Page 1

HPN March 2017

Issue 36

HOSPITAL PROFESSIONAL NEWS IRELAND Ireland’s Dedicated Hospital Professional Publication


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

NEWS: Children’s Hospital amongst ‘most expensive in the world’ Page 5

Palonosetron 250 mcg solution for injection in pre-filled syringe. Active ingredients: 1ml solution contains 50 micrograms palonosetron (as hydrochloride). Indications: Adults: Prevention of acute nausea & vomiting associated with highly emetogenic cancer chemotherapy. Prevention of nausea & vomiting associated with moderately emetogenic cancer chemotherapy. Posology & administration: For intravenous use. Use only before chemotherapy administration. Adults (including elderly): 250 micrograms palonosetron administered as a single intravenous bolus approx. 30 minutes before start of chemotherapy. Palonosetron should be injected over 30 seconds. Paediatric: Use Palonosetron glass vials, as pre-filled syringe not recommended for use in children & adolescents.

REPORT: Common Framework draft for Hospital Pharmacists Page 12

Contraindications: Hypersensitivity to the active substance or to any of the excipients. Warnings and precautions (See SPC for full details): May increase large bowel transit time, patients with a history of constipation or signs of subacute intestinal obstruction should be monitored. At all dose levels tested, palonosetron did not induce clinically relevant prolongation of the QTc interval. Exercise caution in patients who have or are likely to develop prolongation of the QT interval eg. patients with a personal/family history of QT prolongation, electrolyte abnormalities, congestive heart failure, bradyarrhythmias, conduction disturbances & in patients taking anti-arrhythmic agents or other medicinal products that lead to QT prolongation or electrolyte abnormalities. Hypokalemia and hypomagnesemia should be corrected prior to administration. Reports of serotonin syndrome – observe patients for serotonin syndrome-like symptoms. Do not use to prevent or treat nausea & vomiting in the days following chemotherapy if not associated with another chemotherapy administration.

CONFERENCE: Healthcare Enterprise Alliance Page 24

Interactions: Consult SPC for detailed information on interactions. Reports of serotonin syndrome following concomitant use of 5-HT3 antagonists & other serotonergic drugs (including SSRIs and SNRIs). Fertility, pregnancy and lactation: Not recommended, consult SPC. Undesirable effects: Common: Headache, dizziness, constipation, diarrhoea. Uncommon: Hyperkalaemia, hypocalcaemia, hypokalaemia, anxiety, tachycardia, bradycardia, extrasystoles, myocardial ischaemia, sinus tachycardia, sinus arrhythmia, supraventricular extrasystoles, electrocardiogram QT prolonged conduction disorder, hypotension, hypertension, dyspepsia, abdominal pain, hyperbilirubinaemia, arthralgia, allergic dermatitis, urinary retention. Consult SPC for additional adverse reactions. Legal classification: POM. 250 micrograms/5ml €840 10x5ml pre-filled syringe. PA number: PA 566/75/2. Marketing Authorisation Holder: Fresenius Kabi Ltd., Cestrian Court, Eastgate Way, Manor Park, Runcorn, Cheshire, WA7 1NT, UK. Date of Preparation: January 2017. Adverse events should be reported via HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6762517. Website:; E-mail: Also Fresenius Kabi

Palonosetron Potent highly selective 5-HT3-receptor antagonist

Approved therapy for the prevention of nausea and vomiting associated with highly emetogenic chemotherapy & moderately emetogenic chemotherapy Available in a pre-filled syringe Palonosetron 250 micrograms/5ml 10x5ml pre-filled syringe

CPD: HIV and Hep C in Co-infected Patients Page 31 FEATURE: DVT Presentations to an Emergency Department Page 36 AWARDS: Launch of the 2017 Hospital Professional Awards Page 42


HPN March 2016 Issue 36



Capital investment cuts leading to hospital delays P4


Ireland still delivering healthier outcomes P6

The news dominating health headlines this month has been the spiralling costs of Ireland’s new National Children’s Hospital which, according to reports, will be one of the world’s most expensive buildings when it opens its doors in 2020.

Kelly Jo Eastwood

Healthcare leaders must make equality a priority P20


Medicines agreement is saving money argues HEA P24

The controversial children’s hospital which has many criticisms by opposition TDs will cost the state a massive outlay even though it was originally conceived that it would cost just under half the price.

Bowel cancer drug research aims to tailor treatments P41 Launch of the 2017 Hospital Professional Awards P42


The news of the hefty outlay comes ahead of the publication of detailed report that will outline the spiralling costs of the project before the Dáil Public Accounts Committee.


Labour Health spokesperson Alan Kelly has called on the Minister Simon Harris to urgently explain how the costs have spiralled out of control by over 50% when inflation has been practically zero.

Clinical Synopsis: ASCO 2017 P16 41

Feature: Deep Venous Thrombosis P36

Event Gallery P58 58

Hospital Professional News is Circulated to all independent, multiple and hospital pharmacist, pre reg pharmacists, students pharmacy student’s offi cial bodies, government officials and departments, Pharmacy Managers, Manufactures, Wholesalers. Buyers of pharmacy groups and healthcare outlets. Circulation is free to all pharmacists Subscription rate for Hospital Pharmacy 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. Pharmacy Communication Ireland 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 MANAGING DIRECTOR Natalie Maginnis EDITOR Kelly Jo Eastwood 00447876548989 ACCOUNTS Rachel Wilson

Deputy Kelly said, "Minister Harris needs to explain how in the space of 2 years the projected costs of the Children's Hospital have increased by almost ¤350 million to a billion euro. "This will have serious impact on other capital projects including the National Maternity Hospital, new Emergency Departments and increasing bed capacity across the country. It also comes at a time when the National Maternity Strategy is totally without funding.

Feature: Cancer Treatments P50 Clinical Profiles P61

The proposed ¤1bn hospital due to be built on the St James’s site, will be the most costly building ever constructed along with the new Royal Adelaide Hospital in Australia which has ¤2.2 billion to build.


Mobile: 0044 7765 236886 CONTRIBUTORS

Kheshwant S. Gill, Philana Fernandes, Sheila Kelly, Tracey R. O'Donovana, Sharon L.McKenna, Kishore K. Doddakula, Derek G. Power, Declan M. Sodena, Patrick F. Forde Darren Lillis, Christian Lloyd, Peter O'Kelly, Peadar Gilligan, Dr Peter Lachman

DESIGN DIRECTOR Ian Stoddart Design HospitalProfessionalNews

"It's incredible that the Department and the HSE are accepting cost increases of over 50% when inflation is practically zero.” Turn to page 5 for the story. In other news, page 21 gives an insight into a new clinical trial being led by Professor Michael O’Dwyer, Blood Cancer Network Ireland Director and Consultant Haematologist which will see Irish patients with the blood cancer multiple myeloma become the first worldwide to take part in a new drug trial to develop more effective treatment for the cancer. This issue also sees the launch of the 2017 Hospital Professional Awards. Building on the success of the last three years, the event promises to be bigger and better than ever. The Hospital Professional Awards serve to recognise and highlight the ongoing hard work and dedication of Ireland’s leading hospital industry, from Consultants and Pharmacists to allied professionals. The event will be held on Saturday, September 16th in the Clayton Hotel, Dublin. Turn to page 42 for details of how to enter.

HOSPITAL PROFESSIONAL NEWS IRELAND Ireland’s Dedicated Hospital Professional Publication HPN • March 2017

4 News

Impact of cuts compounding hospital delays The President of the Irish Hospital Consultants Associations (IHCA), Dr Tom Ryan has outlined his concerns that the cumulative impact of cuts in capital investment over the last decade in acute hospital facilities and equipment is compounding the delays in providing the high quality care that patients deserve. Dr Ryan said, “Inadequate and antiquated equipment is one of the critical factors contributing to growing waiting lists and the cancellation of elective surgeries, as acute hospitals simply just do not have the infrastructure, in terms of equipment and bed capacity, to treat the number of patients requiring medical and

surgical care. In effect our acute hospital infrastructure is crumbling due to the lack of investment over the last decade. This is forcing hospitals to ration the delivery of healthcare to patients on a daily basis. “The reality is that the gaping bed capacity and equipment problems are not being addressed with any sense of urgency. Nothing approaching adequate funding has been included in the multiannual capital budgets to address these critical deficits. While we welcome the State’s commitments to develop the National Children’s Hospital and the relocation of older maternity hospitals to new sites, the reality is that funding

for these essential and pressing developments has not been formally provided. Furthermore, the funding to maintain basic current facilities and equipment and expand bed capacity throughout our overstretched acute hospital is totally inadequate.” The IHCA President said that he cannot stress strongly enough the pressing and immediate need to increase the number of acute, ICU and rehabilitation beds required to provide patients with the care they deserve. Any realistic plan, to relieve emergency department overcrowding and address the growing waiting lists, must include an increase in acute hospital bed capacity, otherwise the health

system will continue to fail the public at large. There is an obvious need for new ideas and fresh thinking in our health service,” he said. “It is no coincidence that the ongoing consultant recruitment and retention crisis is escalating in an environment of a crumbling hospital infrastructure, the persistent breaching of contracts by employers and the discrimination against new entrant consultants. There are hundreds of vacant consultant posts across the country which will never be filled unless investment is made in both our hospitals and our doctors,” concluded Dr Ryan.

Poor pay a key factor in doctor retention The Irish Medical Organisation (IMO) has told the Public Service Pay Commission that poor pay was a key factor in the health service struggling to recruit adequate numbers of doctors. The IMO told the Commission the number of practising doctors per 1,000 of population (2.8) was well below the EU average of 3.4 practising doctors per 1,000 of population.

The IMO made the comments at a presentation today to the Public Service Pay Commission. Dr. John Duddy, President of the IMO, highlighted five key points on the manpower crisis:

• 250 consultant posts remain unfilled across Ireland

• 70% of NCHDs in Ireland cited poor pay as a key motivation to consider working abroad

• Ireland has a very low percentage of practising doctors compared to European average (2.8 in Ireland v 3.4 in Europe per 1,000 of population).

• 9% of doctors aged between 25 and 34 left the Irish medical register in 2015

• Ireland has second highest reliance on foreign-trained medical practitioners in OECD.

Dr Duddy said while pay was not the only problem in the Irish health services, it was significant. “Our pay rates for NCHDs, consultants and public health doctors are not competitive with other Englishspeaking jurisdictions and this is a strong “push-factor” for doctors to leave Ireland,” he said.

School of Pharmacy Alumni Celebration The RCSI School of Pharmacy welcomed its first graduates back to the college for the School's inaugural Alumni reunion event which honoured the Class of 2006 upon the 10-year anniversary of their graduation. Staff members, both past and present, joined the graduates for a presentation and reception held in the college which featured speeches by Professor Hannah McGee, Dean of the Faculty of Medicine and Health Sciences, RCSI, founding Head of School, Professor John Kelly and present Head of School, Professor Paul Gallagher. The event also featured significant contributions from event chair, Dr Judith Strawbridge and a

March 2017 • HPN

Deirdre Healy, who delivered the keynote address at the event, pictured with ProfessorHannah McGee, Dean of the Faculty of Medicine and Health Sciences, RCSI keynote address by a member of the class, Ms Deirdre Healy, who provided an overview of her unique experiences working as a clinical pharmacist for Medicines San Frontier and an insight into her present role within the World Health Organisation. The event marked the first significant engagement with the School's alumni and all involved were delighted to attend and participate to recognise the achievements of the School's first class.


Children’s Hospital to be ‘one of world’s most expensive’ According to reports the new National Children’s Hospital in Dublin which will open its doors in 2020 will be one of the world’s most expensive buildings when completed. The proposed ¤1bn hospital due to be built on the St James’s site, will be the most costly building ever constructed along with the new Royal Adelaide Hospital in Australia which has ¤2.2 billion to build. The controversial children’s hospital which has many criticisms by opposition TDs will cost the state a massive outlay even though it was originally conceived that it would cost just under half the price. The news of the hefty outlay comes ahead of the publication of detailed report that will outline the spiralling costs of the project before the Dáil Public Accounts Committee.

The new National Children's Hospital, due for completion in 2020

blamed for the bill for the new facility at the St James’s campus in Dublin almost doubling. Katherine Zappone, Children and Youth Affairs Minister, has defended the cost and claimed it would be proportionate to the quality of the services. The new state of the art facility will reportedly have 473 beds that will see all three of the country’s major children’s hospitals under one roof. Minister for Health Simon Harris has said he intends to bring a memorandum to Cabinet in the coming weeks on the construction of the new hospital.

The government has defended the cost of the new national children’s hospital, suggesting that if it is the most expensive in Europe it must be “the best”.

Addressing the Joint Oireachtas Committee on Health, Mr Harris said he wanted to see construction work on the hospital start this year. He also criticised figures published in the media on the projected cost of the hospital, saying they were “not comparing apples with apples”.

High construction costs and additional facilities have been

Mr Harris said that when he received the figures for the costs

of the hospital he would carry out his own due diligence. HSE Director General Mr Tony O’Brien has previously said there was not sufficient funding to complete Government priority projects in health due to construction inflation, and higher specifications to comply with clinical standards and building regulations. Aside from the children’s hospital, these projects include the ¤380 million renewal of nursing homes, the ¤295 million transfer of the National Maternity Hospital to St

Vincent’s hospital, and the ¤160 million move of the Central Mental Hospital to Portrane. It is also proposed to spend ¤110 million on oncology services, and ¤100 million apiece on primary care centres and disability projects. BAM Ireland, one of Ireland’s largest building contractors, has been selected as the preferred bidder to build the hospital for a price understood to be close to ¤1 billion. This does not include the cost of IT or equipment for the hospital, which is likely to exceed ¤100 million in each instance.

National Standard for Dispensing and a National Standard for Procedures The Health Information and Quality Authority (HIQA) has published two national standards aimed at supporting the development of eHealth systems, which can enhance the quality, accessibility and efficiency across all healthcare services through the secure, timely, accurate and comprehensive exchange of clinical and administrative data. These systems can ultimately lead to the provision of safer, better care. • National Standard for a Dispensing Note Dataset and Clinical Document Architecture specification available at : national-standard-dispensing-note-including-clinical-document-architecture-specifiction. • National Standard for a Procedure Dataset including a Clinical Document Architecture specification available at: national-standard-procedure-dataset-including-clinical-document-architecture-specification

Big jump in users of medicine information website A total of 4,661,057 visitors were recorded accessing the medicine information website in 2016, an increase of 12% on 2015. Run by the Irish Pharmaceutical Healthcare Association (IPHA), is the most comprehensive source of information on medicinal products available in Ireland and is widely regarded as an invaluable reference source by healthcare professionals and the general public. It is currently the 2nd most popular health website in Ireland.

The information for each product comes in the form of a Summary of Product Characteristics (known as the SPC or SmPC), and Patient Information Leaflet (known as the PIL, Package Leaflet or PL) where relevant, which are approved by the Health Products and Regulatory Authority or European Medicines Agency as part of the process of authorising the product for sale or supply in Ireland. The site is continuously updated by pharmaceutical companies whenever new products are launched or the information in the

SPC or PIL of an existing product changes. Latest analysis shows that new visits in 2016 were up by 12% on the same period in 2015 at 2,840,883. Visitors viewed an average of 1.65 pages per visit and the average time on the site for each visit was 1.15 minutes. This suggests that visitors were searching within the site and spending time viewing product information.

O’Connor said, “The use of the web by those seeking health information continues to grow and it is critical to patient safety that this information is accurate and reliable. That visits to www. continue to grow, is a clear indication that the site is viewed as the primary source to rapidly find high quality, up to date, regulatory authority approved information.”

Commenting on the visitor data, IPHA Chief Executive Oliver

HPN • March 2017

6 News

Ireland delivering better, safer health outcomes Dr Colm Henry, National Clinical Advisor, Acute Hospitals

increased from 536,700 in 2011 to 648,600 in 2016 and was set to reach 1.434 million by 2041.

lived and how well you lived were firstly where you were born and secondly to whom you were born.

“Public health measures have a far greater effect on health outcomes than hospitals. About 10% of measurable health outcomes depend on hospitals.”

“Public health measures have a far greater effect on health outcomes than hospitals. About 10% of measurable health outcomes depend on hospitals.”

At present, it was estimated that in Ireland that 1 million people suffered from one of the 4 chronic diseases – cardiovascular disease, diabetes, cancer and chronic respiratory disease.

Dr. Henry emphasised that the future of healthcare in Ireland lay in public health measures and encouraging patients to have their conditions treated at the most appropriate level – either at home, by their GP, or at outpatients, at day case or as inpatients in the correct Level hospital.

The chronic disease burden was increasing by 4% each year and at present accounted for 40% of admissions to hospital, 75% of bed days used, 55% of hospital expenditure in Ireland and 80% of GP consultations.

When people criticised the Irish health services they should be told that we were delivering better and safer outcomes than 10 years ago, to an increased population, a significantly increased elderly population, with more complex cases and less capacity, Dr. Colm Henry, National Clinical Advisor, Acute Hospitals told a meeting of the HMI South in the Erinville Hospital, Cork, last week.

have changed, there had been significant changes in the last decade.

Speaking on” Challenges and solutions: patient safety in Irish hospitals,” he said that while nothing appeared to

Dr. Henry said the number of people in Ireland over the age of 65 – who could be expected to suffer more chronic diseases – had

Overall mortality had been reduced by 16.7%, mortality from IHD, stroke and cancer was also down, there had been a 55% increase in hospital discharges and ALOS was reduced, while the number of acute beds had been reduced 13.5%.

Dr. Henry said that one of the challenges was that people in this country was that Emergency Departments were too popular. People felt that if they were ill, the ED was the best place to go, despite the fact that they were not the most appropriate place for people with chronic diseases. A survey had shown that if people had the option of having their problem addressed that day by a GP, 60% would still opt to go to an ED. He said that hospitals often confused what they did with healthcare/ There was a wealth of international research that showed the determinants of how long you

This would mean patients would be treated faster, more appropriately and major hospitals freed up to treat complex cases. Dr, Henry said that the medical workforce should be aligned to the needs of the healthcare system, with skill mix correlated with the needs of the system, in Model II, III and IV hospitals Training provided to doctors should also be appropriate, adaptive and capable of responding to the changing needs of the patient and the health service. We needed an increase in training posts at the expense of non training posts and it was important to ensure the geographical spread of trainees.

Intervention to international debate on medicines prices The Organisation for Economic Co-operation and Development (OECD) has published a report raising concern at the pressures being placed upon public health spending as a result of rising prices for medicines. The report draws particular attention to the struggle payers face in meeting the high cost of medicines that are targeted to very small populations, a trend likely to be exacerbated by the growth of 'personalised' or 'precision' medicine. The report 'New Health Technologies: Managing Access, Value and Sustainability' also singles out a simultaneous problem, in respect to new treatments for wide populations, March 2017 • HPN

such as for hepatitis, which might be very effective, but remain unaffordable to many who would benefit in almost all OECD countries because of their high budget impact. The report therefore recommends that the prices paid for technologies "must reflect their real-world health benefits compared to alternatives, and be adjusted based on evidence about their actual impact." Seeking important changes to existing procedures, the OECD suggest that payers must be equipped with the necessary powers to adjust prices and withdraw payment for ineffective technologies.

In order to achieve a necessary re-balancing of power between payers and manufacturers, the report authors recommend heightened transparency and co-operation between payers and international joint procurement initiatives, as tested in Europe and Latin America. Pricing agreements, which link the final price paid to the actual performance of the drug, as used in Italy and England, may also be effective if management and administration costs are controlled and the clinical data and evidence collected made widely available to the scientific community. Finally, the report also evidences the causes of concern from

the trend of many biomedical technologies being approved and adopted based on limited evidence of their safety and effectiveness. The report finds assessment of their performance in real world conditions to be rare which "compromises safety, is wasteful and no longer sustainable". Therefore the report recommends greater efforts to "harness the potential of health data more effectively. Use of personal health data creates major opportunities for health system improvement, research and disease surveillance, but requires the right governance frameworks to realise these benefits while managing the privacy risks."

Now for the treatment of pretreated mCRC

Make time for more moments that matter


Available on High Tech Scheme (from 01-02-2017)

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

qLonsurfÂŽ (trifluridine/tipiracil) Abbreviated prescribing information: COMPOSITION*: Lonsurf 15 mg/6.14 mg: film-coated tablet containing 15 mg trifluridine and 6.14 mg tipiracil (as hydrochloride). Lonsurf 20 mg/8.19 mg: film-coated tablet containing 20 mg trifluridine and 8.19 mg tipiracil (as hydrochloride). INDICATION*: Treatment of adult patients with metastatic colorectal cancer who have been previously treated with, or are not considered candidates for, available therapies including fluoropyrimidine-, oxaliplatinand irinotecan-based chemotherapies, anti-VEGF agents, and anti EGFR agents. DOSAGE AND ADMINISTRATION*: Recommended starting dose: 35 mg/m2/dose taken orally twice daily on Days 1 to 5 and Days 8 to 12 of each 28-day cycle, within 1 hour after completion of the morning and evening meals. Dosage calculated according to body surface area, not exceeding 80 mg/dose. Possible dosing adjustments based on individual safety and tolerability: 3 permitted dose reductions to a minimum dose of 20 mg/m2 twice daily, dose escalation permitted after a dose reduction. CONTRAINDICATIONS*: Hypersensitivity to the active substances or to any of the excipients. WARNINGS*: Bone marrow suppression: Complete blood cell counts must be obtained prior to initiation of therapy, prior to each cycle and as needed. Treatment must not be started if absolute neutrophil count <1.5 x109/L, if platelet counts <75x109/L, or if unresolved Grade 3 or 4 non-haematological clinically relevant toxicity. Patient should be monitored closely for infections, appropriate measures should be administered as clinically indicated. Gastrointestinal toxicity: anti-emetic, anti-diarrhoeal and other measures should be administered as clinically indicated, dose modifications should be applied as necessary. Renal impairment: not recommended if severe renal impairment or end-stage renal disease. Patients with moderate renal impairment should be more frequently monitored for haematological toxicities. Hepatic impairment: not recommended if moderate or severe hepatic impairment. Proteinuria: monitoring by dipstick urinalysis recommended prior to starting and during therapy. Excipients: contain lactose. INTERACTIONS*: Precautions: medicinal products that interact with nucleoside transporters CNT1, ENT1 and ENT2, inhibitors of OCT2 or MATE1, human thymidine kinase substrates (e.g. zidovudine), hormonal contraceptives. FERTILITY*. PREGNANCY AND BREASTFEEDING*: Not recommended. CONTRACEPTION*: For women and men, highly effective contraceptive measures must be used during treatment and for 6 months after stopping treatment. DRIVE & USE MACHINES*: Fatigue, dizziness or malaise may occur. UNDESIRABLE EFFECTS*: Very common: Neutropenia, leukopenia, anaemia, thrombocytopenia, decreased appetite, diarrhoea, nausea, vomiting, fatigue. Common: Lower respiratory tract infection, upper respiratory tract infection, febrile neutropenia, lymphopenia, monocytosis, hypoalbuminaemia, insomnia, dysgeusia, neuropathy peripheral, dizziness, headache, flushing, dyspnoea, cough, abdominal pain, constipation, stomatitis, oral disorder, hyperbilirubinaemia, Palmar-plantar erythrodysaesthesia syndrome, rash, alopecia, pruritus, dry skin, proteinuria, pyrexia, oedema, mucosal inflammation, malaise, hepatic enzyme increased, blood alkaline phosphatase increased, weight decreased. Uncommon: Septic shock, enteritis infectious, lung infection, biliary tract infection, influenza, urinary tract infection, gingival infection, herpes zoster, tinea pedis, candidiasis, bacterial infection, infection, cancer pain, pancytopenia, granulocytopenia, monocytopenia, erythropenia, leukocytosis, dehydration, hyperglycaemia, hyperkalaemia, hypokalaemia, hypophosphataemia, hypernatraemia, hyponatraemia, hypocalcaemia, gout, anxiety, neurotoxicity, dysaesthesia, hyperaesthesia, hypoaesthesia, syncope, paraesthesia, burning sensation, lethargy, visual acuity reduced, vision blurred, diplopia, cataract, conjunctivitis, dry eye, vertigo, ear discomfort, angina pectoris, arrhythmia, palpitations, embolism, hypertension, hypotension, pulmonary embolism, pleural effusion, rhinorrhoea, dysphonia, oropharyngeal pain, epistaxis, enterocolitis haemorrhagic, gastrointestinal haemorrhage, pancreatitis acute, ascites, ileus, subileus, colitis, gastritis, reflux gastritis, oesophagitis, impaired gastric emptying, abdominal distension, anal inflammation, mouth ulceration, dyspepsia, gastrooesophageal reflux disease, proctalgia, buccal polyp, gingival bleeding, glossitis, periodontal disease, tooth disorder, retching, flatulence, breath odour, hepatotoxicity, biliary dilatation, skin exfoliation, urticaria, photosensitivity reaction, erythema, acne, hyperhidrosis, blister, nail disorder, joint swelling, arthralgia, bone pain, myalgia, musculoskeletal pain, muscular weakness, muscle spasms, pain in extremity, sensation of heaviness, renal failure, cystitis noninfective, micturition disorder, haematuria, leukocyturia, menstrual disorder, general physical health deterioration, pain, feeling of body temperature change, xerosis, blood creatinine increased, electrocardiogram QT prolonged, international normalised ratio increased, activated partial thromboplastin time prolonged, blood urea increased, blood lactate dehydrogenase increased, protein total decreased, C-reactive protein increased, haematocrit decreased. Post-marketing experience: interstitial lung disease reported in Japanese patients. OVERDOSE*. PROPERTIES*: Trifluridine is an antineoplastic thymidine-based nucleoside analogue and tipiracil hydrochloride is a thymidine phosphorylase (TPase) inhibitor. Following uptake into cancer cells, trifluridine, is phosphorylated by thymidine kinase, further metabolised in cells to a deoxyribonucleic acid DNA substrate, and incorporated directly into DNA, preventing cell proliferation. However, trifluridine is rapidly degraded by TPase and readily metabolised by a first-pass effect following oral administration, hence the inclusion of the TPase inhibitor, tipiracil hydrochloride. PRESENTATION*: Pack of 20 or 60 film-coated tablets. LES LABORATOIRES SERVIER, 50 rue Carnot, 92284 Suresnes cedex France. Marketing Authorisation: EU/1/16/1096/001-006. Legal Category: POM. Date of Text: April 2016. Further information available from: Servier Laboratories Ireland Ltd, Block 2, West Pier Business Campus, Old Dunleary Road, Dun Laoghaire, Co. Dublin, Tel (01) 6638110, Fax (01) 6638120, * For complete information, please refer to the Summary of Product Characteristics on mCRC=metastatic ColoRectal Cancer Date of preparation of this item: January 2017. 1617C1LNPress.

Empower Crohn’s patients to live life their way1

Conor Byrne


Prescribing Information Humira (adalimumab) 40mg solution for injection in pre-filled pen or pre-filled syringe or Humira 40mg/0.8ml solution for injection for paediatric use. Refer to Summary of Product Characteristics (SmPC) for full information. Presentation: Each 0.4 ml single dose pre-filled pen or pre-filled syringe contains 40mg of adalimumab. Each 0.8 ml single dose vial contains 40mg of adalimumab. Indications: Rheumatoid arthritis (RA), adults: In combination with methotrexate (MTX) for moderate to severe, active RA with inadequate response to disease-modifying anti-rheumatic drugs (DMARDs) including MTX. In combination with MTX for severe, active and progressive RA when not previously treated with MTX. Can be given as monotherapy if intolerance to or when continued treatment with MTX is inappropriate. Reduces rate of progression of joint damage on X-ray and improves physical function, in combination with MTX. Polyarticular juvenile idiopathic arthritis (pJIA), paediatrics 2 years and above: In combination with MTX, for active pJIA, with inadequate response to one or more DMARDs; or monotherapy if intolerance to or when continued treatment with MTX is inappropriate. Enthesitis-related arthritis (ERA), paediatrics 6 years and above: For active ERA with inadequate response to or intolerance to, conventional therapy. Psoriatic arthritis (PsA), adults: For active and progressive PsA with inadequate response to DMARDs. Reduces rate of progression of peripheral joint damage on X-ray in polyarticular symmetrical subtypes of the disease and improves physical function. Ankylosing spondylitis (AS), adults: For severe active AS with inadequate response to conventional therapy. Axial spondyloarthritis without radiographic evidence of AS (nr-axSpA), adults: For severe nr-axSpA with objective signs of inflammation (elevated CRP and / or MRI), and an inadequate response to, or intolerance to nonsteroidal anti-inflammatory drugs (NSAIDs). Crohn’s disease (CD), adults: For moderately to severely, active CD with inadequate response, contraindication or intolerance to corticosteroid and/or an immunosuppressant therapy. Crohn’s disease (CD), Paediatrics 6 years and above: For moderately to severely active CD with inadequate response, contraindication or intolerance to conventional therapy including primary nutrition therapy and a corticosteroid, and/or an immunomodulator. Psoriasis (Ps), adults: For moderate to severe chronic plaque psoriasis who are candidates for systemic therapy. Psoriasis, paediatrics 4 years and above: For severe chronic plaque psoriasis with inadequate response, or if topical therapy and phototherapies are inappropriate. Hidradenitis suppurativa (HS), adults: For active moderate to severe hidradenitis suppurativa (acne inversa) in patients with an inadequate response to conventional systemic HS therapy. Ulcerative colitis (UC), adults: For moderately to severely active UC with inadequate response, contraindication or intolerance to conventional therapy including corticosteroids and 6-mercaptopurine (6-MP) or azathioprine (AZA). Uveitis, adults: For non-infectious intermediate, posterior and panuveitis with inadequate response to corticosteroids, in need of corticosteroid-sparing, or in whom corticosteroid treatment is inappropriate. Dosage and administration: Specialist physicians experienced in the diagnosis and treatment of the condition, to initiate and supervise treatment. Ophthalmologists to consult with an appropriate specialist before initiation of treatment. Provide patients with special alert card. Patients may self-inject after proper injection training, with physician approval and appropriate medical follow-up. Optimise other concomitant therapies. RA,adults: 40mg dose every other week. Concomitant MTX should be continued. During *

Not a real patient. Reference: 1. Colombel J-F, Sandborn WJ, Rutgeerts P, et al Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology 2007; 132 (1): 52-65. Date of Preparation: August 2016


monotherapy patients may require 40 mg each week if they experience a decrease in clinical response. Treatment beyond 12 weeks should be reconsidered if no clinical response in that time. Consider need for dose interruption, e.g. before surgery or if serious infection occurs. Re-introduction after 70 days dose interruption gave same magnitudes of clinical response and similar safety profile as before dose interruption. pJIA, paediatrics 2 years and above: pJIA, paediatrics 2-<4 years: 24mg/m² body surface area up to 20mg maximum single dose every other week (see SmPC for height/weight dosing chart). pJIA, paediatrics 4-12 years: 24mg/m² body surface area up to 40 mg maximum single dose every other week (see SmPC for height/weight dosing chart). pJIA, paediatrics 13 years and above: 40mg every other week regardless of body surface area. Treatment beyond 12 weeks reconsidered if no clinical response in that time. ERA, paediatrics 6 years and above: 24mg/m² body surface area up to a maximum single dose of 40mg every other week. (see SmPC for height/weight dosing chart). PsA, AS and nr-axSpA, adults: 40 mg every other week. Treatment beyond 12 weeks should be reconsidered if no clinical response in that time. CD: Adults: Induction:80mg at Week 0 followed by 40mg at Week 2. For a more rapid response, 160mg at Week 0 (either as 4 injections in 1 day or 2 injections/ day for 2 consecutive days), 80mg at Week 2; risk of adverse events higher during induction. Maintenance: 40mg every other week. If decrease in clinical response, can increase dose to 40 mg weekly. Corticosteroids may be tapered in maintenance phase in accordance with clinical guidelines. Patients with no response by Week 4 may benefit from continued therapy to Week 12. Treatment beyond 12 weeks should be reconsidered if no clinical response in that time. CD, paediatrics 6 years and above<40Kg: Induction: 40mg at Week 0, 20mg at Week 2. For a more rapid response: 80mg at Week 0 (2 injections in 1 day), 40mg at Week 2; risk of adverse events higher during induction. Maintenance: 20mg every other week. If insufficient response, consider 20mg every week. Treatment beyond 12 weeks should be reconsidered if no clinical response in that time. CD, paediatrics 6 years and above ≥40Kg: Induction: 80 mg Week 0, 40 mg at Week 2. For a more rapid response: 160 mg at Week 0 (4 injections in 1 day or 2 injections/day for 2 consecutive days), 80 mg at Week 2; risk of adverse events higher during induction. Maintenance: 40 mg every other week. If insufficient response, consider 40 mg every week. Treatment beyond 12 weeks should be reconsidered if no clinical response in that time. Psoriasis, adults: 80mg induction dose at week 0, 40mg every other week from week 1. Treatment beyond 16 weeks should be reconsidered if no clinical response in that time. Beyond 16 weeks, patients with inadequate response can increase dosing frequency to 40 mg every week. If adequate response is achieved with an increased dosing frequency, dose may subsequently be reduced to 40 mg every other week. If there is inadequate response to the increased frequency, carefully reconsider treatment. Psoriasis, Paediatrics 4 years and above: 0.8 mg per kg body weight (maximum of 40 mg/dose) weekly for the first 2 doses and then every other week (see SmPC for weight dosing chart). Treatment beyond 16 weeks should be reconsidered if no response in that time. HS: Adults: 160mg initially at Day 1 (four 40mg injections in one day or two 40mg injections per day for two consecutive days), followed by 80 mg two weeks later at Day 15 (two 40mg injections in one day). Two weeks later (Day 29) continue with a dose of 40 mg every week. Antibiotics may be continued if necessary. Concomitant topical antiseptic wash on HS lesions should be used on a daily basis. Treatment beyond 12 weeks should be reconsidered if no clinical response in that time. Reintroduction after interruption: 40 mg every week. Evaluate periodically the benefit and risk of continued long-term treatment. UC: Adults:

Induction: 160mg at week 0 (4 injections in 1 day or 2 injections / day for 2 consecutive days) and 80mg at week 2. Maintenance: 40mg every other week. During maintenance, corticosteroids may be tapered in accordance with clinical practice guidelines. If insufficient response, consider 40mg every week. Treatment beyond 8 weeks should be reconsidered if no clinical response in that time. Uveitis: Adults: 80 mg induction dose at week 0, 40 mg every other week from week 1. Experience of initiating treatment with Humira alone is limited. Treatment can be initiated in combination with corticosteroids and/or other non-biologic immunomodulatory agents. Two weeks after initiating treatment, concomitant corticosteroids may be tapered in accordance with clinical guidelines. Evaluate on a yearly basis, the benefit and risk of continued long term treatment. Contraindications: Active tuberculosis (TB), severe infections (e.g. sepsis), and opportunistic infections; moderate to severe heart failure (NYHA class III/IV);hypersensitivity to adalimumab or any of the excipients. Precautions and Warnings: Clearly record trade name and batch number of administered product to improve traceability of biological medicinal product. Infections: Patients are more susceptible to serious infections especially if impaired lung function. Monitor for infections, including TB, before, during and for 4 months after treatment. Do not initiate treatment with an active infection, until it is controlled. Consider risk/benefit prior to treatment in patients exposed to high risk of TB or endemic mycoses. Evaluate new infections during treatment and monitor closely. Stop treatment if new serious infection or sepsis, and treat appropriately. Exercise caution in patients with a history of recurring infections or who are predisposed to infections. Serious infections: Serious infections, including those with hospitalisation or death reported in patients receiving treatment. TB: Consult SmPC for details. Reactivation and new onset TB, both pulmonary and extra-pulmonary (disseminated) reported. Screen all patients before therapy initiation for active or latent TB. If active TB is diagnosed Humira therapy must not be initiated. If latent TB is suspected, consult a physician with appropriate expertise and follow local treatment recommendations for prophylaxis prior to initiation of Humira. Despite prophylaxis TB reactivation has occurred on Humira. Other opportunistic infections: Opportunistic infections observed in patients receiving Humira. Stop treatment in patients with signs and symptoms of such infections. Consult with physician with appropriate expertise for diagnosis and administration of empiric antifungal therapy in these patients. Hepatitis B Reactivation: Reactivation has occurred in chronic carriers (i.e. surface antigen positive) tested for HBV infection before initiating treatment. HBV carriers should consult with a specialist physician and be closely monitored for reactivation of HBV infection throughout therapy and for several months following termination of Humira. If reactivation occurs stop treatment and initiate appropriate anti-viral and supportive treatment. Neurological events: Caution in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders and consider stopping treatment if these disorders develop . Rare association with new onset or exacerbation of symptoms and/or radiographic evidence of central and peripheral demyelinating disease. Known association between intermediate uveitis and central demyelinating disorders. Evaluate patients with non- infectious intermediate uveitis before therapy initiation and regularly during treatment to assess for pre-existing or developing central demyelinating disorders. Allergic reactions: Reports of serious allergic reactions including anaphylaxis received. For serious allergic or anaphylactic reaction stop Humira immediately and initiate appropriate therapy. Malignancies and lymphoproliferative disorders: A possible risk of malignancy,

including lymphoma and leukaemia, in all patients including paediatric patients, treated with TNF antagonists. Monitor all patients, especially those with a medical history of extensive immunosuppressant or PUVA treatment for non-melanoma skin cancer prior to and during Humira therapy, caution in COPD patients, and in patients with increased risk of malignancy due to heavy smoking. Consider the potential risk with the combination of AZA or 6-MP and Humira (hepatosplenic T-cell lymphoma has occurred). Risk of hepatosplenic T-cell lymphoma cannot be excluded. Caution in patients with a history of malignancy. Risk for developing dysplasia or colon cancer is unknown. Patients with UC, prior history of dysplasia or colon carcinoma to be screened for dysplasia before therapy and during treatment. Haematologic reactions: Adverse events of the haematologic system reported with Humira. Patients should seek immediate medical attention if signs and symptoms of blood dyscrasias. Vaccinations: Patients may receive concurrent vaccinations, except for live vaccines. Bring paediatric patients up to date with all immunisations prior to Humira treatment Congestive heart failure: See contraindications. Caution is advised in mild heart failure (NYHA class I/II). Discontinue treatment for new or worsening symptoms of congestive heart failure. Autoimmune processes: Autoimmune antibodies may form. Stop treatment if development of a lupus-like syndrome with positive antibodies against double- stranded DNA. Surgery: Consider the long half-life of Humira for planned surgical procedures. Closely monitor for infections. Small bowel obstruction: Failure to respond to treatment for CD may indicate the presence of fixed fibrotic stricture requiring surgical treatment. Elderly: Serious infections were higher in patients over 65 years of age, some of whom had fatal outcomes. Consider risk of infection. Interactions: Combination of adalimumab with other biologic DMARDS (e.g. anakinra and abatacept) or other TNF-antagonists is not recommended. Fertility, pregnancy and lactation: Not recommended during pregnancy. Women of childbearing potential should use adequate contraception and continue its use for at least five months after the last Humira treatment. Women must not breast-feed for at least five months after the last treatment. Side Effects: Very common â&#x2030;Ľ 1/10: Infections, leucopaenia, anaemia, lipids increased, headache, abdominal pain, nausea and vomiting, elevated liver enzymes, rash (including exfoliative rash), musculoskeletal pain, injection site reaction. Serious, including fatal, side effects have been reported including infections/sepsis, intestinal perforation, opportunistic infections, TB, endemic mycoses, demyelinating disease, malignancies including lymphoma (including hepatosplenic T-cell lymphoma), leukaemia and skin cancer (including melanoma and merkel cell carcinoma), cytopenias, worsening heart failure, myocardial infarction, pulmonary embolism, pleural effusion, pulmonary fibrosis, cerebrovascular accident, interstitial lung disease, lupus, Stevens-Johnson syndrome, angioedema, anaphylaxis, sarcoidosis, hepatitis, liver failure and worsening of symptoms of dermatomyositis. Prescribers should consult the SmPC for the complete list of reported side effects. Legal Category: POM. Marketing Authorisation Numbers/Presentations: Vial: EU/1/03/256/001; Pre-filled Syringe: EU/1/03/256/013; Pre-filled Pen: EU/1/03/256/017. Further information is available from AbbVie Limited, 14 Riverwalk, Citywest Business Campus, Dublin 24. HCPs 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:; E-mail: Date of revision of PI: June 2016 PI/256/017

10 News

Latest hospital data shows key improvements The HSE published performance data for the months October, November and December 2016, showing significant improvements in many areas including mental health and acute coronary syndromes. The HSE Acute Coronary Syndrome Programme is ensuring patients suffering from a STEMI (major) heart attack have direct access to standardised services in designated centres around Ireland. This means that STEMI heart attack patients have rapid access to high quality services, which is safe and sustainable for the health service. International evidence shows that the emergency procedure primary Percutaneous Coronary Intervention (PPCI), also referred

to as an angioplasty, is the most effective treatment for STEMI patients, if the PPCI centre can be reached within 90 minutes of diagnosis. PPCI involves the insertion of a wire into the artery to open it using a balloon to allow the blood to flow to the heart muscle again. The ACS programme has been responsible for PPCI being rolledout nationally and results show a major shift towards the treatment of STEMI patients with PPCI in Ireland. In 2014, 92% - of eligible patients received PPCI compared with a report of 55% in 2011. By the end of 2016, 93.9% of STEMI patients received PPCI exceeding the target of 85%. The need to ensure rapid access to thrombolysis (clot busting

drugs) for stroke patients has been well acknowledged. The HSE has set distinct targets to ensure that those patients who are suitable for this treatment are in a position to receive it in a timely and appropriate manner. In that regard, by the end of 2016, 13.9% of patients with stroke (confirmed acute ischaemic stroke) had received thrombolysis exceeding the target of nine per cent.

The demand for access to acute hospital beds means that hospitals should be managing the length of stay of each patient – that they only stay for a defined period and are discharged as soon as is medically and clinically possible. On that basis, targets set in 2016 for hospitals were exceeded by the end of year, with an average of 6.8 days achieved – ahead of the seven day target.

With the acknowledged and well recognised pressures on Emergency Departments in recent months, the published data illustrates the outcome of significant investment and focus. This includes a reduction in the number of patients experiencing a delayed discharge from 559 in January last year to 436 by the end of the year.

Within mental health services, 96% of people referred for an adult mental health appointment were seen within twelve weeks, ahead of the target of 90%, while 99% of those referred to mental health service for older people were seen within twelve weeks, ahead of the target of 98%.

Business Woman of The Year Award for Kay Kay Connolly, Chief Operating Officer (pictured left) of St Vincent’s University Hospital, Dublin was awarded the prestigious Management Professional of the Year Award at the IMAGE Business Woman of the year Awards 2016. Over 400 nominations were received for the 10th anniversary of the awards with just one in four nominations being shortlisted. Ms Connolly was the only public sector nominee and winner at the awards, competing with corporate enterprises.

Actavis Ireland Supports Work of Cork Sexual Violence Centre Actavis Ireland is delighted to support the great work of the Sexual Violence Centre in Cork. The Centre has been providing a service to victims of sexual violence in Cork City and County since 1983. The donated funds will go towards the cost of materials for raising awareness of sexual assault and consent amongst 2nd and 3rd level students in Cork. Pictured at the cheque presentation are Marguerite Tierney, Product Manager, Actavis Ireland and Mary Crilly, Director of the Sexual Violence Centre, Cork.

March 2017 • HPN

She was nominated for the awards by St. Vincent’s University Hospital. The award criteria covered her various roles, responsibilities and achievements, her capability to deal with challenges in business, insights into her key personal characteristics and her strategic plans for the future of her organisation. Speaking about her award, she said, “It was an honour and a privilege to win the Management Professional of the Year Award at the 2016 Image Business Woman

of the Year Awards. The calibre of the other shortlisted nominees in my category was extremely impressive. This recognition is important for all women in healthcare and especially for women working in management in an acute hospital setting. The award acknowledges the challenges and sacrifices that have to be made on a professional and on a personal level in order to succeed in managing operations across large and complex organisations.”

12 Report

Hospital Pharmacy Training Framework Draft published The European Association of Hospital Pharmacists (EAHP) has published a draft version of a potential common training framework (CTF) for hospital pharmacy in Europe. The publication comes ahead of an online Delphi method consultation on its content that will commence on 27 February 2017. Individuals and associations interested in providing their viewpoint have until 20 February 2017 to register to participate. The draft framework was developed over 18 months by a pan-European group of 16 hospital pharmacists, led by Dr Andreia Bruno of the Portuguese Pharmaceutical Society. The working group developed the draft framework in 3 phases: 1: Consolidating information and understanding on the current status of hospital pharmacy education across Europe; 2: Review and analysis of the hospital pharmacist competencies provided by national programmes; and, 3: Proposing the core knowledge, skills and competencies that should form a draft common training framework for hospital pharmacy in Europe. Background references for the proposed framework included the 44 European Statements of Hospital Pharmacy, the 2011 European Commission sponsored project Pharmine,

as well as the curricula for a broad range of existing hospital pharmacy post graduate education programmes across Europe. The framework will support the raising of standards in hospital pharmacy practice and thereby enhance the quality of, safety of, and equity of access to, patient care in every European country. It will provide a key tool for all countries in delivering the vision of the 44 European Statements of Hospital Pharmacy. Why a common training framework in hospital pharmacy? The 44 European Statements of Hospital Pharmacy, agreed via EAHP’s national member country platforms, and in partnership with European patient and healthcare professional organisations, set out the vision of what hospital pharmacy should aspire to achieve in all countries. What is now required are the tools for the profession to achieve this vision, and uppermost among these is the educational background to fulfill tasks that go above and beyond that provided for in the initial MPharm qualification. These include such areas as medicines production and compounding, interface management, rare diseases, advanced therapies and the conduct of clinical trials. By agreeing at a panEuropean level the framework

of competencies required to achieve the European Statements of Hospital Pharmacy, all countries can have clarity, and a benchmark, as to what education is necessary to underpin the highest performance of their hospital pharmacy profession. In short, the path to improvement is further illuminated. An eventual common training framework of legal standing will achieve a step towards change in hospital pharmacist labour mobility and open new doors to the sharing of best practices, knowledge and improvement opportunities. The ultimate guiding mission of all involved in the common training framework project is to enhance the quality of, safety of, and equity of access to, patient care in every European country. The hospital pharmacist’s role in achieving this mission cannot be realised without fundamental educational underpinning to advanced practice. Speaking of the publication, Dr Andreia Bruno, chair of the Working Group that developed the draft framework, said, "What our working group discovered was that, although structures for hospital pharmacy (formal and informal) across Europe may differ, the skills and competencies delivered at the end of the process are really quite similar. They all meet the same needs of leveraging the pharmacist's expertise and potential within the hospital

setting, where acute conditions, rare diseases, complex and specialised medicinal therapies, clinical trials and many other particularities have a strong presence. The draft framework therefore offers a synthesis of practice realities across Europe based upon firm foundations such as the 2011 Pharmine project and existing hospital pharmacy curricula. “Now we are providing scrutiny opportunity to the wide variety of impacted stakeholders via a Delphi method consultation.” Meanwhile CTF Working Group 2 is conducting an exercise of gathering existing evidence and carrying out primary research in support of the project. This includes a literature review around the topic of hospital pharmacy education, as well as an exploration of the experiences and attitudes of hospital pharmacists towards the matter of labour mobility. EAHP Past-President, Dr Roberto Frontini, leads Working Group 2. Finally, CTF Working Group 3 takes on a series of communications tasks including, but not limited to: • monitoring of developments relevant to the project at the EU and national levels; • conducting liaison with the European Commission and other professions developing common training framework approaches; and,

Figure 1

March 2017 • HPN

XOFIGO® prolongs the overall survival of patients with castration-resistant prostate cancer (CRPC) by intensive treatment at sites of bone metastases. Introduce Xofigo® for patient progressing on second-generation hormonal therapy1,2

v This medicinal product is subject to additional monitoring. Adverse events and product complaints should be reported. To report an adverse event or a product complaint about a Bayer product, please call Bayer on 01 2999 313. Adverse events and product complaints may also be reported to HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website:; e-mail: Xofigo 1100 kBq/mL solution for injection (radium Ra 223 dichloride) Please refer to full Summary of Product Characteristics (SmPC) before prescribing. Composition: Active ingredient: radium Ra 223 dichloride (radium-223 dichloride, 1100 kBq/ml, corresponding to 0.58 ng radium-223 at the reference date). Each vial contains 6 mL of solution (6.6 MBq radium-223 dichloride at the reference date). Contains sodium. Indication: Treatment of adults with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastases. Dosage and Administration: Xofigo should be administered only by persons authorised to handle radiopharmaceuticals in designated clinical settings and after evaluation of the patient by a qualified physician. Recommended dose is an activity of 55 kBq per kg body weight, given at 4 week intervals for 6 injections. Safety and efficacy beyond 6 injections with Xofigo have not been studied. Xofigo is administered by slow intravenous injection (generally up to 1 minute). The intravenous access line or cannula must be flushed with isotonic sodium chloride 9mg/ml (0.9%) solution for injection before and after injection of Xofigo. No dosage adjustment is considered necessary in elderly patients, patients with hepatic impairment or in patients with renal impairment. Safety and efficacy of Xofigo in children and adolescents below 18 years of age have not been studied. Contraindications: No known contraindications. Warnings and Precautions: Bone marrow suppression, notably thrombocytopenia, neutropenia, leukopenia and pancytopenia, has been reported. Haematological evaluation of patients must be performed at baseline and prior to every dose. In case there is no recovery in values for absolute neutrophil count (ANC) and haemoglobin within 6 weeks after the last administration of Xofigo despite receiving standard of care, further treatment with Xofigo should only be continued after careful benefit/risk evaluation.

Patients with evidence of compromised bone marrow reserve e.g. following prior cytotoxic chemotherapy and/or radiation treatment (EBRT) or patients with advanced diffuse infiltration of the bone (EOD4; “superscan”), should be treated with caution as an increased incidence of haematological adverse reactions such as neutropenia and thrombocytopenia has been observed. Limited available data indicates that patients receiving chemotherapy after Xofigo had a similar haematological profile compared to patients receiving chemotherapy after placebo. Crohn’s disease and ulcerative colitis: due to the faecal excretion of Xofigo, radiation may lead to aggravation of acute inflammatory bowel disease, therefore Xofigo should only be administered to these patients after a careful benefit-risk assessment. In patients with untreated imminent or established spinal cord compression, treatment with standard of care, as clinically indicated, should be completed before starting or resuming treatment with Xofigo. In patients with bone fractures, orthopaedic stabilisation of fractures should be performed before starting or resuming treatment with Xofigo. In patients treated with bisphosphonates and Xofigo, an increased risk of development of osteonecrosis of the jaw (ONJ) cannot be excluded. In the phase III study, cases of ONJ have been reported in 0.67% patients (4/600) in the Xofigo arm compared to 0.33% patients (1/301) in the placebo arm. However, all patients with ONJ were also exposed to prior or concomitant bisphosphonates and prior chemotherapy. Xofigo contributes to a patient’s overall long-term cumulative radiation exposure and therefore may be associated with an increased risk of cancer and hereditary defects. No cases of Xofigo-induced cancer have been reported in clinical trials in followup of up to three years. Depending on the volume administered, Xofigo can contain up to 2.35 mmol (54 mg) sodium per dose. Undesirable effects: Very common: thrombocytopenia, diarrhoea, vomiting, nausea; Common: neutropenia, pancytopenia, leukopenia, injection site reactions; Uncommon: lymphopenia. Classification for supply: Medicinal product subject to restricted medical prescription. Marketing Authorisation Holder: Bayer Pharma AG. 13342 Berlin. Germany. MA number(s): EU/1/13/873/001. Further information available from: Bayer Ltd., The Atrium, Blackthorn Road, Dublin 18. Tel: 01 2999313. Date of Preparation: October 2015

References: 1. Mohler JL, Armstrong AJ, Bahnson RR, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Prostate Cancer. Version 2.2016. National Comprehensive Cancer Network; 2016:1-108. 2. Mottet N, Bellmunt J, Briers E, et al. Guidelines on Prostate Cancer. European Association of Urology; 2015 :1-156. 3. Xofigo® (radium Ra 223 dichloride) solution for injection Summary of Product Characteristics (SmPC), Bayer Pharma AG, 13342 Berlin, Germany, 2016.

© 2016 Bayer Pharma AG. September 2016. L.IE.MKT.09.2016.0632

14 Report He went on to say the Common Training Framework is a tool with many uses. For example, as an inspiration for the development of competency-based education and training programmes for hospital pharmacy, especially in those countries where formal structures of this kind may be under consideration. A common training framework must meet the following conditions, as set out in the 2013 Directive amendments): • the common training framework enables more professionals to move across Member States; • the profession is regulated, or the education and training leading to the profession is regulated in at least one third of the Member States;

• ensuring clear understanding of the project amongst the EAHP membership, wider hospital pharmacy profession and associated stakeholder community, as well as providing opportunities for their input. EAHP President Joan Peppard leads this Working Group. Representatives from EAHP's common training framework (CTF) project recently presented at the annual Congress of the Italian Society of Hospital Pharmacy (Società Italiana di Farmacia Ospedaliera -SIFO) and encouraged all interested individuals and organisations to register to participate in the consultation on its content. Dr Roberto Frontini, Immediate Past President of EAHP, facilitated a dedicated panel session about the CTF at the Congress in Milan on Saturday

3rd December. The event heard the perspectives of providers of hospital pharmacy education in Italy, an Italian hospital pharmacist working in Spain, a representative of the European Pharmaceutical Students Association (EPSA), and Professor Ian Bates, Chairman of the Steering Committee of the Common Training Framework. EAHP Policy and Advocacy Officer, Richard Price, gave a presentation on the background to the common training framework, and the intended practical value to be achieved by its creation. Speaking about the need for a vision, Mr Price states that EAHP surveys were evidencing slower rates of practice development in many parts of Europe. To fulfill EAHP’s professional development mandate a shared vision of practice was necessary.

• it shall be irrelevant whether the knowledge, skills and competences have been acquired as part of a general training course at a university or higher education institution or as part of a vocational training course; • the common training framework shall be based on the European Qualifications Framework for lifelong learning; • It has been prepared following a transparent due process. The leader of the working group developing the draft content of the framework, Dr Andreia Bruno, gave a presentation on how her pan-European group of hospital pharmacists embarked upon the project of defining core competencies of the hospital pharmacy profession common across European countries. Ms Peppard will present the EAHP’s common training framework (CTF) project during the third keynote speech “Introducing the Common

The ultimate guiding mission of all involved in the common training framework project is to enhance the quality of, safety of, and equity of access to, patient care in every European country. The hospital pharmacist’s role in achieving this mission cannot be realised without fundamental educational underpinning to advanced practice March 2017 • HPN

Training Framework (CTF)” – at the 22nd Congress of the EAHP, 22nd to 24th March 2017, in Cannes. The keynote will focus on competency-based approaches to training, staff development and assessment which are increasingly viewed as a central strategy for improving the effectiveness of those who provide care. This presentation will describe the potential benefits and risks of a competency-based approach to hospital pharmacy advanced practice and it will illustrate the progress of competence-based approaches in Europe where barriers to mutual recognition of education and training systems still exist for many professions including hospital pharmacy. Furthermore, a quality approach to the ongoing management of such a framework will also be considered. At the end of the seminar participants should • Have an increased awareness of the competencies required of a hospital pharmacist; • Understand the potential for development of a European recognition of the title ' hospital pharmacist'; and • Recognise the importance of quality assurance of post graduate education. You can view the draft Common Training Framework by visiting The 22nd Congress of the European Association of Hospital Pharmacists (EAHP) takes place in Cannes, France, from 22nd to 24th March 2017, the event will take as its overall theme: 'Hospital pharmacists – catalysts for change'. Keynote speeches will emphasise major futurefocused talking points within the profession, such as: 'New medicines at any cost?'; 'Big Data: hype or help?'; and, 'Introducing the Common Training Framework'. Almost 30 seminars will explore a diversity of practice and science topics such as: performance management; hospital accreditation; the growing role of hospital pharmacists in the outpatient setting; health technology assessment; automation; predicting the future of healthcare; ImmunoOncology; and, the Falsified Medicines Directive.

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16 Clinical Synopsis

ASCO 2017 Genitourinary Cancers Symposium The 2017 Genitourinary (GU) Cancers Symposium is a three-day scientific and educational meeting designed to meet the needs of physicians and other members of the cancer care and research community who diagnose, treat, and study GU malignancies across the world. In educational sessions, expert faculty will offer a multidisciplinary perspective on new research and its clinical application with an emphasis on value in cancer care across the spectrum of GU cancers. Oral abstract presentations and poster sessions will highlight the latest, cutting-edge science, and keynote lectures from internationally renowned speakers will address the most clinically relevant research in the field of GU oncology. Five studies exploring key issues in the treatment of genitourinary cancers will be presented at the 2017 Genitourinary Cancers Symposium, taking place February 16-18 at Rosen Shingle Creek in Orlando, Florida. These noteworthy abstracts investigate several approaches to the treatment and management of prostate cancer, bladder cancer, and advanced kidney cancer. Abstract 132: Clinical significance of AR mRNA quantification from circulating tumor cells (CTCs) in men with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone (Abi) or enzalutamide (Enza). Author(s): John Silberstein, Brandon Luber, Hao Wang, Changxue Lu, Yan Chen, Yezi Zhu, Maritza N. Taylor, Michael Anthony Carducci, Mario A. Eisenberger, Jun Luo, Emmanuel S. Antonarakis; The James Buchanan Brady Urological Institute, The Johns Hopkins Hospital, Baltimore, MD; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Department of Urology, The John Hopkins University School of Medicine, Baltimore, MD Background: AR-targeting agents remain the backbone of mCRPC therapy. We previously reported an association between AR-V7 mRNA detection in CTCs and resistance to Abi/Enza (NEJM 2014). Here, we report the prognostic significance of full-length androgen receptor (AR-FL) mRNA quantification from CTCs in pts starting Abi or Enza. Methods: We prospectively enrolled mCRPC pts starting Abi or Enza, and examined the prognostic value of AR-FL detection using a CTC-based mRNA assay (modified AdnaTest, Qiagen). We examined PSA50 responses, PSA progression free survival (PSA-PFS), clinical/radiologic PFS (PFS), and overall survival (OS). We constructed multivariable (MVA) Cox regression models adjusting for AR-V7 status, PSA level, Gleason sum, number of prior therapies, prior Abi/Enza use, prior taxane use, presence of visceral disease, and ECOG score. Results: We enrolled 202 pts (median f/u 12.9 mo). AR-FL status was negative in 97/202 pts (48%), < median in 52/202 (26%) and > median in 53/202 (26%). Higher AR-FL levels correlated with positive AR-V7 detection (35.5 copies [range: 2.5–1209] in AR-V7+ vs 1.4 copies [range: 0–172.5] in AR-V7–, P< .001), as well as lower PSA50 responses (55.4 copies in nonresponders vs 6.7 copies in responders, P< .001). In Kaplan-Meier analysis, PSA-PFS, PFS and OS differed significantly between AR-FL negative, AR-FL < median, and AR-FL > median (Table). In MVA models, AR-FL level (as a continuous variable) was prognostic for PSA-PFS (HR 1.06, 95%CI 1.00–1.12, P= .04) and trended with prognosis for PFS (HR 1.04, 95%CI 0.99–1.11, P= .13) and OS (HR 1.07, 95%CI 1.00–1.15, P= .06). AR-V7 status was also independently prognostic for all outcomes in MVA analyses. Conclusions: This study demonstrates CTC-derived AR-FL copy number is prognostic for clinical outcomes in Abi/Enza-treated mCRPC pts. In addition to AR-V7 status, AR-FL quantification could serve as another molecular biomarker of Abi/Enza sensitivity after analytical validation/standardization. Abstract 141: Association of changes in circulating cell-free plasma DNA (cfDNA) and circulating tumor cells (CTC) during treatment with clinical outcome from olaparib in castration-resistant prostate cancer (CRPC): Exploratory analyses from the TOPARP-A trial. Author(s): Joaquin Mateo, Helen Mossop, Jane Goodall, David Lorente, Nuria Porta, Suzanne Carreira, Susana Miranda, Zafeiris Zafeiriou, Christy Ralph, Suneil Jain, Robert J. Jones, Syed A. Hussain, Tony Elliott, Andrew Protheroe, Berni Ebbs, Lorna Leonard, Diletta Bianchini, Penelope Flohr, Emma Hall, Johann S. De Bono; The Institute of Cancer Research & The Royal Marsden, London, United Kingdom; Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, United Kingdom; The Institute of Cancer Research, London, United Kingdom; Servicio Oncologia Medica Hospital Universitario La Fe, Valencia, Spain; Clinical Trials and Statistics Unit, The Institute of Cancer Research, Sutton, United Kingdom; St. James's Institute of Oncology, St. James's University Hospital, Leeds, United Kingdom; Queen's University Belfast, Belfast, United Kingdom; University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom; University of Liverpool, Clatterbridge Cancer Centre NHS Foundation Trust, Wirral, United Kingdom; The Christie Hospital, Manchester, United Kingdom; Churchill Hospital, Oxford Medical Oncology Department, Oxford, United Kingdom; The Institute of Cancer Research, London, London, United Kingdom Background: Response biomarkers are needed to optimize treatment switch decisions in CRPC patients. CTC and cfDNA may have clinical utility as response biomarkers; we studied them during olaparib treatment in a phase II trial in CRCP (Mateo et al NEJM 2015). Methods: CTC were enumerated using CellSearch (Jannsen Diagnostics) and cfDNA was extracted with the QIASymphony circulating DNA kit (Qiagen) from blood samples taken at baseline, 4- and 8-weeks (wk) of therapy. Radiological progression-free survival (rPFS) was defined as time from starting treatment to progression by RECIST 1.1, bone scan (PCWG2) or death. Overall survival (OS) was defined as time from starting treatment to death. CTC changes were categorized based on conversion from ≥ 5 to < 5 CTC/7.5ml blood and on ≥ 30% decline (Lorente et al Eur Urol 2016). cfDNA changes were evaluated as percentage change from baseline (continuous and binary). The prognostic value of CTC and cfDNA changes were assessed by Landmark analysis and Cox models with time-varying covariates; p-value < 0.01 were considered significant to account for multiple tests. Results: Overall, 13/47 (28%) and 16/42 (38%) evaluable patients had a CTC conversion at 4- and 8-wk respectively. A CTC conversion after 4-wk of olaparib associated with longer rPFS (median 8.9 vs 2.7 months [m], p = 0.001); a similar association was found at 8-wk. A 30% CTC decline at 4-wk also associated with longer rPFS (median 4.4 vs 2.6 m, p = 0.004). CTC conversion as a time-varying covariate associated with longer OS (HR 0.26, 95%CI 0.14-0.50, p < 0.001). Median baseline cfDNA was 31.6 ng/ml (IQR 19.4-57.1); 46 and 42 patients were evaluable for cfDNA changes at 4- and 8-wk. Percentage changes in cfDNA at 4- and 8- wk associated with rPFS (HR 1.01 and 1.005; p = 0.005 and 0.002 respectively) but association with OS was not significant. cfDNA declines ≥ 50% at 8- wk associated with longer rPFS (median 8.9 vs 2.7 m, p = 0.007) and OS (17.0 vs 10.1 m, p = 0.004). Conclusions: Decreases in CTC counts and cfDNA concentration associate with improved outcome from olaparib (rPFS, OS) in the TOPARP-A trial. Clinical trial information: NCT01682772 March 2017 • HPN

FIRST LINE CLL GAZYVARO ▼(obinutuzumab) is the only antibody with proven superiority vs. MabThera 1 (rituximab) in first-line CLL ®


ENGINEERED FOR S U P E R I O R I T Y EFFECTIVE IN THE R E A L W O R L D 1 Indication: GAZYVARO in combination with chlorambucil is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL) and with comorbidities making them unsuitable for full-dose fludarabine based therapy.

ABRIDGED PRESCRIBING INFORMATION (For full prescribing information refer to the Gazyvaro Summary of Product Characteristics [SmPC]). Gazyvaro®▼ (obinutuzumab) 1,000 mg concentrate for solution for infusion Indication: Chronic Lymphocytic Leukaemia (CLL): In combination with chlorambucil for the treatment of adult patients with previously untreated CLL and with comorbidities making them unsuitable for full-dose fludarabine therapy. Follicular Lymphoma (FL): In combination with bendamustine followed by Gazyvaro maintenance for the treatment of patients with FL who did not respond or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen. Dosage & Administration: Administer as an IV infusion through a dedicated line after dilution, with full resuscitation facilities immediately available and under supervision of an experienced physician. Do not administer as IV push or bolus. Prophylaxis and premedication for Tumour Lysis Syndrome (TLS): Patients with high tumour burden and/or a high circulating lymphocyte count (>25 x 109/L) and/or renal impairment (CrCl) <70mL/min) are considered at risk of TLS and should receive prophylaxis. Prophylaxis should consist of adequate hydration and administration of uricostatics e.g. allopurinol, or suitable alternative treatment such as urate oxidase (e.g. rasburicase), starting 12-24 hours prior to start of therapy. Patients should continue to receive repeated prophylaxis prior to each subsequent infusion, if deemed appropriate. Prophylaxis and premedication for infusion-related reactions (IRRs): Hypotension, as a symptom of IRRs, may occur during Gazyvaro infusions; consider withholding antihypertensives for 12 hours prior to and throughout each infusion and for the first hour after administration. Administer premedication before each infusion - see SmPC for further details. Duration of treatment: CLL, in combination with chlorambucil: 6 treatment cycles each of 28 days duration. Dose: Cycle 1: 1,000 mg split over Day 1 (100 mg) and Day 2 (900 mg; if the first bag is completed without modifications of the infusion rate or interruptions, the second bag may be administered on day 1, with no need for dose delay or repetition of premedication); 1,000 mg on Day 8; and 1,000 mg on Day 15 of a 28-day treatment cycle. Cycles 2 - 6: 1,000 mg on Day 1. FL: Induction with 6 cycles of 28 days in combination with bendamustine, followed by Gazyvaro single-agent maintenance (if patients responded or had stable disease after induction) once every 2 months for two years or until disease progression (whichever occurs first). Maintenance: 1,000 mg. Administration: Monitor closely for IRRs. CLL, in combination with chlorambucil: Cycle 1: Day 1 (100 mg): Administer at 25 mg/ hr over 4 hours. Do not increase the infusion rate. Day 2 (or Day 1 continued) (900 mg): If no IRR occurred during the previous infusion, administer at 50 mg/hr. Infusion rate can be escalated in increments of 50 mg/hr every 30 minutes to a maximum of 400 mg/hr. Cycle 1: Day 8 and Day 15 and Cycles 2 - 6: Day 1 (1,000 mg): If no IRR occurred during the prior infusion, when the final infusion rate was 100 mg/hr or faster, administer at 100 mg/hr, with escalation by 100 mg/hr increments every 30 minutes to a maximum of 400 mg/hr. FL, in combination with bendamustine: Cycle 1: Day 1(1,000 mg): Administer at 50 mg/ hr. The rate of infusion can be escalated in 50 mg/hr increments every 30 minutes to a maximum of 400 mg/hr. Cycle 1: Day 8 and Day 15 and Cycles 2 - 6: Day 1 (1,000 mg): If no infusion related reaction occurred during the prior infusion when the final infusion rate was 100 mg/hr or faster, infusions can be started at a rate of 100 mg/hr and increased by 100 mg/hr increments every 30 minutes to a maximum of 400 mg/hr. Maintenance: Every two months for two years or until disease progression (whichever occurs first). Management of IRRs may require temporary interruption, reduction in rate of infusion, or treatment discontinuations – see SmPC for further details. Contraindications: Hypersensitivity to any component of this product. Warnings & Precautions: Include the trade name and batch number of the administered product in the patient records to improve traceability of biological medicinal products. IRRs: Most frequently observed during infusion of first 1,000 mg with most patients having no IRRs during subsequent administrations. Mitigation measures to reduce IRRs should be followed (see SmPC). IRRs may be related to cytokine release syndrome which has also been reported in Gazyvaro treated patients. Patients with a high tumour burden and/or high circulating lymphocyte count in CLL (> 25 x 109/L) may be at increased risk of severe IRRs. Patients with renal impairment (CrCl < 50 mL/min) and with both Cumulative Illness Rating Scale (CIRS) > 6 and CrCl < 70 mL/min are more at risk of IRRs, including severe IRRs. Do not administer further infusions if patient experiences acute life-threatening respiratory symptoms, a Grade 4 (life threatening) IRR or, a second occurrence of a Grade 3 (prolonged/recurrent) IRR (after resuming the first infusion or during a subsequent infusion). Carefully monitor patients who have pre-existing cardiac or pulmonary conditions throughout the infusion and post-infusion period. For patients at acute risk of hypertensive crisis evaluate the benefit and risks of withholding anti-hypertensive medicine. Hypersensitivity reactions including anaphylaxis: Anaphylaxis has been reported. Hypersensitivity may be difficult to distinguish from IRRs. If a hypersensitivity reaction is suspected during infusion, stop the infusion and permanently discontinue Gazyvaro. Patients with known IgE mediated hypersensitivity to obinutuzumab must not be treated. TLS: TLS has been reported – see Dosage & Administration for suggested prophylaxis. All patients considered at risk should be carefully monitored during the initial days of treatment with a special focus on renal function, potassium, and uric acid values. Neutropenia: Severe and life-threatening neutropenia including febrile neutropenia has been reported and patients with renal impairment (CrCl <50 mL/min) are more at risk. Patients with neutropenia should be closely monitored with regular laboratory tests until resolution. Treat in accordance with local guidelines and consider administration of G-CSF. Consider dose delays with severe or life-threatening neutropenia. For severe neutropenia lasting > 1 week, antimicrobial prophylaxis strongly recommended throughout the treatment period until resolution to Grade 1 or 2. Antiviral and antifungal prophylaxis should be also considered. Cases of late onset neutropenia (occurring >28 days after treatment end) and prolonged neutropenia (lasting >28 days after treatment end) have also been reported. Thrombocytopenia: Severe and life-threatening thrombocytopenia including acute thrombocytopenia (occurring within 24 hours after infusion) has been observed during treatment and patients with renal impairment (CrCl <50 mL/min) are more at risk. Fatal haemorrhagic events have also been reported in Cycle 1 of treatment. A clear relationship between thrombocytopenia and haemorrhagic events has not been established. Monitor patients closely especially during the first cycle; perform regular laboratory tests until event resolution, consider dose delays in cases of severe or life-threatening thrombocytopenia. Transfusion of blood products at the discretion of the treating physician. Use of any concomitant therapies which could worsen thrombocytopenia events should be taken into consideration particularly during the first cycle. Worsening

of pre-existing cardiac conditions: May occur as part of an IRR and can be fatal. Patients with a history of cardiac disease should be monitored closely and hydrated with caution to prevent fluid overload. Infections: Do not administer Gazyvaro in the presence of an active infection and exercise caution when considering use in patients with a history of recurring or chronic infections. Fatal infections have been reported. In patients with both CIRS>6 and CrCl<70 mL/min, an increased incidence and severity of infections was observed. Hepatitis B reactivation: HBV reactivation, some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with anti-CD20 antibodies including Gazyvaro. Perform HBV screening (including HBsAg and HBcAb-status) before initiating treatment. Patients with active hepatitis B disease should not be treated and those with positive hepatitis B serology should consult liver disease experts before start of treatment and be monitored and managed to prevent hepatitis reactivation. Progressive Multifocal Leukoencephalopathy (PML): PML has been reported and PML diagnosis should be considered in any patient presenting with new-onset or changes to pre-existing neurologic manifestations. Evaluation of PML includes consultation with a neurologist, brain MRI and lumbar puncture. Treatment should be withheld during investigation of potential PML; permanently discontinued if PML confirmed and refer patient to a neurologist. Immunisation: The safety of immunisation with live or attenuated viral vaccines following Gazyvaro therapy has not been studied and vaccination with live virus vaccines is not recommended during treatment and until B cell recovery. Drug Interactions: No formal drug-drug interaction studies have been performed. A risk for interactions with other concomitantly used medicinal products cannot be excluded. Obinutuzumab is not a substrate, inhibitor or inducer of CYP450, UGT enzymes and transporters such a P-glycoprotein; therefore no pharmacokinetic interactions expected with drugs known to be metabolised by these enzyme systems. Fertility, Pregnancy & Lactation: Women of childbearing potential must use effective contraception during and for 18 months after treatment. Gazyvaro should not be administered to pregnant women unless the possible benefit outweighs the potential risk. Side Effects and Adverse Reactions: Very common (≥ 1/10): Upper respiratory tract infection, sinusitis, neutropenia, thrombocytopenia, anaemia, cough diarrhoea, constipation, arthralgia, pyrexia, asthenia, IRRs. Common (≥1/100 to <1/10): urinary tract infection, nasopharyngitis, oral herpes, rhinitis, pharyngitis, lung infection, influenza, squamous cell carcinoma of skin, leukopenia, lymph node pain, TLS, hyperuricaemia, depression, ocular hyperaemia, atrial fibrillation, cardiac failure, hypertension, nasal congestion, rhinorrhoea, dyspepsia, colitis, haemorrhoids alopecia, pruritus, night sweats, eczema, back pain, musculoskeletal chest pain, pain in extremity, bone pain, dysuria, urinary incontinence, chest pain, WBC count decreased, neutrophil count decreased, weight increased. Elderly: Patients with CLL aged ≥75 years experienced more serious adverse events leading to death than patients < 75 years. No clinically meaningful differences in safety according to age in the pivotal study in iNHL. Refer to SmPC for full listings of adverse events. See 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). Presentations & Marketing Authorisation Number: 1,000 mg of obinutuzumab in 40 mL (25 mg/mL) pack of 1 vial (EU/1/14/937/001). Marketing Authorisation Holder: Roche Registration Limited, 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, United Kingdom. Gazyvaro is a registered trade mark. Further information is available from Roche Products (Ireland) Limited, 3004 Lake Drive, Citywest, Naas Road, Dublin 24. Telephone: (01) 4690700. Fax: (01) 4690791. Date of Preparation: June 2016 ▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you become aware of. In the event of a suspected adverse event, please report it to: The Drug Surveillance Centre, Roche Products (Ireland) Limited Telephone: (01) 4690700 Fax: (01) 469 0793 Email: Alternatively, suspected adverse reactions should be reported to: The Pharmacovigilance Section, Health Products Regulatory Authority (HPRA) Telephone: (01) 676 4971 Fax: (01) 676 2517 Website: Email: References: 1. Goede V et al. N Engl J Med 2014; 370:1101-1110 and Supplementary Appendix Date of item: September 2016. IE/GAZ/0515/0004(2)

18 Clinical Synopsis Abstract 280: BC2001 long-term outcomes: A phase III randomized trial of chemoradiotherapy versus radiotherapy (RT) alone and standard RT versus reduced high-dose volume RT in muscle-invasive bladder cancer. Author(s): Emma Hall, Syed A. Hussain, Nuria Porta, Malcolm Crundwell, Peter Jenkins, Christine Lisa Rawlings, Jean Tremlett, Charlotte Friend, Clive Stubbs, Rebecca Lewis, Nicholas D. James, Robert Anthony Huddart, on behalf of the BC2001 Investigators; Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, United Kingdom; University of Liverpool, Liverpool, United Kingdom; Clinical Trials and Statistics Unit, The Institute of Cancer Research, Sutton, United Kingdom; Royal Devon & Exeter NHS Foundation Trust, Exeter, United Kingdom; Cheltenham General Hospital, Cheltenham, United Kingdom; South Devon Healthcare NHS Foundation, Torbay, United Kingdom; Brighton and Sussex University Hospitals NHS Trust, Brighton, United Kingdom; Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, United Kingdom; University of Birmingham and Queen Elizabeth Hospital, Brimingham, United Kingdom; Institute of Cancer Research, Sutton, United Kingdom Background: BC2001 showed that adding chemotherapy (5FU+MMC) to radiotherapy significantly improved rates of muscle invasive bladder cancer (MIBC) locoregional control (LRC) [James 2012] but that reduced high dose volume RT rather than standard RT did not significantly reduce late side effects [Huddart 2013]. Here we present an update of the time to event outcomes after a median 10 years follow up. Methods: Under the 2x2 partial factorial design, 458 pts were randomised to RT (178) or cRT (182) (CT comparison) and/or to stRT (108) or RHDVRT (111) (RT comparison). Primary endpoint was LRC, secondary endpoints included overall survival (OS), bladder-cancer specific survival (BCSS), metastasis free survival (MFS) and salvage cystectomy rates. Results: Median follow up was 118 months (95%CI: 112-122). LRC and invasive LRC (ILRC) were improved with cRT (Table 1). Though no statistically significant differences between groups were found in OS, cRT exhibited a trend towards improvement in BCSS, significant when adjusted by known prognostic factors. Similar trend was found for MFS. Salvage cystectomy rate was lower for cRT (2-year rate, cRT:11% vs RT:17%, p=0.03). No differences between stRT and RHDVRT were found for any trial endpoint. Conclusions: With extended follow-up, an improvement in LRC and a reduced salvage cystectomy rate is confirmed with cRT. After adjustment for known prognostic factors this results in an improvement in BCSS. This updated data supports the use of cRT with 5FU/MMC and confirms this should be a standard of care for this patient population. Clinical trial information: ISRCTN68324339. Abstract 431: A phase II study of atezolizumab (atezo) with or without bevacizumab (bev) versus sunitinib (sun) in untreated metastatic renal cell carcinoma (mRCC) patients (pts). Author(s): David F. McDermott, Michael B. Atkins, Robert J. Motzer, Brian I. Rini, Bernard J. Escudier, Lawrence Fong, Richard Wayne Joseph, Sumanta K. Pal, Mario Sznol, John D. Hainsworth, Walter Michael Stadler, Thomas E. Hutson, Alain Ravaud, Sergio Bracarda, Cristina Suarez, Toni K. Choueiri, YounJeong Choi, Mahrukh A. Huseni, Gregg Daniel Fine, Thomas Powles; Beth Israel Deaconess Medical Center, Boston, MA; Georgetown Lombardi Comprehensive Cancer Center, Washington, DC; Memorial Sloan Kettering Cancer Center, New York, NY; Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; Institut Gustave Roussy, Villejuif, France; University of California, San Francisco, San Francisco, CA; Mayo Clinic, Jacksonville, FL; City of Hope, Duarte, CA; Yale University School of Medicine, New Haven, CT; Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN; The University of Chicago, Chicago, IL; Texas Oncology, Dallas, TX; Groupe Hospitalier Saint Andre - Hopital Saint Andre, Bordeaux Cedex, France; Ospedale San Donato Azienda USL-8, Perugia PG, Italy; Vall d'Hebron University Hospital, Universitat Autonoma de Barcelona, Barcelona, Spain; Dana-Farber/Harvard Cancer Center, Boston, MA; Genentech, Inc., South San Francisco, CA; Barts Cancer Institute-Queen Mary University of London, London, United Kingdom Background: While targeting VEGF improves outcomes for mRCC pts, resistance invariably develops, often within the first year. Here, we describe the efficacy and safety of atezo (anti-PD-L1) with bev (anti-VEGF) and atezo monotherapy vs sun (TKI) in first-line mRCC. Methods: Treatment-naïve mRCC pts were enrolled in a hypothesis generating Ph II study (IMmotion150; NCT01984242) and randomized to atezo 1200 mg IV q3w + bev 15 mg/kg IV q3w, atezo alone or sun 50 mg PO QD 4 wk on/2 wk off. Crossover to atezo + bev after disease progression was allowed for pts receiving atezo or sun. PD-L1 expression was scored on tumor-infiltrating immune cells (IC, SP142 IHC assay). Coprimary endpoints were PFS (RECIST v1.1 by independent review [IRF]) in ITT pts and pts with PD-L1 expression on ≥ 1% of IC (PD-L1+). Results: Baseline characteristics were comparable across arms and between ITT and PD-L1+ pts. The majority of sun and atezo pts subsequently received atezo + bev. Median survival follow up was 20.7 mo. The PFS HR in ITT pts for atezo + bev vs sun was 1.00 and 1.19 for atezo vs sun. In PD-L1+ pts, the PFS HR for atezo + bev vs sun was 0.64 and 1.03 for atezo vs sun (table). Tx-related Gr 3-4 AEs were seen in 40%, 16% and 57% of pts in the atezo + bev, atezo and sun arms, respectively. AEs leading to death occurred in 3%, 2% and 2% of pts, respectively. Conclusion: Atezo + bev resulted in encouraging antitumor activity in the PD-L1+ subgroup of first-line RCC pts. Atezo + bev safety is consistent with the known profile of atezo and bev individually. The clinical benefit of atezo + bev vs sun will be evaluated in the ongoing Ph III study IMmotion151 (NCT02420821). Clinical trial information: NCT01984242 Abstract 434: Evolution of circulating tumor DNA (ctDNA) profile from first-line (1L) to second-line (2L) therapy in metastatic renal cell carcinoma (mRCC). Author(s): Sumanta K. Pal, Guru Sonpavde, Neeraj Agarwal, Nicholas J. Vogelzang, Sandy Srinivas, Naomi B. Haas, Sabina Signoretti, Richard B. Lanman, Kimberly Banks, Toni K. Choueiri; City of Hope, Duarte, CA; University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL; Huntsman Cancer Institute-University of Utah Health Care, Salt Lake City, UT; Comprehensive Cancer Centers of Nevada, Las Vegas, NV; Stanford University, Stanford, CA; Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA; Brigham and Women's Hospital, Boston, MA; Guardant Health, Inc., Redwood City, CA; Dana-Farber/Harvard Cancer Center, Boston, MA Background: Treatment of mRCC typically entails mechanistically distinct agents across the 1L and 2L setting. Activity of these agents may be predicated on selective pressure that modulates RCC biology. ctDNA is a platform to conveniently ascertain temporal changes in genomic profile. Methods: Data was obtained from pts with mRCC who received ctDNA profiling as a part of routine clinical care at progression using a CLIAA-certified platform evaluating 70 genes. Genomic alterations (GAs) were pooled for the entire cohort. A comparison of 1L vs. 2L was performed, with grouping based on conventional practice patterns (1L regimens included sunitinib, pazopanib and bevacizumab, and 2L regimens included everolimus, axitinib, cabozantinib, and nivolumab). Results: ctDNA results from 224 pts with mRCC were assessed (gender: 149 M, 75 F; average age: 62; histology: 89 clear cell, 37 non-clear cell, 98 unknown). GAs were detected in 78.6% of pts. The most frequent GAs in the overall cohort included TP53 (35%), VHL (23%), EGFR (17%), NF1 (16%), and ARID1A (12%). 64 and 56 pts were coded as receiving 1L and 2L agents, respectively. The average number (range) of ctDNA alterations detected was 2.9 (1-14) in 1L and 3.7 (1-16) in 2L with median (range) ctDNA variant allele fractions of 0.23 (0.05-9.92) in 1L and 0.24 (0.04-47.14) in 2L. The highest disparity in GA frequencies in 2L vs. 1L were in TP53 (49% vs. 25%), VHL (29% vs. 25%), NF1 (20% vs. 15%), EGFR (17% vs. 21%), and PIK3CA (17% vs. 8%). Isolating 2L pts who specifically had 1L VEGF-therapy documented, these differences were even more prominent in comparison to 1L pts: TP53 (64% vs. 31%), PIK3CA (29% vs. 8%), and NF1 (29% vs. 4%). Conclusions: In the largest assessment of ctDNA in mRCC to date, the majority of pts demonstrated clinically relevant GAs. Increasing p53 and mTOR pathway (e.g, NF1, PIK3CA) alteration in 2L pts with 1L VEGF-directed therapy may underlie mechanisms of resistance. Increasing GA frequency from 1L to 2L pts may have implications for immunotherapeutic approaches.

March 2017 • HPN

19 Below are some additional scientific programme abstracts submitted for the Symposium. A single-arm trial evaluating one cycle of BEP as adjuvant chemotherapy in high-risk, stage 1 non-seminomatous or combined germ cell tumors of the testis (NSGCTT). Author(s): Robert Anthony Huddart, Johnathan K. Joffe, Jeff D. White, Paul Hutton, Rebecca Lewis, Danish Mazhar, Colin Osborne, Deborah Piercy, Laura Wiley, Stephanie Witts, Lauren Maynard, Emma Hall, Michael H. Cullen, on behalf of the 111 Trial Management Group; Institute of Cancer Research, Sutton, United Kingdom; St. James's University Hospital, Leeds, United Kingdom; Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom; University Hospital Birmingham NHS Trust, Birmingham, United Kingdom; Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, United Kingdom; Addenbrooke's Hospital, Cambridge, United Kingdom; No affiliation, United Kingdom; Institute of Cancer Research Clinical Trials and Statistics Unit, Sutton, United Kingdom; University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom The standard post-orchiectomy treatment for UK patients (pts.) presenting with high-risk stage 1 NSGCTT is 2 cycles of bleomycin, etoposide (360mg/ m2) & cisplatin (BE360P) chemotherapy or surveillance with BEPx3 at recurrence. 111 (CRUK/09/011) investigates whether BE500P x1 would achieve recurrence rates similar to BE360P x2. Methods: Pts aged ≥16 yrs post-orchiectomy for vascular invasion positive stage 1 NSGCTT or combined seminoma + NSGCT, with normalised tumour markers, received 1 cycle of bleomycin30000IU day 1, 8 & 15, etoposide165mg/m2 day 1, 2 & 3, &cisplatin50mg/m2day 1 & 2. All pts received a prophylactic antibacterial & GCSF. Pts were assessed for tumour markers q2m, q3m, q4m in years (yrs) 1, 2, 3, respectively and q6m in yrs 4 & 5. CT scan of chest, abdo and pelvis was performed at 6, 12, 24 & 60months (m) with chest x-ray at other visits. Toxicity was assessed using NCI CTCAE v3. Recurrences were independently reviewed. A sample size of 236 pts excludes a 2-yr recurrence rate of ≥5% if ≤6 recurrences were observed (80% power, 5% α). Results: Between 18/2/2010 and 31/7/2014 246 pts. were recruited at 33 UK centres; 54% with NSGCTT, 46% with combined GCT. Median follow-up was 39.1m (IQR 30.0-50.8). Four patients had malignant recurrences at 5, 8, 12 and 27m. 2 yr recurrence rate in 236 treated pts = 1.3% (95% CI: 0.4 to 4.0%). All 4 pts with recurrences were treated with 2ndline chemotherapy +/- surgery, 3 are alive and free from disease, 1 died at 9m with refractory disease. In addition there were 3 non-malignant recurrences at 7, 10 and 13m with teratoma differentiated in retroperitoneal nodes (3, 4 and 4.4cm). All these pts are disease-free post RPLND surgery. 41% pts had grade 3-4 CTCAE at end of treatment (neutropenia: 31% and febrile neutropenia: 7%). The 2 yr overall survival is 99.2% (95% CI: 96.7, 99.8%). Conclusions: BE500P is safely deliverable & 2 yr recurrence rate is similar to that seen with 2 cycles BE360P. The adoption of BE500P x1 as standard would reduce overall exposure to chemotherapy in this young pt population. 111 is the biggest formal, prospective trial to date investigating adjuvant BEPx1 in high-risk stage 1 NSGCTT. Clinical trial information: ISRCTN37875250. A clinical trial for the safety and immunogenicity of a DNA-based immunotherapy in men with biochemically (PSA) relapsed prostate cancer. Author(s): Neal D. Shore, Elisabeth I. Heath, Luke T. Nordquist, Heather H. Cheng, Kamalnayan Bhatt, Nicholas Carroll, Kimberly Kraynyak, Jessica Lee, Jan Van Tornout, Brian Sacchetta, Scott T. Tagawa, Rahul Atul Parikh, Ronald F. Tutrone, Jorge A. Garcia, Young E. Whang, Jianqing Lin, William Kevin Kelly, Ildiko Csiki, Mark L. Bagarazzi; Carolina Urologic Research Center, Myrtle Beach, SC; Barbara Ann Karmanos Cancer Institute/ Department of Oncology, Wayne State University, Detroit, MI; Urology Cancer Center and GU Research Network, Omaha, NE; University of Washington, Seattle, WA; Inovio Pharmaceuticals, Plymouth Meeting, PA; Inovio Pharmaceuticals, Blue Bell, PA; Weill Cornell Medicine/Meyer Cancer Center, New York, NY; University of Pittsburgh Medical Center, Pittsburgh, PA; Chesapeake Urology Research Associates, Baltimore, MD; Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; The University of North Carolina at Chapel Hill, Chapel Hill, NC; The Sidney Kimmel Cancer Center at Thomas Jefferson University, Philadelphia, PA; GSK, Malvern, PA Background: Introducing amino acid sequence changes in highly expressed self-antigens for androgen sensitive prostate cancer pts might be sufficient to break tolerance, thus a DNA vaccine was developed using SynCon PSA and PSMA (INO-5150) that share 96.8 and 91.6% sequence identities to these native antigens, respectively. Administration of these antigens to prostate cancer pts along with plasmid encoded adjuvant IL-12 (INO-9012) via electroporation (EP) using the CELLECTRA5P device is postulated to break tolerance, resulting in an antigen-specific immune response which could lead to stabilization of disease progression. Methods: This Phase I, open-label, multicenter study included prostate cancer pts post-definitive therapy with a rising PSA ≥ 1.0 ng/ml after surgery, or ≥ 2.0 ng/ml above nadir after RT and PSA doubling time > 3 months, testosterone > 150 ng/dL and no evidence of metastasis within 12 months. INO-5150 with or without INO-9012 was administered IM followed by EP in 4 arms: low (2 mg) or high dose (8.5 mg) INO-5150 alone or with 1 mg INO-9012 on Day 0 and at week 3, 12, and 24 in 60 planned pts (15 pts/arm). DLT assessments were performed after dosing of the first 3 pts of each arm at Week 4. Results: Enrollment is complete in all 4 arms and at data cut-off (10Oct16), 62 enrolled pts received at least one, 60 pts received 3 and about half, 28 pts (10 in arm A, 8 in B, 7 in C, and 3 in D) received all 4 vaccinations. Safety: there were no DLTs noted. Four pts had five Grade 3 SAEs noted as pre-syncope, cardiac disorder, hospitalization for fall, ALT and AST elevation. No Grade 4-5 AEs were noted. Grade 1-3 treatment-emergent AEs occurred in 50 (81%) pts: 12 (75%) in arm A, 13 (87%) B, 13 (87%) C, and 12 (75%) in D. The most common AEs were injection site pain (24/39%), erythema (13/21%), swelling (12/19%), bruising (10/16%), hyperglycemia (8/13%) and fatigue (6/10%), all Grade 1-2. Assessments of immunological response, PSA kinetics and correlation with clinical outcome are ongoing and will be presented. Conclusions: INO5150 (+) or (-) INO-9012 is generally safe and well-tolerable at all 4 dose levels in a biochemically relapsed prostate cancer patient population. Clinical trial information: NCT02514213 Conditional biochemical recurrence-free survival and cancer-specific mortality after radical prostatectomy at long term follow-up. Author(s): Silvia Garcia Barreras, Rafael Sanchez-Salas, Igor Nunes-Silva, Fernando P. Secin, Victor Srougi, Mohammed Baghdadi, Eric Barret, François Rozet, Marc Galiano, Xavier Cathelineau; Institut Mutualiste Montsouris, University Paris-Descartes, Paris, France; CEMIC University Hospital and San Lazaro Foundation, Capital Federal, Argentina Background: To estimate the conditional biochemical recurrence-free survival (BCR) rates and cancer-specific mortality (CSM) for men with clinically localized prostate cancer (PCa) treated with radical prostatectomy (RP) at our institution. Methods: A total of 3576 patients underwent laparoscopic radical prostatectomy (LARP) and 2619 men were treated with robotic radical prostatectomy (RARP) in the last 15 years. BCR of primary treatment was defined as PSA > 0.2 ng/dl. PCa death was defined as patients who died with metastasis in an androgen independent setting. Kaplan-Meier and Cox regression methods were used to estimate the conditional survival probabilities and CSM. Results: The median follow-up was 8.49 years (IQR 4.0112.97). A total of 92 (1.48%) patients (80 LARP and 12 RARP) died of disease. Positive surgical margins (PSM) were identified in 1202 patients (19.4%); of these, 664 (55.24%) had organ confined disease and 523 (43.51%) had extraprostatic extension (EPE). BCR-free survival rate was found significantly higher with RARP (83% vs 77% for LARP at 10 years; p < 0.001). For patients with PSA < 10 ng/dl BCR-free survival at 10 years was 80% vs 64% for PSA 10-20 ng/dl, and 59% for PSA > 20ng/dl; p > 0.001. Conditional probability of BCR after surgery 1st year was 6.7%. Those who reach the 2nd year of surgery without recurrence had a relapse probability of 4%, (cumulative probability 9.8%) That probability falls to 3.5% after the 3rd year (cumulative probability 13%), 2% after the 4th year (cumulative probability 15%) and is 2.1% after the 5th year (cumulative probability 17%). After 10 years of follow-up without recurrence, the possibility of relapse was 0.8%, (cumulative probability 21%). Men without BCR had a clinical trend of higher CSM at 10 years (7% vs 2% no BCR; p 0.06). Within the patients who develop BCR, those with BCR in the first three years of follow-up had higher CSM (9% vs 4% for BCR after 3 years; p 0.04). Conclusions: BRC free survival outcomes are affected by risk factors associated with type of surgery and prognosis in PCa. The period elapsed from RP is associated with BCR-free survival and the risk of recurrence decrease with increasing survival.

HPN • March 2017

20 News

Leaders Need To Make Equity A Priority The development of the quality movement in healthcare is recent, and can be traced to the IOM report Crossing the Quality Challenge. The IOM defined quality of healthcare in terms of six domains. These are safety efficiency, effective care, timely care, person care and equitable care, writes Dr. Peter Lachman.

Dr Peter Lachman, ISQua Chief Executive Officer

Over the past 16 years the pursuit of quality care has mainly concentrated on patient safety and efficiency, which could include timely care. Nowadays, person centred care is a major focus and there is a lot of good work in this regard. Effective care has been a little problematic as it requires the development of evidenced based care clinical pathways and guidelines which then need to be followed. There has been little in the way of standardisation of care and many people are either over or undertreated. While we have concentrated on trying to make care reliable so that the person receives the right care the first time every time, this aim has not been achieved. Services are now overburdened and this could result in a lack of efficiency, with people waiting to receive the care they need and often in an unsafe way. Nonetheless there has been a lot of progress though this is still fragile. Perhaps as managers of services, we should reflect and assess whether the services we provide are equitable in name and in deed. The final domain that was named by the IOM is equity of care and it is this domain of quality where there has been a distinct lack of progress. An article in the NEJM catalyst Mate and Wyatt discuss the lack of progress in the domain of equity in the USA. It is true that the USA has wide disparities in the delivery of healthcare, particularly based on “race” and ethnicity, as well as class. The USA reflects much of what we have in other countries where the underlying causative factor

March 2017 • HPN

Perhaps as managers of services, we should reflect and assess whether the services we provide are equitable in name and in deed

may be different. It may not be race but could be religion, or class or status. We like to believe that healthcare is available to all in an equal way particularly in the public sector. But like many other problems we need to make sure that care is both equal and equitable. Equity is something that needs to be confronted. Healthcare services are often designed in a way that they become inequitable. It is often where you live that determines what you receive. In the NEJM article, based on the recent IHI framework, they suggest five key interventions which I have adapted for use in Ireland:  Leaders need to make equity a priority – more in deed than in name. One cannot assume that services are equitable and leaders need to make equity a strategic aim.  The services and structures need to be developed to support the delivery of equitable services; this is something that doesn’t just happen.

 Healthcare is not independent of the society and the determinants that result from political and societal decisions. We need to constantly examine these and their impact on service delivery.  Institutional prejudice whether it be based on racism, sexism, classism etc. needs to be addressed actively always.  Healthcare institutions need to partner with community structures to provide a comprehensive service; healthcare does not exist only in the walls of the healthcare facilities. It is easy to read the articles emanating from the USA and say it does not happen here. Perhaps as managers of services we should reflect on the challenges posed by equity and actively assess whether the services we provide are equitable both in name and in deed. There are numerous tools to assess equity. One may be surprised by what one finds and then one can implement a

programme to make a difference. This is a challenge we cannot ignore. Dr Peter Lachman M.D. MPH. M.B.B.Ch., FRCPCH, FCP (SA), FRCPI is ISQua Chief Executive Officer. Dr Lachman was a Health Foundation Quality Improvement Fellow at IHI and has developed the quality improvement programme at Great Ormond Street Hospital where he was the Deputy Medical Director with the lead for Patient Safety. Prior to joining ISQua, Peter was also a Consultant Paediatrician at the Royal Free Hospital in London. Dr Lachman is currently the National Clinical Lead for SAFE, an RCPCH programme and Lead International Faculty at RCPI in Dublin. He co-directs the Leadership and Quality programme to develop clinical leaders in quality improvement and is co-founder and Chairperson of Paediatric International Patient Safety and Quality Community.


Global first for Irish cancer patients Irish patients with the blood cancer ‘multiple myeloma’ are the first patients worldwide to take part in a new drug trial to develop more effective treatment for the cancer. Multiple myeloma is a blood cancer arising from a type of white blood cell called a plasma cell. Plasma cells normally produce antibodies which help fight infection. In multiple myeloma the plasma cells become cancerous and are called myeloma cells. These can produce an excess of a single antibody which is harmful and stops the blood from working properly. Each year in Ireland approximately 250 people are diagnosed with the cancer and 170 succumb to the disease. This innovative Phase 1 clinical trial being led by researchers at NUI Galway will investigate for the first time, whether the addition of a new multiple myeloma treatment, Daratumumab (DARA), to a standard care chemotherapy containing the drugs Cyclophosphamide and Bortezomib (CyBorD), is beneficial for treating newly diagnosed patients. DARA by itself is a very promising new therapy for this particular cancer and has recently been approved for treating relapsed patients. This new trial is the first study worldwide to combine DARA with Cyclophosphamide and will determine whether this combination results in a more effective treatment. Blood Cancer Network Ireland (BCNI) has already recruited the first six patients at University Hospital Galway and Cork University Hospital and the study will soon be extended to BCNI centres in Dublin, thereby giving multiple myeloma patients nationwide access to the trial. BCNI is a ¤2.7 million cancer research and clinical trials initiative funded by the Irish Cancer Society and Science Foundation Ireland which brings together clinicians, scientists, and population health experts across Galway, Cork and Dublin with a shared interest in blood cancer research. Notably this clinical trial is the first homegrown (investigator initiated) trial to be conducted by BCNI. It is the culmination of collaborative research efforts between BCNI scientists and Janssen

Professor Michael O'Dwyer, BCNI Director and Consultant Haematologist

pharmaceuticals which show that Cyclophosphamide treatment can potentially make DARA more effective. It represents a bench-tobedside approach where scientific insights from the laboratory are applied to developing new and improved ways to treat patients. This is the first cancer clinical trial to be sponsored by NUI Galway on behalf of Blood Cancer Network Ireland and it demonstrates the University’s commitment to supporting clinical cancer research. Irish patients on this trial will receive additional benefits, including state of the art monitoring and access to this new treatment free of charge. Commenting on the new trial, Professor Michael O’Dwyer, BCNI Director, lead investigator and Consultant Haematologist at NUI Galway, says, “It is an exciting time for blood cancer research in Ireland. This new trial, a first for BCNI, is another step forward in developing new treatment options for patients living with multiple myeloma. The study is the result of collaborations across a broad range of partners including NUI Galway, Cancer Trials Ireland, the Irish Cancer Society, Science Foundation Ireland, Janssen Pharmaceuticals, the Health Research Board and BCNI investigators and staff. The successful launch of the study is a testament to our shared commitment to finding better treatment options for patients through clinical trials.”

The past two decades have seen major advances in the treatment of multiple myeloma with approval of several new treatments resulting in a doubling in survival over this period. Carefully conducted clinical trials based on benchto-bedside research have been critical for these developments. This trial exemplifies this approach and is an important contribution by Irish researchers and patients to the global fight against multiple myeloma. For more information on the study please visit or (search: NCT02955810). If you would like to refer a patient or have any queries please contact Amanda Bray, the National Research Co-ordinator for BCNI by email at amanda. or contact

Head of Research at the Irish Cancer Society, Dr Robert O’Connor, welcomed this new Phase 1 clinical trial and praised the work of researchers linked to Blood Cancer Network Ireland.

Blood Cancer Network Ireland (BCNI) is a ¤2.7 million collaborative cancer research initiative jointly funded by the Irish Cancer Society and Science Foundation Ireland. This collaborative network of clinicians, scientists, and population health experts across Galway, Cork and Dublin is bringing fresh hope for blood cancer patients across Ireland.

“This latest clinical trial highlights the importance of investing in world class innovative and potentially life-changing Irish cancer research and we hope that the patients taking part will help identify even more improvements in care and outcomes for this disease.”

BCNI will make novel drugs and treatments available to patients with all types of blood cancers across Ireland over the next five years. Blood cancers make up approximately 10% of all cancers and are the fourth most common cause of cancer-related deaths in Ireland.

BCNI aims to provide Irish blood cancer patients with access to novel and innovative cancer treatments through early phase clinical trials (Phase I/II) in five designated cancer care centres across the country. Clinical trials are designed to develop and test new and improved ways to treat cancer; help prevent a return of cancer; and improve comfort and quality of life for those affected by cancer. Advances in treatments for blood cancers depend on clinical trials of new therapies or new combinations of therapies. BCNI trials will focus on novel targeted approaches, including immunotherapy. Many of these trials will be conducted in collaboration with Cancer Trials Ireland. BCNI is led by Professor Michael O’Dwyer, Professor of Haematology at NUI Galway, and involves Professor Mary Cahill, Clinical Professor of Haematology, University College Cork; Professor Paul Browne, Professor of Haematology, Trinity College Dublin; Dr Eva Szegezdi, NUI Galway, and Professor Kerri Clough-Gorr, National Cancer Registry of Ireland, as co-lead investigators. The expansion of BCNI in February 2016 saw consultant haematologist at the Mater University Hospital, Professor Peter O’Gorman, and Consultant Haematologist at Beaumont Hospital, Dr John Quinn, join the network as associate members.

HPN • March 2017

22 News

Drug can reduce risk of developing diabetes by 80% An injected drug that lowers blood sugar levels can reduce the chances of those at risk of developing type 2 diabetes by 80%, according to new Irish research. The drug, liraglutide, promotes weight loss by interacting with the areas of the brain that control appetite and energy intake. The study involved a major international trial conducted over three years in which 2,254 adults with pre-diabetes participated at 191 research sites in 27 countries. The findings of the study were published in the medical journal, The Lancet. The aim of the trial was to evaluate whether liraglutide can safely delay the onset of type 2 diabetes in participants with pre-diabetes. The trial results show that continuous treatment with the drug over three years helped to prevent the risk of developing type 2 diabetes in participants by 80% when combined with diet and exercise. In 60% of those patients, prediabetes was completely reversed and patients returned to healthy blood sugar levels. Of those patients who went on to develop diabetes, those who had been taking the drug took three times longer to develop the disease than those in the placebo group. Liraglutide also helped to sustain greater weight loss when compared to the placebo.

Professor Carel Le Roux, UCD School of Medicine, UCD Conway Institute

Pre-diabetes is a metabolic condition that is closely tied to obesity. If undiagnosed or untreated, it can develop into type 2 diabetes, which is treatable, but not reversible. In Ireland, one in ten of the population have pre-diabetes, and pre-diabetes and obesity are risk factors for type 2 diabetes and its complications. Pre-diabetes progresses into type 2 diabetes in five to ten per cent of sufferers within ten years. These individuals are at risk of a range of conditions that can affect their overall health, including type 2 diabetes and its complications, as well as cardiovascular disease and cancer. Professor Carel le Roux from the UCD Diabetes Complications Research Centre, UCD School of Medicine and Fellow, UCD Conway Institute is an obesity specialist and the corresponding author on the study. “In this study, we wanted to see if this drug in combination with a reduced-calorie diet and lifestyle intervention could delay the onset of type 2 diabetes in a high-risk population with obesity and prediabetes,” he said. “On the basis of our findings, liraglutide 3.0 mg can provide us

with a new therapeutic approach for patients with obesity and pre-diabetes to substantially reduce their risk of developing type 2 diabetes and its related complications.”

The study is entitled: 3 years’ of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial.

Telephone counselling helping smokers quit? Lung cancer is a malignant tumor in the lungs due to uncontrolled growth of cell tissues. Out of those people diagnosed by lung cancer, 85% are long time smokers. It is the most common cancer-related death in men and ranks second as the most common cancer-related death in women next to breast cancer. In 2014, over one billion people are smoking which is nearly 20% of the world population. And although 70% of smokers want to quit smoking, only about 3 - 6% have successfully quit smoking without any help. According to News Medical, researchers have found out that telephone-based smoking cessation counselling is effective to be given to people who just finished lung cancer screening. March 2017 • HPN

Lead researcher Kathryn L. Taylor, PhD, said that they found out that telephone-based smoking cessation counselling is effective right after lung cancer screening. Because during this time, they are thinking about their health and might be ready for change. She also said that offering help at this time might make a big difference and could change lives. This study was published at the Journal Lung Cancer and was led by researchers from Georgetown Lombardi. The research was conducted with 92 participants from three centres namely Medical Center in Massachusetts, MedStar Georgetown University Hospital in Washington D.C. and Hackensack University Medical Center in New Jersey.

In this preliminary study, 92 people who were about to take lung cancer screening agreed to receive either the standard of care or telephone counseling. After their lung cancer screening, each participant were randomize to one of two groups with each group consists of 46 participants. Each group had an equal number of participants with abnormal screening findings, signifying possible precancerous lesions or chronic obstructive pulmonary disease (COPD). Each group also consists of participants with minor abnormal findings as well as those with normal screen findings. None of these participants were diagnosed with lung cancer.

Right after their screening results came out, participants in telephone-counseling group were given their first counseling session. Six 10-15 minute counseling sessions were performed over the next three months. After this period, participants who said they had quit smoking were given a nicotine saliva test in order to confirm their abstinence. After the test, researchers found out that eight participants from the telephone counseling group were verifiably quit smoking. On the other hand, only two did actually quit from smoking from the other group.











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*4mg only Product Information: NiQuitin Mini 4 mg Mint Lozenges (nicotine) and NiQuitin Clear 21mg/24hrs transdermal patches (nicotine). Indications: Treatment of tobacco dependence by relief of nicotine withdrawal symptoms and cravings. Use with behavioural support. Legal category: GSL. PA 1186/18/12 and PA 1186/18/3. Licence Holder: Chefaro Ireland Ltd. First Floor, Block A, The Crescent Building, Northwood Office Park, Dublin 9, Ireland. Information about this product, including adverse reactions, precautions, contra-indications and method of use can be found at: and Date of revision: August 2016.

24 Conference

New pricing agreement not bringing value – says HEA Minister for Health Simon Harris has said that European countries must improve procurement procedures, and ultimately strive for joint procurement, if they are to improve the standard of treatment and care available to patients in the next number of decades.

L-R: Mr David Delaney, HEA, European Markets Director Mylan; Mr Adrian van den Hoven, Director General, Medicines for Europe; Dr Paul Cornes, NHS Oncologist, Bristol Oncology Centre

The comment came from the Minister at conference hosted by the Health Enterprise Alliance (HEA) on Wednesday February 8th, in which the potential savings gleaned by the HSE using biosimilar drugs were discussed by the Minster, as well as Sandra Gannon and Dr Paul Cornes of the HEA . The HEA are a lobby group for the generic drug and biosimilar sector. “I think it’s important to say at the outset that advances in medicine, particularly in hightech and innovative medicine have obviously paid a key role in improving the overall health of the population in this country,” said Minister Harris at the beginning of his speech. “However, this comes at an ever-increasing price.” “The European Union has to start acting together in relation to the purchasing of medicines, and if not in relation to joint procurement, we at the very minimum must start working together in relation to horizon scanning, and in relation to the assessment of new medicines,” the minister said. “How can it possibly be acceptable to industry - but more importantly from my perspective, to patients - that a new medicine coming on the market will have to go through so many assessment processes from so many different countries before that medicine can become available?” he asked the crowd.

L-R: Mr Owen McKeon, Vice President HEA, Country Manager Mylan; Ms Sandra Gannon, President HEA, General Manager Teva Pharmaceuticals Ireland; Ms Deirdre Kelly HEA, Country Manager Consilient Health; Mr Adrian van den Hoven, Director General, Medicines for Europe

to new medicines, but access to medicines in an affordable and sustainable manner,” the minister added. “…ultimately the potential for joint procurement do[es] offer the possibility of putting the medicines bill on a sustainable footing right across the EU.” Biosimilars and potential savings While the Minister acknowledged that convincing doctors to prescribe them posed a challenge, that increasing the use of biosimilars had serious potential at driving down the cost of healthcare in both Ireland and the EU.

The Minister said the bill for hightech and innovative medicines rose from ¤170 million in 2005 to ¤590 million in the past 12 years, an enormous spike in cost, with the two most popular medicines on the budget costing ¤87 million, and ¤52 million respectively in 2010.

Biosimilars are a biologic medical product, which are almost biologically identical to an original medicine, which can be made after the original product’s patent expires. The drugs, advocates say, could potentially save the Irish health service millions of euros.

“As expenditure on medicines is expected to continue an upward trajectory in the next number of years, it is absolutely necessary that we consider new ways the ensure that patients have access

Ireland has the second worst use of biosimilars in the European Union, with the single biosimilar drug on the Irish market, Benepali, selling only three packs by the end of last year.

March 2017 • HPN

Mr Harris also said the Department of Health intended to publish the first national policy on biosimilars at some point in 2017, following the publishing a consultation paper on the potential uses of biosimilar drugs by the HSE in a bid to save money on its budget. The conference also heard that in March 2016, that IMS Health, a leading provider of global health information, estimated that by 2020, biosimilars have the potential to enter the market for several key biologics that have current sales of ¤40 billion euro. They also estimate that the cumulative potential savings from such drugs to health systems in the five major EU markets as are could be in the range of ¤50 billion euro in aggregate in the next five years and potentially reach as much as ¤100 billion.

“The development of new biosimilar medicines being brought to market is a very opportune moment for Ireland to capitalise on and to deliver better, more cost-effective use of medicines,” he said. Criticisms of pricing agreement The conference came following statements from the HEA in June criticising the latest pricing agreement agreed by the IPHA as not providing enough savings to the Irish taxpayer and Irish patient. The group claims such a deal prevents competition, and ultimately stops biosimilars from entering the Irish market. The Irish Pharmaceutical Healthcare Association (IPHA), which represents the research

25 based pharmaceutical industry in Ireland, has, however, strongly refuted claims by the Healthcare Enterprise Alliance (HEA) that the new pricing Agreement negotiated with the State last summer is not bringing value. According to Oliver O’Connor, CEO of the IPHA, “The IPHA Agreement is now delivering savings of ¤12 million per month since it started on 1st August – on target for ¤140m in its first year. It is travesty for others to suggest we are not delivering value. There is no evidence that any other Association or other pharmaceutical companies are delivering savings to the State of anything like this scale. Nor have they set out any plans to do so.” “The Agreement we negotiated with the State is delivering a package of measures with the State that will deliver over ¤785 million in savings to the taxpayer up to 2020. That is the largest ever such package of savings the research-based pharmaceutical has delivered to State…Savings from the entry of biosimilars into Ireland are part of this package and have already started. We estimate that these savings will be over ¤100m.” However, the Irish Pharmaceutical Healthcare Association (IPHA), which represents the research based pharmaceutical industry in Ireland, has strongly refuted claims by the Healthcare Enterprise Alliance (HEA) that the new pricing Agreement negotiated with the State last summer is not bringing value.

L-R: Mr Owen McKeon, Vice President HEA, Country Manager Mylan; Ms Sandra Gannon, President HEA, General Manager Teva Pharmaceuticals Ireland; Ms Deirdre Kelly HEA, Country Manager Consilient Health; Mr Adrian van den Hoven, Director General, Medicines for Europe; Dr Sean Barry, Executive Pharmaceutical Assessor, Health Products Regulatory Authority

Front Row: L-R: Ms Sandra Gannon, President HEA, General Manager Teva Pharmaceuticals Ireland; Mr Adrian van den Hoven, Director General, Medicines for Europe; Ms Deirdre Kelly HEA, Country Manager Consilient Health. Back Row: L-R: Dr Paul Cornes, NHS Oncologist, Bristol Oncology Centre; Dr Sean Barry, Executive Pharmaceutical Assessor Health Products Regulatory Authority; Mr Owen McKeon, Vice President HEA, Country Manager Mylan

IPHA CEO Oliver O'Connor refutes HEA claims

According to Oliver O’Connor, CEO of the IPHA, “The IPHA Agreement is now delivering savings of ¤12 million per month since it started on 1st August – on target for ¤140m in its first year. It is travesty for others to suggest we are not delivering value.There is no evidence that any other Association or other pharmaceutical companies are delivering savings to the State of anything like this scale.Nor have they set out any plans to do so. “The Agreement we negotiated with the State is delivering a package of measures with the State that will deliver over ¤785 million in savings to the taxpayer up to 2020. That is the largest ever such package of savings the research-based pharmaceutical has delivered to State. “Savings from the entry of biosimilars into Ireland are part of this package and have already started.We estimate that these savings will be over ¤100m.”

The IPHA CEO dismissed HEA claims that the Agreement was essentially blocking the uptake of biosimilars due to a 30% price cut in originator biologics when a competitor biosimilar comes on the market: “This claim is totally spurious. The 30% price cut on loss of exclusively is providing the State with savings already.These savings are not contingent on the subsequent uptake or market

share of biosimilars. IPHA agreed this mechanism specifically so that the State can invest in new medicines”. Mr O’Connor noted that many of the biosimilars that will launch in the near future are actually manufactured by IPHA companies. He also noted that as investment in the development of a biosimlar is significantly less than an originator

biologic, the State should expect a biosimilar manufacture to launch with at least a 30% discount. “The pricing Agreement IPHA negotiated with the State is working and is delivering very substantial savings to the State. Prices are set at an average of 14 other EU member states and will be kept at this level each year. ” he concluded.

HPN • March 2017

26 Report

Potential to improve HIV treatment discussed Dr Pamela Collins, National Institute of Mental Health

in physical health which it brings. Nonetheless, a number of cases of depression persist, requiring intervention above and beyond the provision of antiretroviral therapy.

Integrating care for mental disorders and HIV is feasible. This means making the screening and treatment of mental disorders a normative part of HIV care Improved management of depression and other mental health disorders has the potential to improve the outcomes of HIV treatment programmes, Dr Pamela Collins of the National Institute of Mental Health told the Conference on Retroviruses and Opportunistic Infections (CROI 2017) which took place in Seattle recently. Mental health treatment should be integrated into HIV services in resource-limited settings, she said. Diabetes, cardiovascular disease, cancers, lung disease and other non-communicable diseases have an increasing impact on the health and quality of life of people living with HIV. Health services in low- and middle-income countries have been slow to implement programmes to prevent, screen for and treat these diseases, but a number of projects have shown that this work can be integrated with HIV care. Dr Collins noted that mental health disorders are now considered alongside noncommunicable diseases in the third Sustainable Development Goal. But she said that whereas other non-communicable diseases increasingly affect people as they get older, the greatest burden of mental health problems falls in adolescence and young adulthood. Around three-quarters of mental health disorders have begun by the age of 24.

March 2017 • HPN

A global meta-analysis showed that 18% of people had experienced a mental health disorder in the previous year and 29% had done so in their lifetime (23% in low- and middle-income countries, 32% in high-income countries). However, few people receive the treatment they need, especially in resource-limited settings. Mental health disorders commonly occur in people living with chronic health conditions (including HIV). The evidence from a range of conditions, such as diabetes, asthma and arthritis, is that having untreated depression as well as another health condition is associated with being less able to function and having poorer health status. The relationship between mental health disorders and HIV works in both directions, Collins said. Mental disorders can be a risk factor or increase vulnerability to HIV infection. At the same time, people may experience depression or anxiety as they adjust to a diagnosis or live with a chronic illness. Moreover, neuropsychiatric effects of the virus can in some cases lead to cognitive changes or dementia. Providing HIV medical care and antiretroviral treatment specifically is in itself associated with improvements in mental health, due to the improvements

Moreover, around 15% of adults and 26% of adolescents living with HIV cite feeling depressed or overwhelmed as a barrier to HIV treatment adherence. A meta-analysis of studies mostly conducted in the United States suggested that treating depression can improve adherence to antiretroviral therapy. When the interventions specifically targeted depression (rather than treating it as a secondary objective), results were better. Furthermore, the greatest impact was seen in patients with a low CD4 cell count or moderate to severe depression symptoms, or when treatments of a longer duration were used. A recent prospective cohort study from Tanzania found that 58% of women beginning HIV treatment had symptoms consistent with depression, with around a third mentioning each of the following – loss of sexual interest, low energy, worrying too much and blaming themselves. One in six women said they sometimes felt like ending their life. Depression was associated with mortality in this study. Two years after beginning HIV treatment, 6.6% of women with depression symptoms and 3.7% of other women had died. After adjustment for other factors, women with depression symptoms were twice as likely to have died. One of the challenges of addressing mental health is the dearth of mental health workers in many settings. There is one mental health worker per 100,000 people in low-income countries, compared to 52 workers per 100,000 people in high-income countries. Integrating care for mental disorders and HIV is feasible, she said. This means making the screening and treatment of mental disorders a normative part of HIV care. Consensus needs to be achieved on who delivers services – nurses, adherence counsellors,

community health workers, peers or other groups. People seeking services, healthcare providers, managers and policymakers need to be involved in decision making about service integration, she said. National Survey on Stigma and HIV HIV Ireland is marking its 30th anniversary by undertaking a National Survey on Stigma and HIV in partnership with the Mater Hospital/UCD. The survey will explore how living with HIV impacts on people’s day to day lives, especially within the context of stigma and discrimination. Coinciding with UNAIDS Zero Discrimination Day, the survey for people living with HIV went live on Wednesday 1st March. HIV Ireland is asking for people living with HIV to visit its website ( and complete the short survey. With new HIV diagnoses in Ireland increasing to their highest level on record in 2016, Niall Mulligan, Executive Director of HIV Ireland said, ‘‘It is crucial for us to understand all the reasons behind the continued increase of new HIV diagnoses in Ireland. We have seen an increase of 35% since 2011, with a total of 513 people diagnosed as living with HIV in 2016, compared to 485 in 2015 [ – provisional data]. Ireland now has an average of 10 people per week being diagnosed with HIV. Understanding more about people’s personal experiences of living with HIV will help in the response to this very real public health challenge in Ireland today.” On the launch of Zero Discrimination Day, Michel Sidibé, UNAIDS Executive Director stated that ‘the right to health belongs to all. On this #ZeroDiscrimination Day let us commit to ensuring everyone, everywhere can access health care safely, and live life fully with dignity’. The National HIV Stigma Survey will remain live for 6 weeks. Interim results are expected to be available for Irish AIDS Day on Thursday 15th June, with the full report being launched in the latter half of 2017, providing a real insight into the reality of living with HIV in Ireland in 2017.

separation. Caution with metformin: monitor renal function and consider metformin rash, pruritus, fatigue, elevations of ALT, AST and CPK, hypersensitivity, suicidal ideation dose adjustment. Pregnancy/lactation: Not recommended.BUILD Avoid breastA-feediREGIMEN ng. or suicide attemptWITH . Basic NHS costs: 30 tablets £498.75 EU/1/13/892/001. MA holder: DOLUTEGRAVIR Side effects: See SPC for details. Headache, insomnia, sleep/dream disorders, GI ViiV Healthcare UK Ltd, 980 Great West Road, Brentford, Middlesex TW8 9GS. Further disturbance, fatigue, hypersensitivity, anorexia, depression, dizziness, somnolence, information available from Customer Contact Centre, GlaxoSmithKline UK Ltd, lethargy, malaise, cough, nasal symptoms, rash, pruritus, alopecia, arthralgia, Stockley Park West, Uxbridge, Middlesex UB11 1BT. muscle disorders, asthenia, fever, elevationsTHE of ALT, AST andONLY CPK, blood dyscrINI asias, THAT OFFERS: suicidal ideation or suicide attempt, rhabdomyolysis, lactic acidosis, erythema POM S1A multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis. Basic NHS costs: Tivicay is a registered trademark of the ViiV Healthcare Group of Companies STATISTICALLY BOOSTER-FREE Date of approval: August 2015 30 tablets: £798.16 EU/1/14/940/001. holder: ViiV Health+care UK Ltd,TOHIGH 980 RESISTANCE GreatBARRIER SUPERIORMA EFFICACY DOSING Zinc code: UK/DLG/0055/13(7) + West Road, Brentford, Middlesex TW8 9GS. Further information is available from References: 1. Walmsley S et al. J Acquir Immune Defic Syndr. 2015;70(5):515-519. Customer Contact Centre, GlaxoSmithKline UK Ltd, Stockley Park West, Uxbridge, 2. Molina J-M et al. Lancet HIV. 2015;2(4):e127-e136. 3. Orrel C et al. Presented at: Annual Middlesex UB11 1BT. International AIDS Conference; July 18-22, 2016; Durban, South Africa. Abstract THAB0205LB. 4. Raffi F et al. Lancet Infect Dis. 2013;13(11):927-935. 5. TIVICAY (dolutegravir) POM S1A Summary of Product Characteristics. Available from:, accessed: Triumeq is a registered trademark of the ViiV Healthcare Group of Companies September 2016. 6. Triumeq (dolutegravir/avacavir/lamivudine) Summary of Product Date of approval: July 2016 Zinc code: UK/TRIM/0037/14(5) Characteristics. Available from:, accessed: September 2016.


in treatment-naïve patients vs EFV/TDF/FTC, darunavir/r and atazanavir/r (in women) 1-3

0 resistance to dolutegravir-based regimens in treatment-naïve trials to date1-5

with few clinically significant drug-drug interactions5

For your treatment-naïve patients and for patients who may benefit from a change in ART regimen, CHOOSE...

dolutegravir/abacavir/ lamivudine

TRIUMEQ is indicated for the treatment of HIV-infected adults and adolescents above 12 years of age weighing at least 40 kg. Before initiating treatment with abacavir-containing products, HLA-B*5701 status must always be documented. Abacavir should not be used in patients known to carry the HLA-B*5701 allele due to the risk of hypersensitivity reaction. TIVICAY is indicated in combination with other antiretroviral medicinal products for the treatment of HIV-infected adults and adolescents above 12 years of age. Triumeq and Tivicay are contraindicated: in patients with hypersensitivity to dolutegravir, abacavir or lamivudine or to any of the excipients, and with co-administration with dofetilide.5,6

These medicinal products are subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

Prescribing Information Triumeq® dolutegravir 50mg/abacavir 600mg/lamivudine 300mg tablets See Summary of Product Characteristics before prescribing. Indication: HIV in over 12 years and ≥ 40kg. Screen for HLA-B*5701 prior to use. Do not use if HLA-B*5701 positive. Dose: one tablet once daily with or without food. Elderly: Limited data in 65+ yrs. Creatinine clearance <50ml/min or moderate/severe hepatic impairment: Not recommended. Contraindications: Hypersensitivity to any ingredient. Co-administration with dofetilide. Warnings/precautions: Both abacavir and dolutegravir are associated with risk of hypersensitivity reactions (HSR). Do not initiate in HLA-B*5701+ or previous suspected abacavir HSR. Stop Triumeq without delay if HSR suspected. Never reintroduce any dolutegravir- or abacavir-containing product after suspected HSR. Risks of immune reactivation syndrome, osteonecrosis, increased weight, lipids, glucose. Monitor LFTs in Hepatitis B/C co-infection. Inconclusive data on relationship between abacavir and MI; minimise all modifiable CV risk factors (e.g. smoking, hypertension, hyperlipidaemia). Not recommended if dolutegravir required b.d. (with etravirine [without boosted PI], efavirenz, nevirapine, rifampicin, boosted tipranavir, carbamazepine, oxcarbazepine, phenytoin, phenobarbital and St John’s Wort). Use with cladribine not recommended. Use with Mg/Al-containing antacids, calcium, multivitamins or iron requires dosage separation. Caution with metformin: monitor renal function and consider metformin dose adjustment. Pregnancy/lactation: Not recommended. Avoid breast-feeding. Side effects: See SPC for details. Headache, insomnia, sleep/dream disorders, GI disturbance, fatigue, hypersensitivity, anorexia, depression, dizziness, somnolence, lethargy, malaise, cough, nasal symptoms, rash, pruritus, alopecia, arthralgia, muscle disorders, asthenia, fever, elevations of ALT, AST and CPK, blood dyscrasias, suicidal ideation or suicide attempt, rhabdomyolysis, lactic acidosis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis. Basic NHS costs: 30 tablets: £798.16 EU/1/14/940/001. MA holder: ViiV Healthcare UK Ltd, 980 Great West Road, Brentford, Middlesex TW8 9GS. Further information is available from Customer Contact Centre, GlaxoSmithKline UK Ltd, Stockley Park West, Uxbridge, Middlesex UB11 1BT.

dolutegravir 50mg tablets Tivicay® See Summary of Product Characteristics before prescribing Indication: HIV in >12 years and ≥40kg as part of combination therapy. Dosing: 50mg once daily with or without food if no proven/suspected integrase resistance. 50mg twice daily with efavirenz, nevirapine, tipranavir/ritonavir, etravirine (without boosted PI), carbamazepine, oxcarbazepine, phenytoin, phenobarbital, St John’s Wort or rifampicin. Adults with proven/suspected integrase resistance: 50mg twice daily preferably with food. Elderly: Limited data in 65+ yrs. Caution in severe hepatic impairment. Contraindications: Hypersensitivity to any ingredient. Co-administration with dofetilide. Warnings/precautions: Risk of hypersensitivity reactions. Discontinue dolutegravir and other suspect agents immediately if suspected. Risks of osteonecrosis, immune reactivation syndrome. Monitor LFTs in Hepatitis B/C co-infection and ensure effective Hepatitis B therapy. Caution with metformin: monitor renal function and consider metformin dose adjustment. Use with etravirine requires boosted PI or increased dose of dolutegravir. Use with Mg/Al-containing antacids, calcium, multivitamins or iron requires dosage separation. Pregnancy/ lactation: Not recommended. Avoid breast-feeding. Side effects: See SPC for full details. Headache, GI disturbance, insomnia, abnormal dreams, depression, dizziness, rash, pruritus, fatigue, elevations of ALT, AST and CPK, hypersensitivity, suicidal ideation or suicide attempt. Basic NHS costs: 30 tablets £498.75 EU/1/13/892/001. MA holder: ViiV Healthcare UK Ltd, 980 Great West Road, Brentford, Middlesex TW8 9GS. Further information available from Customer Contact Centre, GlaxoSmithKline UK Ltd, Stockley Park West, Uxbridge, Middlesex UB11 1BT.

Adverse events should be reported. For the UK, reporting forms and information can be found at Adverse events should also be reported to GlaxoSmithKline on 0800 221 441.

Adverse events should be reported. For Ireland, adverse events should be reported directly to the HPRA; Freepost, Pharmacovigilance Section, Health Products Regulatory Authority, Earlsfort Terrace, Dublin 2, Tel: +353 1 676 4971, Adverse events should also be reported to GlaxoSmithKline on 1800 244 255.


POM S1A Tivicay is a registered trademark of the ViiV Healthcare Group of Companies Date of approval: August 2015 Zinc code: UK/DLG/0055/13(7)

References: 1. Walmsley S et al. J Acquir Immune Defic Syndr. 2015;70(5):515-519. 2. Molina J-M et al. Lancet HIV. 2015;2(4):e127-e136. 3. Orrell C et al. Presented at: Annual International AIDS Conference; July 18-22, 2016; Durban, South Africa. Abstract THAB0205LB. 4. Raffi F et al. Lancet Infect Dis. 2013;13(11):927-935. 5. TIVICAY (dolutegravir) Summary of Product Characteristics. Available from:, accessed: September 2016. 6. Triumeq (dolutegravir/avacavir/lamivudine) Summary of Product Characteristics. Available from:, accessed: September 2016.

TRIUMEQ and TIVICAY are registered trademarks of the ViiV Healthcare group of companies. ©2016 ViiV Healthcare group of companies All rights reserved.

Triumeq is a registered trademark of the ViiV Healthcare Group of Companies Date of approval: July 2016 Zinc code: UK/TRIM/0037/14(5)

Date of preparation: September 2016 IE/DGR/0016/16

Adverse events should be reported. For the UK, reporting forms and information can be found at Adverse events should also be reported to GlaxoSmithKline on 0800 221 441.

Adverse events should be reported. For Ireland, adverse events should be reported directly to the HPRA; Freepost, Pharmacovigilance Section, Health Products Regulatory Authority, Earlsfort Terrace, Dublin 2, Tel: +353 1 676 4971, Adverse events should also be reported to GlaxoSmithKline on 1800 244 255. TRIUMEQ and TIVICAY are registered trademarks of the ViiV Healthcare group of companies. ©2016 ViiV Healthcare group of companies All rights reserved.

IE_DGR_0016_16_Triumeq_Advert_GSKDC-PT-IRL-2016-10216_D3.indd 1

Date of preparation: September 2016 IE/DGR/0016/16

10/19/2016 1:42:14 PM

28 News Governance essential in first medication safety inspections

Sean Egan, HIQA’s Acting Head of Healthcare Regulation

causes of patient harm in hospital. Medication safety should be a priority area for all acute hospitals as they seek to ensure a high-quality and safe service for patients.” The seven inspections were carried out between November and December 2016 in the following hospitals: Bantry General Hospital, Connolly Hospital, Naas General Hospital, Nenagh Hospital, Mater Misericordiae University Hospital, Sligo University Hospital and University Hospital Waterford. HIQA found a wide variation in the medication safety arrangements in place across the seven hospitals.

The first inspection reports on medication safety in public acute hospitals have been published by the Health Information and Quality Authority (HIQA). Inspections found that where effective medication safety governance arrangements were in place, patients were better protected from potential harm related to medication use. HIQA’s medication safety monitoring programme, which commenced in November 2016, aims to examine and positively influence the adoption and implementation of evidence-based

practice in public acute hospitals regarding medication safety. HIQA monitors medication safety against the National Standards for Safer Better Healthcare. HIQA’s Guide to the Health Information and Quality Authority’s Medication Safety Monitoring Programme in Public Acute Hospitals outlines the requirements for service providers under phase one of the inspection programme. Sean Egan, HIQA’s Acting Head of Healthcare Regulation, said, “Error associated with medication use constitutes one of the major

Sean Egan continued, “These inspections found that while all hospitals have some scope for further improvement, some hospitals were well organised to ensure safer use of medicines for patients, and had good arrangements in place to monitor, identify and manage risk associated with medicines use.” A number of examples of good practice in relation to medication safety were found during these inspections. For example in Naas General Hospital, the Mater Misericordiae University Hospital and Sligo University Hospital HIQA found that; medication safety was effectively supported by senior management in the hospitals, a formal and structured medication safety programme was established, an open incident and

near-miss reporting culture was promoted and a process was in a place for learning from medicationrelated incidents, medication safety audits were carried out and learning was shared with all staff, up-to-date medication policies were in place, and good leadership was shown from key clinical staff to support medication safety. “However, these inspections also found that learning from hospitals that have more advanced medication safety programmes in place should be shared nationally, as more needed to be done in other hospitals to better promote safer use of medicines. A key building block for any medication safety programme is the presence of an effective governance committee – usually known as a Drugs and Therapeutics Committee – which oversees how the hospital anticipates, monitors, identifies and responds to risk related to medicines use. As a first step, poorer performing hospitals in these inspections need to improve the functioning of these committees and, where possible, look to link in with other hospitals to benefit from their experience. Some hospitals also lack some necessary resources which would assist in promoting greater safety in the use of medicines, and further support in this regard may help to assist in improving medication safety.” Read the reports for Bantry General Hospital, Connolly Hospital, Naas General Hospital, Nenagh Hospital, Mater Misericordiae University Hospital, Sligo University Hospital and University Hospital Waterford on

European Swallowing Awareness Day European Swallowing Awareness Day took place earlier this month, March 6th, highlighting how speech and language therapists support people with eating, drinking and swallowing difficulties – often transforming their lives. The event is held to raise awareness around the world of the issue. Eating, drinking and swallowing difficulties have potentially life-threatening consequences. They can result in choking, pneumonia,

March 2017 • HPN

chest infections, dehydration, malnutrition and weight loss. They can also make taking medication more difficult. Swallowing difficulties can result in avoidable hospital admission and in some cases death. They can also lead to a poorer quality of life for the individual and their family. This may be due to embarrassment and lack of enjoyment of food, which can have profound social consequences.

Dysphagia in adults is associated with a number of different conditions, including stroke, progressive neurological disorders, cancer and respiratory conditions. Acutely ill patients in critical care beds, including those with cervical spinal injuries and those with community-acquired pneumonia, Guillain-Barré and influenza can also have dysphagia. Acid reflux can also result in swallowing difficulties.

Early identification and management of dysphagia by speech and language therapists improves quality of life, and reduces the possibility of further medical complications and death. Improved nutrition and hydration have an impact on physical and mental wellbeing. In addition, speech and language therapy for those with dysphagia also produces economic benefits and savings for the wider health economy, including those through avoided hospital admissions.





E 4

30 News

Biosimilars create opportunities for sustainable care Biosimilars create opportunities for sustainable cancer care, says the European Society for Medical Oncology (ESMO) in a position paper published in ESMO Open. The document outlines approval standards for biosimilars, how to safely introduce them into the clinic, and the potential benefits for patients and healthcare systems. Biosimilars present a necessary and timely opportunity for physicians, patients and healthcare systems, says the paper. If suitably developed clinically, manufactured to the correct standards and used appropriately, they can positively impact on the financial sustainability of healthcare systems. A critical consideration regarding the introduction of biosimilars into the clinic centres on the required information concerning all the respective procedures. The position paper aims to describe the issues revolving around biosimilars that are relevant to the field of oncology, especially the prescribers. More specifically, the authors discuss aspects related to definition, forms of biosimilars, labelling, extrapolation, interchangeability, switching, automatic substitution, clinical standards on safety and efficacy, responsibilities among prescribers and pharmacists, potential impact on financial burden in healthcare and the current scenario and future prospects of biosimilars in Europe and the rest of the world. The paper states, ‘With the

anticancer medicines market set to surpass the 140 billion EUR mark by 2020, healthcare decision makers are facing considerable challenges: tackling the issue of sustainability of healthcare systems and improving access to medicines for patients. Biological medicinal products, or those whose active substance is made by a living organism, will represent 19%–20% of the total global share of pharmaceutical sales by 2017, and thus form an essential part of the anticancer medicines offering. ‘Biosimilars (similar versions of the originator biologics) present a necessary opportunity for physicians, patients and healthcare systems. If properly developed clinically, manufactured to the correct standards and used appropriately (with both the physician and patient being well informed), they can positively impact the financial sustainability of healthcare systems, globally. ‘The European Union (EU) has been a pioneer in approving biosimilars, with the approval of 23 biosimilars up to 2016. Prior to the introduction of biosimilars for monoclonal antibodies (moAbs), biosimilars only existed for low molecular weight compounds.’ “Biosimilars are must-have weaponry in financially sustaining healthcare systems on a global scale as well as significantly improving outcomes for an increasing number of patients throughout Europe and the rest of the world,” says ESMO President Professor Fortunato

Ciardiello, Università degli Studi della Campania Luigi Vanvitelli in Naples, Italy. “ESMO calls for strict adherence to approval standards of biosimilars as well as their accelerated introduction into the clinic,” said Professor Josep Tabernero, Chair of the ESMO Cancer Medicines Working Group, from the Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Spain. “Aligned with ESMO´s mission to facilitate equal access to optimal cancer care for all cancer patients, and as clearly set out in its2020 Vision, this paper provides a timely overview on where we are and the ‘where to next’ for biosimilar products and their respective regulatory approval processes.” He continued: “The paper highlights a number of areas that should be carefully considered by all stakeholders including prescribers, pharmacists, nurses,

patients, reimbursement bodies, and manufacturers. Importantly, it also outlines a number of directions that will need to be collectively followed to guarantee the highest safety and efficacy standards of these medicines and ensure that all patients, irrespective of geographical borders, can access the very best evidence based treatments.” “Biosimilars give us the chance to make treatment options for cancer more affordable everywhere,” the ESMO President said. “This ESMO position paper sets out a series of principles that should be fulfilled to ensure that the biosimilars that reach the market are of good quality, safe and effective. Clinicians are starting to ask questions about how to incorporate biosimilars into their daily practice and until now they did not have an authoritative source of information. This paper serves to educate practising physicians on this complex topic.”

Early diagnosis of psoriatic arthritis is key, says Specialists A staggering 46% of people with psoriasis have never heard of psoriatic arthritis. Yet up to 30% of the estimated 73,000 people with psoriasis in Ireland may go on to develop the inflammatory arthritis that can cause pain, swelling and damage to joints.

and feature Marion Morrissey, who has psoriatic arthritis, Consultant Rheumatologist, Professor David Kane and Consultant Dermatologist, Dr Anne-Marie Tobin.

These figures were published in new research launched by the More than Skin Deep campaign, which has developed a series of videos that provide information from experts on psoriatic arthritis including the signs and symptoms and how it can be managed.

According to the new research 87% of people with psoriasis have not received any information on psoriatic arthritis and only 14% responded that they are well informed and know a lot about the condition. However, 90% of people with psoriasis are interested in learning more about the inflammatory joint disease.

The videos are presented by Paul Walsh from RTE’s Doctor’s on Call

“The symptoms of psoriatic arthritis are quite different to those

March 2017 • HPN

of psoriasis in that it’s a disease of joints rather than a disease of the skin. Those affected will experience swelling, pain and stiffness in the joints and will have difficulty moving their joints, particularly the hands, knees or feet”, said Professor David Kane, Consultant Rheumatologist, Trinity College Dublin, Tallaght Hospital and Beacon Hospital. “Early diagnosis of psoriatic arthritis is important. If we intervene and treat early we may be able to put the disease into remission and prevent permanent damage to the joints. I encourage everyone with psoriasis to watch the More than Skin Deep video series to understand the signs and

symptoms of psoriatic arthritis so they can be diagnosed and treated early.” “Typically 85% of people with psoriatic arthritis will first have skin psoriasis. Psoriasis may start with some flaky patches, particularly at the back of the scalp, behind the ears or patches on the elbows. Then about ten years later up to 30% of psoriasis cases may go on to develop psoriatic arthritis”, said Dr Anne-Marie Tobin, Consultant Dermatologist, Tallaght Hospital. The videos are available on Arthritis Ireland and Janssen Ireland’s websites.

CPD 30: Hepatitis C Continuing Professional Development



Authors: Laurent Cotte, Pascal Pugliese, Marc-Antoine Valantin, Lise Cuzin, Eric Billaud, Claudine Duvivier, Alissa Naqvi, Antoine Cheret, David Rey, Pierre Pradat, Isabelle Poizot-Martin, and the Dat’AIDS study Group

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

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

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

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

60 Second Summary There are few data regarding HCV treatment initiation among HIV/HCV co-infected patients. The objective of this study was to analyze the changing patterns of HCV coinfection and HCV treatment initiation over time in a large French cohort of HIV/ HCV co-infected patients at the beginning of DAA’s era and to analyze factors associated with treatment initiation. All HIV/HCV co-infected patients enrolled during 2000–2012 were analyzed. HCV status was defined per calendar year as naïve, spontaneous cure, sustained virological response (SVR), failure or reinfection. HCV treatment initiation rate was determined per year. Trends over time were analyzed using Chi-2 test for trend and linear regression analysis. The effect of covariates on treatment initiation over time was analyzed using generalized estimating equations. Among 34,308 HIV-infected patients enrolled between 2000 and 2012, 5,562 were HCV co-infected. HCV prevalence declined from 38.4 to 15.1 %. HCV treatment initiation rate fluctuated from 5.6 to 7.4 %/year from 2000 to 2007, dropped to 5.6 % in 2011 and increased to 8.5 % in 2012 due to the use of first-generation DAAs (29.1 % of initiations in 2012). The role of HCV genotype 1, CDC stage, fibrosis and recent HCV infection on treatment initiation rate changed over time. A high rate of HCV treatment initiation was observed at the beginning of DAAs era in HIV/HCV coinfected patients. Given the very high efficacy of new DAA-based regimens and if treatment initiation keeps increasing, HCV prevalence among HIV patients will drastically decrease during the forthcoming years.

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

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

Hepatitis C treatment initiation in HIV-HCV coinfected patients Because of shared routes of transmission, hepatitis C virus (HCV) infection is frequent among HIV patients [1] with geographical variations[1–3]. In France, about 16-18 % of HIV patients were HCV co-infected in 2010–2011[4]. Since liver fibrosis is known to progress faster in HIV/HCV co-infected patients compared to HCV monoinfected ones[5, 6], HCV coinfection is associated with a higher morbidity and mortality[7]. After the introduction of combined antiretroviral therapy (cART), liver disease has become the leading cause of death in HIVpositive patients[8–10] suggesting to early initiate HCV treatment in these patients. However, the poor virological results and tolerability of the standard Peg-interferon (PEG-IFN)/ribavirin combination may have slowed down treatment uptake in a population which was considered difficult to treat[11]. Among HIV patients, HCV treatment uptake from 5 to 40 % have been reported worldwide[12–19]. A controlled HIV infection, good compliance to follow-up, being off-drugs, low fibrosis, male gender and HIV-risk factors other than IVDU were reported as predictors of HCV treatment[12–15, 17, 18]. The development of direct acting antiviral agents (DAAs) introduced a new era in HCV treatment with very high sustained virological response (SVR) rates whatever the patient profile and the viral genotype[20]. Similar results have been observed in HIV/HCV co-infected patients leading current international guidelines to consider HCV treatment in this population using the same treatment regimens as in monoinfected ones[21, 22]. Considering the better tolerability and spectacular results of these new treatments, one could expect a rapid increase

in treatment uptake and cure rate in both populations. The objective of this study was to analyze the changing patterns of HCV coinfection and HCV treatment initiation over time in a large French cohort of HIV/HCV co-infected patients at the beginning of DAA’s era and to analyze factors associated with treatment initiation. Patients Patients’ information was collected from the Dat’AIDS cohort, a collaborative network of French HIV treatment centres[23]. All HIV/HCV co-infected patients enrolled in the cohort between 2000 and 2012 were included. Demographic, biological and virological data were collected from NADIS® (Fedialis Medica, Marly le Roi, France), a standardized electronic medical record in which all patients’ data are recorded with no time delay in a structured database, allowing use of the database for epidemiological studies[23]. HCV infection was defined as a positive HCV serology, and/or a detectable HCV-RNA in serum. Each patient with at least one visit during the period was enrolled in the study. Thus, the number of patients followed up each year varies over time depending on new inclusions in the cohort, lost to follow-up or deaths. The status of each patient was defined at the beginning of each calendar year as naive (never treated for HCV), spontaneous cure (confirmed negative HCVRNA in a patient with positive HCV antibodies in the absence of a specific treatment), SVR (negative HCV-RNA more than 6 months following treatment), treatment failure (positive HCV-RNA at the end of treatment or less than 6 months after the end of treatment, regardless of treatment duration), reinfection (positive HCVRNA more than 6 months following the end of a

Continuous Professional Development Modules are sponsored by MSD MSD has no editorial oversight of the CPD programmes included in these modules.


CPD 30: Hepatitis C

Figure 1

as numbers and percentages whereas quantitative variables are presented with the median and interquartile range (IQR). Trends over time were analyzed using Chi-2 test for trend and linear regression analysis.

successful treatment or following a spontaneous cure, or HCV infection with a different genotype (subtypes excluded), regardless of the time period). HCV treatment included standard interferon and PEG-IFN with or without ribavirin and the first-generation DAAs for the more recent years (telaprevir and boceprevir). Ribavirin alone and long-term interferon for anti-fibrosing effect were not considered as an eradication strategy. Treatment periods with interruptions of less than 3 months were considered as the same line of treatment, as well as initiation of a new treatment within 3 months of a previous one. Patients receiving treatment across 2 calendar years were considered as on-treatment the first year, while their final response was defined the following year. Thus, the status of each patient

was only defined once for each calendar year. Virological response was assessed until July 2013 for patients with treatment initiation in 2012. Retreatment for a given year concerned all patients who had been treated any time before this given year. Fibrosis was assessed through liver biopsy, transient elastography (FibroScan®, EchoSens, Paris, France), or FibroTest® (BioPredictive, Paris, France). If two or more evaluations were performed a given year, only one assessment was considered according to the following hierarchical classification: liver biopsy > FibroScan® > FibroTest®. Fibrosis was scored using the METAVIR scoring system[24]. Statistical analysis Qualitative variables are presented

Treatment initiation rate was determined per calendar year, either in the population of patients with a detectable HCV-RNA, or for the naive and the failing sub-populations. The cumulative treatment initiation rate was determined as the percentage of patients followed a given year who had been previously treated or who started treatment this year. The cure rate was determined as the percentage of patients with SVR among all treated patients at that time. Longitudinal analysis of HCV treatment initiation rate was performed using generalized estimating equations (GEE)[25]. This approach allowed us to make inferences at the population level, taking into account the possible within-patient correlation (i.e., non-independence) of treatment initiation over time and to study the influence of covariables on treatment initiation[26]. For each covariable, two types of effects were tested in a multivariate model including the time variable, the covariable and the interaction of the covariable with time. The p-value associated with the covariable effect indicated whether the probability of treatment initiation differed between different levels of the covariable. The p-value associated with the interaction effect indicated whether different evolution of treatment initiation existed according to the levels of the covariable. P-values below 0.05 were considered statistically significant. All analyses were performed using IBM SPSS Statistics for Windows, Version 19.0 (IBM Corp., Armonk, NY, USA) and R[27] for the GEE analysis. RESULTS Patients’ characteristics Among 34,308 HIV-infected patients enrolled between 2000 and 2012 in the Dat’AIDS cohort, 5,562 (16.2%) were co-infected with HCV. Co-infected patients were mostly male (72%) with a median age of 39 years.

Epidemiological characteristics of HIV/HCV co-infected patients over time HCV prevalence declined from 38.4% in 2000 to 15.1 % in 2012 (p < 0.0001). Sex ratio slightly increased from 2.27 to 2.54 during the period (p < 0.0001). The proportion of IVDU decreased regularly from 75.0 % in 2000 to 61.6% in 2012. In parallel, presumed sexual transmission increased from 6.4 to 13.0%. During the study period, 748 patients died, representing an overall mortality rate of 13.4%. Among these patients, 21.8% died from either cirrhosis complications (17.9%) or hepatocellular carcinoma (3.9%) whereas other causes of death included AIDS or AIDS-related cancer (14.6%), cardiovascular disease (7.9%), other cancer (7.9%), and suicide (3.3%). The death rate fluctuated from 0.6 % in 2000 to 1.2% in 2012 but without significant time trend. The most frequent genotype was genotype 1 (53.4%) followed by genotype 3 (24.3%) and 4 (18.6%). The genotype distribution remained almost constant over time. HIV characteristics Twenty-nine percent of the patients had an AIDS diagnosis (CDC stage C). The proportion of patients receiving antiretroviral treatment increased from 74.6% in 2000 to 90.7% in 2012 (p < 00001). During the same period, the median CD4 cell count increased from 376/ mm3 to 561/mm3 (p < 0.0001) and the proportion of patients with an HIV-RNA <200 copies/mL under cART increased from 33.7 to 95.8% (p < 0.0001). Fibrosis evaluation Fibrosis evaluation per calendar year increased during the study period from 8.7 to 25.0% (p < 0.0001), notably in naive patients (from 6.9 to 24.2%) and in patients with a previous virological failure (from 17.7 to 37.7%). If a two-year period was considered, the rate of fibrosis evaluation in 2011–2012 reached 31.7% in naive patients and 52.8% in failing patients. Non-invasive techniques progressively replaced liver biopsy during the period. The proportion of patients with documented cirrhosis or severe fibrosis increased from 18.4% in 2000

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33 to 40.8% in 2004, then declined to 24.5% in 2010 and remained stable thereafter. In 2012, fibrosis stage was F0-1 in 45.5% of patients, F2 in 27.1%, F3 in 8.8% and F4 in 18.7%. HCV treatment initiation rate Among all patients with detectable HCV-RNA, HCV treatment initiation rate increased from 5.6 to 7.4% per year from 2000 to 2007, dropped to 5.6% in 2011 and increased again to 8.5% in 2012. Between 2010 and 2012, 70 patients were treated with DAA among whom 33% were naive and 67% were previous non-responders. From 2010 to 2012, treatment initiations with first-generation DAAs increased from 0.1 to 2.5% and represented 29.1% of all treatment initiations in 2012. First treatment initiation rate dropped to 3.0% in 2011 and increased to 4.2% in 2012 whereas retreatment rate regularly increased from 1.1% in 2000 to 4.2% in 2012. However, since the proportion of naïve patients regularly declined over time, while the proportion of patients having failed a previous treatment increased during the period, the incidence of retreatment among failing patients was every year except 2008 greater than the incidence of first treatment in naïve patients. Therefore, treatment incidence in naïve patients dropped to 4.6% in 2011 and increased to 6.8% in 2012, while retreatment rate in failing patients dropped to 6.7% in 2010 and increased to 11.1% in 2012. Factors associated with HCV treatment initiation over time Several parameters were associated with a greater treatment initiation rate throughout the period, without any time effect, such as an age over 40, male gender, men having sex with men (MSM) as a risk factor for HIV infection, CD4 cell count ≥350/mm3 and an HIV-RNA ≤200 copies/mL. Conversely, HCV genotype was not associated with a greater treatment initiation rate when considering the whole period, while treatment initiation rate was doubled for genotype 1 by comparison with non-1 genotype in 2012 (13.6 vs 5.6%. Treatment was initiated more frequently in patients at CDC stage A-B than in patients at CDC stage C, but this difference tended to decline over time. A similar trend was observed for patients with higher stages of fibrosis, with a rebound in treatment initiation for F3-F4 patients in 2012. Finally,

Figure 2

patients with HCV infection of less than 1 year were treated similarly as patients with older infection during the first years. However, treatment initiation rate of recent infections significantly increased from 2008 onwards. Discussion The Dat’AIDS cohort represents a collaboration between major French HIV treatment centres scattered throughout the country[23] and today includes data on more than 34,000 patients. The present study indicates that HCV prevalence among HIVinfected patients decreased over the past decade, probably due to a decreased proportion of IVDU among newly infected HIV individuals. Since HCV coinfection is more frequent among IVDU than among MSM, the increased proportion of MSM and non-IVDU women among the HIV population over time results in a parallel decrease of HCV prevalence despite the occurrence of acute HCV infections in a sub-population of MSM in the last years. Similar trends have been described in other European and US cohorts[4, 28, 29]. A significant improvement in HIV care was observed during the study, as measured by the proportion of patients with an undetectable HIV-RNA under cART. This improvement both reflects a better cART uptake in this population and a better virological control of HIV infection and results in a significant improvement of the immunological status of the population. Both trends were expected, since transversal analysis of several consecutive cohorts from 2004 to 2012 showed similar patterns[4]. Fibrosis evaluation increased over time, notably after 2004, when non-invasive fibrosis evaluation techniques became widely available. Following the introduction of these techniques, they not only nearly replaced liver biopsy, but the number of patients evaluated every year more than doubled from 2000 to 2012. Variations in the proportion of patients with severe fibrosis or cirrhosis were observed over time. Whether these variations resulted from the inclusion in

the cohort of patients with more recent infection when using noninvasive techniques, or to other factors could not be determined. Interestingly, fibrosis assessment was more frequent among patients with previous virological failure. Since fibrosis score is associated with the probability of complication of chronic hepatitis C and with the probability of response to Peg-Interferon/ribavirin, one can hypothesize that physicians were more willing to precisely quantify the risk/benefit ratio in these patients before considering another treatment course. Until 2002, there was not in France any specific recommendation for HCV treatment in HIV-HCV patients [30]. In 2002, treatment was recommended if the METAVIR score was ≥ F2 or ≥ A2/A3 with a CD4 cell count >200 cells/mm3 [31]. In 2006, recommendations were extended to patients ≥ F2, ≥A2/A3, genotype 2 or 3 whatever the fibrosis score and to genotype 1 patients with HCV RNA <800,000 IU/mL[32]. In 2008, treatment of acute HCV infection was also recommended[33]. Fist-generation DAA, telaprevir and boceprevir became available in April and July 2011, respectively, for the treatment of patients with METAVIR F4 who had previously failed a PEG-IFN therapy. Our study allowed us to precisely describe the evolution of HCV treatment initiation rate (Fig. 1). A particularly high proportion of treated patients of 54.7 % was observed, resulting in a cure rate of 45.2 % of the treated patients. Previous studies have reported

lower treatment uptake in HIV/HCV co-infected patients in various countries, including a recent study within the Swiss HIV cohort, a cohort with a similar number of patients[15]. Differences in the study populations, differences between Health Care Systems and the time at which these studies were conducted may explain part of this difference. However, treatment uptake appears notably higher in cohorts of HIV/HCV co-infected patients than in HCV monoinfected patients. A recent systematic survey in European countries reported treatment uptake as low as 3.5 to 15% in IVDU[34] while treatment uptake of 10 to 23% was reported from a review of studies among US veterans, mainly HCV monoinfected[35]. Whether these differences were related to a better follow-up of co-infected patients under antiretroviral treatment, or to the effect of wider recommendations of treatment for HCV in co-infected patients[21, 22] could not be asserted in this study. Still, our data indicate that in 2012, 40.7% of co-infected patients remained untreated for HCV, among whom 27.5% had either cirrhosis or severe fibrosis and may require a priority access to treatment. A decrease in all treatment initiations was observed between 2007 and 2011 possibly explained by physicians and patients choosing to wait for more potent and better tolerated oral anti-HCV regimens rather than initiating PEG-IFN/ribavirin therapy. A

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CPD 30: Hepatitis C

Figure 3

similar decrease was observed during the same period in the EuroSIDA cohort[12]. This decrease was followed by an increase due to the arrival of the first-generation protease inhibitors (PI) telaprevir and boceprevir which accounted for 29.1% of our treatment initiations in 2012. A similar increase was reported in US veterans, following the approval of these drugs in the US[35]. Our results finally clearly show that treatment initiation is associated with a variety of host and viral factors and that the influence of these parameters could change over time. Among them, older age, male gender, controlled HIV infection, improved CD4 cell count, and non-C CDC stage are classically associated with more frequent treatment initiation[12â&#x20AC;&#x201C;15, 17, 18]. Interestingly, treatment initiation rate in patients with HCV duration below 1 year doubled from 2007 to 2010 reflecting the emergence of acute HCV infection at that time[36, 37] and the perceived benefit of an early treatment[38, 39]. In 2000, the proportion of F3-F4 patients

initiating HCV therapy was almost twice that of F0-F2 patients but this difference regularly decreased until 2011, probably because of the evolution of recommendations of treating HIV/HCV co-infected patients regardless of the fibrosis stage[40]. In 2012, the proportion of F3-F4 patients initiating therapy increased again probably because of availability of first-generation PI being initially recommended in pre-cirrhotic or cirrhotic patients. Since these molecules were effective on genotype 1 only, the proportion of genotype 1 patients initiating treatment drastically increased from 2011 onwards. Our study presents several limitations. Data were obtained from a database mainly used in infectious diseases units. Since care for HCV infection can be shared between infectious diseases units and hepatology units, some data obtained in hepatology units could be missing, simply because the results were not entered in the database. This would be particularly accurate for HCV genotype and fibrosis evaluation.

Thus, the data presented in this study may represent minimal estimates of the true numbers. The study was also not designed to precisely analyze the cause of death. Precise data regarding cirrhosis decompensation were not obtained, and the liver-related mortality reported in the study should also be considered as a minimal estimate rather than a definite rate. However, regular quality control in local and aggregated databases, including completeness analyzes for key data and automated processes within the database to obtain the virological response following HCV treatment all concurred to ensure good quality. Some authors recently showed that low treatment uptake for HCV resulted from a combination of barriers at the system, practitioner, and patient levels[11]. The authors suggested several strategies to enhance HCV treatment uptake in co-infected patients e.g. increasing the number of providers offering HCV treatment, lowering treatment costs, or providing enhanced HCV education and training programs

for practitioners working in the field of HIV or addiction. Conclusion Our study indicates that significant improvements in HIV care, fibrosis evaluation and HCV treatment initiation were already attained among HIV/HCV co-infected patients in France at the beginning of DAAs era, resulting in a previously unseen high treatment uptake. When entering the better tolerated and highly efficacious all oral DAAs combinations era[20], it will be interesting to investigate forthcoming treatment uptake in this population. However, it should be borne in mind that reasonable treatment costs and enlarged treatment indications will probably be necessary to achieve higher rates of treatment uptake. Given the very high efficacy of new DAAbased regimens and if treatment initiation rate keeps increasing, HCV prevalence among HIV patients will drastically decrease during the forthcoming years. References available on request

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HPN Peer Review Call for Clinical Papers/Articles In order to achieve the highest quality and safety of care, we must support current and future hospitals professionals to learn, grow and innovate. Hospital Professional News delivers education to thousands of healthcare professionals including Consultants, Pharmacists and clinical teams, demonstrating cutting edge research that has a direct impact on patient care. Would you like to see your work in print in Ireland's leading hospital professional publication? HPN will be publishing a special Peer Review issue in August, 2017 and we are seeking original article submissions to foster this network of shared learning, focusing on enhanced clinical outcomes. Whether you are a Consultant, Registrar, Pharmacist or other healthcare professional working within any field/discipline, we want to hear from you. We are welcoming submissions from any therapeutic area that is of educational value to the HPN readers, your peers.

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36 Feature

DVT Presentations to an Emergency Department: A Study of Guideline Based Care and Decision Making P-value < 0.05 Darren Lillis, Beaumont Hospital, Dublin, Christian Lloyd, Beaumont Hospital, Dublin Peter O'Kelly, Beaumont Hospital, Dublin, Sheila Kelly, Beaumont Hospital, Dublin (version

was deemed to be significant. Statistical analysis was

10, College Station, Texas).

Peadar Gilligan, Beaumont Hospital, Dublin

Deep Venous Thrombosis (DVT) occurs in 84 people per 100,0001. The 9th Edition of the American College of Chest Physicians guidelines advocate the use of an objective method of risk stratification. Clinical assessment alone has proven unreliable2,3. Algorithms using a combination of a pre-test probability score, D-Dimer, and ultrasonography are now the norm. The most commonly used pretest probability score is the Wells score, which combines patients’ symptoms, signs and history to provide a risk stratification for the possibility of DVT4. D-Dimer is a sensitive but not specific marker for DVT5. Elevated levels are also seen in the presence of infection, inflammation, malignancy, and trauma. Aboveknee or whole-leg ultrasonography are now the imaging modalities of choice. In above-knee-only compression ultrasound, the inability to compress the femoral and popliteal veins under gentle pressure, visualisation of thrombus and lack of augmentation of flow on manual compression of the calf muscles are considered diagnostic of a DVT. Propagation into the proximal venous system of an isolated calf vein DVT generally occurs within 5 to 7 days6. In order to detect extension, repeat compression ultrasonography within one week should be performed according to some authors7,8. Whole-leg ultrasound has been advocated as a once off investigation for DVT9. It detects DVTs in both the proximal and distal venous system, obviating the need for repeat testing. However, debate is ongoing as to whether isolated distal DVTs are clinically relevant, and whether they require anticoagulation with its associated risks3. This study was conducted to assess the investigation of DVT over a one-year period in an adult ED in the context of performance of pre-test probability risk stratification, DDimer, and ultrasound investigation.

March 2017 • HPN

Figure 1: Patient Flow Diagram

Figure 2: Box plot of Wells scores in those not having an ultrasound, those who had a negative ultrasound and those with a positive ultrasound


hours, the assessment was made by the ED medical team.

department by ultrasound radiographers. The images were subsequently interpreted by a radiologist. A retrospective study of all patients who presented to the Emergency Department with suspected

The study was conducted in the Patients with a low pre-test Emergency Department of a large probability as evidenced by teaching hospital providing care to the Wells score and who had a 50,000 ED presentations per Results year. negative During the working week, patients The flow of patients through the investigation algorithm is demonstrate presenting with a possible DVT D-Dimer were discharged. Patients Deep Venous Thrombosis (DVT) were assessed by a Clinical Nurse with a ‘DVT pre-testhad Wellsa low in the year 2010 was performed. 385 patients, 151likely’ (39.2%) pre-test probability, negative D-D Specialist (CNS) service within score and a positive or negative Ethical approval for the study was the department. D-Dimer had an initial above-knee granted by the Beaumont Hospital further investigation. Of the 234 patients who underwent ultrasound sc ultrasound. If this was negative, a This is overseen by the senior Research Ethics Committee. Three decision wasknee made as to whether Emergency Clinician. Each patient sources of potential patientOf the 20 a positive above compression ultrasound scanDVT (CUS). the patient was required to attend was managed according to a details were searched: the DVT an ED review clinic and potentiallynot nurse DVT algorithm consisting of ascan 169 specialist’s logbook, the (82.4%) were deemed to require a repeat ultrasound. Th have a repeat ultrasound. All pre-test probability score (Wells six ultrasound logbooks for 2010 ultrasonographic examinations score), D-Dimer and if indicated, the ED review clinic book clinic, of w whose initial scan was negative wereand sent to the ED review for the year were used. Blood were conducted in the radiology ultrasonography. Outside of these

ultrasonography. Five (14.7%) of these patients had a positive scan. A

DEMONSTRATED POWERFUL PAIN RELIEF1,a For the symptomatic relief of1 Osteoarthritisb

30-60mg once daily

Rheumatoid Arthritisc Ankylosing Spondylitisc

60-90mg once daily

For the short-term treatment of1 Postoperative Moderate Dental Surgery Pain


Acute Gouty Arthritis


once daily, maximum 3 days

once daily, maximum 8 days

60-90mg once daily

ARCOXIA® Film-coated Tablets Prescribing Information Refer to the Summary of Product Characteristics (SmPC) before prescribing. Presentation: Arcoxia 30 mg (blue-green), 60 mg (dark green), 90 mg (white), 120 mg (pale green) film-coated tablets containing 30 mg, 60 mg, 90 mg and 120 mg etoricoxib respectively. Indication: Adults and adolescents 16 years of age and older for the symptomatic relief of osteoarthritis (OA), rheumatoid arthritis (RA), ankylosing spondylitis (AS), and pain and signs of inflammation associated with acute gouty arthritis. Adults and adolescents 16 years of age and older for short-term treatment of moderate pain associated with dental surgery. Dosage and method of administration: Shortest duration of treatment and lowest effective dose should be used as cardiovascular risk may increase with dose and duration of exposure. Need for symptomatic relief and response to therapy should be re-evaluated periodically especially in patients with OA. Administer orally with or without food. OA: 30 mg o.d. If insufficient relief, 60 mg once daily (o.d.) may increase efficacy. RA and AS: 60 mg o.d. If insufficient relief, 90 mg o.d. may increase efficacy, once clinically stabilised titration to 60 mg may be appropriate. Acute gouty arthritis: 120 mg o.d., maximum 8 days treatment. Postoperative dental surgery pain: 90 mg o.d., limited to maximum of 3 days. Do not exceed recommended dose or duration of treatment. Elderly: No dosage adjustments necessary. Exercise caution. Hepatic impairment: do not exceed 60 mg dose in mild dysfunction. Do not exceed 30 mg dose in moderate dysfunction. Renal impairment: No dosage adjustments required in creatinine clearance ≥ 30 ml/min. Contraindications: Hypersensitivity to ingredients, active peptic ulceration or active gastro-intestinal (GI) bleeding, patients who after taking acetylsalicylic acid or non-steroidal anti-inflammatory drugs (NSAIDs) including cyclooxygenase-2 (COX-2) inhibitors experience bronchospasm, acute rhinitis, nasal polyps, angioneurotic oedema, urticarial or allergic-type reactions, pregnancy and lactation, severe hepatic dysfunction, estimated renal creatinine clearance < 30 ml/min, children and adolescents under 16 years, inflammatory bowel disease, congestive heart failure, patients with hypertension whose blood pressure is persistently elevated above 140/90 mmHg and has not been adequately controlled, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. Special warnings and precautions: Gastrointestinal effects: Upper GI complications, some resulting in fatal outcome have occurred with etoricoxib. Caution in patients at risk of developing GI complications with NSAIDs; elderly using other NSAID or acetylsalicyclic acid concomitantly or patients with history of GI disease. Increased risk of GI adverse effects when taken concomitantly with acetylsalicyclic acid. Cardiovascular effects: Class of drugs may be associated with risk of thrombotic events. Careful consideration in patients with significant risk factors for cardiovascular events (hypertension, hyperlipidaemia, diabetes mellitus, smoking). Do not discontinue anti-platelet therapies. Renal effects: Consider monitoring of renal function in patients with pre-existing significantly impaired renal function, uncompensated heart failure or cirrhosis. Fluid retention, oedema and hypertension: Caution in patients with history of heart failure, left ventricular dysfunction or hypertension and in pre-existing oedema. Take measures to discontinue treatment if deterioration of condition. Control hypertension before initiating treatment and monitor blood pressure within two weeks after initiation and periodically thereafter. Hepatic Effects: Monitor patients with symptoms and/ or signs of liver dysfunction, or in whom abnormal liver test has occurred. Discontinue if signs of hepatic insufficiency or persistent abnormal liver function test. General: Caution when initiating treatment in patients with dehydration. Serious skin reactions, some fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported very rarely in association with NSAIDs and some selective COX-2 inhibitors. Serious hypersensitivity reactions (anaphylaxis and angioedema) have been reported. Discontinue at first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity. Etoricoxib may mask fever and other signs of inflammation. Caution when coadministering with warfarin or other oral anticoagulants. Contains lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take Arcoxia. Interactions: Pharmacodynamic Interactions: Oral anticoagulants: Closely monitor prothrombin time International Normalised Ratio in patients also receiving oral anticoagulants, particularly in first days of treatment initiation or etoricoxib dose change. Diuretics, ACE inhibitors and Angiotension II antagonists: Effectiveness of diuretics and other antihypertensive drugs may be reduced. Caution when combining ACE inhibitor or Angiotensin II inhibitor with cyclooxygenase inhibitors due to possible deterioration of renal function, including acute renal failure, especially in the elderly. Consider monitoring renal function after initiation of concomitant therapy, and periodically thereafter. Acetylsalicyclic acid: Not recommended with doses of acetylsalicylic acid above those for cardiovascular prophylaxis (low dose) or with other NSAIDs due to possible increased rate of GI ulceration or other complications. Cyclosporin and tacrolimus: Coadministration of cyclosporin or

tacrolimus with any NSAID may increase nephrotoxic effect. Monitor renal function if concomitantly used. Pharmacokinetic (PK) Interactions: Effect of etoricoxib on other drugs: Lithium: NSAIDs decrease lithium renal excretion and therefore increase lithium plasma levels. If necessary monitor blood lithium closely and adjust lithium dosage. Methotrexate: Monitor for methotrexate-related toxicity when administered concomitantly. Oral contraceptives: Etoricoxib has shown to increase concentration of ethinyl estradiol when coadministered with oral contraceptives; this can increase the incidence of adverse events associated oral contraceptives. Hormone Replacement Therapy: Evidence of increases in estrogenic concentration in concomitant use; consider when selecting post-menopausal hormone therapy for use with etoricoxib. Prednisone/ prednisolone: No clinically important effects. Digoxin: Monitor patients at high risk for digoxin toxicity when administered concomitantly due to possible increase of digoxin Cmax. Drugs metabolised by sulfotransferases: Etoricoxib inhibits human sulfotransferase. Care when concomitantly administering with other drugs primarily metabolised by human sulfotransferases (e.g. oral salbutamol, minoxidil). Drugs metabolised by CYP isoenzymes: Not expected to inhibit cytochrome P450 enzymes. Effect of other drugs on Etoricoxib: Etoricoxib is metabolised by CYP enzymes. Ketoconazole: 400mg o.d. for 11 days did not have clinically important effect on single dose PK of 60 mg etoricoxib. Voriconazole (oral) and Miconazole (oral gel): Coadministration of either with etoricoxib caused slight increased exposure of etoricoxib but not clinically significant. Rifampicin: Co-administration produced decrease in etoricoxib concentrations. Etoricoxib doses higher than those studied are not recommended. Antacids: Does not affect PK of etoricoxib. Pregnancy and lactation: Not recommended. If woman becomes pregnant during treatment, etoricoxib must be discontinued. Do not use during breast feeding. Not recommended when attempting to conceive. Driving and using machines: Patients who experience dizziness, vertigo or somnolence when on treatment should refrain from driving or operating machinery. Undesirable effects: Very common (≥1/10): Abdominal pain. Common (≥1/100, <1/10): Alveolar osteitis, oedema/fluid retention, dizziness, headache, palpitations, arrhythmia, hypertension, bronchospasm, constipation, flatulence, gastritis, heartburn/acid reflux, diarrhoea, dyspepsia/ epigastric discomfort, nausea, vomiting, oesophagitis, oral ulcer, ALT increase, AST increased, ecchymosis, asthenia/ fatigue, flu-like disease. Other important undesirable effects: Upper respiratory infection, leukopenia, hypersensitivity, atrial fibrillation, tachycardia, congestive heart failure, angina pectoris, myocardial infarction, cerebrovascular accident, transient ischaemic attack, hypertensive crisis, vasculitis, gastroduodenal ulcer, peptic ulcers including gastrointestinal perforation and bleeding, pancreatitis, hepatitis, hepatic failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema/ anaphylactic/ anaphylactoid reactions including shock. Additional information available on request. Overdose: Remove unabsorbed material from GI tract, clinical monitoring, institute supportive therapy, if required. Not dialyzable by haemodialysis; not known whether dialyzable by peritoneal dialysis. Legal classification: POM. Marketing Authorisation numbers and pack sizes: Arcoxia 30 mg film-coated tablets: PA1997/1/1 28 pack, 60 mg film-coated tablets: PA1997/1/2 28 pack, 90 mg film-coated tablets: PA1997/1/3 5 and 28 pack, 120 mg film-coated tablets: PA1997/1/4 7 and 28 pack. Marketing Authorisation Holder: Merck Sharp & Dohme BV, Waarderweg 39, 2031 BN Haarlem, The Netherlands. Date of Preparation: August 2016. IRE/A16 0006 References: 1. Arcoxia SmPC, a Doses greater than those recommended for each indication have either not demonstrated additional efficacy or have not been studied. Due to cardiovascular risks, the shortest duration possible and the lowest effective daily dose of ARCOXIA should be used.1 b The recommended dose for osteoarthritis is 30 mg once daily. An increased dose of 60 mg once daily may increase efficacy. The dose for osteoarthritis should not exceed 60 mg daily.1 c The recommended dose for Rheumatoid Arthritis and Ankylosing Spondylitis is 60 mg once daily. An increased dose of 90 mg once daily may increase efficacy. The dose for Rheumatoid Arthritis and Ankylosing Spondylitis should not exceed 90 mg daily. Once stabilised, down-titration to a 60 mg once daily dose may be appropriate.1 Date of Preparation: August 2016 IRE/A16 0007e

Grünenthal Pharma Ltd., Dublin, Ireland,

and again regression analysis of a positivehad outcome showed this to bm clinic and had repeated ultrasonography, a significantly higher 1.082.22,regression P =0.015).analysis of a positive outcome showed this to and again

38 Feature results, presenting complaints and the ultrasound results for patients were all retrieved using the Patient Information Profile Explorer system, an internal information technology system used in the hospital. All data from the computer system were cross-referenced with the information taken from the other three sources. Data for 404 patients was collected. Nineteen (4.7%) were excluded due to an incomplete data set. Logistic regression modelling was used for the statistical analysis with odds ratios (OR), and 95% confidence intervals (CI), used to define relative risk of a positive score. Univariate methods were initially employed, and subsequently multifactorial models were implemented to determine independently significant variables in the presence of potential confounders. Box plots were used to describe D-Dimer and Wells scores between US groups. A P-value < 0.05 was deemed to be significant. Statistical analysis was conducted using Stata (version 10, College Station, Texas).

1.08- 2.22, P =0.015).

Figure 3: Box plot of D-Dimer results in those who did not undergo ultrasound, those who had a negative ultasound and those with a positive ultrasound

Figure 4: Box plot of Wells scores of those recalled after an initially negative ultasound versus those not recalled

Results The flow of patients through the investigation algorithm is demonstrated in figure 1. (on page 36) Of the initial 385 patients, 151 (39.2%) had a low pre-test probability, negative D-Dimer, and did not require further investigation. Of the 234 patients who underwent ultrasound scan, 29 (12.4%) patients had a positive above knee compression ultrasound scan (CUS). Of the 205 with an initially negative scan 169 (82.4%) were deemed not to require a repeat ultrasound. Thirty-six (17.6%) patients whose initial scan was negative were sent to the ED review clinic, of whom 34 had repeated ultrasonography. Five (14.7%) of these patients had a positive scan. As expected, patients who had a positive result on compression ultrasonography were more likely to have a significantly higher mean pre-test probability (Wells) score. Those with a negative scan were more likely to have a higher score than those who received no scan at all. Logistic regression (multifactorial model) for a positive US result showed (Wells) score to be highly significant (OR 3.1, CI 1.76- 5.44, P<0.001). Higher D-Dimer results were found in those with a positive scan. Patients who were referred for an initial ultrasound had significantly higher mean D-Dimer results

March 2017 • HPN

than those who did not have any imaging. Logistic regression for a positive US outcome demonstrated significance for high D-Dimer (OR 1.43, CI 1.161.75, P=0.001). Patients who attended the review clinic and had repeated ultrasonography, had a significantly higher mean pretest probability score and again regression analysis of a positive outcome showed this to be significant (OR 1.55, CI 1.08- 2.22, P =0.015). Discussion The data from the 385 patients included in this study demonstrate significant correlation with previous research conducted by Wells et al.4,5,10 insofar as those patients diagnosed with a DVT were more likely to have a high pre-test probability score (P <0.001, OR 3.1, CI 1.76- 5.44). This confirms that in our department pre-test probability, informs the decision to investigate further. Clinicians were more likely to refer patients to the review clinic if they had higher pre-test probability

scores with a view to a repeat ultrasound being performed, suggesting that, despite a negative initial scan, the clinician remained concerned about the possibility of a DVT. As expected, when the D-Dimer results were correlated between the ‘no ultrasound performed’, ‘negative ultrasound’ and ‘positive ultrasound’ groups, those patients with a DVT were more likely to have higher D-Dimer values (P<0.001, OR 1.4, CI 1.16-1.75). Those with a higher D-Dimer value after an initially negative compression ultrasound were more likely to be sent to the review clinic and have a repeat scan. Therefore, marked elevation of the D-Dimer was associated with ongoing clinical concern, even when initial scans were negative. The pre-test probability scores and DDimer values overlap between the patients not referred for a second scan and those who were. We would suggest that the pre-test score, D-Dimer, history and examination are not taken in isolation but combined to inform the clinical decision as

to whether or not to perform a second ultrasound. This decisionmaking process resulted in only 36 (17.6%) of a possible 205 patients with initially negative scans being asked to attend the review clinic. Five (2.4% of those with an initially negative scan) of whom had a DVT on repeat scan. With regard to repeated above knee only compression ultrasonography or once off whole leg scanning, the recent ACCP guidelines have advocated patient preference, such as those unable to return for serial testing, and institutional access as factors in the decision to utilise one modality over the other3. Bernardi et al. conducted a prospective, randomised, multicentre study of consecutive symptomatic outpatients (n=2098) with a first episode of suspected DVT of the lower extremities11. Patients were randomised to undergo 2-point compression ultrasound with DDimers, or whole-leg ultrasonography. The main outcome measure was a confirmed 3-month incidence of symptomatic

39 venous thromboembolism in patients with an initially normal diagnostic workup. In the compression ultrasound/ D-Dimer group, the initial diagnostic yield was 20.7% (12.4% in our study). Of the 256 patients with a normal compression ultrasound but abnormal DDimer, 5.4% were found to have a proximal DVT on the repeated compression ultrasound (2.4% of patients in our study). Ten patients (26.4%) of the whole leg ultrasound group were diagnosed with an above or belowknee DVT and anti-coagulated. At three-month follow up, the study found that symptomatic venous thromboembolism occurred in 7 of 801 patients (0.9%) in the 2-point compression ultrasound group and in 9 of 763 patients (1.2%) in the whole-leg group. They concluded that the two strategies

were equivalent. In this context, our department’s strategy of performing above-knee ultrasound would appear reasonable. Rather than all patients with an initially negative scan undergoing repeat above knee compression ultrasound, in our study only 16.6% (34/205) of patients did. 14.7% (5/34) demonstrated a DVT on the repeat scan where the initial scan had been negative. Five out of 205 (2.4%) patients who had an initially negative compression ultrasound, demonstrated a DVT on repeat scan. This detection rate from a repeated scan is in line with other large-scale studies, which demonstrate a diagnostic yield of 2%12,13. One hundred and seventy one fewer repeat compression ultrasound scans were performed with a targeted

approach of repeat above-knee ultrasound with the same diagnostic yield as in studies where all patients were re-scanned. The data would suggest that clinicians on the emergency department floor are using pre-test probability scores, D-Dimer results and clinical gestalt to influence their clinical assessment of the patients’ complaint and in deciding on whether or not to perform an initial and repeated compression ultrasound. In doing so, large savings can be made in terms of ultrasonography, staff labour, and the financial burden on patients having to reattend the hospital. This study was performed in a single ED and so may not apply to other settings. Nineteen of the original 404 population had an incomplete data set and were not

included in the study, which may have influenced the results. Kappa values evaluating inter-rater reliability regarding the calculation of Wells Scores were not calculated. Decision making is what doctors do and whilst guidelines assist us, ultimately we make an informed decision in the best interests of our patients. This study demonstrates the same diagnostic yield for DVT on repeat scanning as other international studies but with significantly less repeat diagnostic testing. In the context of an initially negative above-knee compression ultrasound with a positive D-Dimer, where there is ongoing concern, a repeat ultrasound within one week will pick up a small number of deep venous thromboses.


Minister Harris outlines 2017 priorities During 2017 each Hospital Group will be required to develop a Strategic Plan to describe how they will provide more efficient and effective patient services; and demonstrate a co-ordinated approach to the planning and delivery of services within and across the hospital groups.

Minister for Health Simon Harris TD

2017 Priorities Turning back to his priorities for 2017, some of the other positive developments he said he looks forward to delivering include a new National Cancer Strategy, which aims to meet the needs of cancer patients in Ireland for the next decade, and also the publication of an implementation plan for Neuro Rehabilitation Strategy.

This protocol was outlined by the Minister for Health Simon Harris TD as he addressed the Joint Committee on Health, recently. The Minister added, “As part of the Hospital Group structures, we are now starting to see hospitals working together to support each other, providing a stronger role for smaller hospitals in delivering less complex care and ensuring that patients who require true emergency or complex planned care are managed safely in larger hospitals. “There was clear evidence of this under the HSE’s Waiting List Action Plan in 2016 where public hospital capacity was utilised to best effect, for example with Cappagh and Kilcreene Hospitals taking orthopaedic patients from Tullamore, St James’s, Beaumont and Tallaght. Also, University Hospital Limerick undertook a number of vascular surgeries on behalf of the Saolta Hospital Group. The Minister was joined by Ministers Finian McGrath, Minister of State with special responsibility for Disabilities, Catherine Byrne, Minister for Communities and the National Drugs Strategy and Marcella Corcoran Kennedy,

Patient safety Minister for Health Promotion, alongside Mr Jim Breslin, Secretary General at the Department of Health. He echoed that there has been a significant spotlight on aspects of Ireland’s health service which are of great public concern. Cost of Medicines Turning to an issue that Ireland has in common with many other countries - the cost of medicines, the Minister highlighted the increasing costs in advances in medicines. The medicines bill in Ireland has increased from ¤400 million in 1998 to over ¤2 billion in 2016. “Securing access to innovative medicines for citizens at an affordable price is therefore a major challenge and not one that is easily solved,” he said.

“A number of key initiatives have been introduced in recent times, including agreements with industry, the most recent being signed in June last year, as well as the introduction of generic substitution and reference pricing. These initiatives have generated significant savings and reduced prices in Ireland to a more sustainable level. This is to be welcomed. “Nonetheless, the medicines bill is forecast to rise significantly in the years ahead driven primarily by the increased cost and usage of recently introduced medicines and the very strong pipeline of new medicines. Therefore, our financing model for medicines needs to be both sustainable and affordable but the pricing model proposed by industry must also be sustainable and affordable.”

“I am very pleased to report on developments in the area of patient safety. Following approval of a Government memo on a major programme of patient safety reform in November 2015, my Department’s National Patient Safety Office was established and launched in December 2016,” he continued. “The development of a Patient Safety Complaints and Advocacy Policy has already commenced. It is planned that the first National Patient Experience Survey will commence in 2017. This endeavour is a joint partnership between HIQA, the Department of Health and the HSE. “The implementation of Healthy Ireland, the national framework for action to improve the health and wellbeing of our population, also continues to be a priority. HPN • March 2017

40 Advertorial

introduces Vistaprep® into Ireland Tillotts Pharma Ltd, the Irish affiliate of Switzerland-based Tillotts Pharma AG introduced Vistaprep® on 1 February 2017 into the Irish market. Vistaprep® is a polyethylene glycol (PEG) based bowel cleanser indicated for the preparation of the bowel for colonoscopy. Colonoscopy is one of the most common colorectal cancer (CRC) screening methods.1 Colonoscopies are also part of the National Bowel Screening Programme. Bowel (colon, rectal or colorectal) cancer is the second most common newly diagnosed cancer among men and women in Ireland. Each year over 2,000 new cases of colorectal cancer are reported. The number of new cases is expected to increase significantly over the next 10 years, due mainly to an increasing and ageing population.2

laxative effect of Vistaprep® causes temporary diarrhoea or more frequent bowel movements than normal.

Product summary Product name: Vistaprep® powder for oral solution. Active ingredients: Macrogol 3350, sodium chloride, sodium bicarbonate and potassium chloride. Formulation: Powder for oral solution. Indication: Bowel cleansing in preparation for colonoscopy. Dosage and administration: For adults over 18 years of age, 3-4L is orally administered either over a period of four hours generally on the examination day, on the evening before or as a split-dose on the evening before and the remaining amount on the morning of the examination day. Package: One Vistaprep® pack containing four Sachets. Market Authorisation holder: Tillotts Pharma GmbH. References

Vistaprep® is used to prepare three to four litres of citrus-flavoured oral solution with a split-dose option.3 It is currently sold in five European countries through Switzerland based Tillotts Pharma AG affiliates. PEG based bowel cleansers are recommended as first-line therapy in both European and American guidelines for the preparation of the bowel for colonoscopy4-6 and are the gold standard in this area due to good efficacy and safety data5. The sole purpose of Vistaprep® is to cleanse the bowel. Systemic absorption is negligible and excretion is mainly via the faeces. The Vistaprep® Powder for oral solution: Abbreviated Prescribing Information Presentation: Each sachet of white powder contains Macrogol 3350: 105g, sodium chloride: 2.8g, sodium bicarbonate: 1.43g and potassium chloride: 0.37g. Indication: For bowel cleansing in preparation for colonoscopy in adults. Dosage and Method of Use: For oral use. Each sachet Vistaprep® needs to be dissolved in 1 litre of lukewarm water just before use. 3 to 4 litres are drunk over 4 hours on the examination day in portions of 200 to 300 ml solution every 10 minutes until the rectal excretions are clear OR the maximum of 4 litres is consumed. Alternatively, the amount required is taken the evening before OR a portion is taken the evening before and the rest the morning of the clinical procedure. Do not consume any solid food from 2 to 3 hours prior to administration of Vistaprep® until after the examination. Not for use in children under 18 years. Contraindications: Ileus and suspected ileus, gastrointestinal obstruction or perforation, risk of gastrointestinal perforation, hyperflorid colitis, toxic megacolon, gastric emptying disorders. Hypersensitivity to active ingredients, other macrogols, saccharin sodium,

March 2017 • HPN

1. Centers for Disease Control and Prevention. Vital signs: colorectal cancer screening test use – United States, 2012. MMWR Morb Mortal Wkly Rep. 2013; 62:881–8. 2. The National Bowel Screening Programme. Bowel screen for Health professionals. Retrieved from (n.d). 3. Kilgore TW et al. Bowel preparation with split-dose polyethylene glycol before colonoscopy: a meta-analysis of randomised controlled trials. Gastrointest Endosc. 2011; 73:1240-45. 4. Hassan C et al. Bowel preparation for colonoscopy: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy 2013; 45:142-150. 5. Mathus-Vliegen et al. Consensus guidelines for the use of bowel preparation prior to colonic diagnostic procedures: colonoscopy and small bowel video capsule endoscopy, Current Med Res Opin 2013; 29:931-45. 6. ASGE Standards of Practice Committee et al. Gastrointest Endosc. 2015 Apr; 81 (4):781-94.

orange flavor, lemon-lime flavor, colloidal anhydrous silica or any other excipients. Unconsciousness or impaired consciousness, tendency to aspiration or regurgitation, general weakness or impaired swallowing reflex. Precautions: Caution and monitoring required in elderly and patients with reflux oesophagitis, preexisting cardiac arrhythmias, known or suspected SA block or sick sinus syndrome. Can be used with caution with chronic inflammatory bowel disease (but not for use in highly florid stages or toxic megacolon). Not for use in patients with heart failure (NHYA class III and IV), renal insufficiency, liver disease, or severe dehydration. Careful monitoring of electrolyte and fluid balance required in patients at risk, e.g. elderly or debilitated. Caution in patients on controlled sodium or potassium diets or with reduced renal function. Not for use in children. No other solutions or additives should be added to Vistaprep® solution (may result in electrolyte changes or explosive gas mixtures). Interactions: May decrease absorption of oral medication (e.g. delayed-release medicines) administered within several hours before, during or up to 1 hour after taking Vistaprep®. Macrogol 3350 may interfere with

diagnostic enzyme assays (e.g. ELISA). Pregnancy and lactation: Limited data: risk:benefit analysis required. Adverse Events: Diarrhoea is expected. Very common (≥10%): nausea, feeling of fullness, flatulence. Common (≥1% to <10%): vomiting, stomach cramps, anal irritation. Uncommon (≥1/1000 to <1/100): general malaise, insomnia. Very rare (≤ 1/10,000): cardiac arrhythmia, tachycardia, pulmonary oedema, decreased serum calcium, potassium and sodium, neurological effects from disorientation to seizures, urticaria, rhinorrhoea, dermatitis, anaphylactic reaction. Refer to Summary of Product Characteristics for full details. Adverse events should be reported. Legal category: POM. MARKETING AUTHORISATION NUMBER: PA2018/002/001. MA HOLDER: TILLOTTS PHARMA GmbH, Warmbacher Strasse 80, 79618 Rheinfelden, Germany DATE OF PREPARATION: January 2017. Full prescribing information available on request from the Marketing Authorisation Holder or from Tillotts Pharma Ltd., 25 Sandyford Office Park, Dublin 18. Tel: 01 294 2015.

News 41

Research into bowel cancer drugs to have impact on tailored patient treatments Researchers in RCSI (Royal College of Surgeons in Ireland) have conducted further indepth research to predict how patients with bowel (colorectal) cancer will respond effectively to chemotherapy, to ensure that patients will get the most suitable type of treatment from the outset. A large validation study was conducted to support initial findings with the latest research published in the Clinical Cancer Research and Gut (International Journal of Gastroenterology and Hepatology) journals. The research focuses on the need to personalise cancer treatment programmes in order to kill cancer cells while preserving healthy tissue. This prediction tool, developed in RCSI, is a computerised model using insights obtained from research in the field to provide a fast method of determining the sensitivity of an individual patient's cancer cells. It allows the patient to be assessed to see if chemotherapy will be of benefit before treatment starts, allowing for other treatment options to be utilised if the results show that no benefit will be received from chemotherapy. This not only allows the patient to receive more appropriate treatment at an earlier stage it also prevents any possible damage to healthy cells which could be caused by the chemotherapy and reduces other side effects. Professor Jochen Prehn, Professor of Physiology & Director of the

Professor Jochen Prehn, Professor of Physiology & Director of the Centre for Systems Medicine at RCSI

Centre for Systems Medicine at RCSI, said, "Tumours can become unresponsive to chemotherapy as they are made of different types of cells and many develop resistance to chemotherapy drugs. In one particular type of colorectal cancer up to 50-60% of patients prove unresponsive to a commonly used treatment regime. "The tools we have developed from this research will deliver the right chemotherapy or the right treatment plan to the right patient at the right time, hence avoiding unnecessary side-effects and accelerating access to better treatments. "This avoids a situation in which a patient who is not responsive to the drugs has to endure harsh chemotherapy treatment needlessly. By analysing the chemical pathways in a tumour prior to therapy and knowing that the tumour will be responsive also reduces uncertainty, and means that scarce resources can be used to maximum benefit. "The research has also shown that this type of testing may also work in other forms of cancer which is another exciting development," concluded Professor Prehn.

In addition to patient benefit, there is potentially a major cost saving associated with this development for healthcare funders - patients who will not benefit from the chemotherapy, or certain types of chemotherapy, will not receive it resulting in significant healthcare savings. The Dose Response Medical Outcome Model Predictor System, a patent protected technology developed in RCSI, can also be used by the pharmaceutical sector. Developing a new treatment can be a lengthy process costing billions. This test can be utilised to reduce the cost and time involved by allowing the drug makers to evaluate novel therapeutics at an early stage. RCSI is actively exploring partnerships with drug companies.

Director of Research and Innovation at RCSI, Professor Ray Stallings said "RCSI's research strategy has a strong focus on excellence in translational research for the benefit of patients and healthcare systems. Professor Prehn's research exemplifies how RCSI's translational research programmes can improve patient outcomes, reduce healthcare costs and have industrial relevance." This research has been supported by the Science Foundation Ireland, and Health Research Board and the European Commission. According to the Irish Cancer Society almost 2,500 Irish people are diagnosed with bowel cancer each year. It is also the second most common cause of cancer death in Ireland.

New Possibilities into treatments for Cancer, Alzheimer’s and Diabetes The Horizon 2020 funded project TrainERS coordinated by NUI Galway, has released new findings on how communication is coordinated between the inside and outside of a cell. The discovery is set to open up new avenues for further research into treatments for Alzheimer’s, cancer and diabetes. The discovery was made by researchers at the Laboratory of Cell Death Research and Therapy at the University of Leuven in Belgium. TrainERS is being coordinated by Professor Afshin Samali, CÚRAM Researcher and Professor of Biochemistry and Director of the Apoptosis Research Centre (ARC) at NUI Galway. The

findings were published in the scientific journal Molecular Cell of which Professor Samali and his colleagues in Belgium are co-authors. Proteins such as insulin are properly formed in the endoplasmic reticulum (ER), one of the biggest membrane structures in the cell. The ER works like an assembly line and folds the proteins into a three-dimensional shape that is essential for them to function. When there is a problem in the ‘protein folding assembly line’, the accumulation of misfolded proteins can lead to diseases such as Alzheimer’s, cancer, and diabetes. PERK, an enzyme known to detect

protein folding errors in the cell has now also been revealed to coordinate the communication between the inside and the outside of the cell, and is an essential component of this protein folding factory. Patrizia Agostinis, Alex van Vliet, and other team members at the University of Leuven discovered the additional function of PERK. “This protein is known to play a crucial role in maintaining endoplasmic reticulum functions and restoring them if necessary. When PERK detects protein folding errors in the ER it prompts the nucleus of the cell to take action”, explains Patrizia Agostinis, head of the Laboratory of Cell

Death Research and Therapy in the University of Leuven. “We found that PERK also coordinates the communication between the protein folding factory (the ER) and the skin of the cell (the plasma membrane). When the protein folding factory detects low calcium levels, the plasma membrane needs to let calcium flow back in. Calcium is crucial for the proper functioning of the protein folding factory where the calcium is stored, and for the overall health of the cell. This is where PERK comes in: the protein establishes contact between the two cell components so that they can work together to restore the calcium level”, added Ms Agostinis. HPN • March 2017

Awards Hospital Professional


HPN is delighted to announce the launch of the 2017 Hospital Professional Awards The Hospital Professional Awards are the only Awards of their kind in Ireland, bringing together the entire hospital multidisciplinary team to recognise and celebration innovation and dedication whilst providing a platform from which to share ideas and learn best practice from peers and colleagues.

and encompassing all aspects of multidisciplinary working reaffirming the core pursuits of secondary healthcare: excellence in health and innovation.

The Hospital Professional Awards represent a unique and high-profile opportunity to celebrate the excellence and amazing achievements of Ireland’s hospital individuals and teams throughout Ireland from Management to Ward

These multidisciplinary teams are working closer and closer, from background advisor to frontline patient care provider, continuously requiring different skills. The added value is obvious and has resulted – and still results – in best practice.

The Awards recognise outstanding examples of high standards, best practice, innovation and excellence.

These Awards and the examples of innovation that they demonstrate, inspires hospital professionals to think about their role, that of their team and of the hospital profession in which they operate, as a whole. The Hospital Professional Awards ceremony, which will be held in the Clayton Hotel (formerly the Burlington), Dublin on Saturday, September 16th 2017 and will provide a showcase platform for the hospital sector and a great networking opportunity, with over 350 of the industry’s

most influential professionals. This occasion will once again highlight that Ireland’s secondary care arena is rising to the challenges of Ireland’s health service, to celebrate the success of staff and projects but also an opportunity to mix and build networks with industry peers. Application for the Awards are now open on the dedicated Award website www. . This website will have full details of all the awards and includes lots of advice and tips about completing your entry and details of past winners.

Awards Hospital Professional


Award Categories

Roche Oncology Pharmacist of the Year 2017

Accord Innovation in Aseptic Compounding Award 2017

Consultant-led Team of the Year 2017

Innovation in eHealth Award 2017

Hospital Professional of the Year 2017

Professional Contribution Award 2017

Idis Young Hospital Professional of the Year 2017

Medisource Hospital Pharmacy Technician of the Year 2017

Multidisciplinary Working Award 2017

Excellence in Patient Safety Award 2017

Daiichi-Sankyo Hospital Pharmacy Team of the Year 2017

MSD Excellence in Infectious Diseases Project of the Year 2017

Innovation & Service Development Award 2017

Excellence in Respiratory Care Award 2017

Hospital Representative of the Year Award 2017 For an Entry Form or further details contact Kelly Jo Eastwood on 0044 7876548989 or via email on:

Hugh’s House making a real difference for families in Ireland The IPN chosen charity for 2017 is Hugh’s House which was established by Ade Stack and Marty Curley. When their baby son Hugh was ill in hospital, Ade Stack and Marty Curley were thankful they lived in Dublin. They witnessed the struggles of other families travelling from all over the country to visit their sick children, some of whom were unable to cope financially with the expense of accommodation and meals. They were devastated when they saw children, especially babies who rarely had visitors because their families lived too far away. Beautiful baby Hugh passed away in hospital in August 2013, aged eight months, leaving his parents heartbroken. While Temple Street has limited space for parents to stay, it doesn’t allow brothers or

sisters to stay and the Rotunda and Holles Street have no parent accommodation.

weeks and spend 3 months in hospital but go on to have normal and happy lives.

Marty and Ade saw how much Hugh loved his brothers Theo and Fred visiting and after he passed away, they purchased and renovated a house on Belvedere Place named Hugh’s House to provide accommodation for seven families at a time. In partnership with Aer Lingus they also created a beautiful garden to act as a sanctuary. “We saw marriages break up like slow car crashes with the stress,” says Ade. “There were people sleeping on the floor beside their sick children for months with no privacy and nowhere to have a chat.”

There is no charge, all meals are provided and a team of volunteers clean and work in the house. Each beautiful family room has been fitted out and decorated by a family who lost a beloved child, making them very special. Now, an adjacent second house has been acquired, that will provide dinners and provide respite to families who arrive when a child is dying, for example, but have nowhere to congregate or talk. Hugh’s House also provides a communal laundry service for all families to stop them having to bring washing home, it’s the little things that count.

The families are referred through the hospitals and their average stay in the house is three months. Premature babies are born at 23

For more information on Hugh’s house please go to or add us on Facebook. You can also donate to us at

Ade notes: “We do this not because Hugh died, but because he lived. He was so inspiring as he kept going no matter what was thrown at him.”

Part of the Clinigen Group

44 Feature

Epidemiology of diabetes and complications among adults in Ireland Marsha L. Tracey, University College Cork | Michael Gilmartin, Royal College of Surgeons in Ireland Kate O'Neill, University College Cork | Anthony P. Fitzgerald, University College Cork | Sheena M. McHugh, University College Cork Diabetes is a serious global public health issue which has been described as the most challenging health problem in the 21st century[1, 2]. Cases of diabetes have progressively increased worldwide; between 1980 and 2008 there was a two-fold increase in the number of adults with diabetes[3]. Type 2 diabetes is the main driver of the epidemic, accounting for approximately 90 % of all cases[2]. The increasing burden of diabetes is driven primarily by rising levels of obesity and an ageing population[2, 4]. To date there is no national surveillance programme, or national population-based survey of diabetes in Ireland. Therefore it is difficult to quantify or monitor the impact of diabetes at a national level. Estimates from the International Diabetes Federation (2013) suggest that the prevalence of diabetes is in line with global trends. In 2000, the IDF estimated that the prevalence of diabetes was 3.2%[5], this had increased to 6.5% in 2013[2]. Diabetes places a significant burden of care on the individual, health care professionals and the wider health system[1, 6]. Individuals with diabetes are two to four times more likely to develop cardiovascular disease relative to the general population and have a two to five-fold greater risk of dying from these conditions[7, 8]. Diabetes is a significant cause of blindness in adults, non-traumatic lower limb amputations and end-stage renal disease resulting in transplantation and dialysis[2]. Understanding the epidemiology of diabetes is essential to identify public health priorities. Accurate estimates of the burden of diabetes are essential for future planning and evaluation of services. While the IDF provides prevalence estimates for countries and regions, there are substantial variations in time trends as estimates are based on imputations[9, 10]. To date, estimates of diabetes prevalence in Ireland have been largely based on data from the 2007 National Survey of Health and Lifestyles in Ireland (SLÁN)[11]. Country specific prevalence rates have also been reported in the grey literature[2]; however these estimates have been extrapolated using data from the UK.

March 2017 • HPN

The Euro Diabetes Index (2014) stated that there was a lack of reliable data to monitor diabetes related complications in Ireland[12]. To date, a comprehensive overview of the diabetes situation in Ireland has not been carried out. Therefore the rationale for carrying out this systematic review is to provide a comprehensive understanding of the diabetes situation in Ireland and to highlight current gaps in existing knowledge to inform future research. The aims of this review are (1) to systematically identify and summarise studies describing the prevalence of diabetes and the most common microvascular (retinopathy, neuropathy and nephropathy) and macrovascular complications among adults in Ireland between 1998 and 2014; and (2) to explore trends in diagnosed diabetes prevalence between 1998 and 2015. Methods This review was produced according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines for systematic reviews and meta analyses[13]. Key words and study eligibility criteria were determined a priori. Search strategy

Ireland to identify relevant grey literature. Searches were carried out between January 2014 and March 2014. A second search was carried out in December 2015 to ensure the review included all up to date relevant information. Inclusion criteria Studies were eligible for inclusion if they met the following criteria: (1) conducted in the Republic of Ireland between 1998 and 2014; (2) cross-sectional study design or baseline data from longitudinal studies; (3) prevalence estimates reported for adults aged ≥ 18 years, including men and women; (4) data provided on diabetes prevalence (including a self-report of a previous doctor diagnosis and undiagnosed diabetes) and/ or the prevalence of microvascular complications (retinopathy, neuropathy, nephropathy) or macrovascular complications (myocardial infarction, congestive heart failure, stroke or TIA) in persons with diabetes; (5) if prevalence data were not reported, sufficient detail to calculate the numerator and denominator was provided; (6) the total sample size was ≥ 200; (7) adequate information was reported on the methods used.

Both peer-reviewed journal articles and reports were considered for this review. A systematic literature search was carried out in PubMed and Embase databases to identify relevant studies reporting the prevalence of diabetes, microvascular or macrovascular complications among adults within the Republic of Ireland.

Exclusion criteria

Keywords and Medical Subject Headings (MeSH) terms included Ireland, prevalence, diabetes, microvascular, retinopathy, neuropathy, nephropathy, macrovascular and cardiovascular disease. Keywords were combined using the AND or OR operators (Additional file 1). Titles and abstracts of the resulting literature were screened for further consideration. Reference lists of articles were also examined to identify potentially relevant studies.

If multiple articles provided information on a single study, the article detailing the most comprehensive data was selected. Full text articles were retrieved for all potentially eligible studies and were independently reviewed by three authors (MT, MG, and KON).

In addition, a Google search was conducted using the keywords prevalence, diabetes, retinopathy, neuropathy, nephropathy and

Studies containing participants from Northern Ireland, restricted to a specific sub-population (including hospital based studies), solely focused on type 1 diabetes, prediabetes or gestational diabetes were excluded from this review. Model estimates of prevalence were also excluded.

Data abstraction and quality assessment For each eligible study, three reviewers (MT, MG, and KON) individually collected relevant information using a structured data extraction form. The methodological quality of each included study was assessed

using a critical appraisal checklist for studies used in systematic reviews addressing questions of prevalence[14]. This appraisal tool was developed to specifically examine the internal and external validity of prevalence data included in systematic reviews. Methodological quality was considered ‘low’ if three or less criteria were met, ‘moderate’ if four to six criteria were met and ‘high’ if seven to nine criteria were met. Articles were not excluded on the basis of quality. Any inconsistencies in data abstraction and quality assessment between reviewers were resolved through consensus. Statistical analysis A meta-analysis was carried out using STATA version 13.1 (StataCorp, College Station, TX, USA). Studies were grouped into four categories: diagnosed diabetes among adults aged 18+ years; diagnosed and undiagnosed diabetes among adults aged 45+ years; diagnosed diabetes among adults aged 45+ years; undiagnosed diabetes among adults aged 45+ years. Pooled estimates of diabetes prevalence and 95 % confidence intervals (95 % CI) were calculated. Trends in pooled prevalence could not be explored as there was a lack of available data from different time points; therefore an overall estimate was provided for each group. Heterogeneity between studies was assessed by the Chi-square based Q test and I2 statistic. Potential publication bias was evaluated by the Begg’s test. A two-tailed p <0.05 was regarded to be statistically significant. High heterogeneity was found among studies reporting diabetes prevalence (I2 ≥ 75 %, p-value < 0.01) hence, pooled estimates were calculated using randomeffects model using the method of DerSimonian and Laird[15]. The results from the meta-analysis were presented in a forest plot. To determine the robustness of the results, a sensitivity analysis, based on high quality studies, was carried out. A meta-analysis of the prevalence of diabetes complications was inappropriate; factors which influence prevalence estimates (e.g. time since diabetes diagnosis,

Remarkably accurate blood glucose results, illuminated.

Diabetes management is about to be seen in a new light. The easy to use CONTOUR®NEXT ONE smart meter provides remarkably accurate blood glucose readings that are complemented by its unique smartLIGHT™ feature, letting your patients know if they are above, below or in their target range.1,2 Your patients also have the option to seamlessly connect their CONTOUR®NEXT ONE meter with the CONTOUR®DIABETES app to help manage their diabetes, smarter.

For further information on the CONTOUR®NEXT ONE meter contact your local Ascensia Diabetes Care representative or visit References: 1. CONTOUR®NEXT ONE user guide. 2. Christiansen M et al. Accuracy and user performance evaluation of a new blood glucose monitoring system in development for use with CONTOUR®NEXT test strips. Poster presented at the 15th Annual Meeting of the Diabetes Technology Society (DTS); October 22–24, 2015; Bethesda, Maryland, USA. Ascensia, the Ascensia Diabetes Care logo, CONTOUR and smartLIGHT are trademarks of Ascensia Diabetes Care Holdings AG. Apple and the Apple logo are trademarks of Apple Inc., registered in the U.S. and other countries. App Store is a service mark of Apple Inc. Google Play and the Google Play logo are trademarks of Google Inc. © Copyright 2016 Ascensia Diabetes Care Holdings AG. All rights reserved. Date of preparation: November 2016. Code: 07/11/2016/ADA4HCP

46 Feature

Tracey et al. BMC Public Health (2016) 16:132

Page 4 of 13

Figure 1: PRISMA flow chart depicting the selection process of articles included in the systematic review

type of diabetes, method of diagnosis) either varied between studies or were not reported. Instead a narrative synthesis provides a summary of relevant data. Trends in diagnosed diabetes As trends in diabetes prevalence could not be calculated by meta-analysis, original datasets from four national population based studies[16–19], identified during the literature search were obtained and analysed. In each dataset, diabetes was defined by a self-report of a previous doctor diagnosis. A detailed description on study methodology can be found elsewhere[18, 20]. Using data from these national surveys, multivariate Poisson regression models were undertaken to impute annual gender and age-specific (18–39 years, 40–69 years, ≥70 years) rates of diagnosed diabetes and to assess trends over time. The dependent variable was the number of cases of diagnosed diabetes and the exposure variables were year of data collection and age group. An interaction term between calendar year and age group was considered to explore whether the rates of change over time differed across age groups; a non-significant interaction indicated a common linear trend in prevalence. The predict Fig. 1 PRISMA flow chart depicting the selection process of articles included in the systematic review Table 1 Characteristics of studies reporting the prevalence of diabetes or related complications among adults in the Republic of Ireland, 1998–2011 Author

Year of data Study design National or Setting showed lower heterogeneity collection regional

Diabetes prevalence


Sampling frame

Sampling method

Sheily and Kelleher [22]


Creagh et al. [23]


Census Statistic Office (CSO) [27]


Sheily and Kelleher [22]


Balanda et al. [11]


Gallagher et al. [24]


Cross-sectional National


Patients covered by HSE-PCRS pharmacy Total sample GMS, LTI, DPS schemes claims data base 2009 2010

Leahy et al. [25]


Cross-sectional National analysis of longitudinal study

Household & designated health centre

General population

OConnor et al. [26]


Cross-sectional Regional

Primary care centre Patients

March 2017 • HPN

Sample size Males Age

Study quality

3493974 3490877

CI: 5.1 %–5.3 in combined prevalence rates 2.7 %) in 1998 to 5.2 % (95 % (%) (out of%) 9) in 2015 (years) for undiagnosed and diagnosed diabetes among adults (ptrend = <0.001); representing an absolute mean increase of 0.17 % persample year. In1632 2015, the aged over National 45 yearsHousehold (I2 ≥ 25 %, pGeneral = 0.36); with a pooled Cross-sectional population Electoral register Multistage 47.7incidence 55 7 of diagnosed prevalence of 9.2 % (95 % CI: 8.6–9.8) (Additional file 3). diabetes was 0.2/100 population. Cross-sectional 17 GP practices Primary Careno Patients Practice Stratified random 1018 48.2 50–69 6 Figure 3 illustrates the age-specific prevalence of selfAccording Regional to the Egger’s test, there was evidence oflist reported diagnosed diabetes from 1998 to 2015. In adults publication bias (p = 0.27). Survey National Household General population Census Total sample 3917203 18 5 aged between 18 and 39 years, the prevalence of selfreported doctor diabetes stable Trends in the prevalence of diagnosed time register Cross-sectional National Household Generaldiabetes population over Electoral Multistage sample diagnosed 1745 41.7 55 remained 7 In adults aged 18 years and over, the prevalence of diag- between 1998 and 2015 in both men and women; Cross-sectional Nationalincreased Householdfrom 2.2 General population Geodirectory 10,364 49.5 a significant 18 8 nosed diabetes % (95 % CI: 1.7 %– ptrendMultistage >0.05.probability However, there was increase in -






Multi-stage probability 5377


Practice list




50–69 8

47 Table 2 Characteristics of studies reporting the prevalence of diabetes or complications among adults in the Republic of Ireland, 1998-2011 Year of data Study design collection

National or Setting regional

Sampling frame

Sampling method

Sample Males Age size (%) (years)

Study quality (out of 9)

Kelliher et al. [28]




National Council All person registered for Blind Ireland blind (NCBI)

NCBI database

Total sample



Buckley et al. [29]





People with diabetes

Hospital In-Patient Total sample Enquiry (HIPE) dataset

Marsden et al. [34]




20 general practices

Patients with T1 & T2 DM Practice patient list registered with diabetes structure care programme

Every second person from list

Hurley et al. [30]


Cross-sectional analysis of longitudinal study


General practices with diabetes nurse

Patients with T1 & T2 DM

Practice diabetes register

Farrell & Moran [31]




30 general practices


Tracey et al. [32]


Cross-sectional analysis of longitudinal study



McHugh et al. [33]




30 general practices



Complication prevalence -


723551 51.9

63 (sd 13)


Researchers selected 563 eligible participants


64 (sd 13.4)


Diabetes imitative database

Stratified sampling





General population


Multi-stage probability



Patients with T1 & T2 DM

Practice patient list

All persons with T1&T2DM invited



command was used post analysis Characteristics of selected to calculate the expected rates studies of diagnosed diabetes for each Characteristics of studies that calendar year of the study. The reported the prevalence of gender and age-specific predicted diabetes or diabetes complications rates were applied to 2004–2015 al. BMC Public (2016) 16:132 are Health presented in Tables 1 and 2. In population dataTracey so the et absolute all included studies, data collection number of diabetes cases could were carried out between 1998 be obtained. Annual population and 2011. Studies varied in estimates were obtained from the terms of the study design, setting Central Statistics Office (CSO), (national vs. regional), sampling Ireland[21]. A census took place in Ireland in 2002, 2006 and 2011; data for other study years were CSO inter-censal estimates[21]. Prevalence was calculated by dividing the number of expected cases of doctor diagnosis of diabetes by the total study population and was expressed as a percentage with 95 % CI. Prevalence estimates were presented graphically in Excel.

approach and study quality. Of the 8 studies reporting on diabetes prevalence (Table 1), five articles had been published in peerreviewed journals[11, 23–26], while three estimates were reported in two national reports[22, 27]. Of the 7 studies reporting diabetes complications (Table 2), six had been published in peer reviewed journals[28–33], while one audit[34]


20 years 9



65 (sd 13)


provided data on the prevalence of diabetes related complications. Five studies utilised an objective data source to ascertain the prevalence of complications[28–30,33, 34]. The diagnostic criteria for complications was unclear in three studies[31,31,34] whereas the remaining four used validated diagnostic criteria to identify cases[28–30, 33], however

RESULTS Study selection Results of the literature search and the selection process are summarised in Fig. 1 (page 46). One report[22] provided two estimates for diabetes prevalence from two separate studies[16, 17]. In total, 15 studies were eligible for inclusion; eight reporting estimates on diabetes prevalence and seven reporting estimates on complication prevalence. Of the included studies, the methodological quality was considered moderate in nine studies and high in the remaining studies (Additional file 2).

Figure 2: Forest plot of individual and summary diabetes prevalence estimates of included studies

Fig. 2 Forest plot of individual and summary diabetes prevalence estimates of included studies HPN • March 2017

prevalence among men aged 40 to 69 years between 1998 (3.5 % [95 % CI: 3.4–3.6 %]) and 2015 (6.6 % [95 % CI: 6.5–6.7 %]; ptrend <0.001). The prevalence of diabetes also increased among women in the same age group over the same time period (1998–2.5 % [95 % CI: 2.4–

48 Feature

2.5 %] to 2015- 4.2 % [95 % CI: 4.1–4.3 <0.001). In those aged 70 years and over, a trend in prevalence among both men (19 [95 % CI: 8.0–8.3 %] to 2015- 15.1 % [95 % 15.2 %]) and women (1998- 4.7 % [95 % CI: 4

Figure 3: Prevalence of self-reported doctor diagnosed diabetes among adults in RoI, 1998–2015

Fig. 3 Prevalence of self-reported doctor diagnosed diabetes among adults in RoI, 1998–2015

these criteria differed between studies reporting on the same complication. Prevalence of diabetes in included studies Individual and summary estimates, based on a random-effects metaanalysis are illustrated in Fig. 2 (page 47). There was significant heterogeneity in all groups. Sensitivity analysis only showed lower heterogeneity in combined prevalence rates for undiagnosed and diagnosed diabetes among adults aged over 45 years (I2 ≥ 25%, p = 0.36); with a pooled prevalence of 9.2 % (95% CI: 8.6–9.8) (Additional file 3). According to the Egger’s test, there was no evidence of publication bias (p = 0.27). Trends in the prevalence of diagnosed diabetes over time In adults aged 18 years and over, the prevalence of diagnosed diabetes increased from 2.2% (95% CI: 1.7%– 2.7%) in 1998 to 5.2% (95% CI: 5.1%–5.3%) in 2015 (ptrend = <0.001); representing an absolute mean increase of 0.17% per year. In 2015, the incidence of diagnosed diabetes was 0.2/100 population. Fig. 3 (above) illustrates the agespecific prevalence of self reported diagnosed diabetes from 1998 to 2015. In adults aged between 18 and 39 years, the prevalence of

March 2017 • HPN

self reported doctor diagnosed diabetes remained stable between 1998 and 2015 in both men and women; ptrend >0.05. However, there was a significant increase in prevalence among men aged 40 to 69 years between 1998 (3.5% [95% CI: 3.4–3.6%]) and 2015 (6.6% [95% CI: 6.5–6.7%]; ptrend <0.001). The prevalence of diabetes also increased among women in the same age group over the same time period (1998–2.5% [95% CI: 2.4– 2.5%] to 2015- 4.2% [95% CI: 4.1–4.3%]; ptrend <0.001). In those aged 70 years and over, an upward trend in prevalence among both men (1998–8.2% [95% CI: 8.0–8.3%] to 2015- 15.1 % [95 % CI: 14.8– 15.2%]) and women (1998- 4.7% [95% CI: 4.5–4.8%]to 2015- 10.7% [95% CI: 10.5–10.8%]) was also observed; ptrend <0.001. Prevalence of microvascular and macrovascular complications Five out of seven studies reported the prevalence of retinopathy[27, 29–31, 33]. Among people with type 2 diabetes, a population based study reported the prevalence of diabetic retinopathy to be 8.5% in 2009–2011[30]; a regional study, carried out among primary care patients, found a higher prevalence of 24.8%[31]; however this estimate included patients with type 1 and 2 diabetes and was based on objective data. A similar estimate (25.6%) was reported in a

comparable cohort of primary care patients in a different region[33]. In terms of diabetes-related neuropathy, a divergence in the reported prevalence between studies was also observed. Data from 12 primary care centres in the West of Ireland indicated a prevalence of past documented neuropathy to be 3%[30]. On the other hand, a populationbased study reported a prevalence of 14.6%[32]. These patients had similar average duration since diagnosis (7.8 years[30] vs. 5.0 years[32]); however, the latter estimate was based on self-reported data. Prevalence rates for leg amputations were 1.7% among primary care patients with diabetes[30]. In contrast, the prevalence of nontraumatic lower leg amputation was lower (0.2%) in a population-based study which utilised national hospital discharge data[29]. With reference to nephropathy, prevalence among those with type 2 diabetes was similar in two studies[31, 32]. In the three studies presenting data on macrovascular complications, a marked difference in prevalence was observed. A primary care audit reported a prevalence of 3.5% in patients with type 1 and 2 diabetes[34]. In contrast, among those with type 2 diabetes, a population based study reported a higher prevalence of 15.1%[32].

Conclusion This review provides the first comprehensive overview of the burden of diabetes in Ireland. In the absence of a national diabetes register, the findings in this review provide a robust estimate of the trends in prevalence of doctor diagnosed diabetes among the adult population in Ireland. Findings from this review are in accordance with the Euro Diabetes Index (2014)[12]; there is a lack of information relating to the prevalence of undiagnosed diabetes, macrovascular and microvascular complications. Interpretation of available data was limited due to inconsistencies in reporting, limited availability of objective data and standardisation in diagnostic criteria. We suggest that the true burden of diabetes in Ireland is underestimated[58]. In 2010, the National Clinical Programme in Diabetes was established to improve and standardise patient care in Ireland[59]. Reliable baseline data are needed to monitor improvements in care over time at a national level. Therefore, we suggest that a comprehensive national diabetes register is urgently needed in Ireland. REFERENCES AVAILABLE ON REQUEST


34.7 median OS1



of patients treated with ZYTIGA® plus low-dose prednisolone did not experience grade 3 or 4 corticosteroidassociated adverse event2

reduction in the risk of

48% radiographic progression3 WITH

of median follow up


ZYTIGA maintains a favourable safety profile and is generally well-tolerated1


ZYTIGA® 500 mg Tablets PRESCRIBING INFORMATION. ACTIVE INGREDIENT(S): Abiraterone acetate. Please refer to Summary of Product Characteristics (SmPC) before prescribing. INDICATION(S): Taken with prednisone or prednisolone for the treatment of metastatic castration resistant prostate cancer in adult men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated. The treatment of metastatic castration resistant prostate cancer in adult men whose disease has progressed on or after a docetaxel-based chemotherapy regimen. DOSAGE & ADMINISTRATION: Adults: 1000 mg (2 tablets) single daily dose. Not with food as this increases the systemic exposure (take dose at least two hours after eating; no food for at least one hour post-dose). Swallow whole with water. Take with recommended dose of prednisone or prednisolone of 10 mg daily. Medical castration with LHRH analogue should be continued during treatment in patients not surgically castrated. Children: No relevant use. Hypokalaemia: In patients with pre-existing, or who develop hypokalaemia during treatment with Zytiga, consider maintaining potassium level at ≥4.0 mM. Patients who develop Grade ≥ 3 toxicities (hypertension, hypokalaemia, oedema and other non-mineralocorticoid toxicities) stop treatment and start appropriate medical management. Do not restart Zytiga until symptoms of the toxicity have resolved to Grade 1 or baseline. Renal impairment: No dose adjustment, however no experience in patients with prostate cancer and severe renal impairment; caution advised. Hepatotoxicity: If hepatotoxicity develops (ALT or AST >5x upper limit of normal - ULN), stop treatment immediately until liver function returns to baseline; restart Zytiga at 500 mg (1 tablet) once daily and monitor serum transaminases at least every 2 weeks for 3 months and monthly thereafter (see Special warnings & precautions). If hepatotoxicity recurs on reduced dose, stop treatment. If severe hepatotoxicity develops (ALT or AST 20xULN), discontinue Zytiga and do not restart. Hepatic impairment: Mild (Child-Pugh class A) - no dose adjustment required. Moderate (Child-Pugh class B) - approximately 4x increased systemic exposure after single oral doses of 1,000 mg. Moderate/Severe (Child-Pugh class B or C) – no clinical data for multiple doses. Use with caution in moderate impairment, benefit should clearly outweigh risk. CONTRAINDICATIONS: Pregnancy or potential to be pregnant. Hypersensitivity to active substance or any excipients. Severe hepatic impairment (Child-Pugh Class C). SPECIAL WARNINGS & PRECAUTIONS: Zytiga may cause hypertension, hypokalaemia and fluid retention due to increased mineralocorticoid levels. Cardiovascular: Caution in patients with history of cardiovascular disease. In patients with a significant risk for congestive heart failure (history of cardiac failure, uncontrolled hypertension, ischaemic heart disease) consider an assessment of cardiac function before treating (echocardiogram). Safety not established in patients with left ventricular ejection fraction < 50% or NYHA Class II to IV (pre-chemotherapy) and III or IV (post-chemotherapy) heart failure. Before treatment cardiac failure should be treated and cardiac function optimised. Correct and control hypertension, hypokalaemia and fluid retention pre-treatment. Caution in patients whose medical conditions might be compromised by hypertension, hypokalaemia or fluid retention e.g. heart failure, severe or unstable angina pectoris, recent myocardial infarction or ventricular arrhythmia, severe renal impairment. Monitor blood pressure, serum potassium and fluid retention and other signs and symptoms of congestive heart failure before treatment, then every two weeks for 3 months, and monthly thereafter. QT prolongation observed in patients experiencing hypokalaemia with Zytiga treatment. Consider discontinuation if there is a clinically significant decrease in cardiac function. Hepatotoxicity & hepatic impairment: Measure serum transaminases pre-treatment and every two weeks for first three months, then monthly. If symptoms/signs suggest hepatotoxicity, immediately measure serum transaminases. If ALT or AST > 5x ULN, stop treatment and monitor liver function. Restart treatment after liver function returns to baseline; use reduced dose (see dosage and administration). No clinical data in patients with active or symptomatic viral hepatitis. Rare reports of acute liver failure and hepatitis fulminant, some fatal. Corticosteroid withdrawal: Monitor for adrenocortical insufficiency if prednisone or prednisolone is withdrawn. Monitor for mineralocorticoid excess if Zytiga continued after corticosteroids withdrawn. Bone density: Decreased bone density may be accentuated by Zytiga plus glucocorticoid. Prior use of ketoconazole: Lower response rates may occur in patients previously treated with ketoconazole for prostate cancer. Hyperglycaemia: Use of glucocorticoids could increase hyperglycaemia, measure blood sugar frequently in patients with diabetes. Use with chemotherapy: Safety and efficacy of concomitant use of Zytiga with cytotoxic chemotherapy not established. Intolerance to excipients: Not to be taken by patients with galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption. Take sodium content into account for those on controlled sodium diet. Potential risks: Anaemia and sexual dysfunction may occur in men with metastatic castration resistant prostate cancer including those

taking Zytiga. Skeletal muscle effects: Cases of myopathy reported. Some patients had rhabdomyolysis with renal failure. Caution is recommended in patients concomitantly treated with drugs known to be associated with myopathy/ rhabdomyolysis. SIDE EFFECTS: Very common: urinary tract infection, hypokalaemia, hypertension, diarrhoea, peripheral oedema. Common: sepsis, hypertriglyceridaemia, cardiac failure (including congestive heart failure, left ventricular dysfunction and decreased ejection fraction), angina pectoris, arrhythmia, atrial fibrillation, tachycardia, dyspepsia, increased alanine aminotransferase, increased aspartate aminotransferase, rash, haematuria, fractures (includes all fractures with the exception of pathological fracture). Other side effects: adrenal insufficiency, myocardial infarction, QT prolongation, hepatitis fulminant, acute hepatic failure, myopathy, rhabdomyolysis. Refer to SmPC for other side effects. FERTILITY/PREGNANCY/LACTATION: Not for use in women. Not known whether abiraterone or its metabolites are present in semen. A condom is required if the patient is engaged in sexual activity with a pregnant woman. If the patient is engaged in sexual activity with a woman of childbearing potential, a condom is required along with another effective contraceptive method. Studies have shown that abiraterone affected fertility in male and female rats, but these effects were fully reversible. INTERACTIONS: Caution with drugs activated by or metabolised by CYP2D6 particularly when there is a narrow therapeutic index e.g. metoprolol, propranolol, desipramine, venlafaxine, haloperidol, risperidone, propafenone, flecainide, codeine, oxycodone and tramadol, dose reduction should be considered. Avoid strong inducers of CYP3A4 (e.g. phenytoin, carbamazepine, rifampicin, rifabutin, rifapentine, phenobarbital, St John’s wort). Zytiga is a CYP2C8 inhibitor. Monitor for signs of toxicity if combined with drugs with a narrow therapeutic index eliminated predominately by CYP2C8. May increase concentrations of drugs eliminated by OATP1B1. Food (see Dosage & Administration). Caution with medicines known to prolong QT interval or induce torsade de pointes e.g. quinidine, disopyramide, amiodarone, sotalol, dofetilide, ibutilide, antiarrhythmic medicinal products, methadone, moxifloxacin and antipsychotics. Use of Zytiga with spironolactone is not recommended. Refer to SmPC for full details of interactions. LEGAL CATEGORY: POM. PRESENTATIONS, PACK SIZES & MARKETING AUTHORISATION NUMBERS: Blister Pack, 56 tablets, EU/1/11/714/002. MARKETING AUTHORISATION HOLDER: JANSSEN-CILAG INTERNATIONAL NV, Turnhoutseweg 30, B-2340 Beerse, Belgium. FURTHER INFORMATION IS AVAILABLE FROM: Janssen-Cilag Ltd, 50-100 Holmers Farm Way, High Wycombe, Buckinghamshire, HP12 4EG, UK. © Janssen-Cilag Ltd 2014. Prescribing information last revised: November 2016 Adverse events should be reported. Healthcare professionals are asked to report any suspected adverse events via: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517, Website:, E-mail: Adverse events should also be reported to Janssen-Cilag Limited on +44 1494 567447 or at © Janssen-Cilag Limited 2016 References: 1. Ryan CJ, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapynaive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo controlled phase 3 study. Lancet Oncol 2015; 16: 152–60. 2. Fizazi, K., et al (2015). ASCO GU 2015 (abstract 169). 3. Rathkopf, DE et al. Updated Interim Efficacy Analysis and Long-term Safety of Abiraterone Acetate in Metastatic Castration-resistant Prostate Cancer Patients Without Prior Chemotherapy (COUAA-302). Eur Urol (2014), eururo.2014.02.056. Date of Preparation: February 2017 | PHIR/ZYT/1014/0004(5)

50 Feature

Glycolysis inhibition as a cancer treatment and its role in an anti-tumour immune response Kheshwant S. Gilla,b, Philana Fernandesa, Tracey R. O'Donovana, Sharon L.McKennaa, Kishore K. Doddakulab, Derek G. Powera,c, Declan M. Sodena, Patrick F. Fordea a Cork Cancer Research Centre, Western Gateway Building, University College Cork, Cork, Ireland b Cardiothoracic Surgery Department, Cork University Hospital, Cork, Ireland c Department of Medical Oncology, Mercy University Hospital, Grenville Place, Cork, Ireland

Introduction Intracellular chemical transformations sustain life and this is referred to as metabolism. Organisms grow and reproduce, respond to their environment, and maintain their structure as a result of enzymecatalyzed metabolism. Biochemical reactions in cells ensure daily operations of a cell are accomplished. These reactions are either up- or downregulated depending on the cell's needs and functions. Monitoring of the numerous cellular anabolic (breaking down of organic matter) and catabolic (metabolic component construction) pathways is crucial to ensure they are balanced in a co-ordinated fashion at any given time. Cells organise these reactions into different enzyme-catalyzed pathways to achieve this goal. Metabolic pathways are organised chemical reactions of metabolism where a chemical compound is converted into another one by a series of enzymatic activity. Enzymes are vital to metabolism. This is because they allow the organism to drive energyconsuming reactions that will not occur independently. This is achieved by coupling reactions with spontaneous reactions which release energy. Enzymes speed up reaction rates as they act as catalysts besides allowing the metabolic pathway regulation secondary to changes in the cell's environment or to other cellular signaling. Basic metabolic pathways and their components are similar across vast different species[1]. This is exemplified by a set of carboxylic acid (citric acid intermediates) which is present in all known organisms. The early appearance in evolutionary history and efficiency in retention have likely led to the similarities in metabolism[2,3]. The process of catabolism harvests energy by means of cellular respiration, and in anabolism, cellular components are constructed using energy e.g. nucleic acids and proteins. An example of a metabolic pathway which is common in virtually all cells, both prokaryotic and eukaryotic, is glycolysis.

March 2017 • HPN

Glycolysis Glycolysis pathway of cellular respiration is a series of reactions that constitute the first phase of most carbohydrate catabolism. The word glycolysis is derived from two Greek words and means the breakdown of something sweet. Glycolysis is an oxygen independent metabolic pathway, meaning it does not use molecular oxygen for any of its reactions. It occurs in the cellular cytosol of most organisms. Embden– Meyerhof–Parnas (EMP pathway[4] is the most common type of glycolysis. Other types include the Entner-Doudoroff pathway and various hetero- and homofermentative pathways. The glycolytic pathway can be divided into two phases. Firstly, the preparatory phase (or investment phase) is where ATP is utilised and followed by production of ATP in the second Pay Off phase. In the cell, glucose catabolism occurs via two main pathways, (1) one which involves mitochondrial respiration (longer but energy-efficient pathway) and (2) pathway that does not involve the mitochondria (glycolysis; less energy-efficient and a shorter pathway). Oxidative phosphorylation is a pathway involving mitochondrial respiration. Depending on intracellular requirements and available resources, cells undergo either glycolysis or oxidative phosphorylation to metabolise glucose. Glycolysis is inhibited (‘Pasteur effect’) by the presence of oxygen in most mammalian cells. Oxygen allows the mitochondria to oxidise pyruvate to carbon dioxide and water. The maintenance of energy production in various conditions of oxygen concentrations is met by the mammalian cells' metabolic adaptability. ‘Anaerobic glycolysis’ is whereby glucose ismetabolised via glycolysis instead of mitochondrial oxidation in low levels of oxygen. This results in the conversion of pyruvate into lactate, which is then exported. Interestingly, ‘aerobic glycolysis’ (glycolysis in the presence of oxygen) is also seen in cancer cells. This almost a century-old phenomenon in cancer cells is known as the ‘Warburg effect’, and was hypothesised in 1924 by the German scientist Otto Heinrich Warburg.

Warburg hypothesis/effect Cancer cells mainly produce energy by an increased rate of glycolysis (200 times more as compared to normal tissues of origin) followed by fermentation of lactate in the cytosol of the cell, even if oxygen is plentiful[5]. This is to fulfill their bioenergetic and biosynthetic demands tosupport rapid proliferation. This observation in oncology is called the ‘Warburg effect’. In normal cells however the rate of aerobic glycolysis is lower, and is followed by oxidative phosphorylation in the mitochondria, where pyruvate is oxidated[6–8]. It was postulated by OttoWarburg that this metabolic change is the fundamental cause of cancer[9], a claim now known as the Warburg hypothesis. However, it was then discovered that mutations in oncogenes and tumour suppressor genes are responsible for malignant transformation. Instead of a cause, the Warburg effect is considered to be more of a result of these genetic mutations[10,11]. Cellular metabolism Normal cell metabolism derives about 70% of its energy from the Krebs cycle and only 20% from glycolysis. Most of its energy production is via oxidative phosphorylation. In contrast, cancer cells exhibit a defective tricarboxylic acid (TCA) cycle and derive little or no energy from it. Instead, they derive almost all their energy from glycolysis (fermentation phosphorylation) and in the absence of oxygen. Normal cells operate at normal metabolic levels and reproduce themselves at a regulated phase by possessing hormones and enzymes behaving in balanced manner. Normal functioning cells orderly-divide to proliferate only when in demand. Cancer cells on the other hand are overactive and reproduce themselves in requiring more nutrients. These cells have overactive or underactive enzymes and hormones, and develop an aberrant DNA or gene structure or acquire abnormal number of chromosomes. This continues to be created uncontrollably and ultimately these surpluses of cells form a mass. Tumour cells possess a high rate of glucose uptake and glycolytic metabolism. The majority of their

energy is supplied by glycolysis, whilst maintaining increased rates of lactic acid production. This is important for cancer cell survival in hypoxic environments. Glycolysis in cancer cells Only about 10% of normal cells energy is produced by glycolysis. Mitochondrial respiration contributes to the remaining 90%. A glucose molecule is metabolised into two molecules of pyruvate and NADH+ each, and gains 2 molecules of ATP. This is a markedly smaller amount of energy produced as compared to 38 molecules of ATP produced viamitochondrial respiration. Therefore, to obtain sufficient energy to grow and proliferate, cancer cells require an increased glucose uptake. In hypoxic conditions, glucose via glycolysis is catabolised to lactate to produce ATP. Themitochondriae are unable to produce ATP in oxidative phosphorylation during hypoxia because oxygen is crucial for electron transport. Also, in hypoxic conditions, the monocarboxylate transporters MCT4 (plasma membrane lactate transporter) are up regulated via a HIF-1α mediated mechanism. This enables cells to dispose the accumulation of lactic acid rapidly[12]. Given the small yield of energy via glycolysis, it is understood that not only the metabolic switch to glycolysis from oxidative phosphorylation, but also mitochondrial dysfunction[13,14] is important for cancer cell growth. Cancer cells develop a high glucose uptake rate and glycolysis to produce energy. This increased rate of glycolysis in hypoxia leads to higher levels of lactate, which is sufficient for cancer cell survival. Mitochondrial defects are commonly seen in cancer. The enzymes succinate dehydrogenase (SDH), isocitrate dehydrogenase (IDH) and fumarate dehydrogenase (FDH) in the TCA cycle are affected by mitochondrial DNA (mtDNA) mutations[15]. Besides that, the bioenergetics of cancer cells are affected by genemutations in nuclear DNA (nDNA) of the mitochondria[15]. Thus it is evident that a shift in cancer cell metabolism can be caused by mitochondrial dysfunction. Having said that, there are several

51 90

benefits of aerobic glycolysis that drive cancer cells to favour it over mitochondrial oxidation [16]. The glycolytic rate in cancer cells are accelerated to about 100 fold thereby resulting in higher ATP production[17,18], required for cellular maintenance and sufficient for cancer growth. Besides ATP production, the biosynthesis of macromolecules is essential for tumour cell proliferation[19]. Ribose-5- phosphate and NADPH (essential for nucleic acid and lipid synthesis) are produced via the Pentose Phosphate Pathway (PPP) promoted by the accumulation of these glycolytic intermediates. The antioxidant glutathione (GSH; produced in presence of NADPH) maintains the redox levels and counteracts chemotherapeutic agents thus protecting cancer cells[20,21]. The transketolase (TKTL1) enzyme involved in the PPP has been shown to improve cell survival in stressful times by affecting chemosensitivity of cancer cells to chemotherapeutic drugs e.g. imatinib[22] and cetuximab[23]. In summary, aerobic glycolysis and the PPP provide multiple advantages to cancer cells and help tumour to progress besides resisting them from therapy. And this key signature of cancer metabolism (glycolysis) caters therapeutic intervention targets. Rationale behind targeting glycolysis Targeting the glycolytic pathway has the potential to be utilised as a cancer treatment strategy. Tumour cells have a higher uptake of glucose not only to meet the manifold requirements but also the high-energy demand. Apart from providing energy, intermediates of the glycolytic pathway are also used for anabolic reactions such as glucose-6-phosphate used to synthesise ribose-5phosphate. This is then further used in the synthesis of nucleic acids. Dihydroxyacetone is utilised in lipid synthesis. Tumour cells proliferate rapidly and in an uncontrollable fashion, therefore the increased glucose uptake is not merely a biochemical switch but also ametabolic transformation that is indispensible. Oncogenic activation (e.g. c-myc, Akt) up-regulates glycolytic activity in cancer cells[24] via HIF-1α activation. Akt activates aerobic glycolysis and more this makes cancer cells dependent on glycolysis to survive[25]. The anabolic and catabolic processes in cancer cells are co-ordinated and regulated by networks of signalling pathways such as the mammalian Target of Rapamycin (mTOR). AMPK (energy sensing molecule) is able to influence the

K.S. Gill et al. / Biochimica et Biophysica Acta 1866 (2016) 87–105

Figure 1

activation mechanism of mTOR complex 1 (mTORC1). This in turn either delays or stops the energy consuming synthetic processes [26]. Activation of c-myc and HIF-1α genes regulates the expression of glycolytic enzymes, which in turn are regulated by mTORC1[26–28]. It is evident that cancer cells benefit from aerobic glycolysis with the PPP not only to promote tumour growth but also offering its

therapy resistance. Hence, tumour glycolysis provides the best possible targets for therapeutic interventions. Fig. 1 is a pictorial representation of glycolytic pathway targets. Glycolytic targets In addition to providing sufficient energy, the environment of cancer cell glycolysis also promotes proliferation by providing its building blocks, whilst supressing apoptosis at the same time. Cell

death (ATP-independent) will occur from rapid depletion of ATP as a result of direct glycolytic inhibition. This strategy will also likely damage normal healthy tissues. Non-malignant tissues e.g. smooth and skeletal muscle and normal viscera will be affected as glycolytic inhibition is nonselective. Translational potential of glycolytic inhibitors such as Hexokinase inhibitors and 3-Bromopyruvate are limited because of this reason.

HPN • March 2017

52 Feature Their clinical trials have not been successfully completed. Pre-clinical data suggests the induction of necrosis in cancer and has also shown significant toxicities in animal models at even slightly-above therapeutic doses. Hexokinase Hexokinase (HK) is a tissuespecific isoenzyme which catalyzes the phosphorylation of glucose to glucose-6-phosphate (G6P), after glucose enters the cell via glucose transporters (GLUT). This ATP-dependent reaction is the first step in glycolysis, and is also rate limiting. G6P serves as the starting point for the sugar to enter the glycolic pathway or the PPP, or for glycogen synthesis. HK has four isoforms, and they are designated HK I, II, III, and IV (glucokinase found in hepatocytes) or A, B, C, and D. Among these isoforms, HK-II plays a key role in the development of the Warburg phenotype exhibited by most types of cancer. HK-II isoform is found mainly in skeletal muscle and adipose tissues. Overexpression of HK-II is also seen in some tumour tissues and associated with poor prognosis[29,30]. Phosphorylated HK-IIs are able to bind to the voltage-dependent anion channels (VDACs) found on the outer mitochondrial membrane, besides its glucose phosphorylation activity. Negative feedback inhibition of G6P is prevented by this VDAC-HK interaction to ensure tumour cells entrap enough glucose. VDACHKinteraction also confers HK direct access to ATP generated by mitochondriae. Binding of BAX (protein apoptotic regulator which binds to VDAC in normal cells) is interfered by VDAC-HKII interaction[31]. This VDACHKII association also affects the pro-apoptotic functions of BAX in normal cells, where cytochrome C (located in the inter-membrane mitochondria space) escapes from the mitochondria thus triggering apoptosis. This ultimately leads to tumour cellular apoptosis being prevented. HKs maintain the downhill concentration gradient that favours the facilitated transport of glucose into cells by catalyzing the first step in glycolysis. ‘Trapping’ of glucose and 2-deoxyhexoe glucose analogs (e.g. 2-deoxyglucose, and 2-fluoro2-deoxyglucose) within cells is due to the addition of a charged phosphate group at the 6-position of hexose. This is because charged hexose phosphates cannot easily cross the cell membrane. HKs, besidesGLUT1, exert the main control (71%) of glycolytic flux in hepatocellular and cervical carcinoma cell lines[32]. March 2017 • HPN

Many anti-cancer strategies implicating HK-II as a target have been of big interest recently. Publication of work on identifying HK-I–HK-IV inhibitors goes back to the mid-20th century e.g. dehydroascorbic acid, alloxan and other compounds were found to inhibit liver HK[33]. After phosphorylation byHK, 2-deoxyglucose (2DG), a structural analog of glucose, enters cells through GLUTs and selectively accumulates in cancer cells. This is because they are not able to progress through the glycolytic pathway. Cellular energy metabolism and its survival are likely to be profoundly affected by inhibition of HK. Thus, HK is an attractive target for anticancer agents. Lonidamide is an inhibitor of HK-II and has been shown to induce apoptosis and treat multidrug resistance in multiple cell lines[34–36]. Phase II clinical trials of Lonidamide for benign prostatic hyperplasia treatment have been suspended due to its toxicity on the liver[36,37]. Combination of Lonidamide with Paclitaxel (chemotherapeutic agent) is undergoing clinical trials for cancer treatment[7,38]. 2-DG and 3-bromopyruvate (3-BrPA) are also well known HKII inhibitors [39,40], which have shown to interrupt binding of HKII to the mitochondrion besides inducing cell death by depleting ATP and inhibiting the cell cycle progression. 3-BrPA inhibition of glycolysis causes ATP depletion and this suppresses ATP-binding cassette (ABC) transporter activity and drug efflux leading to more drug retention. This results in the ability of 3-BrPA in overcoming chemoresistance and improving cancer therapeutics. 2-DG induces cancer cell death by depriving intracellular glucose levels. This results in induction of stressrelated proteins[41,42], the generation of free radicals [43], and inhibition of energy metabolism[42–44]. Combination of 2-DG with ionizing radiation (IR) to treat malignant gliomas in recent clinical trials showed it to be well tolerated with low toxicity levels and surrounding normal tissues being unharmed[45–47]. 2-DG was shown to activate pro-survival pathways in cancer cells contrary to the wide believe as an anticancer agent[48]. Hypoxic cells have also demonstrated chemoresistance against 2-DG[49]. This challenges the success of 2-DG as a single agent for antiglycolytic therapy. However, 2-DG showed good outcomes when combined with other treatments[50,51]. Clinical trials for 2DG as a glycolytic inhibitor for prostate cancer (NCT00633087) and intracranial neoplasms

(NCT00247403) have been suspended, mainly due to non-selectivity of the drug thus causing damage to non-cancerous cells too. Phosphofructokinase Phosphofructokinase (PFK) is a glycolytic enzyme that catalyzes the irreversible transfer of a phosphate from ATP to fructose6-phosphate. PFK is considered to be a key regulatory enzyme for glycolysis because of the irreversible nature of this step in glycolysis, and its activity is extremely sensitive to small changes in pH, with its activity dropping as pH decreases[52,53]. PFKs activity is inhibited by allosteric regulation by ATP itself when ATP levels are high in the cell. High intracellular levels of citrate also inhibit PFK activity. The enzyme ATP citrate lyase converts citrate into acetyl-CoA in the cytosol. PFK activity is inhibited because the cell can get enough energy from the citric acid cycle and thus not depend on glycolysis to supply carbons into the citric acid cycle. The two types of PFKs are PFK-1 and PFK-2. Translation of four mRNAs produces the minimum six isoenzymes of 6-phosphofructo-2kinase/fructose-2.6-biphosphatase (PFK-2/FBPase). Concentration of F2,6BP determines PFK-1 activity and thus promoting glycolysis when levels are high. PFK-1 activity is stimulated by fructose-2,6- bisphosphate (F-2,6BP) and is often overexpressed in various primary cancers, metastases and in transformed cells[54]. PFK-2/FBPase expression pattern is often elevated in colon, breast, ovarian and thyroid cancer with a particular preference for PFK-2/FBPase[55]. The PFK inhibitor, chalcone-like 3-(3-pyridinyl)-1-(4-pyrinidyl)-2propene-1-one (3PO), is a PFKFB3-specific inhibitor. 3-PO has been found to decrease intracellular F2,6BP and glycolytic flux in transformed cells and to selectively affect rastransformed cells and decrease tumourigenic growth in several adenocarcinomas in vivo[56]. In non-small cell lung carcinoma (NSCLC), 3-PO has been used in combination with ascorbic acid and was shown to have a synergistic activity. Apoptosis was induced with this combination strategy by an ROS-dependent mechanism[57]. The effects of this compound are yet to be explored in clinical trials. Glucose transporters Glucose transporters (GLUTs) are a wide group of membrane proteins that facilitate the transport of glucose and other substrates over a plasma membrane and entering

into cells as nutrients. 12 GLUTS are encoded by human genome. A sodium-linked transporter system (SGLT) and facilitative GLUTs[58] are the two different types of membrane transporter proteins. These assist the transport of glucose and other sugars through the lipid bilayer of the cell membrane down its concentration gradient. GLUT-1 is related to chemo- or radiotherapy responses and rectal cancer stages[59]. Human cell lines of breast and lung cancer (NSCLC) were shown to reduce in cellular proliferation by 50% and 75% respectively by inhibiting GLUT-1, and also mediated apoptosis[60]. Overexpression of GLUT-1 and/ or GLUT-3 is associated with poor prognosis of several types of human tumours[61,62]. GLUT-1 transporter is a potential target for anticancer therapy as inhibition of its expression is associated with reduction in tumour growth[63]. Phloretin, a natural type of phenol found in the leaves of apples and pears, is a competitive GLUT inhibitor. It has been shown to inhibit tumour growth and/or trigger apoptosis in leukaemia, melanoma, liver, colon, and breast cancers in vitro and in xenograft models. Another flavonoid, silybin (flavonolignan) was tested in men with prostate cancer[64] and liver cancer (trials NCT00487721 and NCT01129570). It showed this drug to have low tissue penetration and therefore needed high doses for effectiveness[64]. In contrast to flavonoids, fasentin, WZB117 and STF-31 are prominent inhibitors of GLUT-1 that induce glucose deprivation, starvation and subsequent death in renal cell carcinoma cell lines and animal models[65]. Overexpressed GLUTs have been explored as receptors to carry nanoparticles loaded with drugs across the blood-brain barrier (BBB). Jiang et al. demonstrated that 2-DGmodified polymer nanoparticles showed efficient GLUT-mediated transcytosis across BBB as well as endocytosis into glioma cells enabling targeted delivery of paclitaxel for brain glioma therapy[66]. These results show that the Warburg effect confers distinct characteristics to tumour cells that can be selectively targeted for anti-cancer therapy[65]. Pyruvate dehydrogenase kinase Mitochondrial activators increase mitochondrial influx and subsequently increasing mitochondrial function. They have proven to be a strategy towards inhibiting cancer growth. For example, dichloroacetate (DCA)–pyruvate dehydrogenase kinase (PDK) inhibitor acutely increases glucose oxidation (GO). Dromparis P et al. showed

53 that the mitochondriae of cancer cells are not permanently damaged but rather suppressed, because GO occurs exclusively in the mitochondria. There is a solid reason for developing similar inhibiting-molecules as anticancer therapies. A study showed that DCA depolarised the hyperpolarised membrane potential of non-small cell, Glioblastoma multiforme (GBM) and breast cancer cell mitochondriae. This suggests the restoration of mitochondrial function[67]. By enhancing GO and lowering the production of lactate, DCA decreases the glycolysis to GO ratio. Xenotransplant tumour size was shown to reduce in size when treated with DCA and it also lessened the aggressiveness of breast cancer[68]. Non-cancerous cell mitochondriae were not affected with DCA treatment but cancer cells treated with DCA showed to have activated Kv-channels, increased mROS and inhibited NFAT. Many other studies in colon[69], prostate[70], and endometrial[71] also showed regression in tumour size when treated with DCA. Mitaplatin (cisplatin + DCA) is a cancer selective drug and treatment which induces mitochondrialdependent apoptosis. Furthermore, it also overcame the resistance towards cisplatin initially thus reducing proliferation of tumour. Metabolic modulators and immune-glycolytic therapeutic implications The immunology of tumourmicro environment is very complex and makes the development of modulators of metabolism challenging. The main reasons of limited success of cancer immunotherapy include poor infiltration of effector cells into solid tumours and poor host responses towards tumour antigens. Furthermore, the intrinsically immunosuppressive nature of the tumour microenvironment adds to this poor success rate. The effectivity of cancer immunotherapy depends on the balance of immune responses from tumour protection towards its rejection[197–199]. The microenvironment of tumours is therefore also to be considered in order to achieve better antitumour responses in future. Spontaneous regression has been witnessed in metastatic melanoma treated with adoptive cell therapy (ACT) using autologous tumour infiltrating lymphocytes (TIL) [200–202]. (Table 1.) Targeting tumour hypoxiainducible factor-1 Hypoxia inducible factors (HIF) are comprised of an oxygen

labile α subunit (HIF-α) and a β-subunit, expressed throughout various cell types irrespective of oxygen levels[203]. HIF-1α (one of three isoforms) expression in tissues is universal and was the first to be discovered[204] whereas HIF-2αs are expressed in the vasculature endothelium. Tumour microenvironment is hypoxic (≤2% oxygen) and HIF-1 modulates metabolism in these conditions. HIF-1α levels are not only regulated by oxygen levels but also by cytokines IL-1β and TNF-α[205]. Furthermore, DNA binding of HIF-1 stimulated by p44/42 MAP kinase can also increase HIF-1 levels[206]. It is an important signaling molecule for proliferation and growth of tumours. Aerobic glycolysis is promoted in increased pyruvate levels[207]. HIF-1αbinds to GLUT1 [208] and glycolytic enzymes to facilitate this metabolic switch. For example, cancer cell dependence on oxidative phosphorylation is reduced due to low levels of acetyl-CoA (converted from pyruvate) because of increased PDK activity; secondary to HIF-1α mediated hypoxia responsive ele elements[209]. This leads to lactate build-up in cells. This switch inmetabolism preserves cellular viability in hypoxic times. Increased levels of HIF-1 activation promote tumour growth, angiogenesis and metastasis by reducing cytochrome c levels causing caspase-9 and -3 inactivation that prevents cell death[210] suggesting poorer prognosis, whilst low activity levels of HIF are associated with decreased tumourmetabolism, growth and vascularity[211]. Hypoxic macrophages and DCs also switch their metabolism to glycolysis by HIF-1α and mTOR. Activated lymphocytes undergo similar metabolic changes to hypoxic cells. This questions the role of HIF-1s in tweaking T cell activation. Immune cells need to survive and function properly in hypoxic conditions too, and this highlights the importance of HIF-1 activation[107]. In activated T cells, GLUT1 expressions are increased secondary to HIF-1 induced gene expressions that improve viability and survival of immune cells during aerobic glycolysis[212,213]. Furthermore, T cell differentiation is also regulated by HIF-1. However, Tregs are powered via lipid oxidation[136]. Innate cell functions e.g. ATP generation, glycolytic enzymes and GLUT1 expressions, are modulated by HIF-1 levels, as seen in macrophages and neutrophils[214]. When HIF-1 levels are low, innate cell functions deteriorate and thus resulting in decreased abilities in T cell activation and its pathogen

killing capabilities[115,215]. This is coupled by weakened granulocyte responses and APC phagocytosis in hypoxic conditions[216,217] leading to poor host defenses. However by affecting the innate and adaptive immune cells, both HIF-1 and chronic inflammation can initiate tumour advancement and autoimmunity. Glycolysis upregulated by HIF-1α has been linked with tumour-associatedmacrophages (TAMs), which are macrophages containing perinecrotic and hypoxic tumour tissues that aid in tumour angiogenesis and growth. Both HIF-1 and HIF-2 levels are raised in malignancy e.g. in bladder, colon, ovarian, pancreatic, prostate, hepatocellular, and glial cancers. HIF-1α has been widely studied as a glycolytic target for cancer therapy, both at pre-clinical and clinical stages[218], given its extensive involvement in regulating glycolysis. Cytotoxic agents are developed with aim to block HIF-1α expression, transcription and translation and also to interrupt binding of targets. Digoxin for example inhibits HIF-1 gene expression and tumour proliferation[219], besides blocking RORγt dependent TH17 differentiation[220]. HIF-1 represses Treg differentiation and therefore inhibiting HIF may elevate suppressive T cells. This phenomenon may be advantageous in protecting against self-antigen recognition. Active CD8 T cells may still be able to kill tumours if HIF-1 is blocked. Other approaches of HIF-1 blockade include induction of HIF-1α degradation by HSP90 inhibitor and 1-β-2 methoxyestradiol, HRE-binding HIF-1 inhibition by doxorubicin and daunorubicin, and also bortezomib which inhibits HIF-1 transcription[221,222]. More recentgenetic approaches targeting HIF-1αinhibition include siRNA therapy EZN-2968, tested in hepatic metastasis. However, issue of toxicity arose in a number of patients with this approach[223]. Micro-RNA (miRNA)-mediated therapy is also being tested in glycolytic inhibition. miR100 (mTOR signaling inhibitor) has been identified in clear cell ovarian cancer[224]. Delivery of these promising HIF-1 inhibitors should be encapsulated with nanoparticles to ensure targeted delivery and avoiding nonspecific toxicity, as demonstrated by successful antitumour siRNA delivery to hypoxic tumour sites[225]. Targeting uncoupling proteins Mitochondrial ATPs are produced by coupling the electron transport chain (ETC) and ADP-ATP phosphorylation. However, this process is not efficient in

the presence of uncoupling proteins (UCP), which are anion transporters of the mitochondrial inner membrane[226]. Besides that, UCPs also reduce the production of mitochondrial-free radicals[227] for example by decreasing pyruvate entry into the TCA cycle[228,229], and are also involved in thermogenesis e.g. UCP1 involvement in thermogenesis activity of brown tissue[230]. Three main uncoupling proteins which are UCP1, UCP2 and UCP3 have different uncoupling activities[226,231] and play different roles in mitochondrial physiology[232]. UCP2 knockout results in resistance to infections[233,234] due to NF-κB activation and increased levels of reactive oxygen species (ROS) in immune cells, making UCP2 an immunometabolic target. High levels of mitochondrial UPC2 are found in activated T cells owing to its need for high proliferation via glycolysis. Low ROS levels are also necessary for expressing genes and signaling activity[235]. Uncoupling the ETC when high levels of ROS are generated resets homeostasis, particularly in the innate immune and T cell interplay. UPC2 is proglycolytic and is shown by its ability to stabilise the glyceraldehyde 3- phosphate dehydrogenase (GAPDH) in cancer cell cytoplasm[236]. UCP2 supports the glycolytic flux by its antioxidant effects of GAPDHoxidation and nuclear translocation inhibition. With this, they prevent cancer cells from stimulating cell death mechanisms. UCP2 decreases glucose-stimulated insulin release[237]. This enables them to control the autoreactive T cell responses. Increased levels of UCP2 are found in leukaemia, kidney, colorectal, lung, breast, prostate, ovarian, bladder, oesophageal and testicular cancers[238]. Uncouplers have not been utilised in the treatment of autoreactive T cells. Rottlerin (a chemicalmitochondrial uncoupler) has been shown to decrease apoptosis in autoimmune-diseased alveolar macrophages [239]. A fatty-liver (non-alcoholic) diseased model showed to have reduced insulin resistance when treated with 2,4-dinitrophenol[202]. This drug also causes adhesion build-up particularly seen in postperitoneal surgery[240]. Uncouplers are cell-specific making them a potential therapy target for immune diseases (high oxidative stress). Uncoupling inhibitors on the other hand can be used to treat standard chemotherapyresistant cancers[241]. Targeting tumour glycolysis Immune cells are highly dependent on glucose metabolism. HPN • March 2017

54 Feature


K.S. Gill et al. / Biochimica et Biophysica Acta 1866 (2016) 87–105

Table 1 Current glycolytic and immune modulator clinical trials. Modulator



Tumour type targeted


Study number

Vemurafenib plus Cobimetinib Response to neoadjuvant CT based on AT IR in localized breast cancer 2-deoxy-2-(18)fluoro-D-glucose (FDG)


BRAF/MEK inhibitor

Metastatic melanoma

Phase 2


Abraxane with or without Tigatuzumab


Gene expression profile and the proliferation/apoptotic markers Cancer testis antigen (CTA) TGGB2

EMD 273066


EMD 273066 is an experimental biological drug that may increase the immune response to certain cancers


Brachyury protein



2-Deoxy-D-glucose AP23573 Ipilimumab and Fotemustrin

Hexokinase mTORC1 Anti-CTLA-4 monoclonal antibody

Vaccine it teaches immune cell to target which protein is present in some tumour cells, and it can help tumour cells spread to other parts of the body. Anti-androgen treatment started before or after sipuleucel-T leads to superior augmentation of immune response to sipuleucel-T Inhibits the metabolism of glucose in the cells of the body Inhibits mTORC1 Ipilimumab augments the effects of chemotherapy in animal models relies on the ability of the cytotoxic agent to induce apoptosis of tumour cells

K562-GM allogene

Immunotherapy for melanoma

Determine the correlation between histopathological response Breast cancer (pCR) and induction of tumour immunity in response to neoadjuvant chemotherapy FDG PET measure the response to immune checkpoint Melanoma, renal cell blockade therapy carcinoma, non-small lung cancer Humanised monoclonal antibody combined with Abraxane to Breast cancer serve as targeting agent for triple negative breast cancer patients Patients with allogenic tumour express high levels of multiple CTA in combination with depletion with T regulatory cells Expression of TGFB2/GMCSF following transcription by electroporation and irradiation of autologous cancer tissue

switch of metabolismto oxidative Antiglycolytics limit immunity e.g. Rapamycin inhibits glucose phosphorylation from glycolysis. metabolism by blocking them Delivery methods of glycolytic Tregs are powered via lipid oxidation [136]. Innate cell functions e.g. ATP TOR downstream of PI3K-Akt and modulators generation, glycolytic enzymes and GLUT1 expressions, are modulated ultimately lowering proliferation Current treatment by HIF-1 levels, asreduced seen in macrophages and cancer neutrophils [214]. When rate of cells due to T and involves surgery,and chemotherapy, HIF-1 levels are low,also innate deteriorate thus resulting B cell activity. It can leadcell to functions radiotherapy or a combination hyperglycaemia because this in decreased abilities in Tof cell activation and its pathogen killing capabilof these. With the aid of cancer blockade. Rapamycin can affect T ities [115,215]. This is coupled by weakened granulocyte responses and imaging technologies, the removal cell memoryconditions at APCdifferentiation phagocytosisand in hypoxic [216,217] leading to poor host becomes more tumour-selective. the immune cell level. Furthermore, defenses. However by affecting the innate andmay adaptive Tumours recur immune because cells, besides causing a glycolytic switch cancer cells tumour are not completely both HIF-1 and chronic inflammation can initiate advancement to oxidative phosphorylation whilst eliminated from the body. and autoimmunity. by HIF-1α has beenDisease linked increasing CD8 T cellGlycolysis memory upregulated recurrence is a major challenge response quality, rapamycin with tumour-associated-macrophages (TAMs), which are macrophages in cancer treatment. Numerous can also imitate dietary restriction containing perinecrotic and hypoxic tumour tissues that aid in tumour anticancer reagents have been and improve longevity[242] in angiogenesis and growth. developed to suppress the memory T cells. Rapamycin HIF-1 HIF-2 levels in malignancy e.g. in bladder, growth of residual or inoperable canBoth initiate Tregand development in are raised [243,244]pancreatic, prostate, hepatocellular, tumours. The identification of colon, ovarian, and glial cancers. CD4 T cells and also [245,246] glycolytictarget inhibitors for cancer HIF-1αinfection has beenrates widely studied as a glycolytic for cancer therapy, higher has led to the specific are seen with rapamycin both at pre-clinical and clinical stages therapy [218], given its extensive involvedestruction of neoplastic cells in treatment because of its ment in regulating glycolysis. Cytotoxic agents are developed with aim several types of cancer. However, immunosuppressive capabilities. to block HIF-1α expression, transcription and translation and also to inmany types of cancer still require 3-Bromopyruvate (HKDigoxin for example inhibits HIF-1 gene exterrupt binding of(3BP) targets. effective anticancer drugs. To inhibitor) is an anti-glycolytic pression and tumour proliferation enhance [219], besides blocking anticancer activityRORγtwhilst also used in cancer treatment. minimizing adverseTreg effects and 17 differentiation [220]. HIF-1 represses differentiadependent T H Cell death occurs with 3BP toxicity to healthy surrounding tion and therefore inhibiting treatment as intracellular ATP HIF may elevate suppressive T cells. This tissues, the cancer-selective [247] levels deplete . 3BP is selective phenomenon may be advantageous in protecting against self-antigen delivery of therapeutic to cancer cells and therefore it ismay still recognition. Active CD8 T cells be able to kill tumours if HIF-1 molecules is desired. less toxic to healthy surrounding is blocked. Other approaches of HIF-1 blockade include induction of Viral or non-viral route is the main tissues[248,249], and treatment with HIF-1α degradation by HSP90 inhibitor and 1-β-2 methoxyestradiol, category of drug delivery methods. it can increase tumour immunity HRE-binding HIF-1 inhibition by doxorubicin daunorubicin, Each type and of vector has their and with higher infiltration of killer cells also bortezomib inhibits HIF-1 advantages transcription [221,222]. More reand limitations. whilst diminishingwhich the restraining tumourmicroenvironment. cent genetic approaches targeting HIF-1α inhibition siRNA therInnovations in include micro/nanoparticle designs,However, new drugs e.g.of toxicity apy EZN-2968, tested in hepatic metastasis. issue Localized treatment especially gene silencing intra-tumoural approach induces with posttranscriptional arose in a number of patients this approach [223]. Micro-RNA nucleotides, advanced new anti-tumour CD8 memory T cells. T being (miRNA)-mediated therapy is also tested inand glycolytic inhibition. biomaterials result in new drug cells may be harmed via systemic delivery methods. treatment with 3BP because of the

March 2017 • HPN


Phase 0


Phase 2


Phase 1


Phase 1


Phase 1


Phase 1


Prostate cancer

Phase 2


Lung, breast, prostate Solid tumours Malignant melanoma

Phase 1/2 Phase 2 Phase 2

NCT00633087 NCT00110188 NCT01654692

Sarcoma, melanoma, germ cell tumour Advance and non-curable solid tumour Ovarian, prostate, colorectal or non-small cell lung cancers Lung, breast, prostate, ovarian

Viral drug delivery system

peptide from influenza virus

haemagglutinin (HA), gene transfer Drug delivery refers to various receptor-mediated approaches and formulations, miR100 (mTOR signaling inhibitor)efficiency has beenofidentified in clear cell gene delivery systems has been different incorporated ovarian technologies cancer [224]. Delivery of these promising HIF-1 inhibitors enhanced. HVJ liposomes have into developing vectors and should be encapsulated with nanoparticles to ensure targeted delivery been widely used in animal different systems for transporting and avoiding nonspecific toxicity, models as demonstrated by successful for cancer treatment. a pharmaceutical composite. In preventsites melanoma antitumour delivery to hypoxicTotumour [225]. growth, doing so, thesiRNA desired therapeutic melanoma-associated antigen effect has to be safely achieved. gene or RNA has been injected Viral delivery systems, virosomes, 6.2. Targeting uncoupling proteins into spleen or skeletal muscle[281]. consist of viral envelope This has successfully invoked components of inactivated viral Mitochondrial ATPs are produced by coupling electron transport immunity to the prevent melanoma particles. They act as a vehicle for growth. Newer viral vaccine chain (ETC) and ADP-ATP phosphorylation. However, this process is not therapeutic molecules. systems offer advantages over efficient in the presence of uncoupling proteins (UCP), which are anion Virosomes are composed of a conventional however, transporters bilayer. of the mitochondrial membranevaccines; [226]. Besides that, phospholipid Glycoproteins inner they have their own limitations UCPs production radicals [227] [282,283] on the also viral reduce surface the protrude from of mitochondrial-free and side effects . These viral [273–275] these vesicle surfaces . pyruvatevaccines for example by decreasing entry into the adenovirus TCA cycle types [228, include Virosomes do not a in thermogenesis 229], and are alsocontain involved e.g. UCP1 involvement 2 and 5, pox-, lenti-, retro-, and in lot of preservative and their alphaviruses, adeno-associated thermogenesis activity of brown tissue [230]. Three main uncoupling preparation usually does not virushave and lastly the herpes simplex proteins which are UCP1, UCP2[276] and UCP3 different uncoupling acinvolve complicated techniques . virus (HSV). tivities [226,231] and play different roles in mitochondrial physiology Virosomes are able to transport They can delivery antigens to due [232]. UCP2 knockout results in resistance to infections [233,234] macromolecules e.g. drugs, specific subsets of immune cells nucleic acids, and proteins to to NF-κB activation and increased levels of reactive oxygen species effectively such as the APCs erythrocytes, hepatocytes, (ROS) in immune cells, making UCP2 an can immunometabolic which potentially act astarget. immune cellsofand glioma High levels mitochondrial UPC2 are found in activated T cells adjuvants. Viral vectors can owing be effectively[277– 279]. In conventional combined Low with ROS otherlevels vaccines and to its need for high proliferation via glycolysis. are also drug delivery systems, the administered to result in enhanced necessary for expressing therapeutic molecules get genes and signaling activity [235]. Uncoupling immune responses. Both RNA and the ETC when levelsthe of ROS are generated resets homeostasis, degraded prior tohigh reaching DNA viruses have been used as target cells. However, virosomes particularly in the innate immune and T celltointerplay. UPC2 is provaccines express the antigenic/ are able to and deliver these drug glycolytic is shown by its ability therapeutic to stabilise protein the glyceraldehyde in vivo and to3molecules to target cells by potent specific humoral phosphate dehydrogenase (GAPDH)stimulate in cancer cell cytoplasm [236]. virosomelysosome membrane [284] and cellular immune responses UCP2 supports the glycolytic flux by its antioxidant effects of GAPDH ox-. fusion without being affected by Non-viralWith drug this, delivery idation nuclear translocation inhibition. theysystem prevent the host and defense mechanism. cancer cells from stimulating mechanisms. UCP2 of decreases Many recombinant virus based cell death A promising technology the delivery systems haveinsulin emerged delivery variety of compounds glucose-stimulated release [237]. Thisofenables them to control lately and these have been used Increased to target sitesofisUCP2 liposomes the autoreactive T cell responses. levels are found in for gene therapy and for vaccine and liposomal-based delivery [280] systems. Liposomes are a nonpurposes . By combining fusion

55 viral delivery system and are used as a vehicle for administration of macromolecules into cells. In liposomes, water-soluble molecules incorporate into a lipid bilayer-vesicle. They have been utilised to target tumour tissues by systemic administration. To improve the transfection efficiency and to reduce the cytotoxicity of the lipoplex, numerous cationic lipids have been synthesised[285–288]. Lipoplex with HLA-B7 and b-2 microglobulin genes were found to induce antitumour immunity in HLA-B7-negative melanoma patients. Also, Allovectin-7 (a liposomal drug) has been clinically tested to treat metastatic melanoma[287]. Glioblastoma patients in Japan were treated with the IFN-b gene. These were delivered by cationic liposomes which were composed of N-(a-trimethy-lammonioacetyl)didodecyl- D-glutamate chloride (TMAG)[289] dilauroyl phosphatidylcholine, and dioleoyl phosphatidylethanolamine. Doxil which is a liposomal preparation composed of the high phase-transition temperature phospholipid hydrogenated soy phosphatidylcholine (HSPC) and cholesterol, is currently in use for the treatment of recurrent breast cancer[290, 291]. Synthetic polymers Currently, synthetic polymers are the most actively researched areas of biomedicine. They have easily adjustable characteristics. Polymerbased nanoparticle delivery systems e.g. polymeric nanoparticles, polymeric micelles, and dendrimers are newly innovative candidates to not only diagnose but also to monitor disease status and treat cancer diseases. This is mainly due to their special features of enhanced permeability, biocompatibility and biodegradability, improved bioavailability and transport efficiency, low toxicity depot effect, and lastly targeted delivery[292]. Less toxic synthetic polymers like poly-D,L-lactide-coglycolide (PLGA) and polylactic acid (PLA) also provide biological compatibility[293]. ‘Smart’ polymers undergo conformational changes in response to changes in the environment such as the temperature and surrounding pH[294]. They are able to employ in different fields and in response to specific physiological triggers they are able to release the contained drugs. Polymeric micelles are block-copolymers, which consist of two distinct linear polymers, are conjugated to therapeutic molecules by an electrostatic interaction, hydrophobic interaction or metal complex formation. Doxorubicin was encapsulated into PEG

bpolyaspartic acid copolymer. PEG-b-polyaspartamide with a 1,2- diaminoethane side chain is used as a block-copolymer for DNA encapsulation. This micelle for DNA encapsulation enhanced the penetration into tumour tissue and enabled gene expression in the hypoxic state[295]. The amount of doxorubicin in tumours by pH-sensitive micelles was approximately fourfold higher than that by pH-insensitive micelles, and more efficient tumour regression was achieved by pH-sensitive micelles than by conventional micelles[296]. Atelocollagen is a bovine type I collagen that is treated with pepsin and solubilised by protease. However, its physical properties are virtually identical to those of natural collagens, which are not solubilised. Natural substances do not possess the superior characteristics found in atelocollagen. The atelocollagen (gel biomaterial in clinical use) has a positive charge and can be a carrier of DNA and siRNA[297]. The siRNA existed in tumour tissue for more than one week when the siRNA/atelocollagen complex was intravenously injected into tumour bearing mice. Intravenously administered SiRNA-atelocollagen complex into mice with bone metastasis from human prostate cancer[298] revealed marked suppression of metastatic tumours in both types of siRNA in an in vivo imaging analysis. Natural polymers Other polymer-based delivery systems include cationised gelatins. These gelatins are prepared by the introduction of amine residues to the carboxyl groups of gelatin via chemical means. Crosslinking cationised gelatin with glutaraldehyde result in cationised gelatin hydrogels. These hydrogels have different in vivo degradabilities as the carrier of DNA. The plasmid DNA incorporated gelatin prolongs the duration of gene expression. The antitumour plasmid DNA of NK4s (protein made up of theNH2terminal hairpin and the fourkringled domains of hepatocyte growth factor) biological activity is promoted by the controlled release technology[299]. NK4 is an HGF antagonist that inhibits the ability of HGF to promote tumour metastasis and angiogenesis. The mice with which received subcutaneous injection (controlled release approach) of hydrogel microspheres had significant prolonged survival as compared to mice that received NK4 plasmid DNA in solution. Chitosan, prepared from chitin by deacetylation, is a positively charged linear polysaccharide

consisting of one to four linked Nacetyl- D-glucosamine and D-glucosamine subunits, and interacts strongly with negatively charged DNA[300]. Chitin is a component of fungi and exoskeleton of crustaceans' cell walls. Chitosan is a nontoxic polymer and can be digested by enzymes in the blood and human intestines. These enzymes include chitinases or lysozymes. Interest to this polymer as a drug delivery system in pharmaceutical research was based on the abovementioned special characteristics of chitosan. Galactosylated, trimethylated and N-dodecylated chitosan[285] are examples of chitosan derivatives. Chitosan is also used for the intravenous delivery of siRNA for cancer therapy[301]. Another form of DNA delivery into cultured cells is polyethylenimine (PEI). The proton sponge effect causes the escape of DNA from the endosome to the cytoplasm, enhanced by PEI[302]. Stearic acid modified PEIbased nanoparticles (more effective combination than PEI/siRNA complex) were developed to deliver siRNA against signal transducer and activator of transcription 3 (STAT3) to suppress mouse melanoma in vivo[303]. Physical methods of drug-delivery Drug deliveries mediated by different physical methods have grown significantly over the past decade and a half. Systems of drug delivery aim to deliver the therapeutic amounts of drug to targeted sites in the body, and to promptly achieve and maintain the desired drug concentrations[304]. Physically facilitating drug-delivery (PFDD) systems can be classified mainly as photo-, ultrasound-, magnetic-, and electrical based modulation systems. This vast literature on PFDD is impossible to be covered in this review. Physical methods to push the DNA into cells have been developed to enhance gene delivery based on naked DNA injection, firstly reported for skeletal muscle[305] and subsequently reported for other tissues such as the thyroid, cardiac muscle, skin and liver[306]. Conclusion Increased aerobic glycolysis is commonly exhibited in cancer cells. In order to generate ATP, malignant cells adapt to metabolic changes making them addicted to and dependent on glycolysis. Cancer cell survival is at an advantage given the alterations in energy metabolism with increased glycolytic enzymatic activity and other molecules promoting longevity. Increased glycolysis results in an acidic tumour microenvironment making it

conducive for a selection of cancer cells with high survival capacity. The immune condition of tumour microenvironments is an important factor in tumour prevention, development, and progression. Significant evidences have been provided in several studies regarding the correlation of disease outcome with tumour microenvironment status. The future of cancer immunotherapies depends on recognizing the concept of switching the immune response to a tumour-destructive profile, instead of a tumourpromoting one. Manipulating immunological parameters in the tumour microenvironment may be adequate in tipping the balance of host response towards effective immunity. The complex metabolic switch, immuneglycolytic interactions and tumour microenvironment present a major challenge in cancer treatment. The development of combination therapies (e.g. combination therapy with ipilimumab and electrochemotherapy)[335] which increase therapeutic benefits and reduce its side effects are necessary for the group of patients who do not benefit from a single checkpoint blockade. The burgeoning field of nanodelivery system has shown tremendous promise in circumventing many of the drawbacks associated with conventional drug delivery approaches. This has opened avenues to revisit application of several discontinued chemotherapeutic agents for the treatment of different medical conditions. Recent literature survey clearly indicates that the advantages of nanocarriers have also led to numerous reports on delivery of drugs targeted against glycolytic pathway. In solid tumours, drug penetration is a critical aspect to consider when looking at therapeutic strategies. With the advent of novel tumour- penetrating nanoparticles, these nanodelivery systems open the possibility of delivering therapeutic agents into tumour parenchyma. Apart from using small molecule and biologics individually in targeting aerobic glycolysis, combination therapy with small molecules and nucleic acids is another potential approach that can be explored. Combination delivery of therapeutics using nanoparticlebased delivery systems has been successfully reported to achieve synergistic effects of therapeutic agents especially in multidrugresistant cancer.

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56 News

3D Model unveiled at Connolly Hospital Eilish Hardiman, Chief Executive, Children's Hospital Group

Connolly Hospital recently unveiled a 3D model of the planned Paediatric Outpatients and Urgent Care Centre that is scheduled to open on the grounds of Connolly Hospital in 2018. Elected Orichteas officials were briefed on the services that will be offered at the new Centre as part of the new national model of care for paediatric services that will see children and young people in Dublin receive acute paediatric care as close to their home as is medically appropriate. As part of the new children’s hospital project, planning permission was also granted in April 2016 for two new Paediatric

Outpatients and Urgent Care Centres in Dublin – one at Connolly Hospital on the North side of Dublin and one at Tallaght Hospital on the South side of Dublin. While the new children’s hospital on a shared campus with St James’s Hospital will open in 2021, the Paediatric Outpatients and Urgent Care Centres at Connolly and Tallaght Hospitals will open on a phased basis from 2018. The Paediatric Outpatients and Urgent Care Centres will provide urgent care paediatric services, including short stay observation beds, and outpatients clinics such as general paediatrics and orthopaedics for fracture clinics

- all supported by therapies, phlebotomy, general X Ray and Ultrasound services - child sexual abuse counselling services and, at the Connolly centre, primary care dental services. Typically, the centres will care for children and young people who have a common, minor illness or injury which cannot be managed by a GP (primary care) but does not require the acute services of an Emergency Department. In advance of the centres opening, there will be a full information and awareness programme to ensure that families, the public and GPs understand the services that will be available and to encourage families to avail of services in close proximity to their homes. Meanwhile, the new children’s hospital on a campus shared with St James’s Hospital will provide specialist (tertiary) level care to children from all over Ireland, and also secondary healthcare services for children who live within the M50 and in the Greater Dublin Area. Eilísh Hardiman, Chief Executive, the Children’s Hospital Group,

said, “The vast majority of children and young people who attend our three children’s hospitals in Dublin and the Greater Dublin Area are treated on a sameday basis and do not require to be admitted to an inpatient bed. In the children’s hospital at Tallaght Hospital, for example, 85% of children attending its Emergency Department in 2016 were assessed, treated and discharged on the same day. The new Outpatients and Urgent Care Centres are designed to allow us to deliver the right care, in the right place, at the right time, ensuring that children and young people return home as soon as possible, which is what every child and their parents want.” Margaret Boland, General Manager, Connolly Hospital added, “We have been working with the Children’s Hospital Group and the NPHDB for some time now on the development of the Paediatric Outpatients and Urgent Care Centre at Connolly Hospital and we look forward to the delivery of this fine new facility to our campus by the end of next year. This new facility is in keeping with our master plan for the hospital and we look forward to children and young people having access here on the campus to paediatric services delivered by the Children’s Hospital Group.”

Liver Scan service launches at Beacon Clinic Professor Suzanne Norris, Ireland’s leading Hepatologist and Gastroenterologist, has launched FibroScan as part of her Liver Wellness Programme at Beacon Hospital’s Consultants Clinic. With results available in 15 minutes, and a full consultant’s report in 48 hours, Fibroscan is a quick, painless and sensitive test to evaluate liver disease. Beacon Consultants Clinic at Beacon Hospital is the first private facility in Ireland to offer this noninvasive, pain-free liver scan to detect signs of liver disease. FibroScan is a medical device to measure liver stiffness/elasticity and is a tool to help diagnosis. It is a painless and non-invasive method for evaluating fibrosis or scarring in the liver; the service

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eliminates the need for a liver biopsy in most cases. It uses ultrasound to create waves and measures the speed at which these waves are reflected by the liver. As it is non-invasive, a Fibroscan can be repeated regularly without risk, unlike a liver biopsy. Professor Suzanne Norris said, “The wider public most often associate liver disease with excessive alcohol consumption but there is a need for education on the issue. In fact, Non Alcoholic Fatty Liver Disease (NAFLD / Fatty Liver) has now become the most common cause of liver disease; patients who are overweight or obese, have high cholesterol or diabetes are key risk groups. As well as knowing

one’s cholesterol level or blood pressure values, everyone should be aware of their liver score.” Fatty Liver is defined as an excess of fat on the liver in the absence of increased alcohol intake. It is a common condition that affects up to 30% of the general population and is the most common cause of chronic liver disease in developed countries. There are several factors that increase the risk of developing NAFLD, including: diabetes, high blood pressure, high cholesterol and being overweight or obese. Having now become the most common cause of liver disease in the developed world, it is believed to affect more than 1 in 5 people globally. Professor Norris continued, “Detecting liver scarring (fibrosis)

early provides an opportunity to adapt your lifestyle to prevent it becoming more widespread, leading to an even more severe chronic liver disease. A FibroScan is quick, easy and painless way to find out if fibrosis or fatty deposits exist within the liver. Liver Wellness provides a complete approach to liver health care, and in addition to Fibroscan will also provide access to novel blood tests, including genetic markers, and access to emerging new therapies. I look forward to working with other services at Beacon Hospital to deliver the best possible outcomes for patients on a multidisciplinary basis.”

The only licensed treatment for the reduction in recurrence of overt hepatic encephalopathy (OHE)1

At home they are still at risk; ...TARGAXAN® rifaximin-a reduces the risk of recurrence of overt hepatic encephalopathy.1

Long-term secondary prophylaxis in hepatic encephalopathy (HE)2 TARGAXAN® 550 mg film-coated tablets. REFER TO FULL SUMMARY OF PRODUCT CHARACTERISTICS (SmPC) BEFORE PRESCRIBING. Presentation: Film-coated tablet containing rifaximin 550 mg. Uses: Targaxan is indicated for the reduction in recurrence of episodes of overt hepatic encephalopathy in patients ≥ 18 years of age. Dosage and administration: Adults 18 years of age and over: 550 mg twice daily, with a glass of water, with or without food for up to 6 months. Treatment beyond 6 months should be based on risk benefit balance including those associated with the progression of the patients hepatic dysfunction. No dosage changes are necessary in the elderly or those with hepatic insufficiency. Use with caution in patients with renal impairment. Contraindications: Contraindicated in hypersensitivity to rifaximin, rifamycin-derivatives or to any of the excipients and in cases of intestinal obstruction. Warnings and precautions for use: The potential association of rifaximin treatment with Clostridium difficile associated diarrhoea and pseudomembranous colitis cannot be ruled out. The administration of rifaximin with other rifamycins is not recommended. Rifaximin may cause a reddish discolouration of the urine. Use with caution in patients with severe (Child-Pugh C) hepatic impairment and in patients with MELD (Model for End-Stage Liver Disease) score > 25. In hepatic impaired patients, rifaximin may decrease the exposure of concomitantly administered CYP3A4 substrates (e.g. warfarin, antiepileptics, antiarrhythmics, oral contraceptives). Both decreases and increases in international normalized ratio (in some cases with bleeding events) have been reported in patients maintained on warfarin and prescribed rifaximin. If co-administration is necessary, the international normalized

ratio should be carefully monitored with the addition or withdrawal of treatment with rifaximin. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation. Ciclosporin may increase the rifaximin Cmax Pregnancy and lactation: Rifaximin is not recommended during pregnancy. The benefits of rifaximin treatment should be assessed against the need to continue breastfeeding. Side effects: Common effects reported in clinical trials are dizziness, headache, depression, dyspnoea, upper abdominal pain, abdominal distension, diarrhoea, nausea, vomiting, ascites, rashes, pruritus, muscle spasms, arthralgia and peripheral oedema. Other effects that have been reported include: Clostridial infections, urinary tract infections, candidiasis, pneumonia cellulitis, upper respiratory tract infection and rhinitis. Blood disorders (e.g. anaemia, thrombocytopenia). Anaphylactic reactions, angioedemas, hypersensitivity. Anorexia, hyperkalaemia and dehydration. Confusion, sleep disorders, balance disorders, convulsions, hypoesthesia, memory impairment and attention disorders. Hypotension, hypertension and fainting. Hot flushes. Breathing difficulty, pleural effusion, COPD. Gastrointestinal disorders and skin reactions. Liver function test abnormalities. Dysuria, pollakiuria and proteinuria. Oedema. Pyrexia. INR abnormalities. Legal category: UK - POM, Ireland - Prescription only. Cost: UK - Basic NHS price £259.23 for 56 tablets. Ireland - €262.41 for 56 tablets Marketing Authorisation number: UK - PL 20011/0020. Ireland - PA 102/29/1 For further information contact: Norgine Pharmaceuticals Limited, Norgine House, Moorhall Road, Harefield, Middlesex, United Kingdom UB9 6NS Telephone: +44(0)1895 826606 E-mail: Ref: UK/XIF5/0116/0173(1) Date of preparation: October 2016.

United Kingdom - Adverse events should be reported. Reporting forms and information can be found at Adverse events should also be reported to medical information at norgine Pharmaceuticals Ltd on 01895 826606. Ireland - 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:; e-mail: adverse events should also be reported to Medical Information at norgine Pharmaceuticals on +44 1895 826606. References: 1. TARGAXAN ® 550 Summary of Product Characteristics. Available for the UK from: uk/emc/medicine/27427 [Accessed October 2016]. Available for Ireland from: http://www.medicines. ie/medicine/15936/SPC/TARGAXAN+550mg+filmcoated+tablets/ [Accessed October 2016]. 2. Mullen KD, et al. Clin Gastroenterol Hepatol 2014;12(8): 1390-97. Product under licence from Alfa Wassermann S.p.A. TARGAXAN is a registered trademark of the Alfa Wassermann group of companies, licensed to the Norgine group of companies. NORGINE and the sail logo are registered trademarks of the Norgine group of companies. UK/XIF5/0416/0201(1) Date of preparation: October 2016.

58 Event Gallery UL researcher awarded prestigious global fellowship Dr Mary O’Keeffe

"Back pain is the leading cause of disability in the world and I hope by strengthening both my research and communication skills I can one day contribute to improving the lives of millions of people worldwide for the better. Good science and research are powerful weapons and have the potential to do great things. Knowledge is power! I am very fortunate to be this position and I am excited for all the opportunities ahead," she added. A University of Limerick, Health Research Institute researcher has been awarded a prestigious global fellowship to further her research into lower back pain. Physiotherapy researcher Dr Mary O’Keeffe is the first UL graduate to receive the Marie SkłodowskaCurie Global Fellowship from the European Commission. The award will enable Dr O’Keeffe to attend the George Institute for Global Health at University of Sydney, nahpt conf flyer 2017:Layout 1




Australia, one of the top ten research institutions in the world for scientific impact. There, she will be hosted for two years by Professor Chris Maher who is the world leader in lower-back-pain research. "I absolutely love research and think it has great potential to have a positive impact on the economy, health system and most importantly the patients and public all over the world," Dr O'Keeffe commented.

While at the George Institute for Global Health, Dr O’Keeffe will be trained in mediation, moderation

National Association of Hospital Pharmacy Technicians of Ireland

Crowne Plaza Hotel, Santry, Dublin 9

Saturday 1st April 2017 Registration from 8.30am Presentations Workshops Pharma Exhibition Networking Opportunities Poster competition: 2 categories sponsored by Actavis Conference Fee (including Lunch): Hospital Pharmacy Technician Online Registration €25.00* and Gala Dinner €10.00 Community Pharmacy Technicians, Qualified Assistants and Visitors €25.00 and Gala Dinner €10.00 Students and Gala Dinner

€15.00 €10.00

*Membership is included in Conference Fee. Early Bird Fee will close 28th February. €30 thereafter + €10 Gala Dinner. Online registration will close two weeks prior to conference.

Pharmacy Team, Our Lady's Hospital, Navan

“I am delighted to have been awarded this prestigious fellowship. Post PhD can be hard and a confusing time to decide 'where do I go and what do I do next?' This fellowship gives me a-oncein-a-life-time opportunity to further my training and development in a world class research team and this will build my capacity to become a leading light in my field of back pain," Dr O'Keeffe concluded.

Registration on line For further information contact

Hospital Pharmacy Technicians Annual Conference The National Hospital Pharmacy Technicians Association (NAHPT) Annual Conference will take place this year on Saturday, April 1st, 2017 in the Crowne Plaza Hotel, Santry. Registration will open from 8.30am and the conference agenda includes presentations, workshops and pharmaceutical exhibition. There will also be two categories within the poster competition, sponsored by Actavis. For registration on line visit or contact President Laura Lyons for more information on

Bon Secours donate ¤10,000 to ChildVision As part of the Community Initiative Programme, the Bon Secours Hospital Dublin recently donated ¤10,000 to ChildVision – National Education Centre for Blind Children. The money will provide a program of Equine Assisted Occupational Therapy (EAOT) Visually impaired children will be able to avail of horse riding sessions with a Horse Riding Instructor and an experienced side walker. The children will benefit greatly from the connection with the horses, the sensory experience of the horse’s movement and the increased demand of their postural control and the increased confidence that will be gained through such an experience. Pictured at the cheque presentation are Sr Goretti Spillane of the Pastoral Care Team in the Bon Secours Hospital Dublin, Ruth Hickey of ChildVision and Mike Tonery Hospital Manager Bon Secours Hospital Dublin.

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The fellowship also involves an internship with Wiserhealthcare, an international and interdisciplinary collaboration to reduce overdiagnosis and overtreatment of conditions like lower back pain.

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Annual Conference

Dr O’Keeffe will conduct advanced analysis of her PhD multicentre randomised controlled trial which investigated the role of a personalised multidimensional treatment for chronic low back pain within the Health Service Executive. Her doctoral research was undertaken through a competitive PhD scholarship from the Irish Research Council.

and economic evaluation and will be involved in pharmacological and exercise trials. The fellowship also involves skills development in networking, grantsmanship, project management, leadership and student supervision and communications training with a media office and a multi award winning health journalist, Dr Ray Moynihan, co-author of Selling Sickness-How the World's Biggest Pharmaceutical Companies are Turning us All into Patients.

59 Cystic Fibrosis Ireland launch nationwide appeal Cystic Fibrosis Ireland ambassadors, RTÉ Fair City actor Jenny Dixon, and celebrity chef, Chef Adrian, have come up roses for 65 Roses Day taking place on Thursday April 13. The duo recently stepped out to launch the appeal at The Hugh Lane Gallery in Dublin and nailed their purple colours firmly to the Cystic Fibrosis Ireland mast! The charity, which is Ireland's national charity for people with cystic fibrosis, and that supports people with cystic fibrosis and their families across the country, will be hosting Cystic Fibrosis National Awareness Week, from April 10 to 16. As part of this, its flagship fundraising appeal 65 Roses Day – so-named after the way in which young children are first taught to say the words "cystic fibrosis" – will take place on Thursday April 13.

CUH team wins Bernard Connor Bursary 2016 A team from the rheumatology department at Cork University Hospital has won the AbbVie-sponsored 2016 Bernard Connor Bursary. Dr Grainne Murphy, Dr Sinead Harney, Dr John Ryan and Dr Roberta Visevic of CUH received the accolade for their project entitled ‘Implementation of a nailfold capillaroscopy in clinical practice with enhanced patient education’. The 2016 adjudication panel – comprising of Professor James O’Donnell of St James’s Hospital; Dr Bernadette Carr, Director of VHI Healthcare; and Mr Dara Gantly, Editor of the Irish Medical Times – chose the winner because of the effectiveness and achievability of the team’s proposed addition to Irish clinical practice. The aim of the project is to introduce nailfold capillaroscopy

as a routine clinical practice via a dedicated clinic. Such a development would allow for the diagnosis and definition of primary and secondary Raynaud’s phenomena to determine whether a patient will experience the full spectrum of connective tissue disorders or none at all. The application included an integrated educational resource to allow for greater understanding amongst patients. Patient information collected at the clinic will form a research database, funded by the bursary. Dr Bernadette Carr of Vhi Healthcare said: “The winning entry presented an effective improvement in clinical practice in Irish Rheumatology departments and we were delighted to be able to provide the team in Cork University Hospital with the resources to continue their work.

The development of a designated capillaroscopy clinic will bring reassurance and support to patients nationwide, which is what impressed us as judges.” 2016 marks the 11th year of the Bernard Connor Bursary, backed

by biopharmaceutical company AbbVie. The bursary is named after Dr. Bernard Connor, originally from Co Kerry, who was a key figure in clinically diagnosing ankylosing spondylitis.

EU Funding for fight against lung disease ¤2.4 million funding under the European Union’s INTERREG VA Programme has been reached for a pioneering cross-border research project, designed to better understand and alleviate the impact of lung disease. In total, ¤7.7 million has been offered to the Dundalk Institute of

Technology (DkIT), in partnership with Queen’s University Belfast (QUB) and University of the West of Scotland (UWS), to deliver the ‘BREATH’ (Border and Regions Airways Training Hub) project. The project will involve a strong crossborder partnership between the School of Pharmacy and Centre for Experimental Medicine (CEM)

at Queen’s University, the Smooth Muscle Research Centre (DkIT), and the Institute of Biomedical & Environmental Health Research (UWS). It will establish a world-class cluster of researchers, involving collaborations between scientists and clinicians, that will help address the causes, treatment and potential prevention of chronic obstructive pulmonary disease (COPD). COPD is an incurable respiratory condition characterised by progressive airflow reduction, breathing difficulties and irreversible lung damage Dr Lorraine Martin, School of Pharmacy, Queen’s University, Dr Lorcan McGarvey, Dr Fionnuala Lundy,both from CEM and Gina McIntyre, CEO, SEUPB

(emphysema). It significantly impairs quality of life and has a high cost to health services and the wider economy. In 2011 the annual economic burden of COPD across the EU was estimated at approximately ¤141.4 billion. COPD-related hospital admission is higher in Ireland than any other developed country and the condition is also particularly prevalent across Scotland and Northern Ireland. Dr Lorraine Martin, School of Pharmacy, Queen’s University is leading on the project along with colleagues, Drs Lorcan McGarvey and Fionnuala Lundy from CEM. She explained, “This disease is frequently underrecognised and under-treated, therefore there is a real need for impact in terms of prevention, treatment and management.” HPN • March 2017

60 Event Gallery RCSI hosts COPD Study Day How Can We Improve Adherence To Help Patients With Chronic Respiratory Disease? An interprofessional study day for pharmacists and physiotherapists was hosted by the School of Pharmacy in collaboration with the School of Physiotherapy on February 3rd 2017. The day-long educational outreach event, which was attended by over 60 pharmacists and physiotherapists, including RCSI alumni, featured workshops in the areas of competencies for interprofessional collaborative practice and adherence skills sharing and presentations from experts in the fields of pharmacy and physiotherapy including Mr Patrick Karikari, A UK-based medicines optimisation pharmacist, Ms Claire Egan, Clinical Specialist Physiotherapist, Beaumont Hospital, Professor Richard Costello, Respiratory Consultant, Beaumont Hospital and Ms Maureen O'Sullivan, Research Pharmacist, Queen's University Belfast. The study day

Speakers at the study day Ms Maureen O'Sullivan, Mr Patrick Karikari and Ms Claire Egan

School of Pharmacy alumni Kerrie Finnan (second left) and Lisa Foley (second right) with the School's Dr Cristín Ryan

was supported by an independent education grant by GlaxoSmithKline Ireland and provided for a beneficial forum for pharmacists and physiotherapists to engage with each other and

share learnings with a view to enhancing treatments for patients with chronic respiratory disease.

Public Service Award for St Francis Hospice St. Francis Hospice Dublin has won the “Best Public Service Excellence Award” at the Fingal Dublin Chamber of Commerce Business Excellence and Corporate Responsibility Awards 2016. The award was in recognition of the best practice establishment and development of the volunteer service at St. Francis Hospice Blanchardstown since 2012. There were 15,500 hours of volunteer service per annum at St. Francis Hospice Blanchardstown in 2016. Eighty-nine volunteers worked across 19 different roles. The independent judges said in awarding the Excellence Award for the volunteer service, “The winner of this award demonstrated how they have delivered a best in class service provision which is now shaping national standards. Their careful implementation and clear understanding of their stakeholders’ needs has brought outstanding benefits to all involved”. On receiving the award Fintan Fagan, CEO, St. Francis Hospice Dublin, said “I would like to take the opportunity to thank all our volunteers for their selfless commitment to caring for our patients and their families. Sincere thanks are also extended to the people of North Dublin for volunteering and for their ongoing support of the hospice.”

Irish Pain Society 16th Meeting The 16th Annual Scientific Meeting of the Irish Pain Society took place last year in the Radisson Blu Royal Hotel, Dublin. Pictured are some of those who attended.

Ms Sophia Saetes, Dr Line Caes, Dr Olivia Kirtley

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Dr Joe McVeigh, Ms Aine O’Riordan, Ms Rachel McVeigh, Dr Mary Peyton

Ms Aoife Smith Mundipharma, Mr Conor Rothwell, Ms Andy Cochrane, Clinical Research Prize, Ms Louise Corcoran Non Clinical Research Prize, Prof David Finn President Irish Pain Society, Ms Joanne O’ Brien President Elect

Clinical R&D 61 LONG-TERM SAFETY AND EFFICACY EXTENSION STUDY DATA OF ALPROLIX® PUBLISHED Swedish Orphan Biovitrum have annouced that interim results from the B-YOND extension trial, which studies Alprolix® [Coagulation Factor IX (Recombinant), Fc Fusion Protein] in previously treated subjects with severe haemophilia B, were published in the March 2017 issue of Thrombosis and Haemostasis. The study results reinforce the long-term safety and efficacy of prophylactic treatment with Alprolix over a median duration of more than three years in adults/ adolescents and more than a year and a half in children under 12 years of age. The primary outcome measure was development of inhibitors (neutralising antibodies that can interfere with activity of the therapy); no patients treated with Alprolix in the study developed inhibitors. B-YOND is an ongoing open-label, nonrandomised extension study, and eligible previously-treated patients who completed B-LONG or Kids B-LONG could enrol in one of three treatment groups: weekly prophylaxis, individualised prophylaxis, and modified prophylaxis. An episodic treatment arm is also available only to adult and adolescent participants. At the time of the interim data cut, 116 male subjects (93 from B-LONG and 23 from Kids B-LONG) were enrolled in the study. In the individualised prophylaxis treatment group, as of the B-YOND interim data cut, a total of 26 adolescent/adult subjects out of 30 (86.7%) had a dosing interval longer than one week with a median dosing interval of 13.7 days, and paediatric subjects aged 6 to < 12 years had a median dosing interval of 10.0 days. Fifteen of 26 (57.7%) adult/adolescent subjects in the individualised prophylaxis treatment group had a dosing interval of every 14 days or longer. The overall median annualized bleeding rate (ABR) at the time of the B-YOND interim data cut was 2.3 for adult/adolescent participants in both the weekly and individualised prophylaxis treatment groups, and 2.4 for those in the modified prophylaxis study arm. Participants receiving on-demand therapy, or treatment when a bleeding episode occurred, had a median ABR of 11.3. Among children under age six (n=9), the median ABR in the weekly prophylaxis group was zero. For children between six and 12 years old, the median ABR was similar in the weekly (2.7; n=10) and individualized (2.4;

n=5) prophylaxis groups. The one participant from the 6 to < 12 years cohort who was in the modified prophylaxis group had an ABR of 3.1. In the B-YOND study as of the interim data cut, Alprolix was well tolerated and adverse events (AEs) were typical of the haemophilia B populations studied. The most common AEs were headache (n=14, 12.1%) and common cold (n=13, 11.2%), and the majority of AEs were considered by the investigator to be unrelated to Alprolix treatment. A total of 39 serious AEs (SAEs) were reported in 23 participants (19.8%) treated with Alprolix. All SAEs were assessed by the investigator as unrelated to Alprolix, with the exception of one SAE of renal colic in an adult/adolescent participant with a medical history of previous clot colic; the event resolved and did not lead to study discontinuation. In the study as of the interim data cut, there were no reports of serious allergic reactions or anaphylaxis associated with Alprolix, no vascular thrombotic events, and no deaths.

AMGEN ANNOUNCE TOWER STUDY RESULTS Amgen have announced that the New England Journal of Medicine published results from the Phase 3 TOWER study evaluating the efficacy of Blincyto® (blinatumomab) versus standard of care (SOC) chemotherapy in high-risk adult patients with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL), one of the most aggressive B-cell malignancies. Results from the analysis showed that median overall survival (OS) was 7.7 months (95 percent CI: 5.6, 9.6) for BLINCYTO versus four months (95 percent CI: 2.9, 5.3) for SOC (hazard ratio [HR] for death=0.71; p=0.012). The TOWER study is the confirmatory study for the Phase 2 trial that supported the U.S. Food and Drug Administration’s (FDA) accelerated approval designation for Blincyto® in 2014. Blincyto is a bispecific CD19-directed CD3 T cell engager (BiTE®) antibody construct. The survival benefit for Blincyto was independent of allogeneic stem cell transplant (alloSCT), as the median OS, censored at the time of alloSCT, was 6.9 months for Blincyto versus 3.9 months for SOC. Improvement in OS was generally consistent regardless of age, prior salvage therapy or prior alloSCT. The magnitude of this benefit appeared greatest in earlier lines of salvage. Neutropenia and infection greater than or equal to grade 3 appeared less frequently with Blincyto compared to SOC,

while neurological events appeared at a similar rate between arms. Evaluation of key secondary endpoints showed that remission rates were also higher for Blincyto versus SOC. In the Blincyto group, 34 percent of patients achieved complete remission versus 16 percent in the SOC group. Patients receiving Blincyto also had a higher rate of combined complete remission or complete remission with partial or incomplete hematologic recovery (44 percent versus 25 percent). Among patients with complete remission or complete remission with partial or incomplete hematologic recovery, 76 percent in the Blincyto group versus 48 percent in the SOC group achieved minimal residual disease (MRD) negative status, a measure of eradication of residual disease at the molecular level. Also among these patients, the median duration of remission was 7.3 months in the Blincyto group versus 4.6 months in the SOC group. For the key secondary efficacy endpoint of event-free survival, six month estimates in the Blincyto and chemotherapy groups were 30.7 percent and 12.5 percent, and the HR was 0.55 (95 percent CI: 0.43, 0.71), favoring Blincyto. Safety results among subjects who received Blincyto were comparable to those seen in the Phase 2 studies in adult patients with Ph- relapsed or refractory B-cell precursor ALL. For the most common adverse events (greater than or equal to 10 percent incidence rate) in the Blincyto arm, only three events (cough, pyrexia, cytokine release syndrome) occurred at an incidence rate that was at least 5 percent higher for Blincyto compared to SOC chemotherapy.

NEW DATA SHOWS STELARA MAINTAINED CLINICAL RESPONSE AND REMISSION AFTER TWO YEARS OF TREATMENT Janssen-Cilag International NV (“Janssen”) have announced new two-year data from the ongoing IM-UNITI long-term extension (LTE) study evaluating the efficacy and safety of subcutaneous (SC) STELARA® (ustekinumab) in patients with moderate to severe Crohn’s disease. The data presented at the 12th Congress of the European Crohn’s and Colitis Organisation (ECCO) showed that treatment with ustekinumab maintained clinical response and remission for up to two years with no new safety signals observed. “Maintaining control of disease symptoms is paramount in the treatment of Crohn’s disease. The two-year clinical response and remission rates from the

IM-UNITI study provide further evidence that ustekinumab can be an effective therapeutic option for people living with this chronic and often debilitating disease,” said Dr Eoin Slattery, Consultant Gastroenterologist and Clinical Lead for Endoscopy, University Hospital Galway. Of the 1,281 patients enrolled in the maintenance study, 397 patients who achieved a response to ustekinumab at week 8 following an induction phase were randomised to receive SC ustekinumab 90mg every 8 weeks (Q8W) or every 12 weeks (Q12W), or placebo during a maintenance (0–44 week) period, before entering the LTE (44–252 week) period. A one-time dose adjustment to ustekinumab 90mg Q8W was permitted in patients in the randomised group who met loss of response criteria between weeks 8–32. Clinical efficacy data were collected every 12 weeks and safety data were collected every 4 weeks from the end of the maintenance trial (week 44) until the maintenance study was unblinded and then at Q8W or Q12W dosing visits during the LTE period; data at week 92 are reported here. Among randomised patients who entered the LTE period and continued to receive ustekinumab through week 96, 79.2% of patients receiving ustekinumab Q12W and 87.1% of patients receiving ustekinumab Q8W were in remission, while 90.9% of patients and 94.3% of patients showed clinical response at week 92, respectively. Among all ustekinumab-treated patients who continued to receive ustekinumab through week 96, remission and response rates at week 92 were 70.7% and 84.7%, respectively (as observed). Safety event rates per hundred years of follow up were comparable in ustekinukab-treated patients compared to placebo-treated patients from week 44 through to week 96. Among all ustekinumabtreated patients, there were two deaths (sudden death, asphyxia). There were two non-NMSC (non-melanoma skin cancer) malignancies reported between weeks 44 and 96, a seminoma in a ustekinumab-treated patient and a papillary thyroid cancer in a placebo-only-treated patient.1 “The 96 week data from the IM-UNITI study complement data previously presented from the UNITI programme. We look forward to sharing future results from the UNITI programme, and remain committed to improving overall outcomes for people living with Crohn’s disease,“ said Dr Leisha Daly, Country Director, Janssen Ireland. HPN • March 2017

62 Clinical R&D NEW DATA ON LONG-TERM REMISSION OF COMPLEX PERIANAL FISTULAS IN CROHN'S DISEASE PATIENTS WITH CX601 Takeda Pharmaceutical Company Limited (TSE: 4502) ("Takeda") and TiGenix NV (Euronext Brussels and Nasdaq: TIG) ("TiGenix") have announced new data from the Phase 3 ADMIRECD clinical trial, which indicated that investigational compound Cx601, a suspension of allogeneic adipose-derived stem cells (eASC), maintained long-term remission of treatment refractory complex perianal fistulas in patients with Crohn's disease over 52 weeks.[1] Results were presented at the 12th Congress of the European Crohn's and Colitis Organisation (ECCO). The ADMIRE-CD trial is a randomized, double-blind, controlled, Phase 3 trial, designed to investigate the efficacy and safety of the investigational compound Cx601 for the treatment of complex perianal fistulas in patients with Crohn's disease. Patients were randomized to a single administration of Cx601 cells or placebo (control), both added to standard of care. A significantly greater proportion of patients in the Cx601 group versus in the control group achieved clinical and radiological combined remission[*] (56.3% and 38.6%; p=0.010), and clinical remission (59.2% and 41.6%; p=0.013) at week 52 in the modified intentionto-treat population (mITT). Of those mITT patients who had shown combined remission at week 24, a greater number in the Cx601 group versus the control group reported no relapse at week 52 (75.0% and 55.9%). The rates and types of treatment related adverse events (non-serious and serious) and discontinuations due to adverse events were indicated to be similar in both groups (Cx601: 20.4%; control: 26.5%). Crohn's disease is a chronic inflammatory disease of the gastrointestinal tract, which is thought to affect up to 1.6 million people in Europe. Complex perianal fistulas are a complication for people living with Crohn's disease and there are limited treatment options. Recognizing the rare and debilitating nature of the disorder and lack of treatment options, in 2009 the European Commission granted Cx601 orphan designation for the treatment of perianal fistula. In March 2016, TiGenix announced that it submitted the Marketing Authorization Application (MAA) to the European Medicines Agency March 2017 • HPN

(EMA) for Cx601, and a decision by the EMA is expected in 2017. Additionally, in September 2016 orphan drug status was received from the Swiss Agency for Therapeutic Products (Swissmedic) regarding Cx601 for the rare disease complex perianal fistulas in Crohn's disease. "Perianal fistulizing Crohn's disease is difficult to treat with currently available therapies and often leads to pain, swelling, infection and incontinence," said Dr Asit Parikh, head of Takeda's Gastroenterology Therapeutic Area Unit. "Existing therapies are limited and associated with complications and a high failure rate. Cx601 may offer patients an alternative treatment option." "These data highlight that the efficacy and safety of a single administration of Cx601 were maintained during one year of follow up," said Dr Marie Paule Richard, Chief Medical Officer at TiGenix. "It is important to also note that the definition of combined remission used in the ADMIRE-CD study, which includes both clinical and radiological assessment by MRI, is more stringent than the criteria commonly used in previous large scale, randomized clinical trials evaluating perianal fistulas in Crohn's disease, based only on clinical assessment."

TRUXIMA LAUNCHED IN IRELAND Mundipharma and its network of independent associated companies will launch Truxima (rituximab) in the UK, Germany, Italy, Netherlands, Belgium, Republic of Ireland and Luxembourg, following authorisation by the EMA. Truxima is the first biosimilar monoclonal antibody authorised by the European Commission (EC) for the treatment of cancers, including diffuse large B-cell lymphoma, follicular lymphoma and chronic lymphocytic leukaemia. The marketing authorisation of Truxima was granted by the EMA on the basis of a rigorous comparability exercise that included preclinical and clinical testing. As a result, it has been demonstrated via quality, nonclinical and clinical data that all major physicochemical characteristics and biological activities of Truxima were comparable to those of the reference product. Like the reference product, Truxima is therefore authorised for the treatment of diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic leukaemia, rheumatoid arthritis,

granulomatosis with polyangiitis and microscopic polyangiitis. Monoclonal antibodies are biologics – large, complex molecules isolated from natural sources, human, animal or microorganism. Biologics have led to significant improvements in the treatment of cancers since their introduction in 1998, but growing usage has resulted in a high financial burden on European healthcare systems at a time when newer innovative cancer therapies are also competing for funding in cost conscious times. In 2015, the reference product (Mabthera) was the world’s top selling cancer drug, costing healthcare systems over US$7.1 billion worldwide. As Truxima is intended to cost less than the reference product, it is hoped that cost savings from using a biosimilar rituximab will enable access for patients in need of new innovative cancer therapies. Truxima is the second biosimilar monoclonal antibody to be marketed and distributed by the Mundipharma network in Europe, having launched infliximab, the first biosimilar monoclonal antibody, in 2015.

POSITIVE RESULTS FOR LYNPARZA AstraZeneca has announced positive results from its Phase III OLYMPIAD trial comparing Lynparza (olaparib) tablets (300mg twice daily) to physician’s choice of a standard of care chemotherapy in the treatment of patients with HER2-negative metastatic breast cancer harbouring germline BRCA1 or BRCA2 mutations. Patients treated with Lynparza showed a statistically-significant and clinically-meaningful improvement in progression-free survival (PFS) compared with those who received chemotherapy (capecitabine, vinorelbine or eribulin). Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: “These results are positive news for patients with BRCA-mutated metastatic breast cancer, a disease with a high unmet need, and are the first positive Phase III data for a PARP inhibitor beyond ovarian cancer. This is highly encouraging for the development of our broad portfolio which aims to treat multiple cancers by targeting DNA damage response pathways.” Initial findings from the OLYMPIAD study indicate that the safety profile of Lynparza was consistent with previous studies.

PFIZER RECEIVES POSITIVE CHMP OPINION IN EUROPE FOR XELJANZ® Pfizer Healthcare Ireland announced recently that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion recommending XELJANZ® (tofacitinib citrate) 5 mg twice daily (BID) for the treatment of patients with moderate to severe active rheumatoid arthritis (RA). The CHMP’s opinion will now be sent to the European Commission (EC) for final decision. If approved, XELJANZ in combination with methotrexate (MTX) will be indicated for the treatment of moderate to severe active RA in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying antirheumatic drugs. XELJANZ can be given as monotherapy in case of intolerance to MTX or when treatment with MTX is inappropriate. “More than 2.9 million people are currently living with moderate to severe rheumatoid arthritis in Europe. Even with multiple therapeutic options, many of these people may not adequately respond to currently available treatments, including methotrexate,” said Dr Declan O’Callaghan, Medical Director, Pfizer Healthcare Ireland. “The positive CHMP opinion for tofacitinib is an important milestone as we work to bring this new oral treatment option to people in the European Union living with moderate to severe active rheumatoid arthritis.” The marketing authorisation application (MAA) included data from the Oral Rheumatoid Arthritis Phase 3 TriaLs (ORAL) global development program in RA. This program consisted of six completed clinical trials, ORAL Start, ORAL Solo, ORAL Standard, ORAL Sync, ORAL Scan, and ORAL Step, in addition to two open-label long-term extension (LTE) studies. At the time of the MAA submission, the ORAL development program had accumulated more than 19,000 patient-years of drug exposure in over 6,100 patients with follow-up observations of up to eight years in one of the LTE studies. Tofacitinib is part of the Janus kinase (JAK) inhibitor class of medications. This will be a new class of medicines for the treatment of moderate to severe active RA in the EU.

63 JUST A DROP OSTOMY DEODOURISER Just A Drop Ostomy Deodouriser is ideal for those with ostomy bags as it works to eliminate odours in the toilet bowl and is also safe to use in the pouch. Each time the pouch is emptied one or two squirts are placed directly in the toilet bowl or inside the ostomy pouch. Just a Drop is safe, effective, non-toxic and easy to use. Just a Drop is available in handy 30ml and 240ml. The GMS codes are: Just A Drop 30ml - 93929 Just A Drop 240ml - 93940

NEW MODEL FOR SAVING LIVES FROM FUNGAL DISEASE GAFFI (Global Action Fund for Fungal Infections) has published its third annual report demonstrating progress made in its mission to reduce illness and death associated with fungal disease worldwide. A new model for reducing illness and death from fungal disease is being implemented in Guatemala and is providing the basis for a new toolkit to effectively educate health professionals, diagnose infections and supply affordable treatment. GAFFI’s focus is to leverage this emerging toolkit and work with health professionals, governments and partner organisations to combat fungal infections in AIDS and TB patients. However, the challenges are complex and large and GAFFI is again calling on global health agencies, decision makers and medical opinion leaders to work with them to do more to save what they believe are over a million preventable deaths every year. GAFFI President Dr David Denning, who is Professor of Infectious Disease in Global Health at The University of Manchester says by mapping the incidence of global disease in the world’s worst affected counties, what has become critical is the importance of improved access to antifungal drugs.

He explains, “GAFFI’s pioneering project in Guatemala paves the way for other regions and countries. Rapid non-culture tests, fast sample transport, advanced clinical training, mobile phone ordering and results delivery are transformational together. By scaling this and related models across the globe we will achieve our ambitions. In 2017 our key priorities remain establishing improved access for non-culture diagnostics and antifungal drugs.” A Geneva-based Foundation, GAFFI is the major advocacy and fund raising body for a number of implementing partners, including governments and both national and international global health agencies.

RECOMMENDATION FOR BROADENING AUTHORISATION FOR DARZALEX Janssen-Cilag International NV has announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended broadening the existing marketing authorisation for Darzalex® (daratumumab).

If approved by the European Commission, daratumumab can be used in combination with lenalidomide and dexamethasone; or bortezomib and dexamethasone, for the treatment of adult patients with multiple myeloma (MM) who have received at least one prior therapy. Despite the incredible work of the oncology community over the past decade, MM remains an incurable blood cancer that occurs when malignant plasma cells grow uncontrollably in the bone marrow. The Positive Opinion of the CHMP was based on a review of data from the Phase III MMY3003 (POLLUX) study, published in The New England Journal of Medicine in October 2016,3 and the Phase III MMY3004 (CASTOR) study, also published in The New England Journal of Medicine in August 2016. The safety profile of daratumumab in combination with standard-of-care regimens was consistent with monotherapy studies. In combination with lenalidomide, and

dexamethasone (POLLUX) the most common adverse events of grade 3 or 4 during treatment were neutropenia (51.9%), thrombocytopenia (12.7%), and anaemia (12.4%). Daratumumab-associated infusion-related reactions occurred in 47.7% of the patients and were mostly of grade 1 or 2. In combination with bortezomib and dexamethasone (CASTOR) three of the most common grade 3 or 4 adverse events reported were thrombocytopenia (45.3%), anaemia (14.4%), and neutropenia (12.8%). Infusionrelated reactions that were associated with daratumumab treatment were reported in 45.3% of the patients; these reactions were mostly grade 1 or 2 (grade 3 in 8.6% of patients), and in 98.2% of these patients, they occurred during the first infusion. “This positive opinion recognises progress in the treatment of multiple myeloma and has the potential to offer new treatment options to eligible patients”, said Torben Plesner, MD, Vejle Hospital, Vejle, Denmark, a daratumumab clinical trial investigator. “Daratumumab has already demonstrated singleagent efficacy in highly refractory patients. Now, consistent with these data, the results when used in combination with standard-ofcare regimens after one prior line of therapy are also encouraging.” Daratumumab first received conditional approval from the European Commission (EC) in May 2016, indicated as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor (PI) and an immunomodulatory agent, and who have demonstrated disease progression on the last therapy. Daratumumab was the first CD38-directed monoclonal antibody approved for use worldwide.

SANOFI PASTEUR AND MEDIMMUNE COLLABORATE ON MONOCLONAL ANTIBODY Sanofi and its vaccines global business unit Sanofi Pasteur have announced an agreement with MedImmune, the global biologics research and development arm of AstraZeneca, to develop and commercialize a monoclonal antibody - called MEDI8897 - for

the prevention of Respiratory Syncytial Virus (RSV) associated illness in newborns and infants. According to the Centres for Disease Control and Prevention, RSV is the most common cause of lower respiratory tract infections in children younger than 1 year of age in the United States and worldwide. MEDI8897 is a highly potent monoclonal antibody (mAb) that neutralizes RSV by binding the RSV fusion (F) protein expressed on virions and infected cells; it has been engineered to have a long half-life so that only one dose would be needed for the entire RSV season. It is being developed for the passive immunization of the infant population. MEDI8897 is currently being investigated in a Phase IIb study in preterm infants with plans for a Phase III trial in healthy full-term infants. MEDI8897 received fast-track designation from the U.S. FDA in 2015. "RSV is considered to be the most important missing indication in the vaccination schedule of newborns," said David Loew, Sanofi Executive Vice President and head of Sanofi Pasteur. "As a global leader in the pediatric vaccine industry, this deal with MedImmune therefore makes perfect sense for Sanofi Pasteur. RSV causes major, seasonal worldwide outbreaks and the severity is predominant among young infants," he continued. "We look forward to working with MedImmune to offer a solution to this common lowerrespiratory disease when infants are most vulnerable." Under the terms of the agreement, Sanofi Pasteur will make an upfront payment of ¤120 million and pay up to ¤495 million upon achievement of certain development and sales-related milestones. The two companies will share all costs and profits equally. MedImmune will continue to lead all development activity up to the first approval, and AstraZeneca will retain MEDI8897 manufacturing activities. Sanofi-Pasteur will lead the commercialization activities for MEDI8897.

HPN • March 2017

As an adjunct to diet and exercise for appropriate patients with type 2 diabetes








NOW EVEN MORE REASONS TO CHOOSE JANUVIA® FIRST AS A PARTNER TO METFORMIN1 Januvia or Janumet. For Januvia only– Renal Impairment: Lower dosages are recommended in patients with moderate and severe renal impairment, as well as in ESRD patients requiring haemodialysis or peritoneal dialysis- see Dosage. For Janumet only - Lactic acidosis and renal function: a very rare, but serious, metabolic complication can occur due to metformin accumulation. Cases in patients on metformin have occurred primarily in diabetic patients with significant renal failure. Reduce incidence by assessing other associated risk factors. If suspected, discontinue treatment and hospitalise patient immediately. Determine serum creatinine concentrations regularly, i.e. at least once a year in patients with normal renal function and at least two to four times a year in patients with serum creatinine levels at or above the upper limit of normal and in elderly patients. Decreased renal function in elderly patients is frequent and asymptomatic. Exercise special caution where renal function may become impaired, e.g. when initiating antihypertensive or diuretic therapy or when starting treatment with a non-steroidal anti-inflammatory drug (NSAID). Surgery: due to metformin hydrochloride content of Janumet, discontinue treatment 48 hours before elective surgery with general, spinal or epidural anaesthesia. Do not resume earlier than 48 hours afterwards and only after renal function is normal. INTERACTIONS For Janumet only - Alcohol: avoid alcohol and medicinal products containing alcohol due to risk of lactic acidosis. Cationic agents that are eliminated by renal tubular secretion (e.g., cimetidine): these may interact with metformin by competing for common renal tubular transport systems. Consider close monitoring of glycaemic control, dose adjustment within the recommended posology and changes in diabetic treatment when these agents are co-administered. Iodinated contrast agents in radiological studies: intravascular administration of these agents may lead to renal failure, resulting in metformin accumulation and a risk of lactic acidosis. Discontinue Janumet prior to, or at the time of the test and do not reinstitute until 48 hours afterwards, and only after renal function is found to be normal. Combination requiring precautions for use: glucocorticoids (given by systemic and local routes) beta-2-agonists, and diuretics have intrinsic hyperglycaemic activity. Inform the patient and perform more frequent blood glucose monitoring, especially at the beginning of treatment. If necessary, adjust dose of the anti-hyperglycaemic medicine during therapy with, or on discontinuation of the other medicine. ACE-inhibitors: as these may decrease the blood glucose levels, if necessary, adjust dose of the antihyperglycaemic during therapy with, or on discontinuation of the other medicine. PREGNANCY AND LACTATION: Do not use during pregnancy or breast-feeding. Animal data do not suggest an effect of treatment with sitagliptin on male and female fertility. Human data are lacking. SIDE EFFECTS Refer to SmPC for complete information on side effects There have been no therapeutic clinical trials conducted with Janumet tablets however Janumet is bioequivalent to co-administered sitagliptin and metformin. Sitagliptin: Serious adverse reactions including pancreatitis and hypersensitivity reactions have been reported. Hypoglycaemia has been reported in combination with sulphonylurea and insulin. The following adverse reactions were reported from both clinical trials and post-marketing experience: Sitagliptin only: Common: hypoglycaemia, headache, Uncommon: dizziness, constipation and pruritus. Sitagliptin with metformin: Common: hypoglycaemia, nausea, flatulence and vomiting; Uncommon: somnolence; upper abdominal pain, diarrhoea, constipation and pruritus. For Januvia and Janumet: Post-marketing experience additional side effects have been reported (frequency not known): hypersensitivity reactions, including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, exfoliative skin conditions including Stevens-Johnson syndrome (see precautions), and bullous pemphigoid; acute pancreatitis, including fatal and non-fatal haemorrhagic and necrotising pancreatitis (see precautions); impaired renal function, including acute renal failure (sometimes requiring dialysis); vomiting; pain in extremity, arthralgia, myalgia, back pain and arthropathy; interstitial lung disease. Januvia: Description of selected adverse reactions Adverse experiences reported regardless of causal relationship to medication and occurring more commonly in patients treated with sitagliptin included upper respiratory tract infection, nasopharyngitis, osteoarthritis and pain in extremity. In the Trial Evaluating Cardiovascular Outcomes with sitagliptin (TECOS), after a median follow up of 3 years, sitagliptin, when added to usual care, did not increase the risk of major adverse cardiovascular events, or the risk of hospitalisation for heart failure compared to usual care without sitagliptin in patients with type 2 diabetes and established cardiovascular disease. PACKAGE QUANTITIES Januvia 25 mg, 50 mg and 100 mg film-coated tablets 28 tablets Janumet 50mg/850mg and 50mg/1000mg film-coated tablets 56 tablets Legal Category: POM. Marketing Authorisation Numbers Januvia 25 mg: EU/1/07/383/002 Janumet 50 mg/850 mg: EU/1/08/455/003 Januvia 50 mg: EU/1/07/383/008 Janumet 50 mg/1000 mg: EU/1/08/455/010 Januvia 100mg: EU/1/07/383/014 Marketing Authorisation Holder Merck Sharp & Dohme Limited, Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, UK Date of revision: January 2016 © Merck Sharp & Dohme Ireland (Human Health) Limited, 2016. All rights reserved. Further information is available on request from: MSD, Red Oak North, South County Business Park, Leopardstown, Dublin 18 or from Date of preparation: October 2016. Adverse events should be reported. Reporting forms and information can be found at Adverse events should also be reported to MSD (Tel: 01-299 8700)

Reference: 1. Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373(3):232–242.

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


JANUVIA® (Sitagliptin) JANUMET® (Sitagliptin/metformin hydrochloride) ABRIDGED PRESCRIBING INFORMATION Refer to Summary of Product Characteristics (SmPC) before prescribing. PRESENTATION Januvia® 25 mg, 50 mg and 100 mg film-coated tablet each containing 25 mg, 50 mg or 100 mg of sitagliptin respectively. Janumet® 50 mg/850 mg and 50 mg/1000 mg tablets each containing 50 mg sitagliptin and 850 mg or 1000 mg metformin hydrochloride. INDICATIONS For adult patients with type 2 diabetes mellitus Januvia is indicated to improve glycaemic control: as monotherapy • in patients inadequately controlled by diet and exercise alone and for whom metformin is inappropriate due to contraindications or intolerance as dual oral therapy in combination with • metformin when diet and exercise plus metformin alone do not provide adequate glycaemic control • a sulphonylurea when diet and exercise plus maximal tolerated dose of a sulphonylurea alone do not provide adequate glycaemic control and when metformin is inappropriate due to contra-indications or intolerance • a PPARγ agonist (i.e. a thiazolidinedione) when use of a PPARγ agonist is appropriate and when diet and exercise plus the PPARγ agonist alone do not provide adequate glycaemic control as triple oral therapy in combination with • a sulphonylurea and metformin when diet and exercise plus dual therapy with these medicinal products do not provide adequate glycaemic control. • a PPARγ agonist and metformin when use of a PPARγ agonist is appropriate and when diet and exercise plus dual therapy with these medicinal products do not provide adequate glycaemic control. Januvia is also indicated as add on to insulin (with or without metformin) when diet and exercise plus stable dosage of insulin do not provide adequate glycaemic control. Janumet: as an adjunct to diet and exercise to improve glycaemic control in patients inadequately controlled on their maximal tolerated dose of metformin alone or those already being treated with the combination of sitagliptin and metformin. • in combination with a sulphonylurea (i.e., triple combination therapy) as an adjunct to diet and exercise in patients inadequately controlled on their maximal tolerated dose of metformin and a sulphonylurea. • as triple combination therapy with a PPARγ agonist (i.e., a thiazolidinedione) as an adjunct to diet and exercise in patients inadequately controlled on their maximal tolerated dose of metformin and a PPARγ agonist. • as add on to insulin (i.e., triple combination therapy) as an adjunct to diet and exercise to improve glycaemic control in patients when stable dosage of insulin and metformin alone do not provide adequate glycaemic control. DOSAGE AND ADMINISTRATION Januvia - One 100 mg sitagliptin tablet once daily, with or without food. Janumet - The dose of antihyperglycaemic therapy with Janumet should be individualised on the basis of the patient’s current regimen, effectiveness, and tolerability while not exceeding the maximum recommended daily dose of 100 mg sitagliptin. For patients not adequately controlled on metformin alone, the usual starting dose should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) plus the dose of metformin already being taken. For patients switching from co-administration of sitagliptin and metformin, Janumet should be initiated at the dose of sitagliptin and metformin already being taken. For patients inadequately controlled on dual combination therapy with the maximal tolerated dose of metformin and a sulphonylurea or with maximal tolerated dose of metformin and a PPARγ agonist or with maximal tolerated dose of metformin and insulin, the dose should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and a dose of metformin similar to the dose already being taken. All patients should continue their recommended diet with an adequate distribution of carbohydrate intake during the day. Januvia and Janumet - In combination with a sulphonylurea or with insulin, consider a lower dose of sulphonylurea or insulin, to reduce risk of hypoglycaemia. Renal impairment: For Januvia only: When considering sitagliptin with another anti-diabetic product, its use in patients with renal impairment should be checked. Moderate impairment (CrCl ≥30 to <50 mL/min), the dose is 50 mg once daily. Severe impairment (CrCl <30 mL/min) or with end-stage renal disease (ESRD), the dose is 25 mg once daily. Mild impairment, no dose adjustment. Assessment of renal function is recommended prior to initiation of Januvia and periodically thereafter. For Janumet only: Should not be used in patients with moderate or severe renal impairment (creatinine clearance < 60 ml/min). Hepatic impairment: For Januvia only - no dosage adjustment necessary for patients with mild to moderate hepatic impairment. Januvia has not been studied in patients with severe hepatic impairment and care should be exercised. However, because sitagliptin is primarily renally eliminated, severe hepatic impairment is not expected to affect the dose of sitagliptin. For Janumet only – do not use. Elderly < 75 years: For Januvia only - no dosage adjustment necessary. For Janumet only - use with caution as age increases. Monitoring of renal function is necessary to aid prevention of metformin-associated lactic acidosis. Children: no data available. CONTRAINDICATIONS For Januvia - Hypersensitivity to active substance or excipients. For Janumet - Hypersensitivity. Diabetic ketoacidosis and diabetic pre-coma. Moderate and severe renal impairment (creatinine clearance < 60 ml/min). Acute conditions with the potential to alter renal function such as dehydration, severe infection, shock. Intravascular administration of iodinated contrast agents. Acute or chronic disease which may cause tissue hypoxia such as cardiac or respiratory failure, recent myocardial infarction, shock. Hepatic impairment. Acute alcohol intoxication, alcoholism. Lactation. PRECAUTIONS AND WARNINGS For Januvia and Janumet - General: do not use in patients with type 1 diabetes or for diabetic ketoacidosis. Acute pancreatitis: Use of DPP 4 inhibitors has been associated with a risk of developing acute pancreatitis Inform patients of the symptom of acute pancreatitis: persistent, severe abdominal pain. Resolution of pancreatitis has been observed after discontinuation of sitagliptin, but very rare cases of necrotising or haemorrhagic pancreatitis and/or death have been reported. If pancreatitis is suspected, Januvia or Janumet and other potentially suspect medicinal products should be discontinued; if acute pancreatitis is confirmed, Januvia or Janumet should not be restarted. Caution should be exercised in patients with a history of pancreatitis. Hypoglycaemia when used with other anti-hyperglycaemic medicinal products: Rates of hypoglycaemia reported with sitagliptin were generally similar to rates in patients taking placebo. Hypoglcaemia has been observed when sitagliptin was used in combination with insulin or a sulphonylurea (see side effects). Therefore consider a lower dose of sulphonylurea or insulin to reduce the risk of hypoglycaemia when administering Janumet or Januvia. Hypersensitivity reactions: Serious hypersensitivity reactions have been reported, including anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Onset occurred within the first 3 months after initiation of treatment with some reports occurring after the first dose. If suspected, discontinue

HPN March 2017  
HPN March 2017