives. A description of how staff, providers, patients, communities, and other stakeholders will be involved in the programme. A plan for evaluating the performance of the programme, including progress in meeting stated improvement goals, organizational effectiveness of current programme committees, and robustness of existing quality improvement work plans. A detailed roadmap of implementation, which changes annually, that specifies improvement priorities and quality improvement activities that will be advanced as part of the programme’s activities.

ensure TB care is of high-quality should not end within national borders. Instead, countries such as Ireland must collaborate internationally, particularly with countries with a high burden of TB, to improve care quality and end TB. Useful Resources McGill, Quality of Tuberculosis Care ebook https://www.mcgill.ca/tb/files/tb/ quality_tb_care_ebook.pdf Podcast: High-quality Care for Tuberculosis Elimination with Dr. Hannah Alsdurf https://resident360.nejm.org/ curbside-consults/high-qualitycare-for-tuberculosis-eliminationwith-dr-hannah-alsdurf O’Connell, J., de Barra, E. & McConkey, S. Systematic review of latent tuberculosis infection research to inform programmatic management in Ireland. Ir J Med Sci (2021). https://doi.org/10.1007/s11845021-02779-w O'Connell, J., de Barra, E., McNally, C., & McConkey, S. (2021). A Survey of Latent Tuberculosis Screening and Treatment Practices in a Tertiary Centre. Irish medical journal, 114(7), 406. http://www.imj.ie/wp-content/ uploads/2021/08/A-Survey-ofLatent-Tuberculosis-Screeningand-Treatment-Practices-in-aTertiary-Centre.pdf Dorman, S. E., Nahid, P., Kurbatova, E. V., et al.,Tuberculosis Trials Consortium (2021). FourMonth Rifapentine Regimens with or without Moxifloxacin for Tuberculosis. The New England journal of medicine, 384(18), 1705–1718. https://doi. org/10.1056/NEJMoa2033400 Reza, T.F., Nalugwa, T., Farr, K. et al. Study protocol: a cluster randomized trial to evaluate the effectiveness and implementation of onsite GeneXpert testing at community health centers in Uganda (XPELTB). Implementation Sci 15, 24 (2020). https://doi.org/10.1186/ s13012-020-00988-y

Table 2. Components of a quality management programme Source adapted from: Ikeda, D. J., Basenero, A., Murungu, J. et al. (2019). Implementing quality improvement in tuberculosis programming: Lessons learned from the global HIV response. Journal of clinical tuberculosis and other mycobacterial diseases, 17, 100116.

Source adapted from: Ikeda, D. J., Basenero, A., Murungu, J. et al. (2019). Implementing quality improvement in tuberculosis programming: Lessons learned from the global HIV response. Journal of clinical tuberculosis and other mycobacterial diseases, 17, 100116. HOSPITALPROFESSIONALNEWS.IE | HPN • JANUARY 2022

62 Mental Health

A longitudinal assessment of depression and anxiety in the Republic of Ireland before and during the Covid-19 pandemic Philip Hylandab, Mark Shevlinc, Jamie Murphyc, Orla McBridec, Robert Foxa, Kristina Bondjersd, Thanos Karatziase, Richard P. Bentallf, Anton Martinezf, Frédérique Vallièresb a Department of Psychology, Maynooth University, Ireland - bTrinity Centre for Global Health, Trinity College Dublin, Ireland c School of Psychology, Ulster University, Northern Ireland - dDepartment of Neuroscience, Uppsala University, Sweden e School of Health & Social Care, Edinburgh Napier University, Scotland - fUniversity of Sheffield, England

Philip Hyland

Mark Shevlin

Jamie Murphy

Orla McBride

Robert Fox

Frédérique Vallières

longitudinal studies comparing mental health before and after the outbreak of COVID-19 found that there was a small increase in mental health problems in the immediate aftermath of the outbreak (i.e., March-April 2020), however these increases returned to pre-pandemic levels within several weeks (i.e., by May-June 2020) (Robinson et al., 2021). This study did note, however, that increases in depression were greater than those for anxiety, and the reductions over time for depression were less pronounced.

Introduction Following the global outbreak of COVID-19, numerous commentaries warned of dire mental health consequences (Carvalho, Moreira, de Oliveira, Landim, & Neto, 2020; Reger, Stanley, & Joiner, 2020; Xiang et al., 2020). It has been claimed that the pandemic is ‘having wideranging effects on population mental health’ (Campion, Javed, Sartorius, & Marmot, 2020, p. 1),

and the President of the Royal College of Psychiatrists in the United Kingdom (UK) warned that ‘the prevalence of mental health issues is also expected to grow enormously due to the repercussions of the virus and the lockdown on mental health’ (Torjesen, 2020). While the societal impact of this crisis cannot be understated as of March 22nd 2021, there have been 123.2 million cases

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of COVID-19 and 2.7 million deaths worldwide (Roser, Ritchie, Ortiz-Ospina, & Hasell, 2021), along with 255 million full-time job losses resulting in $3.7 trillion in lost labour income (International Labour Organization, 2021) – the empirical evidence available to date indicates that there has been little effect on the mental health of the general population. A systematic review and metaanalysis from January 2021 of 65

Using nationally representative data from the general adult population of the Republic of Ireland that was gathered prior to the outbreak of the COVID-19 pandemic (i.e., February 2019), and then again at two intervals during the early phase of the COVID-19 pandemic (i.e., MarchApril 2020 and April-May 2020), we sought to add important information regarding population mental health changes pre- and post the outbreak of COVID-19 by addressing three objectives. First, we examined if there were changes in the proportion of Irish adults who screened positive for major depression and generalized anxiety disorder (GAD) between February 2019 and March-April 2020. Second, we examined if there were changes in the proportion of Irish adults who screened positive for major depression and GAD across six weeks of lockdown. Third, we identified risk factors that predicted screening positive for major depression and GAD across the six-week lockdown period.

63 Methods Participants and procedures In February 2019, a nationally representative quota sample of adults from the Republic of Ireland (N = 1,020) was collected as part of a project to ascertain the frequency of trauma exposure and trauma-related psychopathology in the general population (see Hyland et al., 2020). Following the outbreak of COVID-19, a new longitudinal project was initiated as part of the COVID-19 Psychological Research Consortium study (McBride et al., 2020). For this project, we gathered a new and independent nationally representative quota sample of Irish adults. These samples were recruited in an identical manner. An Irish-based survey company, Qualtrics, was employed to collect both samples, and Qualtrics recruit participants from existing online, nationally representative panels of survey participants. A target sample of 1,000 adults was set for both samples, and quotas were based on sex, age, and geographical distribution. The sample statistics for these variables match known population parameters derived from the most recent census (Central Statistics Office of Ireland, 2020). This information is available from the first author upon request. Qualtrics contacted panel members by email, text, or inapp notification, and requested their participation in a survey of approximately 20 minutes in length. At the initial contact, participants were given no information about the topic of the survey so as to minimize selection bias. If potential participants followed the provided link to complete the survey, they were provided with detailed information about the nature of the survey prior to providing their informed consent. The inclusion criteria for both samples were that participants were resident of the Republic of Ireland, could read and write in English, and were aged 18 years or older. Ethical approval for the 2019 survey was granted by Maynooth University, and ethical approval for the 2020 surveys was granted by the University of Sheffield and Ulster University. The sample recruited in February 2019 included 1,020 participants. The sample recruited in MarchApril 2020, which marked Wave 1 of the COVID-19 Psychological Research Consortium study, included 1,041 participants. Wave 1 was conducted between March 31st and April 5th; the first week of Ireland's initial lockdown.

All those who participated at Wave 1 were recontacted and asked to take part in a second wave of data collection which occurred approximately six weeks later between April 30th and May 14th; this coincided with the end of Ireland's initial lockdown period. In total, 506 participants agreed to participate at Wave 2 (participation rate = 48.6%). Compared to nonresponders, responders at Wave 2 were significantly older, more likely to have been born in Ireland, to be of Irish ethnicity, to be living in a town, suburb, or rural location, to be retired, to have a pre-existing health condition, were less likely to have a confirmed or suspected COVID-19 infection, and to have screened positive for major depression and GAD. Statistical methods to adjust for responder bias are described in the data analysis section. Measures The same measures were used in all surveys. Depression and anxiety Major depression was measured using the nine-item Patient Health Questionnaire-9 (PHQ-9) (Kroenke, Spitzer, & Williams, 2001). Participants indicate how often they have been bothered by each symptom over the last two weeks on a four-point Likert scale that ranges from 0 (Not at all) to 3 (Nearly every day). Screening positive for major depression was indicated by using the wellestablished cut-off score of ≥ 10, and this produces adequate sensitivity (.85) and specificity (.89) (Kroenke et al., 2001). The psychometric properties of the PHQ-9 scores have been widely supported (Manea, Gilbody, & McMillan, 2012), and the internal reliability of the scale scores in the February 2019 (α = .93), March-April 2020 (α = .91), and April-May 2020 (α = .91) samples were excellent. GAD was measured using the Generalized Anxiety Disorder 7-item Scale (GAD-7) (Spitzer, Kroenke, Williams, & Lowe, 2006). Participants indicate how often they have been bothered by each symptom over the last two weeks on a four-point Likert scale that ranges from 0 (Not at all) to 3 (Nearly every day). Screening positive for GAD was indicated by a score of ≥ 10, and this cut-off score has adequate sensitivity (.89) and a specificity (.82) (Spitzer et al., 2006). The GAD-7 scale scores have been shown to produce reliable and valid scores in community studies (Hinz et al., 2017), and the internal reliability of the scale scores in the February

2019 (α = .94), March-April 2020 (α = .94), and April-May (α = .94) samples were excellent.

is inappropriate for demonstrating internal consistency in such cases (Eisinga et al., 2013).

Sociodemographic variables

3.4.2. Resilience

Ten sociodemographic variables were measured in the March-April 2020 sample including sex (0 = Male, 1 = Female), age, nationality (0 = Irish, 1 = Non-Irish), ethnicity (recoded as 0 = Irish, 1 = NonIrish), area of residence (recoded 0 = suburb, town, or rural location, 1 = city), highest educational achievement (recoded as 0 = did not attend university/third-level education, 1 = attended university/ third-level education), 2019 annual income (recoded as 0 = Less than ¤20,000, 1 = ¤20,000-¤29,999, 2 = ¤30,000-¤39,999, 3 = ¤40,000¤49,999, 4 = ¤50,000 or more), working in an occupation that involves face-to-face contact with the public (0 = No, 1 = Yes), living alone (0 = No, 1 = Yes), and having a pre-existing health condition such as heart or lung disease, diabetes, or cancer (0 = No, 1 = Yes).

The Brief Resilience Scale (BRS) (Smith et al., 2008) is a six-item measure where all items are answered on a five-point Likert scale ranging from 1 (Strongly disagree) to 5 (Strongly agree). Higher scores reflect higher levels of resilience, and the BRS has been shown to produce scores with excellent psychometric properties in the general population (Soer et al., 2019). The internal reliability of the scale scores in this sample was good (α = .86).

COVID-19 pandemic variables Six COVID-19 pandemic related variables were measured including having lost income due to COVID-19 (0 = No, 1 = Yes), suspected or confirmed COVID-19 infection status for oneself (0 = No, 1 = Yes), suspected or confirmed COVID-19 infection status for a friend or loved one (0 = No, 1 = Yes), perceived risk of being infected by COVID-19 over the next month (measured using a slider scale ranging from 0 [No risk] to 100 [Great risk]), anxiety about the COVID-19 pandemic (measured using a slider scale ranging from 0 [Not at all anxious] to 100 [Extremely anxious]), and worries about one's finances due to the COVID-19 pandemic (measured using a response scale ranging from 1 [Not worried at all] to 10 [Extremely worried]).

3.4.3. Locus of control The Locus of Control Scale (LoCS) (Sapp & Harrod, 1993) measures three forms of locus of control; ‘Internal’, ‘Chance’, and ‘Powerful Others’. Each subscale includes three questions, and all questions are answered on a seven-point Likert scale that ranges from 1 (Strongly disagree) to 7 (Strongly agree). Higher scores reflect higher levels of each form of locus of control. The internal reliability of the ‘Internal’ (α = .67) and ‘Chance’ (α = .63) subscale scores were acceptable, and the reliability of the ‘Powerful others’ subscale scores was good (α = .78). 3.4.4. Identification with others The Identification with all Humanity Scale (IWAHS) (McFarland, Brown, & Webb, 2013) is a nine-item scale. Participants respond to three statements with reference to three groups: people in my community, people from Ireland, and all humans everywhere. The response scale ranges from 1 (Not at all) to 5 (Very much) and higher scores reflect greater identification with others. The internal reliability of the IWAHS scale scores in this sample was excellent (α = .91).

Psychological variables

3.4.5. Death anxiety

Personality traits

The Death Anxiety Inventory (DAI) (Tomás-Sábado, Gómez-Benito, & Limonero, 2005) is a 17-item scale where respondents indicate their agreement with each statement on a five-point Likert scale that ranges from 1 (Totally disagree) to 5 (Totally agree). Higher scores reflect higher levels of death anxiety, and the DAI scores have been shown to have good psychometric properties (TomásSábado et al., 2005). The internal reliability of the DAI scores in this sample was excellent (α = .92).

The Big-Five Inventory (BFI) (Rammstedt & John, 2007) measures the five personality traits of Openness, Conscientiousness, Extraversion, Agreeableness, and Neuroticism. Each trait is measured by two items on a five-point Likert scale ranging from 1 (Strongly disagree) to 5 (Strongly agree). Higher scores reflect higher levels of each personality trait, and the BFI has been shown to produce scale scores with good psychometric properties (Rammstedt & John, 2007). Internal reliability estimates are not reported due to the fact that each trait is measured using two items, and coefficient alpha

3.4.6. Intolerance of uncertainty The Intolerance of Uncertainty scale (IUS) (Buhr & Dugas, 2002) includes 12 items that are

HOSPITALPROFESSIONALNEWS.IE | HPN • JANUARY 2022

64 Mental Health answered on a five-point Likert scale that ranges from 1 (Not at all characteristics of me) to 5 (Entirely characteristic of me). Higher scores reflect higher levels of intolerance of uncertainty, and the IUS has been shown to produce scores with excellent psychometric properties (Buhr & Dugas, 2002). The internal reliability of the IUS scores in this sample was good (α = .87). 3.4.7. Loneliness The three-item Loneliness Scale (Hughes, Waite, Hawkley, & Cacioppo, 2004) was designed for use in large-scale population surveys. Respondents indicate how often they feel that they lack companionship, feel left out, and feel isolated from others. Responses are based on threepoint scale of ‘Hardly ever’ (1), ‘Sometimes’ (2), and ‘Often’ (3). Higher scores reflect higher levels of loneliness. The internal reliability of the scale scores in this sample was good (α = .86). 3.4.8. Somatic problems The Patient Health Questionnaire-15 (PHQ-15) (Kroenke, Spitzer, & Williams, 2002) is a 15-item measure that asks participants, “Over the last 2 weeks, how often have you been bothered by any of the following problems?” and lists commonly reported physical problems (e.g., back pain, gastrointestinal complaints, chest pains, lacking energy). We excluded the ‘menstrual problems’ item due to its gender-specific nature that would preclude analysis of the entire sample. The response options are ‘Not bothered at all’ (0), ‘Bothered a little’ (1), and ‘Bothered a lot’ (2). A total scale score of the 14 items was computed where higher scores reflect more somatic problems. The internal reliability of the scale scores in this sample was good (α = .83). Data analysis The data analysis plan included three steps. First, a twotailed z-test was conducted to compare the proportions of people screening positive for major depression and GAD in the February 2019 and March-April 2020 samples. Second, changes in the proportion of people screening positive for major depression and GAD from Wave 1 (i.e., in March-April 2020) to Wave 2 (i.e., April-May 2020) were compared using structural equation modelling (SEM). A SEM approach was used so that missing data were handled using full information robust maximum

likelihood estimation (Schafer & Graham, 2002), which is recognised as the optimal method for managing missing data (Li & Stuart, 2019; Witkiewitz et al., 2014). This analytical process involves two steps, and analyses were conducted separately for major depression and GAD. A null or ‘constrained’ model is specified first where the proportions (e.g., of major depression) are constrained to be equal over time, and the variances and covariances are freely estimated. An alternative or ‘unconstrained’ model is then specified where the proportions are freely estimated at both waves. The constrained and unconstrained models differ by one degree of freedom so improvement in model fit can be tested using a loglikelihood ratio test (LRT), which follows a chi-square (χ2) distribution. Additionally, the models can be compared using the Bayesian Information Criteria (BIC) index, and the model with the lowest value is statistically superior. These analyses were performed using Mplus version 8.2 (Muthén & Muthén, 2017). Third, binary logistic regression analyses were used to identity predictors of screening positive for major depression and GAD at Wave 2 (i.e., April-May 2020). These models were run separately for major depression and GAD. In both models, the predictor variables (all measured at Wave 1) included ten sociodemographic variables, six pandemic related variables, and fourteen psychological variables. Additionally, both models controlled for major depression and GAD status at Wave 1, respectively. To control for responder bias at Wave 2, an inverse probability weighting procedure was applied (Cohrs, Maes, Moschner, & Kielmann, 2007). These analyses were performed using SPSS version 26. Results Objective 1: Changes in Major Depression and GAD from 2019 to 2020 In February 2019, 29.8% (95% CI = 27.0%, 32.6%) of the sample screened positive for major depression compared to 22.8% (95% CI = 20.2%, 25.3%) of the sample in MarchApril 2020. This represented a statistically significant change in major depression (z = 3.63, p < .001). There was no statistically significant difference (z = 1.26, p = .208) in the proportion of people

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who screened positive for GAD in February 2019 (22.3%, 95% CI = 19.7%, 24.8%) and March-April 2020 (20.0%, 95% CI = 17.6%, 22.4%). Objective 2: Changes in major depression and GAD during six weeks of lockdown The BIC and LRT results supported the ‘null’ models of major depression and GAD, indicating that that there were no statistically significant changes in the proportion of people who screened positive for these disorder during the six weeks of lockdown. Objective 3: Predictors of screening positive for major depression and GAD The logistic regression model of major depression was statistically significant (χ2 (33) = 446.62, p < .001) and correctly classified 85.1% of participants. Adjusting for major depression status at Wave 1, Wave 2 major depression was predicted by younger age, residing in a town, suburb, or rural location, lower levels of resilience, higher levels of loneliness, and higher levels of somatic problems. The logistic regression model of GAD was also statistically

significant (χ2 (34) = 418.86, p < .001) and correctly classified 88.5% of participants. Adjusting for Wave 1 GAD status, Wave 2 GAD was predicted by being female, working face-to-face with the public, not having been infected by COVID-19, greater financial worries due to the pandemic, higher levels of trait Openness, lower levels of trait Conscientiousness, higher levels of internal locus of control, higher levels of death anxiety, higher levels of loneliness, and higher levels of somatic problems. Discussion The global outbreak of COVID-19, and the extraordinary public health measures implemented to slow the spread of the virus, have led to profound changes in people's lives. As was the case in other epidemics (Shultz, Baingana, & Neria, 2015), these changes were met by warnings of potential (Carvalho et al., 2020; Reger et al., 2020; Xiang et al., 2020) and actual (Campion et al., 2020) adverse mental health consequences. However, as time has passed and the evidence has accumulated, we are learning that the COVID-19 pandemic has had little, if any, negative effect on the mental

65 health of the general population (Robinson et al., 2021). Our findings indicate that significantly more people screened positive for major depression a year prior to the outbreak of COVID-19 than during the first week of Ireland's nationwide lockdown measures to control the spread of COVID-19. Additionally, we found that there were no significant changes in the proportion of people who screened positive for GAD during this timeframe. Furthermore, tracking our sample over the six weeks of lockdown revealed that there were no significant changes in the prevalence of both major depression and GAD. These are notable findings considering that meta-analytic data suggests that increases in depression and anxiety were most evident during March-April of 2020, and that the subsequent decreases began to emerge by May 2020 (Robinson et al., 2021). Our longitudinal assessments corresponded with these times, however our results indicated that rates of depression and anxiety were not affected by the outbreak of COVID-19, nor by the lockdown measures implemented to contain the spread of the virus. We also conducted this study to identify risk factors at the start of the pandemic that would predict screening positive for major depression and GAD six weeks later.

Some notable differences were evident for the two disorders. Controlling for major depression status in March-April 2020, major depression in April-May 2020 was significantly predicted by five variables. Younger adults were more likely to screen positive for depression, and this is consistent with other pandemic-related data (Daly et al., 2020; McGinty et al., 2019), and findings from the wider mental health literature (Altemus, 2006; Eid, Gobinath, & Galea, 2019; Kessler et al., 2010). Also consistent with the wider literature were the findings that higher levels of loneliness (McHugh et al., 2020), more somatic problems (Kapfhammer, 2006), and lower levels of resilience (Shapero et al., 2019) predicted screening positive for major depression. One curious result was that individuals residing in a city were less likely to screen positive for depression, and this is unusual because most data suggests that city dwelling is associated with an increased risk of depression (Sampson et al., 2020). This may be an effect unique to the Irish context, but more research will be needed to make any firm conclusions. Nonetheless, given that the predictors of depression during the pandemic period were similar

to those that are meaningful more broadly, and that none of the pandemic related variables predicted depression, it seems likely that risk of depression during this public health crises can be understood on the basis of established risk factors. The picture was slightly different for GAD. A broader set of variables in March-April 2020 predicted GAD status in April-May 2020, controlling for initial GAD status. Some of these variables were those that are well-established risk factors for GAD such as being female (Hyland et al., 2016), lower levels of Conscientiousness and higher levels of Openness (Costache et al., 2020), higher levels of loneliness (Hyland et al., 2019), and more somatic problems (Bekhuis et al., 2016). However, some predictors of GAD were specific to the COVID-19 pandemic. For example, working in a job that involved face-toface contact with the public and not having been infected with COVID-19 both predicted screening positive for GAD six weeks later. Given people's increased risk of exposure to the virus, whose lethality was relatively unknown at that time, it is understandable why these variables predicted greater odds of screening positive for GAD. Moreover, increased levels of death anxiety and higher levels of internal locus of control also predicted GAD. In the context of a global pandemic, increased anxiety related to one's own mortality may be a meaningful factor in driving increases in general anxiety, and the importance of addressing death anxiety during this crisis have been outlined (Menzies & Menzies, 2020). While internal locus of control is generally associated with experiencing fewer mental health problems (Cheng et al., 2013), we found that higher levels of internal locus of control predicted greater odds of screening positive for GAD. One possible explanation for this finding is due to a mismatch between one's internal worldview (i.e., believing that oneself is capable of determining what occurs in life) and the actual state of the world (i.e., living in an environment where there was a rapidly spreading virus, and where daily activities were severely restricted by government mandates). Overall, these results suggest that the specific context of the COVID-19 pandemic plays some role in understanding risk of GAD, although wellestablished risk factors continued to be relevant.

Limitations This study is not without limitations. First, the prevalence estimates of major depression and GAD were based on exceeding a cut-off scores on self-report measures. It is likely that not all of these people would meet diagnostic criteria if assessed via a diagnostic interview, however, these cut-off scores have been shown to have good sensitivity and specificity and are routinely used in clinical assessments and epidemiological research to identify probable diagnostic cases. Second, while the 2019 and 2020 samples were constructed to represent the Irish general population in terms of sex, age, and geographical distribution, these were not probability based samples, nor were we able to recruit individuals who were institutionalised (e.g., in prison, hospital, people living in homelessness, asylum seeking/ refugee centres etc.), many of whom have higher rates of mental illness compared to the general population (Fazel, Wheeler, & Danesh, 2005; Fazel, Geddes, & Kushel, 2014; Fazel, Hayes, Bartellas, Clerici, & Trestman, 2016). These sampling limitations represent threats to the generalisability of our findings to the entire adult population of Ireland. Third, in the longitudinal portion of the study we were only able to recontact about half of the participants who took part at the first assessment, and these responders differed from those who did not respond at wave 2. We applied robust statistical methods to control for the sample attrition, however, these methods cannot entirely control for sampling bias. Conclusion The findings of this study indicate that (1) the outbreak of COVID-19 did not lead to an increase in major depression or GAD in the general adult population of the Republic of Ireland, (2) major depression and GAD did not change in frequency during the early phase of the pandemic, (3) major depression was predicted by a small number of well-established (and nonpandemic related) risk factors, and (4) GAD was predicted by a larger number of risk factors, some of which were specific to the pandemic context. These findings add to a growing body of evidence that mental health disorders have not increased in frequency in the general population as result of, or during, the COVID-19 pandemic.

HOSPITALPROFESSIONALNEWS.IE | HPN • JANUARY 2022

66 Bladder Disorders

Treatment of Recurrent Urinary Lm/gmTract 52 dInfections: exertemeP A guide with evidence elbats erutarepmet moor A Written by Charles J O Connor (pictured) And, Ellen O Beirne, Patrick Collins, Mohammed Hegazy, Gregory Nason - Mater Misercordiae University Hospital

more suspicious and likely to be investigated. UTIs present with the symptoms described above. Dysuria is discomfort or burning passing urine, abdominal pain, flank pain, or fatigue may also be present with UTIs. Conservative management Acute bacterial cystitis is defined Treatment of urinary tract infections, as with many by the American Urological conditions, starts first with lifestyle Association (AUA)/Canadian modifications. Some of these Urological Association (CUA)/ include but are not limited to: good Society of Urodynamics, Female hygiene, good sexual hygienePelvic Medicine & Urogenital voiding pre and post intercourse, Reconstruction (SUFU) as “A double voiding if a UTI may be culture-proven infection of the brewing, wiping from front to back, urinary tract with a bacterial avoiding constipation, increasing pathogen associated with acuteone’s fluid intake (at least two litres onset symptoms such as dysuria in of water a day). Increasing fluid conjunction with variable degrees intake was the subject of a 2020 of increased urinary urgency and systematic review by Scott et al frequency, haematuria, and new or which showed low evidence for the worsening incontinence”. These same; however, given the minimal can be classed as uncomplicated potential for harm, this should be (occurring in a urinary tract with encouraged.5 no factors that would promote a Urinary tract infection (UTI)) vs Women can be referred to the complicated (occurring in a British Association of Urological patient at higher risk for a UTI Surgeons (BAUS) information with factors that could potentially leaflet on UTIs, which is very decrease treatment efficacy). informative.6 If infections are These can be further classified not settling despite treatments into persistent and recurrent. and patients are experiencing Persistent UTIs are those where a bacterium is not eradicated in the urine two weeks after sensitivity adjusted treatment.1 24:41 1202/40/72 How do we define recurrent urinary tract infections (UTIs)? According to the European Association of Urology (EAU), recurrent UTIs can be defined as more than 2 in 6 months or more than 3 in 12 months.2 UTIs are more common in females, with a lifetime incidence of 50-60%, with males having a lifetime incidence of 13-14%.3, 4 This would make a UTI occurring in a man

etartnecnoThis c emechanism tulid-ofoaction t-yisdaer

pain or haematuria, then they should be screened for any sources of recurrent infection. Sources of recurrent infections include urological pathologies including but not limited to: urethral strictures, bladder stones, vesicoureteric reflux, cystoceles, hydroureter/hydronephrosis and kidney stones. Supplements

Cranberry products: Cranberry products were the subject of a recent randomised study in which patients taking cranberry or cranberry with vitamin C were shown to have increased oxalate excretion. Oxalate excretion is a risk factor for renal stone development, so cranberry products should be avoided in patients with a history of renal stones.7 A recent systematic review and meta-analysis of randomised controlled trials (RCT’s) by Fu et al. 2017 found cranberry products to be beneficial- particularly cranberry tablets (low-quality evidence). The AUA/CUA/SUFU guideline recommends cranberry tablets (Grade C evidence (low level of certainty)).1 EAU makes no recommendation regarding cranberry- but fails to mention Fu’s review in their guideline.2 NICE remain equivocal on this recommendation stating nonpregnant women may wish to try cranberry as a self-care treatment.8 D-mannose: This supplement works by inhibiting bacterial adherence to urothelial cells.

Figure 1. Commonly used vaginal oestrogen therapy [1]

interesting as roughly 80% of UTI’s are caused by E. Coli, which are thought to use pilli to adhere to the bladder wall. One RCT showed that 2 grams of D-mannose daily was significantly superior to placebo and as effective as 50 mg nitrofurantoin in preventing recurrent UTIs.9 AUA/CUA/SUFU currently advises they cannot recommend d-mannose due to the limited evidence available for it.1 EAU advises that this RCT is “indicative but not sufficient for a recommendation”, whereas NICE advises that some women “may wish to try D-mannose, as a selfcare treatment”.2, 8 Vaginal oestrogens: Vaginal oestrogens are definitely recommended for preventing recurrent UTIs in postmenopausal and some perimenopausal women. These recommendations stem from a 2008 Cochrane review by Perotta et al., which showed good evidence for the same, with oestrogen creams noted to be superior.10 AUA/CUA/SUFU endorses oestrogens (Grade B evidence (moderate level of certainty)).1 EAU also recommends oestrogens (low level of evidence).2 NICE also recommends oestrogens with the caveat of warning patients regarding possible side effects of breast tenderness and vaginal bleeding. Patients can remain on oestrogens but should be reviewed at least once a year by their general practitioner.8 Figure 1. Details the different oestrogen regimens

1 ddni.A_noitpO_4v_eruhcorB_pp4_4A_dexertem

Formulation

Composition

Strength and Dosage

Vaginal tablet

oestradiol hemihydrate*

10 mcg per day for 2 weeks, then 10 mcg 2–3 times weekly

Vaginal ring

17β-oestradiol

2 mg ring released 7.5 mcg per day for 3 months (changed by patient or provider)

Vaginal cream

17β-oestradiol

2 g daily for 2 weeks, then 1 g 2-3 times per week

Conjugate equine oestrogen

0.5 g daily for 2 weeks, then 0.5 g twice weekly

Figure 1. Commonly used vaginal oestrogen therapy1

JANUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

Pemetrexed Pemetrexed25 25mg/mL mg/mL

Launching Launching AA room roomtemperature temperaturestable stable ready-to-dilute ready-to-diluteconcentrate concentrate

Pemetrexed Pemetrexed25 25mg/mL mg/mL multi-targetedanti-cancer anti-cancerantifolate antifolate agent agent AA multi-targeted In three presentations In three presentations 100mg/4ml 100mg/4ml

500mg/20ml 500mg/20ml

1,000mg/40ml 1,000mg/40ml

PRESCRIBING INFORMATION: Consult the Summary of Product Characteristics for further information. Additional Paediatric population – No relevant use in malignant pleural mesothelioma and non-small cell lung cancer. Renal information is available upon request. Pemetrexed Fresenius Kabi 25mg/ml concentrate for solution for infusion. impairment – (Standard Cockcroft and Gault formula or GFR measured Tc99m-DPTA serum clearance method). In clinical PRESCRIBING INFORMATION: Consult the Summary Characteristics further information. population No relevant use in and non-small lung cancer. Renal Active ingredients: Pemetrexed diacid. One vialofofProduct 4ml concentrate containsfor100mg pemetrexed. One Additional vial of 20ml Paediatric studies patients with –creatinine clearance of ≥malignant 45ml/min pleural requiredmesothelioma no dose adjustments other thancell those recommended concentrate contains pemetrexed. One vial of 40ml Kabi concentrate contains 1,000mgfor pemetrexed. Excipients with impairment for all patients. Not recommended in patients with creatinine clearanceTc99m-DPTA below 45ml/min. Hepatic impairment – Patients information is available upon500mg request. Pemetrexed Fresenius 25mg/ml concentrate solution for infusion. – (Standard Cockcroft and Gault formula or GFR measured serum clearance method). In clinical known effect –Pemetrexed 4ml vial - 964mg 20ml vial –contains 4820mg hydroxypropylbetadex, 40mlvial vialof– 9640mg with hepatic impairment have not been specifically studied. Contraindications: Hypersensitivity to thethose activerecommended substance Active ingredients: diacid.hydroxypropylbetadex, One vial of 4ml concentrate 100mg pemetrexed. One 20ml studies patients with creatinine clearance of ≥ 45ml/min required no dose adjustments other than hydroxypropylbetadex. Indications: One In combination cisplatin -contains treatment of chemotherapy patients with fororalltopatients. any of theNot excipients, breast-feeding, concomitant yellow fever vaccine. Special warnings and precautions use: concentrate contains 500mg pemetrexed. vial of 40mlwith concentrate 1,000mg pemetrexed.naïve Excipients with recommended in patients with creatinine clearance below 45ml/min. Hepatic impairmentfor – Patients 3 and unresectable malignant mesothelioma, first20ml line treatment of locally advanced or metastatic cell lung with Monitor patients for myelosuppression. Pemetrexedstudied. shouldContraindications: not be given until Hypersensitivity ANC returns to ≥to1500 known effect – 4ml vial - 964mgpleural hydroxypropylbetadex, vial – 4820mg hydroxypropylbetadex, 40mlnon-small vial – 9640mg hepatic impairment have not been specifically the cells/mm active substance 3 . Dose reductions for subsequent cycles based on nadir ANC, platelet count anduse: platelet count to ≥ 100,000 cells/mm cancer other than predominantly squamous cell histology. Monotherapy – Maintenance treatment of locally advanced or hydroxypropylbetadex. Indications: In combination with cisplatin - treatment of chemotherapy naïve patients with or to any of the excipients, breast-feeding, concomitant yellow fever vaccine. Special warnings and precautions for 3 maximum non-haematologic toxicity seen from previous cycle. mustANC be instructed acid and metastatic non-small cellmesothelioma, lung cancer other squamous cell histology in patients whose disease and unresectable malignant pleural firstthan linepredominantly treatment of locally advanced or metastatic non-small cell lunghas Monitor patients for myelosuppression. Pemetrexed should notAllbepatients given until returns toto≥take 1500folic cells/mm measure to reduce treatment-related toxicity. withANC, dexamethasone vitamincount B12 astoa≥prophylactic not progressed immediately followingcell platinum-based chemotherapy, second linetreatment treatmentofof locally advanced 3 . Dose reductions for subsequent cyclesPre-treatment based on nadir platelet count(orand 100,000 cells/mm cancer other than predominantly squamous histology. Monotherapy – Maintenance locally advanced or or platelet equivalent) can reduce the incidence and severity of skin reactions. Not recommended in patients with creatinine metastatic non-small cell lung cancer other than predominantly squamous cell histology. Posology and method of metastatic non-small cell lung cancer other than predominantly squamous cell histology in patients whose disease has maximum non-haematologic toxicity seen from previous cycle. All patients must be instructed to take folic acid and clearance of <a45ml/min. Patients with mild to moderate renal insufficiency (creatinine clearance 45-79ml/min) should (or administration: Only administer the supervision of a physician qualified the use of anti-cancer chemotherapy. prophylactic measure to reduce treatment-related toxicity. Pre-treatment with dexamethasone B12 as not progressed immediately followingunder platinum-based chemotherapy, second lineintreatment of locally advanced or vitamin or acetylsalicylic acid (> 1.3g daily) for 2 days before, on the day of, and 2 days following pemetrexed Administer as an intravenous infusion over 10 minutes on the first day of each 21-day cycle. See SmPC for further avoid taking reduce the incidence and severity of skin reactions. Not recommended in patients with creatinine metastatic non-small cell lung cancer other than predominantly squamous cell histology. Posology and method of equivalent) canNSAIDs, information on handling, administering and dilution. In combination with cisplatin – Recommended dose is 500mg/m2 of administration. In patients with mild to moderate renal insufficiency NSAIDs with long elimination half-lives should be administration: Only administer under the supervision of a physician qualified in the use of anti-cancer chemotherapy. clearance of < 45ml/min. Patients with mild to moderate renal insufficiency (creatinine clearance 45-79ml/min) should body surface area (BSA) administered as an intravenous infusion over 10 minutes on the first day of each 21-day cycle. interrupted for at least 5 days prior to, on the day of, and at least 2 days following pemetrexed administration. Patients taking acetylsalicylic acid (>tubular 1.3g daily) for 2 days before, on thefunction day of, and days following pemetrexed Administer as an intravenous infusionis 75mg/m over 10 2minutes on over the two firsthours day of each 21-day30cycle. Seeafter SmPC for further BSA infused approximately minutes completion of the avoid Recommended dose of cisplatin should be NSAIDs, regularlyormonitored for acute necrosis, decreased renal and2 signs and symptoms of 2 In patients with mild to moderate insufficiency NSAIDs with elimination half-lives should information on handling, administering In combination with cisplatin – Recommended dose is 500mg/m pemetrexed infusion on the first and day dilution. of each 21-day cycle. Patients must receive adequate anti-emetic treatmentofand administration. nephrogenic diabetes insipidus. Drainage of thirdrenal space fluid collection prior to long pemetrexed treatment should be be body surface area (BSA) administered as an intravenous infusion over 10 minutes on the first day of each 21-day cycle. interrupted for at least 5 days prior to, on the day of, and at least 2 days following pemetrexed administration. Patients appropriate hydration prior to and/or2 after receiving cisplatin (see also cisplatin SmPC). As single agent – In the treatment considered but may not be necessary. Patients should receive adequate antiemetic treatment and appropriate hydration over two hours approximately minutes 2after of the Recommended dose of cisplatin is 75mg/m beand/or regularly for acute Serious tubularcardiovascular necrosis, decreased renal function andhave signsbeen anduncommonly symptoms of BSA completion administered as an should of non-small cell lung cancer after BSA priorinfused chemotherapy, recommended dose is30500mg/m prior to aftermonitored receiving treatment. and cerebrovascular events pemetrexed infusioninfusion on the over first day of eachon21-day cycle. receive anti-emetic treatment andthe nephrogenic diabetes insipidus. of third usually space fluid prior to pemetrexed treatment intravenous 10 minutes the first dayPatients of eachmust 21-day cycle.adequate Pre-medication regimen: To reduce reported during clinical studies Drainage with pemetrexed, when collection given in combination with another cytotoxicshould agent. be appropriate hydration prior to and/or after receiving cisplatin (see also cisplatin SmPC). As single agent – In the treatment considered but may not be necessary. Patients should receive adequate antiemetic treatment and appropriate incidence and severity of skin reactions, a corticosteroid should be given the day prior to, on the day of, and the day after Concomitant use of live attenuated vaccines is not recommended. Sexually mature males are advised not to father hydration a child 2 administered an prior of non-small cell lung cancer after prior chemotherapy, dose 500mg/m BSA to and/or after treatment. Serious cardiovascular and cerebrovascular have been uncommonly pemetrexed administration. Corticosteroid should be recommended equivalent to 4mg of is dexamethasone orally twice daily. as Patients during treatment andreceiving up to 6 months thereafter. Contraceptive measures or abstinence areevents recommended. Possibility of intravenous over vitamin 10 minutes on the first day eachacid 21-day Pre-medication regimen: To reduce during clinical men studies with pemetrexed, usually on when given in combination with another cytotoxic must infusion also receive supplementation; oraloffolic or acycle. multivitamin containing folic acid (350 tothe 1000 reported irreversible infertility; advised to seek counselling sperm storage before starting treatment. Womenagent. of incidence and severity skin basis. reactions, a corticosteroid should given day priorthe to, seven on thedays day preceding of, and thethe dayfirst after of live attenuated not recommended. mature are advised not to a child micrograms) onof a daily At least five doses of folic acidbe must be the taken during dose Concomitant childbearingusepotential must use vaccines effectiveiscontraception duringSexually treatment withmales pemetrexed. Cases offather radiation pemetrexed administration. Corticosteroid shouldduring be equivalent to 4mgofoftherapy dexamethasone Patients treatment and upintopatients 6 monthstreated thereafter. or abstinence are recommended. of pemetrexed and dosing must continue the full course and for 21orally daystwice after daily. the last dose of during pneumonitis reported with Contraceptive radiation eithermeasures prior, during or subsequent to pemetrexedPossibility therapy; of P_KF_36791 19763_FK_Pemetrexed_A4_4pp_Brochure_v4_Option_A.indd 1 27/04/2021 14:42 24:41 1202/40/7 micrograms) in the(350 weektopreceding pemetrexed. also receive anoral intramuscular of vitamin B12 (1000 particular attention paid totothese and caution with other radiosensitising agents.treatment. Cases of radiation must also receive Patients vitamin must supplementation; folic acidinjection or a multivitamin containing folic acid 1000 irreversible infertility;should men be advised seekpatients counselling on sperm storage before starting Women of injections may be given the first ofbasis. pemetrexed every threeacid cycles vitamin B12 preceding recall reported in patients radiotherapy weeksduring or yearstreatment previously.with Accumulation of cyclodextrins may micrograms) on dose a daily At leastand fiveonce doses of folic mustthereafter. be taken Subsequent during the seven days the first doseon childbearing potential mustwho usereceived effective contraception pemetrexed. Cases of radiation the sameand daydosing as pemetrexed. Monitoring: Before complete bloodand countforincluding cell count occur in patients withinmoderate severe with renal radiation dysfunction. May prior, cause during fatigue,orpatients shouldtobepemetrexed cautioned against of pemetrexed must continue during theeach full dose course of therapy 21 daysdifferential after the white last dose of pneumonitis reported patientstotreated either subsequent therapy; 6791 19763_FK_Pemetrexed_A4_4pp_Brochure_v4_Option_A.indd 1 administration blood chemistry tests should be collected to driving or operating machinery if this occurs. Undesirable effects: (Associated with pemetrexed 27/04/2021 14:42 or in 24:41 1202/4 (WCC)Patients and platelet Prior an to each chemotherapy monotherapy pemetrexed. must count. also receive intramuscular injection of vitamin B12 (1000 micrograms) in the week preceding particular attention should be paid to these patients and caution with other radiosensitising agents. Cases of radiation and hepatic Before thecycles start ofthereafter. any cycle of chemotherapy, patients are required have absolute combination with cisplatin)who Infection, pharyngitis, sepsis, dermo-hypodermitis, neutropenia, leukopenia, decreasedmay maytobe given on recall the firstevaluate dose of renal pemetrexed and function. once every three Subsequent vitamin B12 injections reported in patients received radiotherapy weeks or years previously. Accumulation of cyclodextrins 3 3 andeach platelets 100,000 cells/mm . Creatinine should be cell ≥ 45count ml/min. occur neutrophil count (ANC) Monitoring: ≥ 1500 cells/mm haemoglobin, neutropenia, decreased platelet count, haemolytic anaemia, the same day as pemetrexed. Before dose ≥complete blood count includingclearance differential white in patientsfebrile with moderate to severe renal dysfunction. May pancytopenia, cause fatigue, autoimmune patients should be cautioned against Totalplatelet bilirubincount. shouldPrior be ≤ 1.5 limit of normal. Alkaline phosphatase (AP), aspartate aminotransferase hypersensitivity, anaphylactic taste disorder, peripheral motor neuropathy, peripheral sensory (WCC) and to times each upper chemotherapy administration blood chemistry tests should be collected(AST to or driving or operating machineryshock, if thisdehydration, occurs. Undesirable effects: (Associated with pemetrexed monotherapy or in SGOT) and alanine aminotransferase (ALT or SGPT) should be ≤ 3 times upper limit of normal. AP, AST and ALT ≤ 5 times neuropathy, dizziness, cerebrovascular accident, ischemic stroke, intracranial haemorrhage, conjunctivitis, dry eye, evaluate renal and hepatic function. Before the start of any cycle of chemotherapy, patients are required to have absolute combination with cisplatin) Infection, pharyngitis, sepsis, dermo-hypodermitis, neutropenia, leukopenia, decreased upper limit(ANC) of normal is acceptable if liver has tumour involvement. Dose adjustments: At the start of abesubsequent cycle haemoglobin, increased lacrimation, keratoconjunctivitis sicca, platelet eyelid oedema, surface disease, cardiac haemolytic failure, arrhythmia, 3 platelets ≥ 100,000 cells/mm . Creatinine clearance should ≥ 45 ml/min. neutrophil count ≥ 1500 cells/mm3 and febrile neutropenia, decreased count, ocular pancytopenia, autoimmune anaemia, should be based on nadir haematologic counts or maximum non-haematologic toxicity from the preceding cycle of angina, myocardial infarction, coronary artery disease, supraventricular arrhythmia, peripheral ischaemia, pulmonary Total bilirubin should be ≤ 1.5 times upper limit of normal. Alkaline phosphatase (AP), aspartate aminotransferase (AST or hypersensitivity, anaphylactic shock, dehydration, taste disorder, peripheral motor neuropathy, peripheral sensory therapy. Treatment may be delayed to allow sufficient time for recovery. Upon recovery patients should be retreated embolism, interstitial pneumonitis, stomatitis, anorexia, vomiting, diarrhoea, nausea, dyspepsia, constipation, abdominal SGOT) and alanine aminotransferase (ALT or SGPT) should be ≤ 3 times upper limit of normal. AP, AST and ALT ≤ 5 times neuropathy, dizziness, cerebrovascular accident, ischemic stroke, intracranial haemorrhage, conjunctivitis, dry eye, using the guidelines as follows, which are applicable for pemetrexed Fresenius Kabi used as single agent or in pain, rectal haemorrhage, gastrointestinal haemorrhage, intestinal perforation, oesophagitis, colitis, increased alanine upper limit of normal is acceptable if liver has tumour involvement. Dose adjustments: start of–aNadir subsequent cycle 3 increased lacrimation, keratoconjunctivitis sicca, eyelid oedema, surface disease, cardiac failure, arrhythmia, combination with cisplatin. Haematologic toxicities (dose modify both pemetrexed At andthe cisplatin) ANC < 500/mm aminotransferase, increased aspartate aminotransferase, hepatitis,ocular rash, skin exfoliation, hyperpigmentation, pruritis, should be on nadir≥haematologic or maximum non-haematologic toxicity from75% the ofpreceding cycle Nadir of angina, myocardial infarction, disease, supraventricular arrhythmia, peripheral ischaemia, pulmonary 3 nadir platelets < 50,000/mm regardless of nadir ANC: previous dose. andbased nadir platelets 50,000/mm3, orcounts erythema multiforme, alopecia,coronary urticaria,artery erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis, pemphigoid, therapy.platelets Treatment may be delayed to allow sufficient Upon recovery patients shouldtoxicities be retreated pneumonitis, stomatitis, anorexia, vomiting,oedema, diarrhoea, nausea, dyspepsia, constipation, abdominal 3 with bleeding regardless of time nadir for ANC:recovery. 50% of previous dose. Non-haematologic ≥ Grade embolism, < 50,000/mm dermatitisinterstitial bullous, acquired epidermolysis bullosa, erythematous pseudocellulitis, dermatitis, eczema, prurigo, using the guidelines as follows,- pemetrexed which are applicable for should pemetrexed Fresenius Kabi usedtoasless single pain, rectal haemorrhage, gastrointestinal haemorrhage, perforation, colitis, increased alanine 3 (excluding neurotoxicity) Fresenius Kabi be withheld until resolution than agent or equalortointhe decreased creatinine clearance, increased blood creatinine,intestinal renal failure, decreasedoesophagitis, GFR, nephrogenic diabetes insipidus, 3 combination with cisplatin. Haematologic toxicities (dose modify both pemetrexed and cisplatin) – Nadir ANC < 500/mm aminotransferase, increased aspartate aminotransferase, hepatitis, rash, skin exfoliation, hyperpigmentation, pruritis, patient’s pre-therapy value. Treatment should be resumed accordingly – Any grade 3 or 4 toxicities except mucositis, or renal tubular necrosis, fatigue, pyrexia, pain, oedema, chest pain, mucosal inflammation, increased GGT, radiation 3 3 2 , or nadir platelets < 50,000/mm regardless ANC:dose 75%(mg/m of previous dose. Nadirand erythema and nadir ≥ 50,000/mm multiforme, alopecia, urticaria, erythema, Stevens-Johnson syndrome, epidermal necrolysis, Numbers: pemphigoid, ) of pemetrexed anyplatelets diarrhoea requiring hospitalisation or grade 3 or 4 diarrhoea: 75% of of nadir previous oesophagitis, radiation pneumonitis, recall phenomenon. Legal Category: POMtoxic Marketing Authorisation 3 of nadirpemetrexed ANC: 50% of previous Non-haematologic toxicities ≥ Grade plateletscisplatin. < 50,000/mm bullous,EU/1/16/1115/004, acquired epidermolysis bullosa,Marketing erythematous oedema, pseudocellulitis, eczema,GmbH, prurigo, ) and 100% of previous cisplatin dose (mg/m2). dermatitis Grade 3with or 4bleeding mucositis:regardless 50% of previous dose (mg/m2dose. EU/1/16/1115/003, EU/1/16/1115/005. Authorisation Holder: Freseniusdermatitis, Kabi Deutschland 3 (excluding neurotoxicity) - pemetrexed Freseniustherapy Kabi should be withheld until resolution to less than or equal the of decreased creatinine1,clearance, creatinine, renal failure, decreased GFR, nephrogenic insipidus, Neurotoxicity – Patients should discontinue if Grade 3 or 4 neurotoxicity is observed. CTC Grade 0-1: to 100% Else-Kroner-Straße 61352 Badincreased Homburgblood v.d.Höhe, Germany. Further Information: See the SmPC for diabetes further details. 2 2 patient’sprevious pre-therapy value. Treatment should resumed – Any grade 3 or 4 toxicities except mucositis, or of renal tubular necrosis, pyrexia, pain, oedema, chestarepain, GGT, radiation ). CTCaccordingly Grade 2: 100% of previous pemetrexed dose (mg/m ) and 50% pemetrexed and cisplatin dose be (mg/m Adverse events should fatigue, be reported. Healthcare professionals askedmucosal to reportinflammation, any suspectedincreased adverse reactions via ) of pemetrexed andany oesophagitis, any diarrhoea or grade 3 treatment or 4 diarrhoea: 75% of previous doseKabi (mg/m radiation pneumonitis, recall IRL phenomenon. POM+353 Marketing Numbers: with pemetrexed Fresenius if a 2patient experiences previousrequiring cisplatinhospitalisation dose (mg/m2). Discontinue HPRA Pharmacovigilance, Earlsfort Terrace, - Dublin 2, Tel:Legal +353 Category: 1 6764971, Fax: 1 6762517.Authorisation Website: www.hpra.ie, 2 or non-haematologic Grade pemetrexed 3 or 4 toxicity 2 2dose or immediately if Grade 3 or E-mail: medsafety@hpra.ie. Adverse events should also be reported to FreseniusHolder: Kabi Limited via email ) and reductions 100% of previous cisplatin dose (mg/m ). 4 EU/1/16/1115/003, cisplatin.haematologic Grade 3 or 4 mucositis: 50% of previous doseafter (mg/m EU/1/16/1115/004, EU/1/16/1115/005. Marketing Authorisation Fresenius KabiPharmacovigilance. Deutschland GmbH, neurotoxicity is observed. Elderly – Notherapy dose reductions those recommended for CTC all patients are100% necessary. GB@Fresenius-Kabi.com. Preparation: May 2021 Job code: API/Pemetrexed/02 Neurotoxicity – Patients should discontinue if Grade other 3 or 4than neurotoxicity is observed. Grade 0-1: of Else-Kroner-Straße 1, 61352Date BadofHomburg v.d.Höhe, Germany. Further Information: See the SmPC for further details. previous pemetrexed and cisplatin dose (mg/m2). CTC Grade 2: 100% of previous pemetrexed dose (mg/m2) and 50% of Adverse events should be reported. Healthcare professionals are asked to report any suspected adverse reactions via 2 previous cisplatin dose (mg/m ). Discontinue treatment with pemetrexed Fresenius Kabi if a patient experiences any HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517. Website: www.hpra.ie, haematologic or non-haematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 E-mail: medsafety@hpra.ie. Adverse events should also be reported to Fresenius Kabi Limited via email Pharmacovigilance. neurotoxicity is observed. Elderly – No dose reductions other than those recommended for all patients are necessary. GB@Fresenius-Kabi.com. Date of Preparation: May 2021 Job code: API/Pemetrexed/02

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

Fresenius Kabi Ireland

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

Date of Prep: May 2021 Ref: IV/ONCO/PEME/01/2021

Website: www.fresenius-kabi.com/ie/ Email: FK-enquiries.ireland@fresenius-kabi.com

Date of Prep: May 2021 Ref: IV/ONCO/PEME/01/2021

68 Bladder Disorders Hiprex/methenamine hippurate: This acts as a bacteriostatic and requires acidic urine in order to act. This could mean getting patients to take vitamin c or drink orange juice. This is not licensed for over-the-counter dispensing in Ireland, but it is in Australia. The evidence for this medication is lacking. A Cochrane review by Lee et al. in 2012 concluded that hiprex may prevent UTIs in patients without renal tract abnormalities but not in those with abnormalities. The rate of adverse events was low but poorly described.11 This medication is considered less suitable for prescribing, but is still an option. AUA/CUA/SUFU were unable to recommend its use based on the evidence available.1 EAU does not mention hiprex in their guideline.2 Based on the evidence that hiprex was inferior to nitrofurantoin for prophylaxis, NICE were unable to recommend its use.8, 12 OM-89: This is a less well-known form of UTI prophylaxis. This is an oral vaccine which is a form of immunoactive prophylaxis. This has been shown to be superior to placebo for reducing UTIs in female patients in RCTs, as well as having a good safety profile. AUA/CUA/SUFU could not make a recommendation on this given a 2015 RCT by Wagenlehner et al.1, 13 EAU currently strongly advise this based on four studies, including a 2013 systematic review and meta-analysis by Beerepoot et al..However, the EAU guideline does not reference this 2015 RCT.2, 14 NICE does not mention immunoactive prophylaxis in their guideline.8

be given for 6 months courses. A trial of then stopping these is reasonable. If the patient’s urinary tract infections recur, then a urine sample should be sent for culture and sensitivity and depending on the sensitivity of the grown organism, the antibiotic can be changed. This is to avoid treating an organism that is not sensitive to a given antibiotic.

in individuals despite antibiotic prophylaxis. When reviewing these patients, it is important to assess their symptoms and differentiate between cystitis-like symptoms and a true UTI with a positive mid-stream urine for Another method of recurrent UTI culture and sensitivity. If these treatment for those with good patients are on prophylactic compliance is self-diagnosis antibiotics, their daily dose can and treatment with short-course be stopped, and they should be regimens. AUA/CUA/SUFU treated with a full dose course. Trimethoprim and nitrofurantoin recommends this (Grade C Their prophylactic antibiotics are the most common. Using evidence) but does appreciate Figure 1. as Commonly oestrogen therapy [1] may then be resumed depending antibiotics single-doseused vaginalthe risk for antibiotic overuse. To on their antibiotic sensitivities. If prophylaxis when exposed to avoid this, these patients should Strengthsymptom and Dosage these infections are persistent, a Formulation trigger was shown Composition to be as be reliable regarding further investigations could be effective, with fewer adverse insight and should endeavour to considered, events. These could be taken send urine cultures before initiation Vaginal oestradiol 10 mcg per day for 2 weeks, thenincluding 10 mcgmeasuring 2–3 a patients flow rate of urine and pre- or post-coitus in those who if possible. EAU recommends 15hemihydrate* tablet times weekly the quantity of urine they have find this is a trigger. Regimens this based on Schaeffer’s 1999 for prophylaxis between the left in their bladder post-voiding prospective cohort study.2, 17 NICE three guidelines slightly. residual). does not recommend based 7.5 (post-void Vaginal ring vary17β-oestradiol 2 mg ringthis released mcg per day for 3Ultrasound months is All three guidelines recommend a quick and safe method to image on the risk of antibiotic overuse (changed by patient oraprovider) trimethoprim and nitrofurantoin, patient’s bladder and kidneys to and lack of RCTs.8 and cephalexin (NICE assess for anomalies. Endoscopy Breakthrough recommending this as second in the1form of times a bladder Vaginal 17β-oestradiol 2 gurinary daily tract for 2 weeks, then g 2-3 perscope week infections can be defined as line).1, 2, 8 Trimethoprim should not (flexible cystoscopy) can also be cream infections occurring with 105 be given in pregnancy, and care equine 0.5 units g daily 2 weeks,considered. then 0.5 gFlexible twice cystoscopy weekly colony-forming perfor millilitre should be taken withConjugate nitrofurantoin is not offered routinely but in a urine culture with an abnormal due to the risk of pulmonary oestrogen should be done without delay in urinalysis (positive nitrite test or fibrosis. The rate of pulmonary atypical cases, for example, renal greater than five white blood cells or hepatic adverse events with calculi, outflow obstruction or per high-powered field or both) nitrofurantoin has been reported urothelial cancer.2 and a clinical course compatible to be 0.001% and 0.0003%, References upon request respectively. Thus, this medication with a UTI.18 These can occur

Figure 2. Prophylactic antibiotic options as per guidelines

Guideline AUA/CUA/SUFU [1]

Antibiotic Trimethoprim Co-trimoxazole Co-trimoxazole Nitrofurantoin Nitrofurantoin Cephalexin Cephalexin Fosfomycin

Dose 100mg 40/200mg 40/200mg 50mg 100mg 125mg 250mg 3g

Frequency OD OD Thrice weekly OD OD OD OD Every 10 days

EAU [2]

Trimethoprim Nitrofurantoin Nitrofurantoin Cephalexin Cephalexin Cefaclor Fosfomycin

100mg 50mg 100mg 125mg 250mg 250mg 3g

OD OD OD OD OD OD Every 10 days

NICE [8]

Trimethoprim Nitrofurantoin Nitrofurantoin Cephalexin Amoxicillin Pivmecillinam

100mg 50mg 100mg 125mg 250mg 200mg

OD OD OD OD OD OD

Antibiotics Prophylactic antibiotics are an effective option for preventing UTIs, with many trials proving their superiority to placebo. It should be noted that the 10 of these trials quoted in the AUA/ CUA/SUFU guidelines are all older than 1995, and while the results are acceptable, they should be interpreted in light of current resistance patterns.1 The goal is to use as few antibiotics as possible as the problem with these is, of course, antibiotic resistance. The lowest dose should be given for the shortest time needed. Antibiotic prophylaxis should

should be avoided in chronic lung disease, and caution should be taken with long-term prescribing.16 Figure 2. Details the different antibiotic regimens according to each guideline

Figure 2. Prophylactic antibiotic options as per guidelines

JANUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

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: medsafety@hpra.ie.

Approval code: BET_2019_0004_IE

70 Irritable Bowel Syndrome

Managing IBS, Diarrhoea and Constipation Written by Clare Foley, SPR and Barry Hall, Gastroenterology Department, Connolly Hospital, Blanchardstown Background Irritable bowel syndrome (IBS) is a common chronic functional gastrointestinal disorder, with an estimated population prevalence of 10%, which more commonly affects women and younger individuals. IBS represents a large proportion of referrals to outpatient gastroenterology services; some studies report IBS related reviews amount to between 10% and 25% of a gastroenterologist’s workload. This disorder has a substantial impact on patients, many of whom report considerable impairment of quality of life as a consequence of their symptoms. Patients face daily challenges with work and socialising. Exact IBS aetiology remains unclear, but a variety of factors have been implicated, including genetics, visceral/gut hypersensitivity, disordered gastrointestinal motility, abnormalities of the brain–gut axis, and alterations in the gut microbiome, that is the gut bacterial population. The Rome IV criteria for the diagnosis of IBS describes the cardinal features of irritable bowel syndrome; abdominal pain, often related to defaecation, which is associated with either a change in stool frequency, a change in stool form or both. IBS can be sub-classified based on the predominant symptom, constipation, diarrhoea, mixed. IBS-C, IBS-D and IBS-M respectively. Investigations A logical and evidenced-based approach is required when investigating patients with possible IBS. Making an early diagnosis, based on a clinical assessment of symptoms, while limiting use of investigations, are key tenets of the management of IBS. Exhaustive investigations to exclude all organic pathology is often counterproductive. An early and positive diagnosis of IBS following logical use of limited investigations, together with a clear explanation, may help patients better accept the diagnosis and facilitate earlier treatment, symptom control as well as minimise associated healthcare costs.

(FCP) should be carried out; a stool sample which assesses for evidence of active inflammation. These investigations can be carried out by GPs at the primary care level. Any abnormality in the above investigations should prompt further urgent gastroenterology investigations. Management Management broadly falls into three categories; medical management, dietary intervention & life-style modification. Perhaps the most important step in the management of IBS, once diagnosed, is providing reassurance and information to the patient in relation to the diagnosis. Providing patients with the tools to control their symptoms with the reassurance that a sinister pathology such as inflammatory bowel disease or colorectal cancer has been outruled is paramount.

as mindfulness practice are some easily achievable interventions. Promoting a healthy exercise regime is often helpful especially in the IBS-C subgroup of patients, where exercise and water intake can improve gut motility and can relieve constipation. Probiotic supplementation aiming to restore healthy gut bacteria are included in the first step of management.

to initiate treatment strategies outlined above. We have recently commenced a randomised control trial in Connolly Hospital utilising an online dietician application “My Gut Solution”. Suitable patients will receive online dietician support/ training prior to any clinic visit with the aim, if successful, being to improve patient outcomes whilst reducing the need for clinic visits.

Medical management with drug therapies are included the next step in the management of IBS. Again it must be emphasised to patients that these medical therapies are used to try achieve symptom control rather than “cure”.

Conclusions

Good communication between the clinician and patient is vitally important. Clinicians should provide a clear explanation about the diagnosis; disorder of gutbrain interaction, associated with alterations in the gut bacteria, genetic predisposing factors and gut hyper-sensitivity. It should be emphasised that symptoms are often chronic, and that treatment, while aiming to improve symptoms, may not relieve them completely.

Step wise drug therapies are utilised depending on the pre-dominant symptoms. For example, first line agents for the management of diarrhoea include anti-diarrhoeal medications such as loperamide. Similarly, anti-spasmodic medications and laxatives are prescribed for the first line management of abdominal pain and constipation, respectively. Second line agents are subsequently utilised if first line treatments are unsuccessful. Second line agents include secretagogues, neuromodulators (amitriptyline) and selective serotonin inhibitors for the management of constipation, abdominal pain and diarrhoea, respectively.

Treatment options are utilised in a stepwise approach commencing with lifestyle advice; general dietary recommendations, exclusion diets to elucidate a precipitating dietary trigger & lifestyle modification such

The ongoing COVID-19 emergency has severely affected outpatient waiting times across the health service in Ireland. Unfortunately, new IBS referrals can be waiting many months for an initial visit

Guidelines for the investigation and management of IBS recommend symptom based investigations with all patients undergoing routine bloodwork and coeliac screening. If diarrhoea is the pre-dominant feature a faecal calprotectin

JANUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

Irritable bowel syndrome can be a chronic, debilitating condition. However, there are some key components to IBS management that can help patients regain control of their lives; these include dietary modifications, increasing exercise and water in-take and medical management of the pre-dominant symptomatology when required. Future work is still required to understand the aetiological cause and subsequent management of irritable bowel syndrome; some studies have shown benefit from faecal microbiota transplantation and multi-disciplinary approaches with cognitive behavioural specialists providing gut-directed therapy (references). However these therapies remain under investigation and widespread implementation is not yet recommended. The following diagram outlines the stepwise approach adopted for the management of IBS and its subdivisions in the outpatient gastroenterology setting1 Black Cj, Ford AC; Rational investigations and best treatment options in irritable bowel syndrome. Frontline Gastroenterology; flgastro-2019-101298

News 71 Approval for First long-acting Option HIV Prevention The first long-acting option to protect women from HIV, proven to reduce women’s HIV risk, has been recommended for use by the World Health Organization (WHO). For nearly two decades, researchers from the School of Pharmacy at Queen’s University Belfast have been supporting development of a new drugreleasing vaginal ring to protect women from infection with the human immunodeficiency virus (HIV). It will be the first longacting option that women can use to reduce their risk of HIV transmission representing an important milestone in prevention technologies. The monthly dapivirine ring, developed by the International Partnership for Microbicides (IPM) with critical research and development support by Queen’s University Belfast and other organizations, is expected to reach market in 2022 in sub-Saharan Africa, where women's needs for urgent prevention is needed. HIV, which if left untreated leads to acquired immunodeficiency syndrome (AIDS), is a major global disease and remains a leading threat to women's health and well-being worldwide. According to recent estimates, 37.7 million people globally were living with HIV in 2020. Despite global progress against the epidemic,

HIV/AIDS continues to be one of the primary causes of death among women of reproductive age in sub-Saharan Africa, who are disproportionately affected by the disease compared to men. However, the numbers of new infections and AIDS-related deaths have decreased steadily every year since 2000, mostly due to widening access to antiretroviral therapy. The ring is made of silicone elastomer, a flexible rubber-like

material that is easy to insert and comfortable to use. The ring works by releasing the antiretroviral drug dapivirine from the ring into the vagina slowly over 28 days. The sustained delivery of the antiretroviral drug, dapivirine, has previously been shown to reduce HIV infection in two large-scale clinical trials, supporting its later market approval. Professor Karl Malcom and Dr Peter Boyd from the School of Pharmacy at Queen’s University

Belfast have long been involved in developing tools for women, including different types of vaginal rings, and are long-time collaborators with the not-forprofit International Partnership for Microbicides (IPM) to develop a range of products designed to protect women against HIV and unintended pregnancy, with a focus on the need for solutions that are long acting and female-controlled.

New Mural Tackles HIV Stigma To mark World AIDS Day on December 1st, the Sexual Health Centre launched ‘End HIV Stigma’ a collaborative community project in partnership with ACT UP and Positive Cork. At the centre of this project is a new mural on Grattan Street, shining a light on the stigma attached to HIV (human immunodeficiency virus). Elinor O’Donovan from the Sexual Health Centre led the project alongside a number of people living with HIV, who advised on the planning and design of the mural. “Medical advances have ensured that people in Ireland can live full, healthy lives with HIV. So, in the last 40 years, how we treat HIV has significantly improved but how we treat people living with HIV has not,” noted Ms O’Donovan.

“I’m hoping that this mural brings the harmful stigma faced by people living with HIV, into public conversation, and highlights that many HIV-positive people are living positive lives.” It is estimated that over 7,000 people in Ireland are living with HIV today. About 15% of that number don't know that they have HIV as they have never been tested or have contracted HIV since their last test. However, a study published by the Sexual Health Centre has shown that misinformation within the Irish population regarding HIV is still prevalent. Many people still believe that HIV can be transmitted through saliva, kissing or sharing utensils. This misinformation reinforces existing stigma and has a strong negative impact on people living with HIV and their families.

This initiative is funded by HSE Arts + Health. Free registration for the panel discussion, ‘End HIV Stigma: A Cork Reflection’, is available at sexualhealthcentre.com/events

HOSPITALPROFESSIONALNEWS.IE | HPN • JANUARY 2022

72 News

Calls for Increased Use of Off-Patent Medicines The European Parliament has adopted a report calling for increased use of off-patent medicines in Europe to improve patient access, highlighting lessons learned during the Covid-19 pandemic and urging the European institutions to address them directly in future healthcare policy initiatives. The Parliament, in its own initiative report, stresses the central role of generic, biosimilar and valueadded medicines as the European Commission works to revise the legislative framework of the European pharmaceutical industry. Off-patent medicines already account for close to 70% of those used by patients in Europe. The

call for increased use of off-patent medicines also implies a tailored regulatory pathway for value added medicines innovation, an area where the EU has been lagging behind the US for years.1 The report highlights that an efficient and optimised regulatory system for pharmaceuticals is also a priority. This includes digitalising regulatory processes and embracing environmentally friendly solutions like electronic patient information leaflets. The report calls on the European Commission to actively remove barriers to competition from loss of exclusivity. This includes reviewing the use of intellectual property incentives and assessing the

framework for off-patent orphan and paediatric medicines. Adapting these frameworks could enable increased access for the rare disease population but a level playing field is needed to facilitate the development and manufacturing of these medicines. Commenting on the European Parliament vote, Medicines for Europe President ad-interim, Rebecca Guntern says, “It is highly encouraging to see the European Parliament take such clear directions to increase access to off-patent medicines. I am particularly pleased to see the European Parliament factor in the lessons learned from COVID-19. Generics, biosimilars and valueadded medicines are key pillars

for the long-term resilience and sustainability of European healthcare systems. “The review of the EU pharmaceutical legislation is a one-time opportunity to make sure Europe has a fit-for-purpose, efficient, digital and simplified regulatory framework. We look forward to continuing our work with the European institutions and Member States in the coming months. We cannot afford to miss this opportunity.” For more on this, see https:// www.cep.eu/fileadmin/ user_upload/cep.eu/Studien/ cepInput_Off_Patent_Innovation/ cepInput_Incentivising_ Pharmaceutical_OffPatent_ Innovation_in_the_EU.p

Breakthrough in Motor Neuron Disease Professor Orla Hardiman, Professor of Neurology, Trinity College Dublin

researchers have now shown that these patterns of brain network disruptions in MND cluster into 4 distinct subtypes that are predictive of how the disease progresses. The team’s findings move the Trinity researchers one step closer to building better and more effective treatments for different sub-categories of the disease.

Researchers at Trinity College Dublin have made a major discovery in understanding motor neuron disease (MND). The research team has found that MND has 4 distinct patterns of changes in electrical signals that can be identified using EEG (electroencephalography).

There are over 500 people in Ireland with MND, and one person is diagnosed every 3 days with the condition. There is currently no effective treatment.

This breakthrough will be extremely valuable in identifying patients for clinical trials and will assist in finding new treatments for this devastating disease.

While trials of new drugs are being undertaken, MND is known to be very heterogeneous with different patterns of disability and life expectancy. Predicting in advance the pattern of disability and life expectancy is one of the major challenges in designing modern clinical trials.

MND is a devastating condition which causes progressive paralysis, changes in thinking, increasing physical disability and ultimately death within an average of two to three years.

The world class electrical signal analysis research developed within Trinity College has discovered different patterns of brain network disruption reflect the underlying disease process. The Trinity

JANUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

The work was performed by Mr Stefan Dukic, a PhD student within the Academic Unit of Neurology at Trinity, under the supervision

of Dr Bahman Nasseroleslami, Fr Tony Coote Assistant Professor in Neuroelectric Signal Analysis. Professor Orla Hardiman, Professor of Neurology and a world leader in MND research says, “This is a very important and exciting body of work. A major barrier to providing the right drug for the right patient in MND is the heterogeneity of the disease. This breakthrough research has shown that it is possible to use patterns of brain network dysfunction to identify subgroups of patients that cannot be distinguished by clinical examination. The implications of this work are enormous, as we will have new and reliable ways segregate patients based on what is really happening within the nervous system in MND.”

News 73 Access to Essential Medicines under Threat Access to off-patent medicines is essential to increase competition, offer accessible and affordable treatments and for the budgetary sustainability of healthcare systems in Europe, as highlighted by a European Parliament report1 adopted recently. Medicines for Europe states however that ‘as EU governments struggle to cope with the economic and financial effects of the Covid-19 pandemic, several countries are proposing further cost containment measures for off-patent medicines, which cover 70% of prescription medicine supply across Europe at just 25% of the total cost.’ Many essential off-patent medicines have already been subject to strict price regulation (often referred to as reference pricing), successive price cutting measures, and budget adjustment measures (such as clawback) for many years.

Says the representative body, “These measures have led to substantial price erosion, which is now compounded by mounting inflation across Europe and the recent increase in global production costs: raw material costs have tripled2, shipping rates are 6 times more expensive3, airfreight costs have more than tripled4, energy costs rose by more than 230% last year5 with overall producer prices increasing by 10%.6

market for important older, less expensive medicine.

“Against this background further price cuts would be simply unsustainable for manufacturers. This creates serious risks for medicines supply and availability. The European Commission has collected a growing body of evidence showing that extreme cost containment policies applied to generic medicines are counterproductive, driving industrial consolidation and supply risks and potential medicine withdrawals from the

Director General of Medicines for Europe, Adrian van den Hoven, says, “Just this week the European Parliament recognized that off-patent medicines provide the majority of accessible and affordable treatments and contribute greatly to the budgetary sustainability of healthcare systems, generating costs savings while underpinning the high quality of healthcare. Our industry is part of the solution, not part of the problem: it’s time

“Medicines for Europe calls on the Commission to react by legally mandating Member States, which use monopsony buying power, to integrate security of supply considerations into the EU Transparency Directive (which governs medicines pricing and reimbursement decisions) and the Public Procurement Directive (which governs medicine tendering).”

to treat it as such. Security of supply needs to be factored into the pharmaceutical policies of Member States. We all need to remember that healthcare is an essential investment, not just a short-term cost.” 1

Report on a pharmaceutical strategy for Europe (2021/2013(INI))

The Print – Pharma industry warns of Covid drug shortages as raw materials prices surge 200% (May 2021)

McKinsey & Company – What’s going on with shipping rates? (August 2021)

Air Cargo News - Airfreight rates expected to continue to rise (November 2021)

Euronews - Why Europe's energy prices are soaring and could get much worse (October 2021)

Eurostat - Producer prices in industry, total - monthly data (Jan 2020 vs September 2021)

New Appointment for Paul Paul Neill, Director, Generic Medicines Ireland with Teva Pharmaceuticals, has recently been appointed as Vice Chairperson of Medicines for Ireland. Paul says, “I'm really proud to have worked for almost 20 years in the Generic Medicines Industry in Ireland and to continue to play my part in developing sustainable and affordable healthcare for Irish Patients.” Best of luck in the new role Paul.

HSE Excellence Awards 2021 The Maternal & Newborn Clinical Management System National (MN-CMS) Team was delighted to be chosen as Finalist in the recent HSE excellence Awards. The award recognised the hard work of the team and in particular the work of Gwen Malone in collaboration with the laboratories and back office staff of CUMH, UHK, The Rotunda and National Maternity Hospital. This work included the development and implementation of new electronic requests for laboratory testing of SARSCoV-2 (COVID-19) tests across all 4 hospitals, and is focused on the incorporation of real

time electronic reporting of all SARS-CoV-2 test results from the individual hospital laboratories into MN-CMS. As part of this, Gwen has developed a customised electronic test request form to include fields for mandatory data required by the labs for statistical reporting to the HSE, CIDR, etc. She has also developed a COVID-19 order set of laboratory investigations, comprising a suite of diagnostic lab tests which is focused around disease management.

test results from anywhere in the hospital, from outpatient clinics, and from remote-access devices.

This greatly speeds up and allows for safer processes both at the patient bedside and within the lab; and allows for instant access to

The rapidly changing nature of SARS-CoV-2 testing in response to scaling of laboratory capacity around the country, challenges

Standardisation across all MN-CMS hospitals and laboratories of the requests and results of SARS-CoV-2 tests streamlines and optimises workflows for clinical staff across hospitals, and allows for the prompt collation of data on both the testing status and test results of patients across multiple hospitals.

with supplies and equipment, and expansion of the scope of referral testing proved challenging to reflect and maintain in an EHR setting but was achieved in a timely manner. The presentation was made by Dr. Colm Henry, CCO, to members of the team.

HOSPITALPROFESSIONALNEWS.IE | HPN • JANUARY 2022

WITH ITS RAPID RESPONSES AND PROVE SEE THE DIFFERENCE XELJANZ®• CAN M XELJANZ®• (tofacitinib) Prescribing Information: Please refer to the Summary of Product Characteristics (SmPC) before prescribing XELJANZ 5 mg or 10 mg film-coated tablets, XELJANZ 11 mg prolonged release tablets or XELJANZ 1 mg/mL oral solution. Presentation: Film-coated tablet containing tofacitinib citrate, equivalent to 5 mg or 10 mg tofacitinib. Prolonged-release tablets containing tofacitinib citrate, equivalent to 11 mg tofacitinib. Oral solution containing tofacitinib citrate, equivalent to 1 mg/mL tofacitinib. Indications: Please note not all presentations are licensed for all indications, please see dosage section for details: In combination with methotrexate (MTX) for the treatment of moderate to severe active rheumatoid arthritis (RA) in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying antirheumatic drugs. Can be given as monotherapy in case of intolerance to MTX or when treatment with MTX is inappropriate. In combination with MTX for the treatment of active psoriatic arthritis (PsA) in adult patients who have had an inadequate response or who have been intolerant to a prior disease modifying antirheumatic drug (DMARD) therapy. For the treatment of adult patients with moderately to severely active ulcerative colitis (UC) who have had an inadequate response, lost response, or were intolerant to either conventional therapy or a biologic agent. For the treatment of active polyarticular juvenile idiopathic arthritis (rheumatoid factor positive [RF+] or negative [RF-] polyarthritis, and extended oligoarthritis), and juvenile psoriatic arthritis (PsA) in patients 2 years of age and older, who have responded inadequately to previous therapy with DMARDs. Can be given in combination with methotrexate (MTX) or as monotherapy in case of intolerance to MTX or where continued treatment with MTX is inappropriate. Dosage: Treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of the condition for which tofacitinib is indicated. Tofacitinib is given with or without food. RA and PsA: The recommended dose is 5 mg orally twice daily or 11 mg once daily which should not be exceeded. Treatment with tofacitinib 5 mg film coated tablets twice daily and tofacitinib 11 mg prolonged release tablet once daily may be switched between each other on the day following the last dose of either tablet. UC: The recommended dose is 10 mg given orally twice daily for induction for 8 weeks. For patients who do not achieve adequate therapeutic benefit by week 8, the induction dose of 10 mg twice daily can be extended for an additional 8 weeks (16 weeks total), followed by 5 mg twice daily for maintenance. Tofacitinib induction therapy should be discontinued in any patient who shows no evidence of therapeutic benefit by week 16. The recommended dose for maintenance treatment is tofacitinib 5 mg given orally twice daily. Tofacitinib 10 mg twice daily for maintenance treatment is not recommended in patients with UC who have known venous thromboembolism (VTE) risk factors, unless there is no suitable alternative treatment available. For patients with UC who are not at increased risk for VTE, tofacitinib 10 mg orally twice daily may be considered if the patient experiences a decrease in response on tofacitinib 5 mg twice daily and failed to respond to alternative treatment options for ulcerative colitis such as tumour necrosis factor inhibitor (TNF inhibitor) treatment. Tofacitinib 10 mg twice daily for maintenance treatment should be used for the shortest duration possible. The lowest effective dose needed to maintain response should be used. Polyarticular JIA and juvenile PsA: The recommended dose in patients 2 years of age and older: 10 kg - < 20 kg: 3.2 mg (3.2 mL of oral solution) twice daily, 20 kg - < 40 kg: 4 mg (4 mL of oral solution) twice daily, and ≥ 40 kg 5 mg (5 mL of oral solution or 5 mg film-coated tablet) twice daily. Patients ≥ 40 kg treated with tofacitinib 5 mL oral solution twice daily may be switched to tofacitinib 5 mg film-coated tablets twice daily. Patients < 40 kg cannot be switched from tofacitinib oral solution. Dose interruption in adults and paediatric patients: Tofacitinib treatment should be interrupted if a patient develops a serious infection until the infection is controlled. Interruption of dosing may be needed for management of dose-related laboratory

abnormalities including lymphopenia, neutropenia, and anaemia. It is recommended not to initiate dosing in patients with an absolute lymphocyte count (ALC) less than 0.75 x 10 9/L, an absolute neutrophil count (ANC) less than 1x10 9 /L or with haemoglobin less than 9 g/dL. It is recommended not to initiate dosing in paediatric patients with an absolute neutrophil count (ANC) less than 1.2 x 10 9/L or with haemoglobin less than 10 g/dL. Renal impairment: No dose adjustment is required in patients with mild or moderate renal impairment. Patients with severe renal impairment the dose should be reduced to 5 mg once daily when the indicated dose in the presence of normal renal function is 5 mg twice daily or 11 mg prolonged-release tablet once daily. Dose should be reduced to 5 mg twice daily when the indicated dose in the presence of normal renal function is 10 mg twice daily. Patients with severe renal impairment should remain on a reduced dose even after haemodialysis. Hepatic impairment: No dose adjustment is required in patients with mild hepatic impairment. Patients with moderate hepatic impairment dose should be reduced to 5 mg once daily when the indicated dose in the presence of normal hepatic function is 5 mg twice daily or 11 mg prolonged-release tablet once daily. Dose should be reduced to 5 mg twice daily when the indicated dose in the presence of normal hepatic function is 10 mg twice daily. Tofacitinib should not be used in patients with severe hepatic impairment. Elderly: No dose adjustment is required in patients aged 65 years and older. Use with caution as increased risk and severity of adverse events. See also Warnings & Precautions for use in patients over 65 years of age. Interactions: Tofacitinib total daily dose should be reduced by half in adult and paediatric patients receiving potent inhibitors of cytochrome P450 (CYP) 3A4 (e.g. ketoconazole) and in patients receiving 1 or more concomitant medicinal products that result in both moderate inhibition of CYP3A4 as well as potent inhibition of CYP2C19 (e.g. fluconazole). Coadministration of tofacitinib with potent CYP inducers (e.g. rifampicin) may result in a loss of or reduced clinical response. Coadministration of potent inducers of CYP3A4 with tofacitinib is not recommended. Only in paediatric patients: available data suggest that clinical improvement is observed within 18 weeks of initiation of treatment with tofacitinib. Continued therapy should be carefully reconsidered in a patient exhibiting no clinical improvement within this timeframe. The safety and efficacy of tofacitinib in children less than 2 years of age with polyarticular JIA and juvenile PsA has not been established. The safety and efficacy of tofacitinib in children less than 18 years of age with other indications (e.g. ulcerative colitis) has not been established. The safety and efficacy of tofacitinib prolonged-release formulation in children aged less than 18 years have not been established. Contraindications: Hypersensitivity to any of the ingredients, active tuberculosis (TB), serious infections such as sepsis, or opportunistic infections, severe hepatic impairment, pregnancy and lactation. Warnings and Precautions: Patients treated with tofacitinib should be given a patient alert card. Use in patients over 65 years of age: Considering the increased risk of serious infections, myocardial infarction, and malignancies with tofacitinib in patients over 65 years of age, tofacitinib should only be used in patients over 65 years of age if no suitable treatment alternatives are available. Combination with other therapies: There was a higher incidence of adverse events for the combination of tofacitinib with MTX versus tofacitinib as monotherapy in RA clinical studies. Tofacitinib should be avoided in combination with biologics and potent immunosuppressants such as azathioprine, 6-mercaptopurine, ciclosporine and tacrolimus. Venous thromboembolism (VTE): Serious VTE events including pulmonary embolism (PE), some of which were fatal, and deep vein thrombosis (DVT), have been observed in patients taking tofacitinib. In a randomised post authorisation safety study in patients with rheumatoid arthritis who were 50 years of age or older with at least one additional cardiovascular risk factor,

a From the start of treatment with XELJANZ in patients with moderately to severely active UC who have had an inadequate response, lost response, or were intolerant to either conventional therapy or a biologic agent. 3 XELJANZ 10 mg BID achieved higher rates of remission (primary endpoint) at week 8 vs placebo in OCTAVE Induction 1 (19% [88/476] vs 8% [10/122]; P=0.007) and OCTAVE Induction 2 (17% [71/429] vs 4% [4/112]; P<0.001)1 XELJANZ 10 mg BID achieved higher rates of clinical response at week 8 vs placebo in OCTAVE Induction 1 (60% [285/476] vs 33% [40/122]; P<0.001) and OCTAVE Induction 2 (55% [236/429] vs 29% [32/112]; P<0.001)1 In OCTAVE Sustain, for patients showing remission or clinical response following induction, XELJANZ 5 mg BID achieved higher rates of remission at week 52 (primary endpoint) vs placebo (34% [68/198] vs 11% [22/198]; P<0.001).1 Decreases in rectal bleeding and stool frequency Mayo subscores were observed as early as day 3 in patients treated with XELJANZ 10 mg BID2

PP-XEL-IRL-0686

November 2021

EN MAINTENANCE OF EFFICACY, AKE FROM THE START1,2,a a dose dependent increased risk for VTE was observed with tofacitinib compared to TNF inhibitors. In a post hoc exploratory analysis within this study, in patients with known VTE risk factors, occurrences of subsequent VTEs were observed more frequently in tofacitinib-treated patients that, at 12 months treatment, had D-dimer level greater than or equal to twice the upper limit of normal (2× ULN) versus those with D-dimer level <2×ULN. For patients with RA with known risk factors for VTE, consider testing D-dimer levels after approximately 12 months of treatment. If D-dimer test result is ≥ 2× ULN, confirm that clinical benefits outweigh risks prior to a decision on treatment continuation with tofacitinib. Tofacitinib should be used with caution in patients with known risk factors for VTE, regardless of indication and dosage. Tofacitinib 10 mg twice daily for maintenance treatment is not recommended in patients with UC who have known VTE risk factors, unless there is no suitable alternative treatment available. Promptly evaluate patients with signs and symptoms of VTE and discontinue tofacitinib in patients with suspected VTE, regardless of dose or indication. Infections: Serious and sometimes fatal infections have been reported in patients administered tofacitinib. Rheumatoid arthritis patients taking corticosteroids may be predisposed to infection. Patients should be closely monitored for infections, with prompt diagnosis and treatment. Treatment should be interrupted if a serious infection develops. As there is a higher incidence of infections in the elderly and in the diabetic populations in general, caution should be used when treating the elderly and patients with diabetes. Tuberculosis: Patients should be evaluated for both active and latent TB prior to being treated with tofacitinib. Patients who test positive for latent TB should be treated with standard antimycobacterial therapy before administering tofacitinib. Viral Reactivation: In clinical studies viral reactivation and cases of herpes zoster have been observed. Screening for viral hepatitis should be performed in accordance with clinical guidelines prior to starting therapy with tofacitinib. The impact on chronic viral hepatitis is not known. Major adverse cardiovascular events (MACE): MACE have been observed in patients taking tofacitinib. In a randomised post authorisation safety study in patients with RA who were 50 years of age or older with at least one additional cardiovascular risk factor, an increased incidence of myocardial infarctions was observed with tofacitinib compared to TNF inhibitors. In patients over 65 years of age, patients who are current or past smokers, and patients with other cardiovascular risk factors, tofacitinib should only be used if no suitable treatment alternatives are available. Vaccinations: Prior to initiating tofacitinib, it is recommended that all patients, particularly pJIA and jPsA patients, be brought up to date with all immunisations in agreement with current immunisation guidelines. Live vaccines should not be given concurrently with tofacitinib. Malignancy and lymphoproliferative disorder: Tofacitinib may affect host defences against malignancies. In a randomised post authorisation safety study in patients with RA who were 50 years of age or older with at least one additional cardiovascular risk factor, an increased incidence of malignancies excluding non-melanoma skin cancer (NMSC), particularly lung cancer and lymphoma, was observed with tofacitinib compared to TNF inhibitors. Lung cancers and lymphoma in patients treated with tofacitinib have also been observed in other clinical studies and in the post marketing setting. Other malignancies in patients treated with tofacitinib were observed in clinical studies and the post marketing setting, including, but not limited to, breast cancer, melanoma, prostate cancer, and pancreatic cancer. In patients over 65 years of age, patients who are current or past smokers, and patients with other malignancy risk factors (e.g. current malignancy or history of malignancy other than a successfully treated non-melanoma skin cancer) tofacitinib should only be used if no suitable treatment alternatives are available. NMSCs have been reported in patients treated with tofacitinib; the risk of NMSC may be higher in patients treated with tofacitinib 10 mg twice daily than in patients treated with 5 mg twice daily. Periodic skin examination is recommended in patients at increased risk for skin cancer. Interstitial lung disease: Caution is

recommended in patients with a history of chronic lung disease as they may be more prone to infection. Asian patients are known to be at higher risk of ILD, caution should be exercised with these patients. Gastrointestinal perforations: Tofacitinib should be used with caution in patients who may be at increased risk, e.g. history of diverticulitis or concomitant use of corticosteroids or NSAIDs. Hypersensitivity: Cases of drug hypersensitivity associated with tofacitinib administration have been reported. Allergic reactions included angioedema and urticaria; serious reactions have occurred. If any serious allergic or anaphylactic reaction occurs, tofacitinib should be discontinued immediately. Laboratory Parameters: Increased incidence of lymphopenia and neutropenia have been reported, and decreases in haemoglobin, which should be monitored in accordance with the SmPC. Monitor ANC and haemoglobin at baseline, 4-8 weeks and 3 monthly, ALC at baseline and 3 monthly. Tofacitinib has been associated with increases in lipid parameters, maximal effects were observed within 6 weeks. Monitoring should be performed 8 weeks after initiation and managed according to hyperlipidaemia guidelines. Increases in liver enzymes greater than 3x ULN were uncommonly reported; use caution when initiating with potential hepatotoxic medicinal products. Gastrointestinal obstruction with a non-deformable prolonged-release formulation: Caution should be used when administering tofacitinib 11 mg prolonged release tablets to patients with pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic). Pregnancy & Lactation: Use of tofacitinib during pregnancy and breast-feeding is contraindicated. Side Effects: RA: The most common serious adverse reactions were serious infections; pneumonia, cellulitis, herpes zoster, UTIs, diverticulitis, appendicitis and opportunistic infections. The most commonly reported adverse reactions during the first 3 months in controlled clinical trials were headache, upper respiratory tract infections, nasopharyngitis, diarrhoea, nausea and hypertension. UC: The most commonly reported adverse reactions in patients receiving tofacitinib 10 mg twice daily in the induction studies were headache, nasopharyngitis, nausea, and arthralgia. Commonly reported adverse reactions (>1/100 to <1/10) across all indications were pneumonia, influenza, herpes zoster, urinary tract infection, sinusitis, bronchitis, viral upper respiratory tract infection, pharyngitis, anaemia, headache, hypertension, cough, abdominal pain, vomiting, diarrhoea, nausea, gastritis, dyspepsia, rash, arthralgia, pyrexia, oedema peripheral, fatigue, blood creatine phosphokinase increased. Refer to section 4.8 of the SmPC for further information on side effects, including description of selected adverse reactions. Legal Category: S1A. Marketing Authorisation Number: EU/1/17/1178/003 – 5 mg (56 film-coated tablets); EU/1/17/1178/007 – 10 mg (56 film-coated tablets); EU/1/17/1178/012 – 11 mg (28 prolonged-release tablets); EU/1/17/1178/015 1mg/mL oral solution. Marketing Authorisation Holder: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium. For further information on this medicine please contact: Pfizer Medical Information on 1800 633 363 or at medical.information@pfizer.com. For queries regarding product availability please contact: Pfizer Healthcare Ireland, 9 Riverwalk, National Digital Park, Citywest Business Campus, Dublin 24, + 353 1 467 6500. ˸ This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 of the SmPC for how to report adverse reactions. Last revised: 10/2021. Ref: XJ 13_0.

References: 1. Sandborn WJ, Su C, Sands BE, et al; for the OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE Sustain Investigators. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2017;376(18):1723-1736. 2. Hanauer S et al. Tofacitinib Induction Therapy Reduces Symptoms Within 3 Days for Patients With Ulcerative Colitis. Clin Gastroenterol Hepatol. 2019;17(1):139-147. 3. XELJANZ Summary of Product Characteristics.

76 News

Cancer in Ireland: NCR Annual Report

The National Cancer Registry Ireland (NCRI) has announced its updated statistics on cancer incidence, mortality and survival for patients diagnosed with cancer in Ireland 1994 – 2019.

attention to other opportunities to improve the health of the nation. The incidence and mortality rates of melanoma skin cancer continue to increase in females, pointing to the importance of sun safety.

Highlights this year include:

“Incidence rates for oropharyngeal and liver cancers are increasing, as are mortality rates for liver cancer in both sexes. This report is a timely reminder that HPV vaccination and adopting a healthy lifestyle can reduce the risk of developing these cancers.

• Five-year net survival averaging 65% for patients diagnosed between 2014 and 2018, a substantial increase from twenty years previously when 42% was the average. • The number of cancer survivors living through or after cancer treatment in Ireland continuing to increase, year on year. At the end of 2019, there were nearly 200,000 patients living after a cancer diagnosis. • Indications of substantial inroads being made in the progress to control the four commonest cancers (prostate, breast, lung and colorectal), which comprise over half of all invasive tumours (other than non-melanoma skin cancers). • Mortality rates falling for these four major cancers (or stabilising for lung cancer in females), and incidence rates falling for both lung and colorectal cancers, in both sexes, though relatively recently for lung cancer in females. Professor Deirdre Murray, Director of the National Cancer Registry said, “The report also draws

“The incidence rate of cervical cancer continues to fall, reflecting the impact of the screening programme. It must be remembered from a service planning perspective, that despite the successes in reducing cancer incidence and mortality rates, the number of patients diagnosed with cancer every year is rising and will continue to rise in future decades as the Irish population continues to grow and the average age increases.” The improved cancer survival figures revealed by the report are being put at serious risk by pandemic-related disruption, according to the Irish Cancer Society. Commenting on the National Cancer Registry Ireland (NCRI) annual report, the Society’s CEO Averil Power said, “While it is heartening to hear that progress is being made for devastating

JANUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

cancers like breast, lung and prostate according to latest figures up to 2019, we are very worried that significantly less cancers were diagnosed last year. “This will present a major challenge for years to come, and is unfortunately no surprise as already struggling cancer services have been stretched to breaking point during the pandemic. Lengthy waiting lists and disruptions to vital diagnostic and screening services are now all too commonplace. “Patients are telling us that they are terrified of having their treatment delayed given the current spike in Covid case numbers and are very distressed about the worrying consequences to their health from catching the virus, and the further risk of treatment delays that this would bring. “The Irish Cancer Society is collaborating with researchers from the Royal College of Surgeons Ireland and others on a much-needed project to get a clearer picture of the impact of the pandemic on cancer services. In the meantime we need the Government to step up and put a massive effort into clearing waiting lists and securing cancer services for patients nearly two years into this crisis. “The NCRI report shows that as many as 1 in 8 cancers that were

predicted to be diagnosed in 2020 were not. Although there has been an encouraging trend of people seeking medical help so far this year, waiting times for diagnostic tests remain too long and these must be addressed as a matter of urgency. “It is frightening to think that there are people in our community with cancer who don’t know it yet.” Earlier this year, another report released by the National Cancer Registry highlighted that at least a third of invasive cancers can be prevented through modifying some of our lifestyle behaviours. The report analysed skin cancer rates in Ireland using just two of the factors that contribute to our skin cancer risk: a single sunburn episode and using sunbeds. It found that these two factors alone contributed to: • More than 400 cases of melanoma, the most serious form of skin cancer. • Almost 3,000 diagnoses of nonmelanoma skin cancer (NMSC). Although melanoma is not the most frequently diagnosed skin cancer, it is associated with significant ill-health, is much more likely to spread to other parts of the body and can be fatal. While NMSC is rarely fatal, treatment may require disfiguring surgery and/or lifetime treatment and monitoring.

KEYTRUDA NOW PUBLICLY AVAILABLE FOR THE ADJUVANT TREATMENT OF RESECTED STAGE III MELANOMA1

WITH THE FLEXIBILTY OF 3 WEEKLY OR 6 WEEKLY DOSING2 44% REDUCTION IN THE RISK OF DISEASE RECURRENCE OR DEATH VS PLACEBO3

Infusion 25mg/mL

3-YEAR RECURRENCE-FREE SURVIVAL (RFS) OF THE OVERALL POPULATION IN KEYNOTE-0543,a 100

75 %

68 %

64%

70 60

60%

40 30

HRb=0.56 (95% CI, 0.47–0.68)

KEYTRUDA

Placebo

47%

Time, months

Number at risk KEYTRUDA 514 Placebo 505

44%

RFS was estimated by the Kaplan-Meier method.3 The HR and its confidence interval (CI) were estimated using the Cox model stratified by stage provided at randomization.3 c Regardless of investigator attribution.4 a

412

374

351

333

314

189

360

298

259

226

215

126

(SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving pembrolizumab. If SJS or TEN is confirmed, pembrolizumab should be permanently discontinued. Other clinically significant immune-related adverse reactions: The following additional clinically significant, immune-related adverse reactions, have been reported in clinical studies or in post-marketing experience: uveitis, arthritis, myositis, myocarditis, pancreatitis, Guillain-Barré syndrome, myasthenic syndrome, haemolytic anaemia, sarcoidosis, encephalitis, myelitis, vasculitis, cholangitis sclerosing and gastritis. Refer to SmPC for information on management of significant immune-related adverse reactions. Complications of allogeneic Haematopoietic Stem Cell Transplant (HSCT): Allogeneic HSCT after treatment with pembrolizumab: Cases of graft-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. Allogeneic HSCT prior to treatment with pembrolizumab: In patients with a history of allogeneic HSCT, acute GVHD, including fatal GVHD, has been reported after treatment with pembrolizumab. Infusion-related reactions: For Grades 3 or 4infusion reactions including hypersensitivity and anaphylaxis, stop infusion and permanently discontinue pembrolizumab. With Grades 1 or 2 infusion reactions, infusion may continue with close monitoring. Premedication with antipyretic and antihistamine may be considered. Overdose: There is no information on overdose with pembrolizumab. In case of overdose, monitor closely for signs or symptoms of adverse reactions and treat appropriately. INTERACTIONS No formal pharmacokinetic drug interaction studies have been conducted with pembrolizumab. No metabolic drug drug interactions are expected. The use of systemic corticosteroids or immunosuppressants before starting pembrolizumab should be avoided because of their potential interference with the pharmacodynamic activity and efficacy of pembrolizumab. Corticosteroids can be used as premedication, when pembrolizumab is used in combination with chemotherapy, as antiemetic prophylaxis and/or to alleviate chemotherapy-related adverse reactions. FERTILITY, PREGNANCY AND LACTATION Women of childbearing potential Women of childbearing potential should use effective contraception during treatment with pembrolizumab and for at least 4 months after the last dose of pembrolizumab. Pregnancy No data on use in pregnant women. Do not use during pregnancy unless the clinical condition of the woman requires treatment with pembrolizumab. Breast-feeding It is unknown whether pembrolizumab is secreted in human milk. A risk to newborns/ infants cannot be excluded. Fertility No clinical data available. SIDE EFFECTS Refer to SmPC for complete information on side effects. Pembrolizumab is most commonly associated with immune-related adverse reactions. Most of these reactions resolved with appropriate medical treatment or withdrawal of pembrolizumab. The most serious adverse reactions were immune-and infusion-related adverse reactions. Monotherapy: Very Common: anaemia, hypothyroidism, decreased appetite, headache, dyspnea, cough, abdominal pain, nausea, vomiting, constipation, musculoskeletal pain, arthralgia, asthenia, oedema, pyrexia, diarrhoea, rash, pruritus, fatigue. Common: pneumonia, thrombocytopenia, neutropenia, lymphopenia, hyponatraemia, hypokalaemia, hypocalcaemia, insomnia, neuropathy peripheral, lethargy, dry eye, cardiac arrhythmia (including atrial fibrillation), hypertension, hyperthyroidism, thyroiditis, insomnia, dizziness, dysgeusia, pneumonitis, colitis, dry mouth, severe skin reactions, vitiligo, dry skin, alopecia, eczema, dermatitis acneiform, erythema, dermatitis, myositis, pain in extremity, arthritis, influenza like illness, chills, AST and ALT increases, hypercalcaemia, increase in blood alkaline phosphatase, blood bilirubin increased, blood creatinine increased, infusion related reaction. Combination with chemotherapy: Very Common: pneumonia, anaemia, neutropenia, thrombocytopenia, hypothyroidism, hyponatraemia, hypokalaemia, decreased appetite, insomnia, dizziness, neuropathy peripheral, headache, dyspnoea, cough, alopecia, nausea, diarrhoea, vomiting, abdominal pain, constipation, rash, pruritus, musculoskeletal pain, arthralgia, pyrexia, fatigue, asthenia, oedema, blood creatinine increased. Common: febrile neutropenia, leukopenia, lymphopenia, infusion related reaction, hyperthyroidism, hypocalcaemia, dysgeusia, lethargy, dry eye, cardiac arrhythmia (including atrial fibrillation), vasculitis, hypertension, pneumonitis, colitis, dry mouth, gastritis, hepatitis, severe skin reactions, dry skin, erythema, dermatitis, myositis, pain in extremity, arthritis, acute kidney injury, influenza-like illness, chills, hypercalcaemia, ALT increase, AST increased, blood alkaline phosphatase increased, blood bilirubin increased. Combination with axitinib: Very Common: hyperthyroidism, hypothyroidism, decreased appetite, headache, dysgeusia, hypertension, dyspnoea, cough, dysphonia, diarrhoea, abdominal pain, nausea, vomiting, constipation, palmar-plantar erythrodysaesthesia syndrome, rash, pruritus, musculoskeletal pain, arthralgia, pain in extremity, fatigue, asthenia, pyrexia, alanine aminotransferase increased, aspartate aminotransferase increased, blood creatinine increased. Common: pneumonia, anaemia, neutropenia, leukopenia, thrombocytopenia, infusion related reaction, hypophysitis, thyroiditis, adrenal insufficiency, hypokalaemia, hyponatraemia, hypocalcaemia, insomnia, dizziness, lethargy, neuropathy peripheral, dry eye, cardiac arrhythmia (including atrial fibrillation), pneumonitis, colitis, dry mouth, gastritis, hepatitis, severe skin reactions, dermatitis acneiform, dermatitis, dry skin, alopecia, eczema, erythema, myositis, arthritis, tenosynovitis, acute kidney injury, nephritis, oedema, influenza like illness, chills, blood alkaline phosphatase increased, hypercalcaemia, blood bilirubin increased PACKAGE QUANTITIES KEYTRUDA 25 mg/mL: 4 mL of concentrate in a 10 mL Type I clear glass vial. Legal Category: POM. Marketing Authorisation numbers EU/1/15/1024/002 Marketing Authorisation holder Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands. Date of revision: June 2021. © Merck Sharp & Dohme B.V. 2021. All rights reserved. Further information is available on request from: MSD, Red Oak North, South County Business Park, Leopardstown, Dublin D18 X5K7 or from www.medicines.ie. PSUSA-202009-II-097 Adverse events should be reported. Reporting forms and information can be found at www.hpra.ie. Adverse events should also be reported to MSD (Tel: 01-2998700) References: 1. https://www.hse.ie/eng/services/list/5/cancer/profinfo/chemoprotocols/melanoma/melanoma%20protocols.html 2. Keytruda Summary of Product characteristics, available from www.medicines.ie 3. Eggermont AMM, Blank CU, Mandala M, et al. Longer follow-up confirms recurrence-free survival benefit of adjuvant pembrolizumab in high-risk stage III melanoma: updated results from the EORTC 1325-MG/KEYNOTE-054 trial. J Clin Oncol. 2020 Sep18;38:3925-3936. 4. Eggermont AMM, Blank CU, Mandala M, et al. Supplementary Appendix to: Longer follow-up confirms recurrence-free survival benefit of adjuvant pembrolizumab in high-risk stage III melanoma: updated results from the EORTC 1325- MG/KEYNOTE-054 trial. (J Clin Oncol. Epub 2020.) doi:10.1200/JCO.20.02110. Red Oak North, South County Business Park, Leopardstown, Dublin D18 X5K7, Ireland.

Date of Preparation: October 2021

IE-KEY-00374

Recurrence-free survival, %

IMMUNE-RELATED ADVERSE EVENTS (IRAES) IN KEYNOTE-0544,c

78 News

Vaccine Hesitancy Down COVID-19 vaccine hesitancy fell by 45 points in 12 months, according to an analysis of surveys conducted by Ipsos MRBI for the Irish Pharmaceutical Healthcare Association (IPHA), the representative body for the research-based biopharmaceutical industry. In November 2020, 17% of people said they would refuse a COVID-19 vaccine. By last month, that figure had dropped to 5%. Between November 2020 and November 2021, the proportion of people undecided about taking a COVID-19 fell from 35% to 2%. That places the overall drop in hesitancy at 45 points. Among 18 to 34-year-olds, the proportion of people who would refuse a vaccine for COVID-19 has dropped from 19% in November 2020 to 6% in November 2021.

The proportion of people in that age category undecided about taking a COVID-19 fell from 38% to 3% in the same period. That means hesitancy among people aged between 18 and 34 dropped by 48 points in 12 months. Around 1.2 million people are aged between 18 and 34 out of a population of about five million. Overall, 93% of people either intend to get vaccinated for COVID-19 or have already received a vaccine for the disease, according to the latest survey*. The research-based biopharmaceutical industry said COVID-19 vaccines are saving and protecting millions of lives around the world. Bernard Mallee, Director of Communications and Advocacy at IPHA, said, “From childhood

to later in life, the development of vaccines has protected us from serious, and sometimes deadly, diseases. In Ireland, smallpox, rubella, polio, tuberculosis, diphtheria, pneumonia and measles used to be part of life. Now, we don’t have to worry about them as much. “Vaccines for COVID-19, developed in record time without compromising on safety and quality, are saving and protecting millions of lives around the world. That COVID-19 vaccine hesitancy is low in Ireland has helped to make us one of the most vaccinated countries in the world. Vaccination reduces serious illness and mortality, giving us a very effective weapon in the battle against COVID-19. “Vaccines, allied with public health measures, protect health

and save lives. The emergence of the Omicron variant, and the increased transmissibility of the Delta variant, show that we need to keep searching for new scientific paths to combat the virus. We are fortunate to live at a time of unprecedented medical innovation. We should continue to trust science and to heed public health advice.” With the exception of clean, safe drinking water, vaccination is among the most successful and cost-effective public health interventions ever. The World Health Organisation estimates that vaccines save up to three million lives every year. IPHA’s new life-course immunisation campaign, ‘Progress. Developed by Vaccines’, is live on Twitter, Facebook and Instagram.

Accord Healthcare Maintain Leading Position Padraic O’ Brien, Managing Director, Accord Healthcare Ireland

The High-Tech medicines scheme was first introduced in Ireland in 1996. The scheme involves the supply & dispensing of High-Tech medicines through community pharmacies. Expenditure on this scheme has continually increased with spend rising by 173% between 2009 and 2019.2 Consistency of supply is extremely important in the context of High-Tech medicines as many of these medicines are prescribed for long term illnesses. Accord Healthcare Ireland’s High-Tech portfolio consists of sixteen

medicines of which they are the leading generic supplier1 in fifteen of these. 2022 will see many new High-Tech launches. Demonstrating their commitment to these medicines Accord conducted market research with Behaviour and Attitudes in 2021. The research demonstrated that 63% of pharmacists who use the High-Tech hub had a positive experience with it.3 On average, pharmacists placed orders for 33 scripts through the hub per month.3 Another positive highlighted in the research is that

JANUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

59% do not have concerns about other therapeutic areas joining the hub.3 Pharmacists also nominated Accord Healthcare Ireland as the supplier they would be most likely to recommend in this research. The reasons for this were; reliability, product availability and price to name a few.4 Padraic O’ Brien, Managing Director of Accord Healthcare Ireland said, “We at Accord Healthcare Ireland have established ourselves as a leader in the generic High-Tech market, we want Irish pharmacists to know that we are always here to support them and to ‘Think High-Tech’s, Think Accord’. We identified the opportunity in this market some time ago and our portfolio has increased by 45% since 2017 alone. We have an extensive range of generic hightech medicines demonstrating our commitment to ensuring more Irish patients have access to the medicines they need when they need them. The next 12 months will be an important time for the High-Tech space and Accord Healthcare Ireland will be playing its part as an industry leader promising a very strong pipeline for the year ahead.” As the generic High-Tech product is priced up to 60%5 below the branded product, when

pharmacists dispense items from the Accord Healthcare Ireland High-Tech portfolio, they are not only helping to provide a quality treatment for Irish patients, they are also helping the state to make considerable savings. In turn, these savings are used to provide access to new medicines allowing more patients access to the treatments they require. Think High-Tech’s, Think Accord. References 1. IQVIA Retail Data accessed November 2021. 2. Figures from The Medical Independent articles; ‘HSE spend on High-Tech Drugs Scheme increases by almost 100%’ and ‘Figures reveal spiralling cost of HSE high-tech drugs’, accessed November 2021. 3. Data on file IE-01721, page 35. 4. Data on file IE-01721, page 11. 5. Framework Agreement between the Association of Pharmaceutical Manufacturers of Ireland and the Department of Health and the Health Service Executive on the Supply Terms, Conditions and Prices of Generic Medicines, section 5.2.

Research 79 School of Medicine launches Ambitious New Research Strategy Director of Research at the School of Medicine, Professor Ursula Fearon

Trinity College Dublin’s School of Medicine has just recently launched an ambitious new research strategy for 2021-2026. The official launch celebrated the School’s research successes and looked to the future where the patient will be front and centre of all research activities and outputs at the School. The recent launch of the School of Medicine’s newly published Research Strategy 2021-2026 was co-hosted by the new Dean of Research, Professor Wolfgang Schmitt and the new Director of Research at the School of Medicine, Professor Ursula Fearon. Professor Schmidt discussed the challenges around research during a global pandemic, and noted the flexibility & resilience shown by researchers & healthcare workers during this time. He praised the broad research & deep culture highlighted in the Strategy and the excellent quality of earlycareer researchers in the School. Professor Schmidt also spoke of the importance of supporting younger researchers in the pursuit of funding. Professor Louise Gallagher, out-going Director of Research at the School and the main architect of the School’s Research Strategy explained the strategy development process and how the vision and values for Research Excellence and Impact took shape. She noted, “We punch above our weight in research outputs, reflecting the strengths within our school.” Speaking on the impact of the School’s research and the positive effect on societal health and wellbeing, she noted, “This is why we do what we do.” Placing Public Patient Involvement (PPI) front and centre of health research planning and communications As evidence of the School of Medicine’s deep commitment to Public Patient Involvement (PPI), Dr Avril Kennan, CEO, Health Research Charities Ireland (the umbrella organisation of charities active in health, medical and social sciences research) was keynote speaker. In her keynote presentation Dr Kennan

emphasised the importance of cocreating research questions as well as increasing diversity in research. Research Vision School of Medicine research will be internationally respected and will lead transformation at the heart of Irish health innovation, delivering improvements in health services and patient care. School of Medicine research will improve good health and wellbeing, as articulated in the UN Sustainable Development Goals.

• Train the health research leaders of tomorrow. • Attract and grow an innovative and diverse multidisciplinary faculty. • Invest in the sustainability of our infrastructures: diversify our funding. • Collaborate with all our stakeholders, including patients, to guide more meaningful impact.

Research Values

New key awards announced by the School of Medicine at the launch

Trinity’s School of Medicine is a research-led school that values cutting-edge innovation, leverages local, national and international collaboration, and is focused on improving human health and healthcare.

A key priority in the school’s strategy was a commitment to establish annual prizes that recognise outstanding contributions to research and the achievements of our early-career researchers.

The School believes that this can be achieved through a blend of curiosity-driven and themefocused strategies that address both fundamental biological questions and health inequities. All our research is performed with the highest integrity and ethical values.

– Trinity College Med Awards Programme

The School values the contributions of stakeholders, patient groups, health NGOs and the public to guide and co-design our research towards meaningful impact.

– Trinity College MED Research Impact Awards 2022

Research Mission • Support excellent and impactful research to improve health and patient outcomes.

As a first step in implementing this strategic objective, details of the ¤50,000 Trinity College Med Awards Programme were announced during the Webinar.

The ¤21,000 Trinity College MED Research Impact Awards Programme 2022 aims to promote and enhance communication of research impact in a language relevant to all stakeholders. Priority will be given to that research with demonstrable and significant benefit to the respective audience

“We punch above our weight in research outputs, reflecting the strengths within our school” Professor Louise Gallagher, out-going Director of Research

or stakeholder group most affected by the research findings. In 2022, there will be 3 awards of ¤7,000 each. The initiative aims to highlight research with potential positive impact on society. – Trinity College MED Research Seed Awards 2022 The ¤30,000 TCD MED Research Seed Awards Programme 2022 will support new and innovative research and enhance the School of Medicine’s ability to compete for large-scale, external awards. In 2022-23, there will be three awards of ¤10,000 each. The initiative aims to advance the research priorities of the School of Medicine’s Strategic Plan, raise the national and international profile of the University through increased competitiveness for funding from sources including the European Commission, Wellcome Trust, Science Foundation Ireland, Irish Research Council and Health Research Board, as well as other external funding agencies. Full details here: https://www. tcd.ie/medicine/research/ awards-2022/

HOSPITALPROFESSIONALNEWS.IE | HPN • JANUARY 2022

80 Clinical R&D DUTCH STEM CELL BIOTECH NEUROPLAST SECURES ¤10 MILLION (US$ 11.5 MILLION) IN SERIES B FUNDING TO FURTHER ADVANCE ITS TRANSFORMATIVE STEM CELL THERAPY FOR TRAUMATIC SPINAL CORD INJURY Dutch clinical phase biotech Neuroplast raised a total of ¤10 million (US$ 11.5 million) in funding from investors Lumana Invest, Brightlands Venture Partners, LIOF, and from the Innovation Credit from the Netherlands Enterprise Agency, to further advance the clinical development of a transformative treatment for Traumatic Spinal Cord Injury (TSCI). Neuroplast will use this Series B funding to obtain conditional EMA market approval for its Neuro-Cells® stem cell therapy. Annually, approximately 29,000 people across Europe and the USA suffer from acute Traumatic Spinal Cord Injury (TSCI), for which effective treatment is currently unavailable. Patients usually experience life-long disability and dependence, with a negative impact on quality of life. Furthermore, associated costs for society at large are estimated at over ¤11.4 billion ($13 billion) per year. With the aim of giving back perspective to people that suffer from primarily inflammation-driven neurological disorders, Neuroplast has developed Neuro-Cells®, a treatment that uses the patient's own stem cells to prevent (further) loss of function during the acute phase after sustaining damage to the spinal cord, to save mobility and independence. Marcel Kloosterman, Managing Partner at Brightlands Venture Partners (BVP), states, "The science behind Neuroplast's technology platform is truly groundbreaking. A future in which patients can make smart use of their own cells to put a stop to further neurological damages and improve potential regeneration is getting closer and closer. For BVP it is a thrill to be part of that fascinating journey." Neuroplast acquired a GMP[1] license and received a European Orphan Designation[2] that allows fast-track development. Furthermore, it has already successfully completed a clinical Phase I trial, in collaboration with Hospital Nacional de Parapléjicos in Spain, that confirmed safety and tolerability, without productrelated adverse events. The Dutch Limburg-based biotech is currently preparing for an international multi-center randomized placebocontrolled Phase II study.

SANOFI REITERATES CONFIDENCE IN STRONG GROWTH OUTLOOK AND SHOWCASES PIPELINE OF INNOVATIVE VACCINE CANDIDATES Sanofi has hosted a hybrid Vaccines Investor Event with key members of the Vaccines leadership team to discuss how the company applies the global Play to Win strategy to pursue growth opportunities and to build an industry-leading vaccines pipeline. Sanofi confirms its mid-term sales guidance announced at the 2019 Capital Markets Day of mid-tohigh single-digit growth1 for its Vaccines business. Sustained growth will be driven by four core franchises of influenza, meningitis, PPH3 & Boosters, as well as the planned launch of nirsevimab, a first-in-class monoclonal antibody for all infant protection against Respiratory Syncytial Virus. These core franchises are well positioned to capture market growth, such as in the global influenza market which Sanofi expects to exceed ¤15 billion by 2030. Sanofi has made significant progress in the field of mRNA technology with the recently established Center of Excellence and the integration of Translate Bio. Results from a first influenza mRNA clinical trial will be shared as well as initial successes in mRNA technology improvements. Of the 10 new vaccine candidates planned to enter the clinic by 2025, six will use mRNA technologies to target diseases with high unmet needs and disease burden such as chlamydia and acne. Sanofi will present the following assets in its growing R&D pipeline:

• A pneumococcal vaccine candidate covering 21 serotypes, with Phase 1/2 clinical trials underway in three target populations; results are expected by end of 2022. • A combination of MenQuadfi and a new meningitis B vaccine candidate to create a best-in-class pentavalent meningococcal vaccine with broader strain coverage; Phase 2 meningitis B read-out is expected by H2 2022 and the initiation of a Phase 1 trial for the pentavalent candidate is planned in 2023. • RSV vaccine candidates for toddlers and older adults to address a high unmet disease burden; Phase 1/2 trial results in toddlers are anticipated in 2022; in parallel, an mRNA vaccine candidate for older adults is planned to enter a Phase 1/2 study in H2 2022.

JANUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

• Next generation influenza programs to deliver differentiated flu vaccines that set a new standard of care; the influenza mRNA QIV program will enter Phase 1/2 trial in 2022 and a Phase 3 trial is planned to start in 2023; Sanofi also deploys proprietary machine-learning to explore the potential for better strain selection in the future. • Opening new growth areas: o Chlamydia: Sanofi has initiated a program to prevent chlamydia infection, a silent cause of infertility in women; a Phase 1 trial of an mRNAbased candidate is planned to start in 2023. o Acne: Sanofi strives to leverage its vaccine technology to develop the first immunotherapy against acne and to enter the clinic in 2023. SANTHERA AND REVERAGEN ANNOUNCE POSITIVE TOPLINE RESULTS WITH VAMOROLONE Santhera Pharmaceuticals (SIX: SANN) and ReveraGen BioPharma, Inc (US: private) have announced new topline results after completion of the VISION-DMD study at week 48. As previously reported, the FDA considered the safety and efficacy data of vamorolone at 24 weeks (period 1) sufficient for an NDA filing. Efficacy assessments at the now reported completion at week 48 (period 2) included Time to Stand (TTSTAND) velocity, 6-Minute Walk Test (6MWT), Time to Run/ Walk 10 meters (TTRW) velocity, and North Star Ambulatory Assessment (NSAA). Vamorolone 6 mg/kg/day showed maintenance of efficacy across all parameters until end of study at week 48, and was statistically superior to 2 mg/kg/day for TTSTAND velocity and 6MWT but not for TTRW velocity or NSAA. For subjects who continued on the same dose of vamorolone throughout the study, the safety profile was consistent between periods with no increase in frequency or severity of adverse events being observed over time. Subjects switching from 24-week treatment with prednisone to vamorolone 6 mg/kg/day showed no loss of efficacy through to the end of the study. In addition, vamorolone treatment at both doses reversed the growth impairment seen during prednisone treatment and was associated with fewer adverse events, including those associated with corticosteroid use. VISION-DMD was a pivotal double-blind Phase 2b study designed to demonstrate efficacy

and safety of vamorolone compared to placebo and prednisone (active control) in the treatment of DMD [1, 2]. In the first 24-weeks (period 1), 121 ambulant boys aged 4 to <7 years were randomized to receive vamorolone (2 or 6 mg/kg/day) or prednisone (0.75 mg/kg/day) or placebo. 114 subjects continued for another 24 weeks (period 2), where those on vamorolone 2 and 6 mg/kg/day continued to end of study on these doses, and those on prednisone and placebo had been previously randomized to receive vamorolone 2 or 6 mg/kg/day after a 4-week tapering period. 112 subjects completed the study. Efficacy of vamorolone established at 24 weeks was maintained over 48-week treatment period Efficacy at week 48 was assessed for measures including TTSTAND velocity, 6MWT, TTRW velocity and NSAA. The size of effect (change from baseline) observed at the primary endpoint at week 24 for vamorolone 6 mg/kg/day was maintained at week 48 for TTSTAND velocity (0.052 vs 0.045 rises/s), NSAA (3.4 vs 3.5 points), TTRW velocity (0.29 vs 0.23 m/s) and improved for 6MWT (37 vs 48 meters). Vamorolone 2 mg/kg/day showed clinically relevant and robust efficacy at week 24 for the predefined hierarchical endpoints of TTSTAND velocity and 6MWT, as well as NSAA which was an exploratory endpoint. At week 48, vamorolone 6mg/kg/day was statistically superior to vamorolone 2 mg/kg/day in TTSTAND velocity (p=0.010) and 6MWT (p=0.047) but not for TTRW velocity (p=0.37) and NSAA (p=0.60). The efficacy benefit seen with prednisone in period 1 was maintained when subjects were switched to vamorolone 6 mg/kg/ day during period 2: TTSTAND velocity (0.28 vs 0.27 rises/s), 6MWT distance (407 vs 408 meters), TTRW velocity (2.20 vs 2.20 m/s) and NSAA (25.6 vs 26.2 points), all absolute values. Vamorolone at both doses was generally safe and well tolerated Of the 114 subjects who entered into period 2, two subjects discontinued treatment (one adverse event, one withdrawn consent). Three serious adverse events thought to be unrelated to study drug were reported during vamorolone treatment. For subjects who continued on the same dose of vamorolone throughout the study, the safety profile was consistent at week 48 compared to the results previously reported at week 24.

81 Growth velocity was preserved at both vamorolone doses. Body mass index (BMI) was stable for subjects continuing on vamorolone 2 and 6 mg/kg/day between assessments at week 24 and week 48 (mean z-score 1.15 vs 1.25 for 6 mg/kg/day; 0.76 vs 0.91 for 2 mg/kg/day where a z-score of 0 would represent the median value of an age-matched general population). Safety and tolerability of switching from prednisone to vamorolone Comparison of the safety outcome parameters of prednisone at week 24, following cross-over to vamorolone 2 or 6 mg/kg/day, showed an improved safety profile. In subjects, who were switched from prednisone to vamorolone 6 mg/kg/day, the number of total adverse events was reduced by 37% (70 vs 44) and the number of adverse events typically associated with corticosteroids was reduced by 60% (40 vs 16). Of particular interest, the number of adverse events reported as behavioral changes decreased by 60% (15 vs 6).

population, a new report shows. The study found that nearly half (42%) have clinically significant socio-emotional problems – which have an impact on home life, classroom learning and the ability to get on with others. Only 14% of these, however, are currently receiving mental health or counselling supports. It finds that the area of greatest difference for deaf and hard of hearing children is in peer difficulties, an area other studies have shown results in an increased lifetime risk of self-harm. The report, ‘Socio-emotional Development in Deaf and Hard of Hearing Children’ is the first of its kind carried out in Ireland and was commissioned by Chime, the national charity for deafness and hearing loss. It has warned that an approach which has involved urgent cases requiring specialist attention being seen by a psychiatrist in the UK at parents’ expense, is unsustainable, and that quicker intervention is required.

Stunting of growth observed with prednisone was reversed during treatment with vamorolone 6 mg/ kg/day in period 2 (mean z-score -0.38 vs -0.12 where a z-score of 0 would represent a normal growth trajectory). An increase of BMI was observed with prednisone in period 1 (mean z-score from 0.94 to 1.40) but stabilized in period 2 with vamorolone 6 mg/kg/day (mean z-score 1.32).

“Peer problems have been shown to increase the risk of self-harm over a lifetime, so the report findings in this area are very concerning,” said Chime CEO, Mark Byrne.

Similar effects for safety and tolerability were observed with the switch from prednisone to vamorolone 2 mg/kg/day.

“Deafness in and of itself is not the cause of these difficulties. Rather, a host of factors often outside their control leave deaf and hard of hearing children more vulnerable to socio-emotional difficulties.

DEAF AND HARD OF HEARING CHILDREN HAVE THREE TIMES RATE OF SOCIOEMOTIONAL DIFFICULTY The rate of socio-emotional difficulties amongst deaf and hard of hearing children is over three times that of the typical hearing

“There are no specialised supports for deaf and hard of hearing children in the socio-emotional area, and a lack of specialist competency in Ireland.

“Issues which can lead to greater risk of socio-emotional difficulties include delayed diagnosis and appropriate intervention, lack of access to sign language and stigma towards deafness and the stresses associated with that.

“Mainstream services struggle to assess and meet the needs of deaf and hard of hearing children with socio-emotional difficulties.” Mr Byrne said the HSE acknowledged in 2017 the need for specialist screening and intervention services for deaf and hard of hearing children with complex needs. In countries such as Sweden, where there is specialist early intervention, scores for deaf and hard of hearing children were similar, if not lower, than the typically hearing population, report author Dr Elizabeth S. Mathews of DCU pointed out. The research used the Strengths and Difficulties Questionnaire (SDQ) used internationally and also on a large sample of the Irish child population in the Growing Up In Ireland study. LEO PHARMA PRESENTS NEW ADTRALZA® (TRALOKINUMAB) DATA

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LEO Pharma A/S, a global leader in medical dermatology, has announced results showing that after two years of continuous treatment with Adtralza, adult patients with moderate-to-severe atopic dermatitis maintained improvements in signs and symptoms, itch severity and sleep interference.1 Findings were shared as an oral presentation during the European Academy of Dermatology and Venereology (EADV) Congress 2021. The interim analysis investigated continued treatment with Adtralza as well as the ability to regain response after pausing and reinitiating Adtralza.1 Long-term efficacy outcomes were assessed in patients (n=345) who had received two years of treatment with Adtralza, including the full 52 weeks in the pivotal Phase 3 parent trials (ECZTRA 1 and 2) and 56 weeks in the ECZTEND trial.1 Patients were split into three cohorts based on the length of time between their last dose of Adtralza in the parent trial and their first dose in ECZTEND. Continuous treatment was defined as ≤5 weeks between the last dose in the parent trial and the first dose in ECZTEND (n=126), interrupted treatment was defined as 6-15 weeks (n=133), and >15 weeks (n=86) was considered a full washout of treatment.1

Brother and sister Lexi (8) and Mason (9) Noone from Kilnamanagh, Dublin, with Dr Elizabeth Mathews of the School of Inclusive and Special Education, Dublin City University

Patients who received continuous treatment with Adtralza over two years reported a high level of long-term control in atopic dermatitis signs and symptoms, as demonstrated by a median Eczema Area and Severity Index score (EASI) improvement from parent trial baseline of 92.7%.1 Maintenance of improvements in patient-reported outcomes, including pruritus (itch) severity and sleep interference, were demonstrated at two years as well. Itch severity and sleep interference were reported using a Numeric Rating Scale (NRS) of 0-10. Patients who received continuous treatment reported improvements in itch severity, with worst weekly NRS score for median pruritus, shifting from severe itch (8.1 out of 10) at parent trial baseline to mild itch (3 out of 10) following two years of treatment.1 These patients also reported improvement in median sleep interference, from severe sleep interference (7.3 out of 10) at parent trial baseline to mild sleep interference (1 out of 10) in ECZTEND.1 During the parent trials, patients recorded their daily itch and sleep interference, and weekly averages of scores were used. During ECZTEND, worst itch severity and sleep interference of the previous week were reported. A decline in the median EASI percentage was observed in the washout cohort within the period without treatment. After one year of treatment in the parent trial, results showed a median EASI percent improvement of 86.9% compared to baseline. Following the washout of treatment (>15 weeks), median EASI percent improvement (vs. parent trial baseline) declined to 68.6%. A median EASI percent improvement equivalent to response at one year in the parent trials was regained within 12 weeks from treatment re-initiation with tralokinumab in ECZTEND.1 The safety of Adtralza treatment was also assessed in this interim analysis and results were consistent with the initial placebocontrolled treatment periods of the parent trials.1 Additionally, LEO Pharma is presenting a post-hoc analysis that evaluated predictors of maintained response with Adtralza dosing every four weeks as a late-breaking oral presentation.2 An interim analysis of COVID-19 cases and SARS-CoV-2 vaccinations during treatment with Adtralza in patients with moderateto-severe atopic dermatitis enrolled in the ECZTEND trial will also be presented as an e-poster.3

HOSPITALPROFESSIONALNEWS.IE | HPN • JANUARY 2022

82 Clinical R&D PIERRE FABRE LAUNCHES THE GREEN IMPACT INDEX

The Pierre Fabre Group is innovating with the launch of the Green Impact Index, a tool which enables the measurement and transparent communication of the environmental and societal impact of cosmetic and family health products. With the Green Impact Index, consumers will be informed of the eco-societal performance of the Group's products, through a simple letter (A, B, C or D). A grade of A or B means that the product is eco-socio-designed to the extent that it meets a sufficient number of environmental and societal performance criteria in line with internationally recognized benchmarks. In addition to informing consumers, the Green Impact Index will enable Pierre Fabre to improve the eco-societal profile of its products, in harmony with the objective of ensuring that half of its portfolio is eco-sociodesigned by 2023. The tool has already been used internally for the past two years to ensure the eco-socio-design of products in the development stages (grade A or B). The Green Impact Index was designed and developed by Green Mission Pierre Fabre, the Group entity that drives and brings together its environmental awareness and sustainable development initiatives. This work is based in particular on the 3,000 Life-Cycle Analyses (LCAs) that the Group has conducted for over 10 years in order to develop a methodology based on the evaluation of 20 criteria: • 14 environmental impact criteria, divided among the eco-design of the packaging, the eco-design of the formula, the impact of the manufacturing of the product and the transportation of raw materials. These 14 criteria represent two thirds of the final score. • Six societal impact criteria, including Made in France, Bio, Fair Trade, Origine France Garantie and Vegan certifications or labeling, as well

as the brand’s corporate social responsibility programs. These 6 criteria represent one third of the final score. The reliability and validity of the methodology have been assessed and endorsed by AFNOR Certification, an independent third-party organization. AFNOR Certification will conduct an annual audit to verify and guarantee the reliability of the ratings carried out by Pierre Fabre on its products. The Green Impact Index will be deployed progressively. The grades of the first products rated from the brands Avène, A-Derma, Ducray, Klorane, René Furterer, Naturactive, Elgydium and Arthrodont have already been published on the Group’s corporate website (link). These initial ratings cover a wide variety of categories (shampoos, dry shampoos, shower gels, face and body creams, acne treatments, toothpastes, essential oils, dietary supplements, etc.) in order to demonstrate the ability of the Green Impact Index to adapt to all types of cosmetic and family health products. New products will be rated and listed monthly and grades will be posted directly on brand websites by the end of the year. "The Green Impact Index is a response to the growing distrust on the part of consumers and patients when it comes to brands and their ability to respect the environment, demonstrate corporate social responsibility and communicate information on these subjects in a transparent and verifiable manner. At Pierre Fabre, we have always been dedicated to our work in these fields, and the Green Impact Index that we are launching today confirms this. For the first time, consumers will be able to choose a cosmetic or family health product with full knowledge of its eco-societal impact and with the assurance of reliable and detailed information, in a simple and straightforward manner," says Eric Ducournau, CEO of the Pierre Fabre Group. MSD IRELAND PUBLISH NEW RESEARCH New research from Ipsos MRBI and healthcare company MSD Ireland launched today has revealed fresh insights into Irish public perceptions of healthcare, now and into the future, following the global Covid-19 pandemic. According to the new research,

JANUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

41% are more vigilant about their personal health now than they were before the Covid-19 pandemic. However, concerns exist around the future of healthcare in Ireland, including how our health services are structured, financed and administered. The research report 'Covid-19 & My Health: Freedom or Fallout?', explores and examines public expectations of healthcare delivery in a post-pandemic Ireland, under the lens of four core pillars of investigation, which includes: My Personal Health, My Health Service, My Access, and My Digital Health. Looking more closely at the pandemic, Covid-19 has caused a re-appraisal of our own personal health. However, the unexpected length of the pandemic has led to a sense of fatigue among the public, with the positive behavioural changes that were improving our health now starting to wane. Personal health remains the top priority and the Irish public want to be involved in how it is managed: * 41% think about their personal health more now than they did before the Covid-19 pandemic. * 91% are willing to be involved in the decision-making process around their treatment plan. * 92% are willing to ask questions if they are unsure of what a doctor or nurse is telling them. Among the key findings, the report has identified a public divide in public optimism versus pessimism for the future of Ireland's healthcare service and confidence levels in the public's healthcare needs being adequately addressed. Looking beyond the pandemic, but factoring in its impact over these last two years, the report highlights varying levels of optimism about our future care: * 40% are optimistic about the Irish healthcare service in the future. * 39% are pessimistic about the Irish healthcare service in the future. * 20% are unsure - neither optimistic nor pessimistic. At the launch of the report, Mairead McCaul, Managing Director, MSD Ireland (Human Health), said, "This report

is intended to continue the important conversations, not just about how Covid-19 will shape how we think about our health into the future, but how we will all collectively think about our healthcare system. "The research clearly highlights the important roles that individual healthcare professionals have in driving trust, confidence, and optimism in Ireland's system. It is important to acknowledge the extraordinary role frontline staff have played in Ireland's response to the various waves of Covid-19, which targeted some of our most vulnerable. On behalf of MSD Ireland, I would like to say a special thank you to all frontline workers and all those that we rely on to keep society healthy through an immensely difficult period." Among the points of criticism observed, respondents called out systemic problems in the Irish health service, including concerns around finance, infrastructure, administration, and a sense of bureaucracy. The potential cost associated with the Covid-19 pandemic is a significant concern, with many believing that healthcare was already in a fragile position prior to the outbreak of COVID-19. Furthermore, focus groups conducted as part of the research highlighted worries that Covid-19 will exacerbate current waiting lists and cause further delays for Irish patients. However, optimism exists for healthcare, with many having faith that healthcare in Ireland is improving over time and will eventually get to a point where it needs to be. The Irish public reserved significant praise for those working on the front line of Irish healthcare, including GPs. Trust in GPs remains strong and, in a shift from hospital settings, the majority of the public (88%) said that they are willing to consider using community-based services in future, such as GPs and pharmacists, rather than hospitalbased services. Furthermore, 85% are willing to consider using alternatives to GPs, such as their local pharmacist, when they require nonurgent healthcare services in the community. The research was released as part of MSD Ireland's ' My Healthcare, My Future' series of research reports and follows a study into the general public's vision for healthcare provision in Ireland in 2016, and trust in online healthcare information in 2019.

83 ANNOUNCEMENT OF INTENTION TO FLOAT ON EURONEXT GROWTH HealthBeacon Limited (in the process of changing its name to HealthBeacon plc) ("HealthBeacon" or the "Company" and together with its subsidiary undertakings, the "Group"), has announced its intention to (i) raise up to ¤25 million of gross proceeds by placing new Ordinary Shares (the "Placing") and (ii) seek admission of all of its Ordinary Shares to trading on the Euronext Growth market of Euronext Dublin ("Admission"). HealthBeacon Highlights • HealthBeacon is an Irish digital therapeutics company that develops products for managing injectable medications for patients in the home. The Company’s mission is to become the world’s leading digital therapeutics platform for injectable medications. The Company is expecting approximately 10x increase in the number of patients using its system from the end of 2021 to the end of 2023. • The HealthBeacon injection care management system (the “HB System”) is the world’s first FDA cleared smart sharps bin that tracks adherence and persistence with medication schedules through the provision of medication management reminders, safe and sustainable sharps disposal devices, educational tools and AI driven data analytics. • Over 550,000 injections have been monitored by the HB System and peer reviewed evidence supports a 19% improvement in therapy persistence by patients, which improves clinical outcomes and significantly improves efficiency in health systems. HealthBeacon has over 30 design and utility patents and several more pending. • The global digital health market is anticipated to be greater than $500bn by 2027 and growth is expected to increase by 37.1% in 2021 (Source: Research and Markets, 2020). In USA, Canada, UK and Europe there are over 30 million people on subcutaneous self-injections and HealthBeacon’s annual target market has the potential to generate c. $10 billion of recurring revenue. • HealthBeacon has successfully grown its customer base to 18 blue chip customers, among them some of the leading global

pharmaceutical companies, and operates in 17 countries. The Company has grown the number of therapeutic areas it caters for from four in 2014 to eight in 2021 and is actively looking to expand into further therapeutic areas, with the goal of serving all patients taking at home subcutaneous injectable medication irrespective of the type of injection or frequency of administration. In 2021, HealthBeacon signed a transformational commercial contract with Hamilton Beach Brands Inc. (“Hamilton Beach”) and is in the process of signing a commercial contract with a speciality pharmacy customer: o Hamilton Beach is HealthBeacon’s exclusive DTC partner in North America. This partnership provides a gateway to the millions of patients in the US and Canada currently on injectable medication. HealthBeacon is anticipating deployment of c. 15k - 25k units in 2022 to this customer. o The speciality pharmacy customer is a full-service pharmacy benefit management and specialty managed care company serving clients throughout North America with access to c. five million patient in the US. HealthBeacon is anticipating deployment of c. 9k -15k units in 2022 to this customer. Reasons for Placing, Admission and Use of Funds The Company is seeking to raise up to ¤25 million through the Placing. The net proceeds of the Placing will be used by the Group to: • Scale its team to support growth across sales and marketing, customer support and operations, finance and product development; • Invest in inventory and working capital to support product roll out; and • Further develop its platform in respect of technology development, research and development and develop a pipeline of future products. In seeking Admission to Euronext Growth, the Directors believe that Admission will allow the Company access to a wide investor audience and establish a recognised platform for access to capital as well as providing shareholders with a liquid market for their shares. Admission will also provide the Group with greater ability to incentivise team members through share incentive schemes, which will assist it in continuing to attract, retain and motivate high calibre team members.

TIME TO GET TOUGH SAYS IRISH HEART FOUNDATION The Irish Heart Foundation has called on the Government to implement stronger air quality regulations immediately, following a report revealing that air pollution remains responsible for an estimated 1,300 premature deaths a year. The charity criticised political resistance to more stringent rules – despite toxic air accounting for almost ten times the 2020 road death toll of 149. The grim findings are contained in the Environmental Protection Agency’s (EPA) Air Quality in Ireland 2020 report. With fine particulate matter from the burning of smoky, solid fuels such as coal, turf and wood remaining the biggest contributor to poor and health harming air quality in Ireland, the health charity wants the forthcoming solid fuel regulations rolled out sooner than planned for the benefit of public health. “Unfortunately, we have seen no reduction from 2019 in the number of lives being lost prematurely to the dangers of air pollution arising from the burning of solid fuels,” said Dr Tim Collins, CEO of the Irish Heart Foundation. “Despite overwhelming evidence showing that there is no safe level of exposure to air pollution, we continue to have resistance from some within Government and on the opposition benches to stronger solid fuel and air quality regulations that are proven to save lives.”

The report outlines how Ireland was above WHO air quality guidelines for particulate matter and other toxic pollutants at 52 monitoring sites across the country – mainly as a result of the burning of solid fuels in villages, towns and smaller cities. “It is crucial that this Government brings in a new Clean Air Act and immediately adopts the WHO air quality guidelines,” said Dr Collins. “Not only will it save lives and clean our air, but it will reduce our greenhouse gas emissions and help create a healthier, greener society for our children, who are most vulnerable to the dangers of air pollution. “It’s shocking that in spite of the massively reduced traffic volumes due to the pandemic, we’ve squandered the opportunity to seriously tackle air pollution to the extent that not a single extra life has been saved. “We now need decisive action to implement a Clean Air Act that adopts more stringent WHO air quality guidelines.” The Irish Heart Foundation says air pollution harms nearly every organ in the body, with the impact most damaging on the cardiovascular system. However, it says persistent delays and resistance to stronger regulations means that countless lives continue to be needlessly lost. Irish Heart Foundation CEO Tim Collins

HOSPITALPROFESSIONALNEWS.IE | HPN • JANUARY 2022

HPN 2022 January

Articles inside

Feature: Glucocorticoid Induced Osteoporosis

Calls for Increased Use of Off-Patent Medicines

Clinical R&D

Ireland ‘far from where it should be’ in Diabetes care

Ambitious new Research Strategy from Trinity College Dublin

Researcher of the Year Award for Professor William Gallagher

Partnership is key to growth hears Private Hospitals Association Annual Conference