HPN March 2016
HOSPITAL PROFESSIONAL NEWS IRELAND Irelandâ€™s Dedicated Hospital Professional Publication
IN THIS ISSUE: NEWS: HSE medicine spend up 28% Page 4
S TA N D A R D S O L U T I O N S
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NEWS: Health products regulator sets strategic direction Page 8 REPORT: Dr Fidelma Fitzpatrick talks on Turning the antibiotic tide Page 9 REPORT: IPHA refute OECD Irish spending claims Page 20 CPD: Hospital based management of Pain Page 23 CLINICAL: Medical Oncology Advances in 2016 Page 28
Fresenius Kabi Ltd Unit 3B Fingal Bay Business Park Balbriggan, Co. Dublin T: +353 (0)1 841 3030 F: +353 (0)1 849 6949 www.fresenius-kabi.ie
FEATURE: Overview and Treatment options for Ovarian cancer Page 32
NEW ONCE-DAILY LIXIANA® ANOTHER STEP AHEAD.
Only LIXIANA combines: ®
Proven efficacy comparable to well-controlled warfarin1,2 Superior reduction in clinically relevant bleeding vs. well-controlled warfarin1,2 Once-daily dosing across both NVAF and VTE indications3 Indicated for: 3 Prevention of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation (NVAF) with one or more risk factors, such as congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke or transient ischaemic attack (TIA) Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults LIXIANA▼ (edoxaban) 60 mg/30 mg/15 mg film coated tablets ▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. See summary of product characteristics prior to prescribing for full list of adverse events. Presentation: 60 mg (yellow) / 30 mg (pink) / 15 mg (orange) edoxaban film coated tablets (as tosilate). Indications: Prevention of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation (NVAF) with one or more risk factors, such as congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke or transient ischaemic attack (TIA) and treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults. Posology and method of administration: NVAF - The recommended dose is 60 mg edoxaban once daily with or without food. Therapy with edoxaban in NVAF patients should be continued long term. VTE - The recommended dose is 60 mg edoxaban once daily following initial use of parenteral anticoagulant for at least 5 days with or without food. Duration of therapy (at least 3 months) should be based on risk profile of the patient. For NVAF and VTE the recommended dose is 30 mg edoxaban once daily in patients with one or more of the following clinical factors: moderate or severe renal impairment (creatinine clearance (CrCl) 15–50 ml/min), low body weight ≤60 kg and/or concomitant use of the following P-glycoprotein (P-gp) inhibitors: ciclosporin, dronedarone, erythromycin, or ketoconazole. The 15 mg dose of edoxaban is not indicated as monotherapy, and should only be used during a switch from edoxaban to VKA (see SmPC for full details). If a dose of edoxaban is missed, the dose should be taken immediately and then continued once daily on the following day. Contraindications: Hypersensitivity to the active substance or to any of the excipients; clinically significant active bleeding. Hepatic disease associated with coagulopathy and clinically relevant bleeding risk. Lesion or condition, if considered to be a significant risk for major bleeding. This may include current or recent gastrointestinal (GI) ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities. Uncontrolled severe hypertension. Concomitant treatment with any other anticoagulants e.g. UFH, low molecular weight heparins, heparin derivatives (fondaparinux, etc.), VKA or NOACs except under specific circumstances of switching oral anticoagulant therapy or when UFH is given at doses necessary to maintain an open central venous or arterial catheter. Pregnancy and breastfeeding. Special warnings and precautions for use: Haemorrhagic risk: Use with caution in patients with increased risk of bleeding such as elderly on ASA and should be discontinued if severe haemorrhage occurs. The anticoagulant effect of edoxaban cannot be reliably monitored with standard laboratory testing. A specific anticoagulant reversal agent for edoxaban is not available. Haemodialysis does not significantly clear edoxaban. Renal impairment: Renal function should be assessed prior to initiation of edoxaban and afterwards when clinically indicated. Not recommended in patients with end stage renal disease or on dialysis. Renal function and NVAF: A trend towards decreasing efficacy with increasing creatinine clearance was observed for edoxaban compared to well-managed warfarin. Edoxaban should only be used in patients with NVAF and high creatinine clearance after a careful benefit risk evaluation. Hepatic impairment: Not recommended in patients with severe hepatic impairment and should be used with caution in patients with mild or
moderate hepatic impairment. Edoxaban should be used with caution in patients with elevated liver enzymes (ALT/ AST > 2 x ULN) or total bilirubin ≥1.5 x ULN. Surgery or other interventions: discontinue edoxaban at least 24 hours before the procedure. If the procedure cannot be delayed, the increased risk of bleeding should be weighed against the urgency of the procedure. Edoxaban should be restarted as soon as haemostasis is achieved. Prosthetic heart valves and moderate to severe mitral stenosis: Not recommended. Haemodynamically unstable PE patients or patients who require thrombolysis or pulmonary embolectomy: Not recommended. Patients with active cancer: Not recommended. Drug interactions: The P-gp inhibitors ciclosporin, dronedarone, erythromycin, or ketoconazole result in increased concentration of edoxaban and a dose reduction of 30 mg is required. Edoxaban should be used with caution with concomitant P-gp inducers (e.g. phenytoin, carbamazepine, phenobarbitol or St John’s Wort). Concomitant high dose ASA (325 mg) or chronic NSAIDs is not recommended. There is very limited experience with dual antiplatelet therapy or fibrinolytic agents. Pregnancy: Not recommended. Breastfeeding: discontinue breastfeeding or edoxaban therapy. Undesirable effects: Common: anaemia, epistaxis, lower GI haemorrhage, upper GI haemorrhage, oral/pharyngeal haemorrhage, nausea, blood bilirubin increased, gamma GT increased, cutaneous soft tissue haemorrhage, rash, pruritus, macroscopic haematuria/urethral haemorrhage, vaginal haemorrhage, puncture site haemorrhage, liver function test abnormal. Uncommon: hypersensitivity, intracranial haemorrhage (ICH), intraocular haemorrhage, other haemorrhage, haemoptysis, surgical site haemorrhage. Rare: anaphylactic reaction, allergic oedema, subarachnoid haemorrhage, pericardial haemorrhage, retroperitoneal haemorrhage, intramuscular haemorrhage (no compartment syndrome), intra-articular haemorrhage, subdural haemorrhage, procedural haemorrhage. Legal category: POM. Package quantities: 60 mg/30 mg – 28 tablets. 15 mg – 10 tablets. Marketing Authorisation (MA) number: EU/1/15/993/001-16. MA holder: Daiichi Sankyo Europe GmbH, Zielstattstrasse 48, 81379 Munich, Germany. Additional Information: Available on request from Daiichi Sankyo Ireland Ltd. Telephone: (01) 489 3000. Fax: (01) 489 3033. Email: firstname.lastname@example.org. Date of preparation: July 2015. ▼ This medicine is subject to additional monitoring. Adverse events and product complaints should be reported. To report an adverse event or a product complaint about a Daiichi Sankyo medicine, please call Daiichi Sankyo Ireland Ltd. on (01) 489 3000. Healthcare professionals are also asked to report any suspected adverse reactions to Daiichi Sankyo medicines to HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: (01) 676 4971; Fax: (01) 676 2517. Website: www.hpra.ie; E-mail: email@example.com.
References: 1. Giugliano RP et al. NEJM 2013;369(22):2093–2104. 2. The Hokusai-VTE Investigators. NEJM 2013;369(15):1406–1415. 3. LIXIANA®, Summary of Product Characteristics, www.medicines.ie, September 2015. Date of item: July 2015. EDX/15/0169
HPN March 2016
Government facing huge hospital crisis P4
HPRA launches 2016-202 strategy P8
As Hospital Pharmacy News was going to press the 2016 election results were filtering in. Former Minister for Health James Reilly was one of the high profile members of the outgoing administration to lose his seat.
Kelly Jo Eastwood
Turning the antibiotic resistance tide? P9 Reducing exacerbations in COPD P14 Agreement on hospital over crowding P19
Dr Reilly was eliminated on the 10th and final count in Dublin Fingal, the constituency where he had topped the poll in 2011. He lost his seat to Sinn Féin’s Louise O’Reilly who joined Fianna Fáil’s Darragh O’Brien, the Independents 4 Change candidate Clare Daly, Fine Gael’s Alan Farrell and Labour’s Brendan Ryan in being elected. When asked why he thought he had lost his seat, Dr Reilly suggested the three years he had served as Minister for Health between 2011 and 1014 had definitely played a role. “My time in Health would not have been exactly helpful. But the country had no money, and hard decisions had to be made,” he said.
Regulars CPD: Management of Pain P23
Meanwhile current Minister for Health Dr Leo Varadkar, as expected, topped the poll but failed to get elected until the third count.
Feature: Treatment of Ovarian Cancer P32
Ireland now enters a time of political uncertainty as the fall-out from these results may not be felt immediately. We will have full coverage in our April issue on what the results mean for health.
Feature: Antiretroviral outcomes in HIV P36
Meanwhile however, the Chairperson of the Consultant Committee of the Irish Medical Organisation (IMO), Dr Peader Gilligan, has warned that the next Government will have to grapple with a crisis of major proportions in Irish hospitals.
Feature: Type II Diabetes P40 Clinical Profiles P46
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PUBLISHER IPN Communications Ireland Ltd Clifton House, Lower Fitzwilliam Street, Dublin 2 (01) 669 0562 MANAGING DIRECTOR Natalie Maginnis firstname.lastname@example.org EDITOR Kelly Jo Eastwood email@example.com 00447876548989 ACCOUNTS Jennifer Dunseath firstname.lastname@example.org
COMMERCIAL MANAGER Ingrid Lyons Ingrid@ipnirishpharmacynews.ie + 353 1 669 0562 + 353 87 777 0480 CONTRIBUTORS Gareth Tyrrell Jens Lundgren Ronan Sheridan Dr Fidelma Fitzpatrick DESIGN Ian Stoddart Design Visual Communications www.pharmacynewsireland.com www.facebook.com/ HospitalPharmacyNews
Dr Gilligan described the emigration of thousands of Irish educated doctors to work abroad and the refusal of doctors to apply for available posts in the hospital sector amounts to “the largest example of an industrial action by Doctors ever seen in the Irish health services”. He said, “This is a mass withdrawal of labour by Doctors who have become disillusioned by the Irish health services and who would rather leave the country than work in an under resourced system”. He said there has been more resignations from Consultant positions in Ireland in the last number of years than at any other time in the history of the State and more unfilled Hospital Doctor positions in Irish hospitals than ever before. Dr Gilligan said; “When we think of industrial action we usually think of people walking out of the job and holding placards whilst chanting slogans setting out the reasons for their action. But what we are seeing now is simply industrial actions by another means.” Turn to page 5 for the full story.
HOSPITAL PROFESSIONAL NEWS IRELAND Ireland’s Dedicated Hospital Professional Publication HPN • March 2016
Government is facing a crisis of major proportions in Hospitals The Chairperson of the Consultant Committee of the Irish Medical Organisation (IMO), Dr Peader Gilligan, has warned that the next Government will have to grapple with a crisis of major proportions in Irish hospitals. Dr Gilligan described the emigration of thousands of Irish educated doctors to work abroad and the refusal of doctors to apply for available posts in the hospital sector amounts to “the largest example of an industrial action by Doctors ever seen in the Irish health services”. He said, “This is a mass withdrawal of labour by Doctors who have become disillusioned by the Irish health services and who would rather leave the country than work in an under resourced system”. He said there has been more resignations from Consultant positions in Ireland in the last number of years than at any other time in the history of the State and more unfilled Hospital Doctor positions in Irish hospitals than ever before. Dr Gilligan said, “When we think of industrial action we usually think of people walking out of the job and holding placards whilst chanting slogans setting out the reasons for their action. But what we are seeing now is simply industrial actions by another means.” He cited repeated failures by the
Dr Peader Gilligan, Chairperson, Consultants Committee, IMO HSE and Department of Health and Children as the root cause of the crisis. He said, “The most recently negotiated Consultant Contract in 2008 was never honoured by the employer and an employer who does not honour the terms of a contract is likely to find it difficult to recruit. "An employer who interprets agreements in a way that disadvantages their employees is likely to lose employees. "An employer that treats employees undertaking the same job less favourably on the basis of the date of their employment is likely to be regarded poorly by employees and those considering employment with them. "In short the HSE and the Department of Health, acting at the behest of the Department of Public Expenditure and Reform are having great difficulty employing sufficient Doctors to provide the services our population needs due to their deserved reputation as poor employers that does not honour contracts. "Over half the interns in this country trained in our medical schools will leave on completion of their first clinical year in practice.
Posts that historically would have been highly sought after at Senior House Officer, Registrar, Specialist/ Senior Registrar and Consultant level throughout Ireland remain unfilled. "There are in excess of 300 vacant permanent Consultant posts in Ireland many currently filled by Doctors who would prefer to remain in locum positions rather than take up a full time Consultancy because of the contractual terms currently on offer to senior Hospital Doctors in Ireland."
themselves available for work and in my view this “industrial action” will continue until Doctors feel they and their patients will be treated fairly. Fair treatment of Doctors and patients involves the adequate resourcing of the health service on an ongoing basis. “In fairness” is an expression used in Ireland frequently but there is an absolute lack of fairness in paying people at different rates that have the same qualifications and assume the same level of responsibility and do the same job."
"Doctors are leaving hospital medicine in Ireland at every level of seniority because they feel disillusioned. They may not be holding placards or chanting their grievances but they are not making
The Irish Medical Organisation is calling on all political parties to put health first and fix the problems in our public health services that have been brought about by years of austerity.
per cent over the past six years; the Paediatric Hospital Group recorded a 24% increase; while the South South West and UL Hospital Groups each saw their expenditure increase by a fifth.
said it should be noted that the increase in expenditure was in four major therapy areas where the treatments offered significant patient outcomes, namely oncology, anti-HIV, rheumatology and hepatitis C.
HSE medicine spend up 28% The gross expenditure on drugs and medicines by the HSE has increased by more than ¤82.5 million over the past six years, reaching nearly ¤378 million last year. Over the period 2010 to 2015, expenditure on medicines in public hospitals rose from approximately ¤295.3m to ¤377.92m — or an increase of nearly 28%. The Ireland East Hospital Group — which includes two of Dublin’s major academic teaching hospitals and some of the country’s biggest spenders, the Mater (¤37.43m) and St Vincent’s (¤31.37m) — accounted for the largest overall spend last year at ¤84.12m, and March 2016 • HPN
the highest increase since 2010 — a 58.5% hike over the past six years. Indeed, spend at the Mater jumped from approximately ¤17.78m in 2010 to ¤37.43m last year — more than a doubling over the six-year period. However, nearly four-tenths of that increase occurred between 2014 and 2015. The other main spenders by hospital included: UCHG (¤33.97m), Beaumont (¤31.56m), St James’s (¤26.83m), CUH (¤26.75m) and University Hospital Limerick (¤19.04m).
The figures, recently supplied by the HSE to Fianna Fáil Health spokesperson Billy Kelleher, reveal that the majority of the increase was in the major hospitals that were also designated cancer centres: 67 per cent, or ¤55 million of the increase, was in the Mater, St Vincent’s, Beaumont, UCHG and CUH.
Both the RCSI and Saolta Hospital Groups each saw their spend on drugs and medicines jump by 37
Commenting on the expenditure, the Irish Pharmaceutical Healthcare Association (IPHA)
The Association also pointed to the UK, where over roughly the same period the NHS appeared to have had a 38.7 per cent increase in hospital pharmacy spending. Although there are differences between the UK and Ireland in terms of drugs being prescribed in either a hospital or community setting, IPHA stressed: “This indicates that Ireland is not in fact out of line with our nearest neighbour.”
Agreement reached on transfer of tasks Minister for Health Leo Varadkar has welcomed approval by Brendan Howlin, Minister for Public Expenditure & Reform of an agreement between the health service and unions to transfer four key tasks from doctors to nurses including taking blood, discharging patients, giving first dose antibiotics and administering drugs intravenously. “Since I was a medical student, people have been talking about nurses taking over these tasks from junior doctors. I am really delighted to have got it over the line as Health Minister,” Minister Varadkar said. “This is a win-win for everyone. Nurses will be able to use their new skills and they will benefit financially in return for taking on this additional work. Junior doctors will benefit as the reduced workload will help us to continue to reduce their working hours
and they will be less likely to miss out on important training time in theatre and in clinics. Patients will benefit as there will be fewer delays when it comes to getting their IV antibiotics, their bloods taken or discharge papers, and there will be fewer delays for patients in the clinic waiting rooms as doctors won’t be expected to be on the wards and in a clinic at the same time as frequently as they are now.” The four tasks and their associated elements are: Intravenous cannulation Phlebotomy Intravenous drug administration (first dose) Nurse led discharge Training will come into effect immediately and it will operate mainly in acute hospitals but also in some district hospitals.
“The agreement on the Transfer of Tasks from non-consultant hospital doctors to nurses and midwives under the related provision in the Haddington Road Agreement has been finalised with the approval of Minister Howlin. This agreement enables the most appropriate person to undertake four specific tasks which were previously undertaken by doctors in training. They will now transfer to nursing personnel when appropriate and necessary for patient care or safety,” Minister Varadkar said. “This is a practical reform at ward level that will make things better for patients and staff alike. It is expected to be cost neutral as the costs of implementation will be offset by reduced unscheduled overtime by doctors. It is also a good example of the Haddington Road Agreement in action with pay being restored in return for valuable changes in work practices and reform.”
Allowing the nurse treating the patient to undertake these four tasks will enhance patient care by ensuring early and timely intervention by the person most appropriate to provide that care. This will ultimately lead to better outcomes for patients leading to quicker recovery times and earlier discharge of patients. This agreement reflects the Government’s commitment to public sector change and reform. This reform compliments the initiatives from the Emergency Department agreement between the HSE and the INMO. It is envisaged that the transfer of tasks from medical staff will allow doctors to undertake tasks more appropriate to their training and will support NCHD compliance with the European Working Time Directive.
5 point plan for meeting the challenges of an ageing society Ahead of its annual Congress in Vienna, the European Association of Hospital Pharmacists (EAHP) has published a new policy statement highlighting the important role of hospital pharmacists in meeting the panEuropean challenge of an ageing society. Unanimously approved by delegates of EAHP's 34 member country associations, the statement identifies 5 main areas for policy attention: • Increasing the uptake of medication reconciliation and review by hospital pharmacists as a key response to polypharmacy; • Additional training for all relevant healthcare professionals in respect of the particular care needs of older patients; • Further embedding of intersector communication and
multi-disciplinary working as critical approaches to meeting the health system challenges of an ageing society; • Regulatory innovation to improve the participation of older patients in clinical trials; • Improvement in best practice sharing and adoption across Europe to ensure the internal health system challenge of an ageing health workforce is successfully met. Commenting on the statement, EAHP President Joan Peppard says, "In the first instance, Europe's ageing society marks a great achievement by our health and social systems, that so many people are living longer and healthier lives. However we recognise the challenges that are emerging, and one of these is multimorbidity with the connected issue of polypharmacy.
“It really must be emphasised to policy makers everywhere that there is a healthcare profession ready and equipped to assist. As the policy statement we publish today makes clear, the evidence in favour of hospital pharmacist led medicines reconciliation and review in reducing overprescription and helping older patients manage their medicines is evident. However, as the results of EAHP's recently published surveys of practice make clear, there
is work still be done to ensure patients get access to the clinical pharmacy services they deserve. “When health system managers think of the ageing society challenge, they should think multimorbidity, think polypharmacy, and think of the hospital pharmacist services that can be further leveraged with their support. Solutions exist, and one of them is called the hospital pharmacist."
HPAI Annual Conference 2016 The 2016 HPAI Annual Educational Conference will take place in the Crowne Plaza Hotel, Santry, Dublin from April 8th - 10th, 2016. Registration will open Friday 15th January. Please note you must have paid your HPAI 2016 Membership Fees before you can register for Conference 2016. Registration is available at (http://hpai2016.exordo.com/login) To avoid disappointment it is important to register as early as possible. Places are filled on a first come, first served basis. Final date for the registration is 25th March 2016.
HPN • March 2016
Study to look at differing approaches to medicines pricing challenge The European Commission has published a new study examining differing approaches by national governments in the EU to the challenge of managing medicines expenditure. The report pays particular attention to the phenomena of external reference pricing, and the prospects for a European approach of 'differential pricing' according to country GDP (Gross Domestic Product). EPR, also known as external reference pricing or international price comparison/benchmarking, is defined in the report "as the practice of using the price(s) of a medicine in one or several
countries in order to derive a benchmark or reference price for the purposes of setting or negotiating the price of a medicine in a given country." EPR is used in 29 countries in the EU, as well as in Iceland, Norway, Switzerland and Turkey, though different approaches are applied in Germany, Sweden and the UK, which employ various forms of EPR, value-based pricing (VBP) and other pricing regulation schemes. According to a survey from last year, the commission found that 20 of the 29 countries that apply EPR use this policy as their sole
or main pricing policy. Countries most frequently referenced to are France, Belgium, Denmark and Spain, followed by Italy, the UK and to a lesser extent, Austria, Germany and Slovakia. But the details of how an EPR scheme is designed differs between countries, the report notes, as 21 countries compare medicine prices at the level of exfactory prices, while eight countries at the pharmacy purchasing price (wholesale price) level. The study identifies ways in which EU countries could improve the operation of external reference pricing, including improving: • the account taken of currently confidential discounts; • the operation of the 'Eurepid database' for sharing information between EU countries on pricing; • coordination between EU countries to have more harmonized method of comparison Meanwhile, the report also examines the feasibility of achieving a system of 'differential pricing', the strategy of selling
the same product to different customers at different prices, in the case of medicines, dependent on country income (or ability to pay). Such approaches have been used in respect to delivering access to vaccines and other vital medicines in low-income countries outside Europe. The study is skeptical to both the possibility of achieving European agreement for such a scheme, as well as the proposed benefits that would be achieved. The study states: "The introduction of a fully-fledged DP scheme in Europe, as a government policy or EC supported policy in full respect of the subsidiarity principle, though not completely impossible, would however require addressing major obstacles in legal, technical, organisational and political terms and might not be the most preferred policy to address challenges in equitable access to medicines." The study was written by Gesundheit Österreich Forschungund Planungs GmbH and funded by the Health Programme of the European Union.
Further investment in blood cancer research Further significant investment in blood cancer research has been announced, that will benefit more patients across Ireland. The Irish Cancer Society charity is committing ¤450,000 over the next five years to support the expansion of Blood Cancer Network Ireland, a new clinical research network for blood cancers. Blood Cancer Network Ireland (BNCI) was established by the Irish Cancer Society and Science Foundation Ireland in 2015 to provide blood cancer patients across Ireland improved access to novel drugs and treatments through early stage clinical trials. On foot of that investment, the Irish Cancer Society has announcing a further commitment of ¤100,000 per annum over the next four and a half years to support and facilitate the Mater University Hospital and Beaumont Hospital to join the clinical research network. As of February, both hospitals have joined existing March 2016 • HPN
Professor Peter O’Gorman
clinical research facilities in NUI Galway, University College Cork, and St James’s Hospital/ Trinity College Dublin to extend the reach of the network into all four Health Service Executive regions. The funding commitment by the Society will support Consultant Haematologists, Professor Peter O’Gorman, Mater University Hospital, and Dr John Quinn, Beaumont Hospital, and clinical research staff to roll out clinical trials to blood cancer patients in the HSE Dublin/ North East region. The network expansion will ultimately enhance access to clinical trials for blood cancer patients attending cancer treatment centres across the HSE Dublin/North East, HSE Dublin Mid Leinster, HSE West and HSE South regions.
Consultant Haematologist at the Mater University Hospital and Professor of Experimental Haematology at Dublin City University, Professor Peter O’Gorman, said joining the network would bring greater hope for more blood cancer patients: “Over the last five years tremendous progress has been made in participation in clinical trials, providing early access to many Irish patients with blood
cancer to the best available treatments. More recently we have started to develop new trials initiated by Irish investigators and joined by international collaborators. Blood Cancer Network Ireland (BCNI) will focus on further developing early phase clinical trials. A key component of the BCNI approach will be developing scientific research and bio banking in tandem with the clinical trial programme.”
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) 1000 mg concentrate for solution for infusion 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 therapy. 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: 6 treatment cycles each of 28 days duration. Dose: Cycle 1: 1000 mg split over Day 1 (100 mg) and Day 2 (or Day 1 continued: if the first bag is completed without modifications of the infusion rate or interruptions, the same bag may be administered on the same day with no dose delay necessary and no repetition of premedication) (900 mg), 1000 mg on Day 8 and 1000 mg on Day 15 of a 28-day treatment cycle. Cycles 2 - 6: 1000 mg on day 1. Administration: Monitor closely for infusion related reactions (IRRs) 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): 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: Administer at 100 mg/hr, with escalation by 100 mg/hr increments every 30 minutes to a maximum of 400 mg/hr. 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 1000 mg with most patients having no IRRs during subsequent administrations. Mitigation measures to reduce IRRs should be followed (see SmPC). Patients with a high tumour burden (peripheral 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. Cases of cytokine release syndrome have been reported with Gazyvaro. 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 more frequently in patients with renal impairment (CrCl <50 mL/min). Patients with neutropenia should be closely monitored with regular laboratory tests until resolution. Treat in accordance with local guidelines and consider administration of granulocyte-colony stimulating factor. Consider dose delays with severe or life threatening neutropenia. For severe and long lasting (>1 week) neutropenia, antimicrobial prophylaxis strongly recommended throughout the treatment period until resolution to Grade 1 or 2. Antiviral and antifungal prophylaxis should be 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 more frequently in patients with renal impairment (CrCl <50 mL/min). 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 all concomitant therapies which could worsen thrombocytopenia events
References: 1. Goede V et al. N Engl J Med 2014; 370:1101-1110 and Supplementary Appendix Zinc code: IE/GAZ/0515/0004 Date of preparation: February 2016
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 hepatitis B virus 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 interaction studies have been performed. 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 have to 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. Undesirable Effects: For full listings please refer to the Gazyvaro SmPC. Most frequently observed adverse drug reactions (ADRs) were IRRs which occurred in the majority of patients during the first cycle (65% with first 1000 mg infusion decreasing to less than 3% with subsequent infusions). Associated symptoms were nausea, chills, hypotension, pyrexia, vomiting, dyspnoea, flushing, hypertension, headache, tachycardia, and diarrhoea. Neutropenia and thrombocytopenia occurred in 41% and 15% patients respectively with incidence of Grade 3-5 infection being 16%. Very common (≥ 1/10): neutropenia, thrombocytopenia, anaemia, diarrhoea, pyrexia, IRRs. Common (≥1/100 to <1/10): urinary tract infection, nasopharyngitis, oral herpes, rhinitis, pharyngitis, squamous cell carcinoma of skin, leukopenia, TLS, hyperuricaemia, atrial fibrillation, hypertension, cough, constipation, alopecia, arthralgia, back pain, musculoskeletal chest pain, WBC count decreased, neutrophil count decreased, weight increased. Serious or potentially serious adverse events: IRRs; TLS; neutropenia; thrombocytopenia; cardiac events; PML (very rarely); bacterial, fungal and new or reactivated viral infection; worsening of pre-existing cardiac conditions; arrhythmias, angina pectoris, acute coronary syndrome, myocardial infarction and heart failure (these events may occur as part of an IRR and can be fatal). Elderly: Patients aged ≥75 years experienced more serious adverse events leading to death than patients < 75 years. See SmPC section 4.8 for instructions on reporting Suspected Adverse Reactions. Legal Category: Product subject to medical prescription which may not be renewed (A). Presentations & Marketing Authorisation Number: 1000 mg of obinutuzumab in 40ml (25mg/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: September 2015
▼ 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:
Alternatively, suspected adverse reactions should be reported to:
The Drug Surveillance Centre Roche Products (Ireland) Limited Telephone: (01) 4690700 Fax: (01) 469 0793 Email: email@example.com
The Pharmacovigilance Section Health Products Regulatory Authority (HPRA) Telephone: (01) 676 4971 Fax: (01) 676 2517 Website: www.hpra.ie Email: firstname.lastname@example.org
Health products regulator sets strategic direction Lorraine Nolan, HPRA, Chief Executive
HPRA Strategic Plan 2016 – 2020
STRATEGIC GOALS AND OBJECTIVES FOR 2016 – 2020
In response to the challenges and opportunities we see in the environment and building on our achievements over the last strategic plan, we have identified five goals for 2016 – 2020. The goals and the underlying logic linking them are shown graphically below.
The Health Products Regulatory Authority (HPRA) has launched its Strategic Plan 2016-2020 which outlines its goals, objectives and high level strategic actions for the next five years. The plan has been prepared in consultation with staff and a range of external stakeholders including those who use health products, and in line with Department of Health priorities. The document states, “In this plan, we have set out the strategic direction which will guide the HPRA over the next five years. It describes the environmental conditions and developments expected over the planning period, the strategic goals we have set, and a clear roadmap to our stakeholders and staff showing how we will achieve these goals. “The strategic objectives and actions are, of necessity, broadly focussed, and will require planning and delivery over a number of years to achieve. The detailed activities will be developed and delivered through the annual business planning cycle. The outputs of annual business plans will, over time, contribute to the achievement of the strategic outcomes we have defined. Effective management of the planning and reporting process is key to ensuring that the outcomes we have set are met for those patients, users and animals who use the products we regulate.” The goals and the underlying logic linking them are shown graphically above. March 2016 • HPN
the integrity of the supply chain to avoid illegal products reaching patients, are significant areas of focus in the HPRA’s five year plan. Strategic Goal 4 – Supporting Innovation: Ireland has a substantial and growing lifesciences industry. The HPRA aims to strengthen its capabilities in providing regulatory assistance to companies developing new products. In addition, new developments taking place in research centres will point to the technologies that the HPRA will need to regulate in the future. Strategic Goal 5 – Internal Capabilities: The HPRA will continue to invest in and develop its internal expertise. Appropriate systems and resources to manage all aspects of the business will be enhanced, so that the HPRA meets the opportunities and challenges presented by external developments. Chairman of the HPRA, Ms Ann Horan, said, “The HPRA’s strategic plan reflects our mission to protect and enhance human and animal health by regulating medicines, medical devices and other health products. It is a robust strategic document that builds on the significant expansion of the HPRA’s remit over a number of years. The direction of the plan clearly outlines the high level actions required to make sure that the health products we regulate are as safe and beneficial as possible for those who use them.”
On the following pages, the objectives are set out for each goal and the corresponding highlevel actions. These will be cascaded down to annual business plans over the course of the and the public need access to The HPRA’s five core strategic strategy.
clear, readily available, high-quality goals which incorporate 17 high information on continue which to basesome In addition, a number now and will through level actions are: of large projects are in progress or all of the years of this strategy. They include: their health decisions. The HPRA Strategic Goal 1 – Optimised - Clinical trials: implementation of new European Regulation will make use of all appropriate - Medical devices: development and implementation of new EU legislation Regulatory Systems: The HPRA channels to communicate - committed Veterinary legislation: development and implementation of new EU legislation is to appropriate comprehensively and effectively - Further development of interchangeable medicines lists regulation of all health products. with healthplan product users and - Redevelopment of IT systems under the current IT strategic To ensure that the regulatory other key audiences. system keeps pace with We will also remain mindful of the need for contingency capacity, as major issues relating to Goal 3 – Access the areas we regulate that mayproducts, arise from time time, may take significant levels ofto developments in health it toStrategic Health Products: The HPRA is resources to effectively manage. will continue to place an emphasis committed to working with all on effective collaboration with stakeholders to enhance access colleagues at European as well as to health products; this includes international levels. We will also working on measures to reduce work in partnership with other 6 medicine shortages and, when national agencies to develop and they occur, managing those deliver on government policies. shortages better. Maintaining Strategic Goal 2 – Better Informed access to current and future health Users: Healthcare professionals products whilst also protecting
According to Chief Executive, Ms Lorraine Nolan, “The actions and activities identified in our strategic plan provide a clear roadmap for the future focus and development of the HPRA. It involved an extensive consultation process where we gained valuable and important insight and feedback. Our final plan published today reflects the key issues and work areas highlighted during that process where we engaged with our expert staff as well as healthcare professionals, government agencies, patient advocacy groups and the large and vibrant health products sector in Ireland. We welcome the opportunity to work in collaboration with all our stakeholders to deliver on our plan in the years ahead.”
‘Our wits versus their genes’ Is it too late to turn the antibiotic resistance tide? “The future of humanity and microbes likely will unfold as episodes of a suspense thriller that could be titled Our Wits Versus Their Genes” – Joshua Lederberg.
Written by Dr. Fidelma Fitzpatrick, Senior Lecturer, Dept of Clinical Microbiology, Royal College of Surgeons in Ireland and Consultant Microbiologist, Beaumont Hospital, Dublin Ireland in 1916 was a very different place as to how it is today. Irish hospital records from this era outline the tragic fate of many of our citizens that acquired infections (Figure 1). This was the pre-antibiotic era, where most people that acquired an infection died of that infection. In 1916, throat infections resulted in either death or long terms consequences such as rheumatic fever and heart failure, skin infections secondary to simple scrapes and cuts often led to limb amputation and childbirth was associated with significant morbidity and mortality. Nowadays, we live in very different times. Antibiotics have transformed medical practice over the last 70 years. Infections that used to kill people are now treatable. The striking reduction in death rates from infections in Ireland is largely due to the availability of antibiotics, in addition to other socio-economic improvements (Figure 2). Antibiotics have also facilitated many of the advances in medical practice that we now take for granted, such as abdominal and orthopaedic surgery, premature infant critical care, cancer chemotherapy and organ transplantation. These procedures would simply not be possible without the use of antibiotics. For example, abdominal surgery would be significantly more hazardous and carry a risk of serious postoperative infection without the use of surgical antibiotic prophylaxis. Indeed, without antibiotics, we would learn to fear infections that now appear very minor such as sore throats and skin infections and would lose the confident way we live our everyday lives, thinking twice before venturing off on that adventure holiday if the consequences of injury resulted in serious illness or indeed death due to infection. One US study in the 1980s estimated that antibiotics had extended the average lifespan by ten years, whereas finding a cure for all forms of cancer
Dr Fidelma Fitzpatrick, Consultant Microbiologist, Beaumont Hospital
would only extend the average lifespan by three years. Therefore, it is fair to say that antibiotics are a precious resource and that the emergence of antibiotic resistance threatens the very way we live our daily lives in addition to the existence of the modern healthcare system. The life-saving impact of antibiotics has come at a price. Antibiotics are one of the commonest drug classes causing adverse drug reactions and/or drug/drug interactions, particularly among elderly patients and are frequently associated with secondary infections such as Clostridium difficile infection and candidiasis. However, the greatest threat to the ongoing efficacy of antibiotics is antibiotic resistance. Bacteria are natural survivors that have existed for billions of years - their existence depends on being able to survive threats such as antibiotics. Once antibiotics began to be commonly used in medicine, antibiotic resistance emerged very soon after. Initially antibiotic resistance was of little consequence as there was always a new antibiotic on the horizon. However, the development of new antibiotics has slowed down significantly with the last new class of antibiotic produced in 2000 and yet bacteria continue to become resistant and survive. Infections with antibiotic resistant bacteria are more difficult to treat due to the limited availability of antibiotics, result in more prolonged illness, additional investigations and hospitalisation and are associated with an increased mortality rate. In 2009 the European Centre for Disease Prevention and Control (ECDC) and the European Medicines Agency (EMA) estimated that antibiotic resistance results in
25,000 deaths in the EU and related costs of over ¤1.5 billion each year in healthcare expenses and lost productivity. In January 2013, the World Economic Forum warned that antimicrobial resistance is one of the major global health security risks that the world needs to tackle and called attention to the fact that losses of gross domestic product from antimicrobial resistance range from 0.4% to 1.6%. A recent UK report demonstrated the human and economic cost of antibiotic resistance, reporting
that a continued rise in antibiotic resistance by 2050 would lead to 10 million deaths annually, a reduction of 2% to 3.5% in global Gross Domestic Product (GDP) and cost the world up to 100 trillion USD. This large death rate is sobering when it is put into context for predictions for other common conditions such as cancer, diabetes and road traffic accidents (Figure 3). Today we are faced with an ever-increasing list of multiple drug-resistant bacteria with fewer and fewer treatment options. In the face of HPN • March 2016
Figure 1: Charitable Infirmary Charitable Trust Patient Register 1918‐1923 (RCSI/CICT/REG/1). Source: Meadhbh Murphy RCSI Heritage Collections’
Figure 1: Charitable Infirmary Charitable Trust Patient Register 1918-1923 (RCSI/CICT/REG/1). Source: Meadhbh Murphy RCSI Heritage Collections’
Dr. Fidelma Fitzpatrick, Senior Lecturer, Dept of Clinical Microbiology, Royal College of Surgeons in
Figure 2: Causes of death in Ireland 1926 – 2006 Data source: Society of Actuaries in Ireland 2011 & Dr. Robert Cunney increasing antibiotic resistance and a reduction in the development of new antibiotics, the global conversation has turned to using the remaining antibiotics wisely with antimicrobial stewardship and preventing spread of antibiotic resistant bacteria with infection prevention and control. So what is the current situation in Ireland? The Health Protection Surveillance Centre (HPSC) collects information in Ireland on antibiotic resistant bacteria that cause invasive infection such as bloodstream infection. MRSA bloodstream infection rates have reduced significantly from almost over 40% in 2004 to 20% today, principally due to the efforts of healthcare staff in identifying colonised patients with screening protocols, eradicating colonisation with decolonisation protocols and preventing further spread by isolating colonised patients in single rooms. However, antibiotic resistant trends in other bacteria are not so positive (Figure 4). Streptococcus pneumoniae which is a common cause of March 2016 • HPN
Ireland and Consultant Microbiologist, Beaumont Hospital, Dublin, IrelandMarch 2016
community-acquired pneumonia and meningitis is increasingly becoming resistant to first line agents such as penicillin and macrolides such as erythromycin. Increasing rates of antibiotic resistance in common bacterial causes of urinary tract infections such as E. coli, frequently results in hospitalisation for intravenous antibiotics, as the pathogen is resistant to all available oral antibiotics Indeed there have been a small but increasing number of reports in Ireland of the ultimate superbug ‘CRE – Carbapenem resistant Enterobacteriacae’ which is resistant to all first and most second line antibiotics, principally but not exclusively from the hospital setting. So what is driving all of this antibiotic resistance? Certainly antibiotic use is a major driver of antibiotic resistance and Ireland is in the mid to high range of antibiotic users when compared to the rest of Europe. However, other factors also come into play. The infrastructure of many of our hospitals and healthcare
facilities is old with very few single rooms available for isolation of patients that are colonised with antibiotic resistant bacteria, frequently resulting in colonised patients being place on open wards, thereby placing other patients at risk of cross-infection. Substandard levels of hand and environmental hygiene facilitate spread of antibiotic resistant bacteria in healthcare facilities. Healthcare staffing levels and hospital activity also impacts on antibiotic resistance rates with increasing reports of cross infection as staffing levels drop and activity increases. Lastly, antibiotic use in other sectors outside health such as veterinary medicine, agriculture, horticulture, and the rest of the environment can impact on antibiotic resistance in humans. As with the healthcare sector, antibiotics are used widely in animal health where they are critical to the treatment and prevention of disease in veterinary practice. Their use in farm livestock is of critical importance
to the food and agriculture sectors, as well as their importance to the protection of animal welfare in the agricultural sector and in companion animals. There are concerns about the potential for spread of antibiotic resistance in food and environmental pollution with antimicrobials e.g. through water contamination and agricultural run-off. Hence the call for a new wave of public health interventions, known as the ‘One Health’ Movement, recognising the interdependencies of the health of people, animals and the environment we live in. The ‘One Health’ concept is a worldwide strategy for expanding interdisciplinary collaborations and communications in all aspects of health care for humans, animals and the environment. Recognising that human health, animal health and ecosystem health are inextricably linked, ‘One Health’ seeks to promote, improve and the defend the health and wellbeing of all species by enhancing cooperation and collaboration between physicians, veterinarians, other scientific health and environmental professionals and by promoting strengths in leadership and management to achieve these goals. Worldwide, there has been much discussion as to how best incentivise pharmaceutical companies to invest in producing new antibiotics and how to improve our current diagnosis of infection. In an ideal world, every doctor/vet wants a test that can be performed at the patients side that not only names the cause of an infection, but also lists what antimicrobial can be used to treat it. Globally, there have been a number of prizes, such as the Horizon and Longitude prizes offered to groups of individuals to develop such solutions in human healthcare. Ireland as with other countries worldwide has started inter-sectoral conversations about antibiotic resistance, in health, vetinary, agriculture, fisheries and food sectors. Essentially, the cornerstones of a ‘one health’ approach for antibiotic-resistance can be described as preventative measures against infection in all sectors, use of legislation and other regulatory instruments (e.g., to prevent over the counter sales of antibiotics or use of antibiotics as growth promoters), incentivising the development of new antibiotics or alternatives and new diagnostics, broad information campaigns on antibiotics and monitoring so that there is the comprehensive collection of data about antibiotic use and resistance – a good example of this is the Danish programme for surveillance of antibiotic
MSD is passionate about pursuing breakthrough science to combat infectious diseases.
There was a time when there were no medicines to fight some of the most common infections â€“ but the introduction of antibiotics in the 1940s changed that. MSD is proud of our legacy of progress in this fight, which includes producing penicillin to help American soldiers during World War II. Our commitment continues. Today, the rise in infections caused by resistant bacteria has become an urgent global health issue. Our researchers are hard at work developing the next generation of antibiotics â€“ and the best ways to use them. We believe that creating new medicines, and using them correctly, are essential in the fight against infectious diseases. And our determination does not stop there. Through engagement with global policy-makers we are working to ensure a sustainable antibiotic future, that not only welcomes innovation, but actively embraces it. Together we can ensure that these life-saving treatments are valued the world over and used appropriately to combat what is undeniably one of the greatest societal challenges of our age. Science will get us half way there,
We are willing to do our part, and continue to work with others. We are in this fight together.
Date of Preparation: December 2015
but effective political and policy collaboration will take us over the line.
12 Report Figure 3: Review on Antimicrobial Resistance – Tackling Drug‐resistant Infections Globally, Feb 2015, available at https://amr‐review.org/sites/default/files/Report‐52.15.pdf
Figure 5: Start Smart and Then Focus – Antibiotic Care Bundle. Available at: http://www.hpsc.ie/A‐ Figure 5: Start Smart and Then Focus – Antibiotic Care Bundle. Available at: http://www.hpsc.ie/A-Z/MicrobiologyAntimicrobialResistance/ Z/MicrobiologyAntimicrobialResistance/CareBundles/AntibioticCareBundle/File,14119,en.pdf CareBundles/AntibioticCareBundle/File,14119,en.pdf
Figure 3: Review on Antimicrobial Resistance – Tackling Drug-resistant Infections Globally, Feb 2015, available at https://amr-review.org/ sites/default/files/Report-52.15.pdf
ensures that antibiotics are used wisely when indicated and stopped when no longer required (Figures 5 and 6). In our daily lives, we can prevent spread of antibiotic resistance by cleaning our hands when appropriate, prevent infections with vaccination (as appropriate), ensuring good nutrition and taking adequate exercise, if prescribed an antibiotic taking it resistance and consumption in exactly as prescribed (including health, animal and food sectors finishing the course and not - Dan Map. With respect to stockpiling antibiotics at home) developing new antibiotics, it and not taking antibiotics for viral is important to remember that infections such as colds and flus. bacteria are incredibly clever and As healthcare providers we have are natural survivors, indeed ‘if you an important role in reinforcing these messages with our patients. reproduced every twenty minutes, Irish data from 2011 outlines the you would get smart quickly too’. degree of misinformation among Simply developing new antibiotics adults regarding Dr. Senior Lecturer, Dept of Clinical Microbiology, Royal College of Surgeons inantibiotics where willFidelma notFitzpatrick, be enough because Ireland and Consultant Microbiologist, Hospital, Dublin, IrelandMarch 2016 one in three took antibiotics the evolution always winsBeaumont and there never has been an antibiotic previous year, one in four believing antibiotics prevented colds from that bacteria cannot develop developing into more serious resistance against. illness or that antibiotics speed up So what can be done? The activist recovery from colds. Interestingly Leroy Eldridge Cleaver remarked, 37% felt that by the time they ‘There is no more neutrality in were sick enough to contact or the world. You either have to be visit a doctor because of a cold, part of the solution, or you’re they would expect a prescription going to be part of the problem’. for antibiotics, thereby equating a This quote can be perfectly prescription for antibiotics as value applied to the current situation for money rather than sensible of antibiotic resistance and our healthcare advice. A number of response. As prescribers, by useful websites are now available consulting guidelines for advice including www.undertheweather. on antibiotic prescribing (e.g., ie which provides advice on how www.antibioticprescribing.ie if people can help themselves get prescribing in primary care), will better from common complaints ensure that the most appropriate and when to contact their doctor antibiotic is prescribed for the for advice; www.hse.ie/antibiotics correct duration. In hospitals, on provides advice on antibiotics daily ward rounds, cleaning our and http://www.e-bug.eu/ which hands as outlined by the WHO provides information for school ‘Five moments for Hand Hygiene’ children on infections and hygiene. when caring for patients and Figure 4: Antibiotic Resistance in Invasive Infection in Ireland, 2004‐2015. As very few new antibiotics reviewing antibiotic prescriptions Source: Stephen Murchan, HPSC. are being developed we must and changing as appropriate,
Figure Surgical Infection Prevention Care Bundle. Available Figure 6: 6:Surgical Site Site Infection Prevention Care Bundle. Available at: http://www.hpsc.ie/A‐ at: http://www.hpsc.ie/A-Z/MicrobiologyAntimicrobialResistance/ Z/MicrobiologyAntimicrobialResistance/InfectionControlandHAI/Surveillance/SurgicalSiteInfectionSu InfectionControlandHAI/Surveillance/SurgicalSiteInfectionSurveillance/ rveillance/CareBundles/File,3454,en.pdf CareBundles/File,3454,en.pdf
Dr. Fidelma Fitzpatrick, Senior Lecturer, Dept of Clinical Microbiology, Royal College of Surgeons in Ireland and Consultant Microbiologist, Beaumont Hospital, Dublin, IrelandMarch 2016
* 2015 data to the end of Q3 only ‐ EARS‐Net data correct as of 21/01/2016
March 2016 • HPN
care, clinical governance and performance. Effective prevention and control systems and an ongoing commitment to education and learning are essential for safe patient care. In 1945, Alexander Fleming who discovered penicillin forecast antibiotic resistance “penicillin should only be used if there is a properly diagnosed reason and, if it needs to be used, use the highest possible dose for the shortest time necessary. Otherwise antibiotic resistance will develop”. Fleming clearly understood the principals of Dr. Fidelma Lecturer, Dept Microbiology, College70 of Surgeons in Figure 4: Fitzpatrick, AntibioticSenior Resistance in of Clinical antibiotic useRoyal almost years ago, Invasive in Ireland, 2004Ireland andInfection Consultant Microbiologist, Beaumont Hospital, IrelandMarch yet Dublin, we are still trying2016 to get the 2015. message across today. It beholds us all, healthcare professionals, Source: Stephen Murchan, HPSC. patients and members of the * 2015 data to the end of Q3 only public to use the ones we - EARS-Net data correct as of have appropriately. 21/01/2016 endeavor to protect those that we have to ensure that they remain effective for the sake of future generations. We cannot return to the pre-antibiotic era so it beholds us all, healthcare professionals, patients and members of the public to use the ones we have appropriately. A strategic approach to antibiotic resistance prevention is fundamental to the delivery of a healthcare system’s objectives in relation to patient safety, quality
Reducing Exacerbations in COPD adult deaths worldwide.9 These commonly include cardiovascular disease and lung cancer, and it was found in 2014 that 85% of COPD deaths were attributed to smoking.1 It is estimated that tobacco will kill approximately 10 million people worldwide every year by 2020.3 Tobacco smoke causes direct injury to airway epithelial cells, inducing a specific, persistent inflammation, which differs to that seen in asthma.9,10 The effects of smoking lead to mucus hypersecretion, alveoli wall destruction and smooth muscle thickening, which leads to a decline in lung function. Combined mucous hypersecretion, reduced clearance, and impairment of the lung defence mechanisms explain why patients with COPD, even when stable, carry potential respiratory pathogens in significant concentrations, predisposing them to infections and acute exacerbations of COPD.11
Strategies by which pharmacists can support patients in minimising the risk of exacerbations in chronic obstructive pulmonary disease, and ways to optimise selfmanagement and overall control of this condition are discussed Chronic obstructive pulmonary disease (COPD) is an umbrella term used to describe irreversible respiratory conditions that include emphysema and chronic bronchitis. It is characterised by airflow obstruction which is present as a result of long-term exposure to noxious particles or gas and for the majority of patients, it is a due to smoking tobacco.1,2 Patients with COPD have airway and parenchymal damage; a result of chronic inflammation and differs from that seen in asthma. Consequently, patients with COPD usually present with symptoms of dyspnoea, chronic cough and chronic sputum production and are most often aged over 35 years.1 COPD is a leading cause of morbidity and mortality worldwide and is associated with an increasing incidence of exacerbations.3 An exacerbation of COPD is defined by a rapid and sustained worsening of symptoms beyond normal day-toMarch 2016 • HPN
day variations; characterised by a change in the patient’s baseline dyspnoea, cough and sputum purulence and/or colour. An exacerbation is associated with worsening of airflow obstruction and its severity is based on clinical symptoms. Each exacerbation results in a more rapid decline of lung function and contributes to disease progression, decreased quality of life and increased mortality.3–5 There are also significant costs incurred to treat exacerbations and the associated cost tends to increase as the disease progresses.3 Precipitated by various factors, exacerbations may be due to aspects such as viral or bacterial upper respiratory tract infections and infection of the tracheobronchial tree.2 Acute exacerbations require frequent medical evaluation and increase the utilisation of health resources, requiring emergency and hospital admissions, especially in those patients with a poor health status.4 Those who frequently exacerbate have worse health-related quality of life.6 Mild exacerbations require increased doses of bronchodilators, such as salbutamol, whereas moderate
to severe exacerbations require treatment with systemic corticosteroids, antibiotics or both and/or admission into hospital or A&E attendance, respectively. Usually the frequency of exacerbations increases as the severity of COPD progresses. Exacerbations increase the rate of lung function decline and impact quality of life.6,7 The primary goal of treatment in COPD is to reduce symptoms, reduce the frequency and severity of exacerbations and improve health status and exercise tolerance.3 There are several strategies that can be employed to achieve this; these include smoking cessation, pulmonary rehabilitation, appropriate pharmacological management and supporting selfmanagement. These management strategies are reflected by the American Thoracic Society (ATS), European Respiratory Society (ERS), Global Initiative for Chronic Obstructive Lung Disease (GOLD) and National Institute for Health and Care Excellence (NICE).3,8 SMOKING CESSATION Tobacco use is a major cause of many of the world’s top killer diseases and is responsible for approximately one in ten
Smoking cessation is therefore considered to be the most clinically and cost-effective way to reduce exposure to COPD risk factors.3,9,10 Smokers have an accelerated decline in lung function as each additional exacerbation in a smoker deteriorates the lung function further. Smoking cessation can slow the progressive loss of lung function and is thought to lessen the decline of forced expiratory volume in 1 second (FEV1) by approximately 35ml per year.10 It benefits all smokers, irrespective of the age at which they quit, making smoking cessation a core component of prevention and treatment of COPD.12 It also reduces the number of hospitalisations and improves quality of life and lowers mortality by 18%.10 PULMONARY REHABILITATION Pulmonary rehabilitation is an individually tailored programme that is designed to optimise the patient’s functional status and reduce symptoms of breathlessness. Physical training can help to reduce the muscle de-conditioning that occurs when the activity of a patient becomes restricted by their breathlessness and fatigue.13 It has been shown to improve health-related quality of life, and has a significant impact on hospital readmissions and
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Further information available from Rowex Ltd., Bantry, Co. Cork, Ireland. Tel No: 027-50077 Fax: 027-50417 PA 711/237/1-2. Medicinal product subject to medical prescription. Ref 1: Red Dot Design Award 2011 – Life Science and Medicine. Available from: http:// en.red-dot.org/design.html (02-16) CCF: 18362
16 COPD Table 1. Benefits of pulmonary rehabilitation in COPD from GOLD (1)
Impact of pulmary rehabilitation
Strength of evidence
Improves exercise capacity
Reduces perceived intensity of breathlessness
Improves health-related quality of life
Reduces hospitalisations and hospital days
Reduces anxirty and depression in COPD
Strength and endurance raining of the upper limbs improves arm function
Benefits extend well beyond the immediate period of training
Improves recovery after a hospitalisation for an exacerbation
Enhances the effect of long acting bronchodilators
Respiratory muscle training can be beneficial, especially combines with general exercise training
mortality rates and is now seen as an integral to the life-long management of individuals with symptomatic chronic respiratory illness.14 Following an acute exacerbation, pulmonary rehabilitation aims to prevent further exacerbations and reduce the severity of exacerbations and associated symptoms to restore the pre-exacerbation functional status. Clinically meaningful improvements have been shown in health-related quality of life, exercise capacity and dyspnoea; having a positive effect on survival rates. An effective rehabilitation programme should be a minimum of six weeks, during which time the effects of muscle de-conditioning are reversed. However, the longer the programme continues, the more effective the results.13,14 PNEUMOCOCCAL VACCINATION AND INFLUENZA The principle identified causes of COPD exacerbations include bacterial and viral infections. Patients who have frequent exacerbations have increased airway bacterial colonisation such as Haemophilus influenzae and Streptococcus pneumoniae. Patients colonised by H.influenzae tend to report more symptoms and increased sputum purulence during an exacerbation that those not colonised, suggesting that the presence of bacterial colonisation may lead to more severe exacerbations. Increased airway inflammation in frequent exacerbations therefore may lead to a faster decline in lung function.15
March 2016 • HPN
Vaccination against influenza is a highly cost-effective intervention to reduce the number of COPD exacerbations and consequences reduces the number of hospital admissions. For pneumococcal vaccines in COPD patients over 65 years of age or in patients under 65 years of age with a FEV1 <40% predicted, administration of the pneumococcal vaccination has been shown to reduce the frequency of community-acquired pneumonia and a 70% reduction in the risk of death.3,14,15 It should therefore be recommended that all patients with COPD are offered a pneumococcal vaccination and an annual influenza vaccination. PHARMACOLOGICAL MANAGEMENT A recent strategy developed by GOLD for the management of COPD categorises patients based on their number of exacerbations and symptoms, to provide a better picture of disease status, as below. Treatment should therefore be tailored to individual’s symptoms and frequency of exacerbations. The Medicines Research Council (MRC) dyspnoea scale and the COPD assessment test (CAT) scores are used to assess physical ability and degree of respiratory control due to COPD.1,3 Pharmacological management for COPD is used to reduce symptoms, reduce the frequency and severity of exacerbations, improve health status and exercise tolerance. This is achieved by modification of the long-term decline in lung function associated with patients with COPD.
Increased breathlessness is a common feature of an exacerbation of COPD and is usually managed by increased doses of short-acting bronchodilators. Short-acting beta-agonists and antimuscarinics act on peripheral airways to reduce air trapping, thereby reducing lung volumes and improving symptoms and exercise capacity. Bronchodilators improve the FEV1 by altering airway smooth muscle tone and aid in the widening of the airways and there is some evidence to suggest that it can reduce exacerbation rates.16
<50% predicted compared to those with moderate degrees of airflow limitation.16 As such, ICS/ LABA combinations have a greater protective effect with regard to exacerbation prevention than either class used in isolation and should be reserved for patients who frequently exacerbate.3,16 Inhaled corticosteroids should not be used in isolation without longacting beta-agonists as this has not been shown to be beneficial in COPD and is unlicenced.
Long-acting bronchodilators (both beta-agonists and antimuscarinics) are convenient and more effective at maintaining symptom relief. They reduce exacerbations, hospital admissions, improve symptoms and lung function and health-related quality of life. The effects of long-acting inhaled antimuscarinic therapy reduce the risk of COPD exacerbations by 20–25%.3,16
The goals of treatment for COPD1,3 are:
In accordance with national and international guidance, inhaled corticosteroids in combination with long-acting beta-agonists (ICS/LABA) are indicated in patients with severe to very severe COPD or in milder patients who experience frequent exacerbations or breathlessness.1,3
– Prevent and treat exacerbations
Regular combination therapy of ICS/LABA has been shown to result in a 25% reduction in the number of exacerbations per patient per annum when compared with monotherapy and placebo.16 Furthermore, the greatest effects were seen in patients with a FEV1
SELF-MANAGEMENT AND RESCUE MEDICATION
• Reduction of symptoms – Relieve symptoms – Improve exercise tolerance – Improve health status • Reduction of risk – Prevent disease progression
– Reduce mortality Central components of reducing risk involve supporting patients to self-manage and respond to their symptoms promptly. National and international guidance advocates the use of self-management education in conjunction with rescue medicines of oral corticosteroids and antibiotics in response to moderate to severe exacerbations.1,3 This approach has been associated with shorter recovery time, improved lung function,
Awards The Hospital Professional News Ireland
Hospital Professional News is proud to announce the launch of the 2016 Hospital Professional Awards, which will be taking place on Saturday, 17th September, 2016 in the Hilton DoubleTree Hotel, Dublin Once again hosted by RTE current affairs broadcaster Miriam O’Callaghan, the Hospital
2016 Date: Saturday, September 17th, 2016 Venue: Hilton DoubleTree Hotel, Dublin
Professional Awards have rapidly become recognised as Ireland’s leading platform to recognise the excellent work carried out by Hospital professionals and their teams. These Awards raise the profile of the industry within Ireland. Our sponsors are amongst the elite of the industry, all of whom see the awards as the
HOSPITAL PROFESSIONAL NEWS IRELAND Ireland’s Dedicated Hospital Professional Publication
perfect vehicle to show their support in this arena. With over 400 Hospital industry professionals in attendance at the 2015 event we are anticipating this year’s to be an over-capacity event and so would advise booking your place now.
Contact Kelly Jo Eastwood on 0044 7876548989 or via email at email@example.com for further details on the Award Categories, which will be launched in full in the April issue of Hospital Professional News.
18 COPD GROUP A
Smoking cessation Reduce occupational and environmental exposures Exercise/physical therapy Good nutrician Influenza and pneumococcal vaccines Pulmonary rehabilitation Pulmonologist referal Address end of life decision making Consider surgery on selected patients
decreased length of inpatient stay and reduced risk of early relapse and treatment failure. As such, patients who have either had, or are at risk of having, a COPD exacerbation should be given selfmanagement advice and rescue medicines.1,3 The Outcomes Strategy for COPD echoes this advice by recommending that self-management education should be provided, with an action plan for worsening symptoms or exacerbations, combined with appropriate rescue medication.17 The main aim of self-management is to prevent exacerbations by empowering patients to develop the required skills and knowledge to identify and treat their exacerbations at an early stage. Guidance suggests that, unless contraindicated, patients who experience such symptoms should promptly: • start oral corticosteroid therapy if their increased breathlessness interferes with activities of daily living. • start antibiotic therapy if their sputum is purulent. • adjust their bronchodilator therapy to control their symptoms. CONCLUSIONS COPD continues to be a public health burden, resulting in significant morbidity, mortality
March 2016 • HPN
and increased costs to the healthcare economy. Flare-ups, or exacerbations, associated with COPD are a major cause of morbidity and account for significant costs in its overall management. Various strategies, such as supporting self-management and pulmonary rehabilitation, can significantly reduce the risks of developing flare-ups in COPD. At a time when healthcare resources are stretched, pharmacists are in a pivotal position to ensure that patients with COPD are supported in successfully employing these strategies.
• Pharmacists have a crucial role in supporting patients to have better control of their COPD, reduce the risk of exacerbations and optimise self-management.
9. Bartal M. COPD and tobacco smoke. Monaldi Arch Chest Dis 2005;63(4):213–25.
11. Pride NB. Smoking cessation: effects on symptoms, spirometry and future trends in COPD. Thorax 2001;56(Suppl II):ii7–ii10.
2. Ferrer M et al. Chronic obstructive pulmonary disease stage and health-related quality of life. Ann Intern Med 1997;127:1072–9.
13. Reardon J et al. Pulmonary rehabilitation for COPD. Respir Med 2005;99 (Supp 2):S19–S27.
3. Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management and Prevention of COPD, 2011. www.goldcopd.org.
14. Spruit MA et al. An official American Thoracic Society/European Respiratory Society Statement: Key concepts and advances in pulmonary rehabilitation. Am J Respir Crit Care Med 2013;188:e13– e64.
• COPD exacerbations are defined as a worsening of baseline symptoms which may include increased breathlessness, sputum production and cough. • Exacerbations result in a decline in lung function, reduced quality of life and increases mortality. • Utilisation of healthcare resources, increases the costs associated with treating COPD exacerbations as the disease progresses. • Several strategies can be used to reduce the risk of exacerbations, including; smoking cessation, pulmonary rehabilitation, pharmacological management and supporting patients to self-manage.
1. National Institute for Health and Care Excellence. CG101. Chronic obstructive pulmonary disease: Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update).
4. Osman LM et al. Quality of life and hospital readmission in patients with chronic obstructive pulmonary disease. Thorax 1997;52:67–71. 5. Gadoury MA et al. Self management reduces both short- and long-term hospitalisation in COPD. Eur Respir J 2005;26:853–7. 6. Anzueto A. Impact of exacerbations on COPD. Eur Respir Rev 2010;19(116):113–18. 7. Rodriguez-Roisin. COPD exacerbations. 5: Management. Thorax 2006;61(6)525–44. 8. World Health Organization. www. who.int/respiratory/copd/en/ (accessed 10 April 2015).
10. Decramer M et al. COPD. Lancet 2012;379(9832):1341–51.
12. Rigotti A. Smoking cessation in patients with respiratory disease: existing treatments and future directions. Lancet Respir Med 2013 May;1(3):241–50.
15. Burge S, Wedzicha JA. COPD exacerbations: definitions and classifications. Eur Respir J 2003;21:(Suppl 41):46s–53s. 16. Decramer M et al. Targeting the COPD exacerbation. Respir Med 2008;102(Suppl 1):S3-15 17. Department of Health. The Outcomes Strategy for Chronic Obstructive Pulmonary Disease (COPD) and Asthma in England. Department of Health, 2011. 18. Dhruve H, Hodson M, Khachi H. COPD exacerbations – is selfmanagement a treatment option. Pharm Manag 2010;29(4):15–21.
Agreement reached on over crowding Steve Tweed, Director, IMO Industrial Relations
The Irish Medical Organisation has reached agreement in the Workplace Relations Commission on IMO participation in new local Emergency Department forums and Group Wide Executive Forum to deal with overcrowding issues. A process has been agreed which will ensure clinician input in the decision making process. Additionally it has been agreed that consideration will be given in regard to membership of the ED Taskforce Implementation Group so as to include representatives from the IMO and other health unions. The IMO has written to the HSE, Work Realations Commission and SIPTU on the proposals put forward on Emergency Departments. “It would not be normal practice for the Irish Medical Organisation (IMO) to comment on a proposal that is subject to a ballot of a sister trade union; however, as the proposal – although not yet agreed - has been implemented and together with events at the end of last week involving SIPTU we believe it is essential that the HSE is fully aware of the potential industrial relations issues that the WRC proposal hold for IMO members and the Lansdowne Road Agreement (LRA). We are aware that SIPTU has been in contact with the HSE and also the WRC,” it says. “There are a number of areas within the WRC proposal that would be unacceptable to the IMO and directly impinge the clinical autonomy of our members, especially Consultants. It is unusual for a proposal to be implemented that directly impact IMO members, and members of other unions, when • we:were not party to the negotiations;
• are not involved in any of the group wide or local hospital mechanisms set out in the proposal.” They have set out their main issues/ observations and we have outlined them below: Group Wide Executive Forum – The CEO/ staff side may require the attendance of other senior managers or “clinicians” from individual hospitals. The IMO cannot agree to our members being requested by representatives of any other union to attend the Group Forum. Any discussion on issues should be through the normal reporting channels, or with the involvement of the IMO; To issue a weekly report to the joint chairs of the ED Taskforce. In addition to attending the Forum the IMO should be provided with copies of all reports; If the final bullet point in this section extends beyond nursing staff then it is a breach of the Lansdowne Road Agreement. The Forum has no jurisdiction to consider the staffing/proactive rostering of clinical teams. Any proposed changes to rostering arrangements has to be subject to local agreement with the clinicians and if no agreement is achieved it is referred in to the dispute resolution mechanism of the LRA. Hospital Level Forum – • Final bullet point refers to the senior nurse manager having “autonomy to immediately address all (IMO emphasis) issues to ensure patient flow”. This implies that the nurse manager has the right to overrule decisions on patient flow made by the ED Consultant/ NCHDs. This is unacceptable and
It would not be normal practice for the Irish Medical Organisation (IMO) to comment on a proposal that is subject to a ballot of a sister trade union; however, as the proposal – although not yet agreed - has been implemented and together with events at the end of last week involving SIPTU we believe it is essential that the HSE is fully aware of the potential industrial relations issues that the WRC proposal hold for IMO members and the Lansdowne Road Agreement (LRA) intrudes on the clinical autonomy of the ED Consultant. Health and Safety – • The reference to prioritising staffing of the ED detracts from the wider issues impacting the ED crisis. Prioritising staffing in other parts of the hospital to allow the movement of patients out of the ED should have an equal if not higher priority; • Listing specific areas where care should be provided in a timely manner undermines the role of the Consultant and/ or NCHD who have a duty to prioritise care as determined by their clinical experience. Job Descriptions – • If the content is restricted to nursing staff then reference to developing policies, etc. may be acceptable, but this requires clarification; • The ADON ED Job Description includes “influence the prioritisation of patient access to diagnostic facilities”. We accept this appears to only talk about engage and influence, however, priority of patient care is for the clinician to determine, not the ADON; • The ADON also will use data from patterns of attendance
to establish patterns of inappropriate attendance. Again, if limited to nursing staff ok, but if it impinges on clinical staff then it is unacceptable; • The same can be said for the last two bullet points in the ADON description. Notwithstanding the above comments the IMO does not believe that this level of concentration on the ED, while not providing the same focus on all other recommendations in the ED Taskforce Report, is simply wrong. It will not resolve the crisis. It is essential that the IMO has: • a representative on the ED Taskforce Implementation Group (we have raised this with you previously); • representatives on the Group Wide Executive Forum and each Hospital Locum Forum; • is fully consulted on any proposed change that has the potential to impact our members, either directly or indirectly. In the meantime, the IMO along with SIPTU has said they will confirm with the WRC that they are seeking any early intervention on this issue.
HPN • March 2016
Despite recent cuts, expenditure on pharmaceuticals in Ireland remains well above the OECD average As in many other OECD countries, pharmaceutical spending in Ireland has been cut in recent years as policy measures were introduced to reign in public spending on health following the financial and economic crisis. Still, spending on pharmaceuticals per capita in Ireland remains higher than in most other OECD countries, and nearly 30% above the OECD average in 2013.
IPHA refute OECD Irish spending claims
That conclusion, based on the report of a ‘preliminary’, unpublished and unverified statistic of the OECD relating to Ireland, takes no account of differences across countries in pharmaceutical expenditure, which the OECD itself notes in its official publications. These differences have a significant impact. For example, expenditure on pharmaceuticals in hospitals is excluded. This results in Denmark, where an estimated half of medicines spend is through hospitals, having an under-stated pharmaceutical spend per capita on the OECD measure.
Expenditure on pharmaceuticals per 2013 (or nearest year) Expenditure on pharmaceuticals percapita, capita, 2013 (or nearest year) USD PPP
Total (no breakdown)
752 721 713 678 666 652 603 596 590 572 536 533 526 515 503 481 459 459 436 397 396 392 381 367 364 326 287 273 240
The Irish Pharmaceutical Healthcare Association refutes the claim in the Sunday Business Post last month and repeated on RTE’s Morning Ireland that Irish pharmaceutical expenditure has now been shown by the OECD to the highest in Europe.
1. Includes medical non-durables (resulting in an over-estimation of around 5-10%) 2. Excludes spending on over-the-counter
The opposite is the case for medicines. Source: OECD Health Statistics 2015, http://dx.doi.org/10.1787/health-data-en. 1. Includes medical non-durables (resulting in an over-estimation of around 5-10%) 2. Excludes spending on over-the-counter medicines. Ireland: because many speciality Source: OECD Health Statistics 2015, http://dx.doi.org/10.1787/health-data-en. medicines are provided in the primary care here but in hospitals many other countries, Ireland has introduced a series of measures to encourage the prescription elsewhere, Ireland’s spend per As insupplied Under our Agreement with via special arrangements each element in order for robust capita is over-stated relative to and consumption of generics to reduce pharmaceutical cost. to Although the theState share of the generic (November 2012-to market through Community Pharmacies. conclusions informing policy other countries. The value of these October 2015), ¤400m has They include medicines such as it nonetheless be drawn. has increased in recent years, remains relatively low compared with other OECD medicines is approximately onebeen saved tumor necrosis factor inhibitors third of HSE Community Drugs countries, both in volume (29% compared with an OECD average of 48%) and in value (16% Finally, it should be recalled that which are supplied through Irish medicines prices are not expenditure. most recent official OECD hospitals in some other average of the compared with an OECD 24%). the highest in Europe reported for Ireland relates to OECD countries.” This would be like a comparison of 2012. Since then, The price of patented medicines expenditure on education including OECD Health Statistics 2015, is very close to the average of a lot of primary schools in one expenditure on medicines in Definitions, Sources and nine EU countries with over 300 country and not in another. the HSE Community Drugs Methods, p.9 million people, including Spain Schemes has been flat while In a note on Ireland, the OECD and the UK Statistics on pharmaceutical volumes have increased; specifically underlines this issue: expenditure within country, and Proven new medicines have the average price per item in especially for cross-country “Note: It is important to emphasize been made available for a the Community Drugs Schemes comparisons, need detailed these are medicines initiated wide range of treatments. has fallen, as it has every year examination of the elements of under the supervision of hospital since 2009 specialists which in Ireland are cost and the specific dynamic for
Stories of Breast Cancer Survival University Hospital Galway (UHG) are the first to play host to an inspiring exhibition that will be touring Ireland over the coming months, having received national attention earlier last year. ‘Out the Other Side: Stories of Breast Cancer Survival’ is a collection of individual stories and photographs of Irish women who have survived breast cancer. The exhibition was developed to offer encouragement to other breast cancer survivors and women living with the disease in Ireland. The installation, which has been developed by Roche in partnership with the Marie Keating Foundation, was launched in UHG on the evening of Monday 7th March. It will be hosted in the Arts Corridor, on the Ground Floor of University Hospital Galway until April 4th 2016.
March 2016 • HPN
For patients with HER2-positive metastatic breast cancer (mBC)1
Evolving therapy, improving outcomes
Kadcyla® (trastuzumab emtansine): The first antibody-drug conjugate (ADC) for patients with HER2-positive mBC1,3
Indication1 Kadcyla, as a single agent, is indicated for the treatment of adult patients with HER2-positive, unresectable locally advanced or metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. Patients should have either: • Received prior therapy for locally advanced or metastatic disease or • Developed disease recurrence during or within six months of completing adjuvant therapy.
ABRIDGED PRESCRIBING INFORMATION (For full prescribing information refer to the Summary of Product Characteristics [SmPC]) KADCYLA®▼ (trastuzumab emtansine) 100 mg powder for concentrate for solution for infusion, 160 mg powder for concentrate for solution for infusion. Indications: Treatment as a single agent of adult patients with HER2-positive, unresectable locally advanced or metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. Patients should have received prior therapy for locally advanced or metastatic disease, or developed disease recurrence during or within six months of completing adjuvant therapy. Dosage and Administration: Kadcyla should only be prescribed by a physician and administered under the supervision of a HCP who is experienced in the treatment of cancer patients. Patients should have HER2-positive tumour status, scored as 3 + by immunohistochemistry or a ratio of ≥ 2.0 by in situ hybridization. To prevent medication errors check vial labels to ensure the medicinal product being prepared and administered is Kadcyla (trastuzumab emtansine) and not Herceptin (trastuzumab). Kadcyla should be administered by a healthcare professional at a dose of 3.6 mg/kg as an intravenous (IV) infusion every 3 weeks (21 day cycle) until disease progression or unacceptable toxicity. Kadcyla should not be mixed with glucose. Use of 0.22 micron in-line polyethersulfone (PES) filter is required for the infusion when the concentrate for infusion is diluted with sodium chloride 9 mg/ml (0.9%) soln for infusion. Initial dose should be administered as 90 minute IV infusion, followed by 90 minutes of observation for infusion-related reactions (IRR’s). If well tolerated, subsequent doses may be administered as 30 minute infusion, followed by 30 minutes of observation. If a dose is missed, it should be administered as soon as possible, adjust the dosing schedule to maintain a 3-week interval between doses. Dose Modification: management of symptomatic adverse event may require temporary interruption, dose reduction or treatment discontinuation. First dose reduction 3mg/kg, second dose reduction 2.5 mgs/kg, if there is a requirement for further dose reduction, discontinue treatment. Kadcyla dose should not be re-escalated after a dose reduction is made. Refer to SmPC for information on dose modification guidelines for increased transaminases (AST/ALT), hyperbilirubinemia, thrombocytopenia, peripheral neuropathy and left ventricular dysfunction. No dose adjustment requirement in elderly. No dose adjustment to the starting dose in needed in patients with mild or moderate renal impairment, patients with severe renal impairment should be monitored carefully. Safety and efficacy has not been studied in patients with hepatic impairment no specific dose reductions can be made. Safety and efficacy has not been established in children and adolescents. Refer to SmPC for further details. Contraindications: Hypersensitivity to active substance or any excipients. Warning and Precautions: In order to improve traceability the trade name of the administered product should be clearly recorded in the patient file. Cases of interstitial lung disease (ILD), including pneumonitis some leading to respiratory distress syndrome or a fatal outcome have been reported, patients with dyspnoea due to complications of advanced malignancy and co morbidities may be at increased risk of pulmonary events. Discontinue treatment in patients diagnosed with ILD and pneumonitis refer to SmPC for further details. Hepatotoxicity in the form of asymptomatic increases in serum transaminases has been reported, transaminase elevations were generally transient with peak elevation after day 8, cumulative effect observed, improvements to grade 1 or normal within 30 days of last dose of Kadcyla in majority of cases. Liver function should be monitored prior to initiation of treatment and each dose. Patients with baseline elevation of ALT may be predisposed to liver injury with a higher risk of a Grade 3-5 hepatic event or liver function test increase refer to SmPC for dose modifications. Serious hepatobiliary disorders including nodular regenerative hyperplasia (NRH) some with a fatal outcome have been observed. Diagnosis of NRH can only be confirmed by histopathology. Consider NRH in patients with clinical symptoms of portal hypertension and cirrhosis- like patterns confirmed by CT scan of liver but with normal transaminases and no other manifestations of cirrhosis. Discontinue treatment with Kadcyla in patient diagnosed with NRH. Discontinue Kadcyla in patients with serum transaminases >3 × ULN and concomitant bilirubin >2 × ULN, refer to SmPC for further details. Left ventricular ejection fraction (LVEF) < 40% has been observed in patients treated with Kadcyla. Risk factors for a cardiac event include advancing age (>50 yrs), low baseline LVEF values (<55%), low LVEF prior to or following paclitaxel in the adjuvant setting, prior or concomitant use of antihypertensives, previous treatment with anthracyclines and high BMI (> 25 kg/m2 ). Baseline cardiac function testing should be performed and every 3 months during treatment. Kadcyla dose should be delayed or treatment discontinued as necessary in cases of LVEF. See SmPC for further details. Do not administer Kadcyla in patients who had Herceptin permanently discontinued due to infusion related reactions. Observe closely for IRR’s, symptoms reported: flushing, chills, pyrexia, dyspnoea, hypotension, wheezing, bronchospasm, and tachycardia. Reactions resolved over several hours to a day after the infusion was terminated. Treatment should be interrupted in patients with a severe IRR and terminated in the event of a life threatening IRR, refer to SmPC. Do not administer Kadcyla in patients who had Herceptin permanently discontinued for hypersensitivity reactions. Observe closely for hypersensitivity/allergic reaction. Discontinue Kadcyla in event of true hypersensitivity reaction refer to SmPC. Patients with thrombocytopenia and patients on anti-coagulant treatment should be monitored closely. Monitor platelet counts prior to each dose. Cases of bleeding events with a fatal outcome have been observed. Kadcyla has not been studied in patients with platelet count of (≤ 100,000/mm3) prior to initiation of therapy. Refer to SmPC for dose modifications. Peripheral neuropathy has been reported. Treatment with Kadcyla should be temporarily discontinued in patients experiencing G3/4 peripheral neuropathy until symptoms resolve or improve refer to SmPC. Patients should be clinically monitored for signs/symptoms of neurotoxicity. This medicinal product contains less than 1mmol sodium (23mgs) per dose. Drug Interactions: No formal interaction studies have been performed. In vitro metabolism studies suggest that concomitant use of strong CYP3A4 and CYP3A5 inhibitors should be avoided
(e.g ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). If concomitant use of CYP3A4 inhibitors is unavoidable, consider a delay in administration of Kadcyla until the CYP3A4 inhibitor has cleared from circulation approximately 3 elimination half-lives of the inhibitors. If Kadcyla treatment cannot be delayed, patients should be closely monitored. Fertility, pregnancy and Lactation: Women of childbearing potential should use effective contraception during Kadcyla treatment and for 7 months following the final dose. Animal studies indicate Kadcyla is teratogenic and potentially embryotoxic. The use of Kadcyla in pregnant and breast feeding women is not advised. Women should be informed of the possibility of harm to the foetus before they become pregnant. Women who become pregnant must immediately contact their doctor, close monitoring by the multidisciplinary team is recommended. Women may breast feed 7 months after concluding treatment. No reproductive and developmental toxicology studies with Kadcyla, refer to SmPC. Side effects and Adverse reactions: The most common serious adverse drug reactions seen in clinical trials with Kadcyla were pyrexia, thrombocytopenia, vomiting, abdominal pain, nausea, constipation, diarrhoea, dyspnoea and pneumonitis. Common ADR’s (≥25%) with Kadcyla were haemorrhage (including epistaxis), increased transaminases, fatigue, musculoskeletal pain, and headache. NCICTCAE G3/4 ADR’s (>2%) were thrombocytopenia, fatigue, increased transaminases, anemia, hypokalaemia, musculoskeletal pain and neutropenia. Very common reaction( ≥ 1/10): urinary tract infection, thrombocytopenia, anemia, hypokalaemia, insomnia, peripheral neuropathy, headache, dizziness, haemorrhage, epistaxis, cough, dyspnea, stomatitis, diarrhoea, vomiting, nausea, constipation, dry mouth, abdominal pain, rash, musculoskeletal pain, arthralgia, myalgia, fatigue, pyrexia, asthenia, chills, transaminases increased. Common reactions (≥1/100 to <1/10): neutropenia, leucopoenia, drug hypersensitivity, dysgeusia, memory impairment, dry eye, conjunctivitis, vision blurred, lacrimation increased, left ventricular dysfunction, hypertension, dyspepsia, gingival bleeding, pruritus, alopecia, nail disorder, palmar-plantar erythrodysaesthesia syndrome, urticaria, peripheral oedema, blood alkaline phosphatase increased, infusion related reactions. Laboratory abnormalities: Both hepatic and haematological abnormalities were observed refer to SmPC for further details. Serious or potentially serious: Pneumonitis (ILD), hepatotoxicity, hepatic failure, nodular regenerative hyperplasia, portal hypertension, Legal Category: POM. Presentations and Marketing Authorisation Numbers: EU/1/13/885/001 for 100mg/5 ml (pack size of one): EU/1/13/885/002 for 160mg/8ml (pack size of one). Marketing Authorisation Holder: Roche Registration Limited, 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, United Kingdom Kadcyla ® 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: 20th April 2015.
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, Alternatively, suspected adverse please report it to: reactions should be reported to: The Drug Surveillance Centre Roche Products (Ireland) Limited Telephone: (01) 4690700 Fax: (01) 4690793 Email: firstname.lastname@example.org
The Pharmacovigilance Section Health Products Regulatory Authority Telephone: (01) 6764971 Fax: (01) 6762517 Website: www.hrpa.ie Email: email@example.com
If a pregnancy occurs while using Kadcyla or within 7 months following the last dose of Kadcyla, please immediately report pregnancy to the Roche Adverse Event Line at Tel: (01) 4690700, Fax: (01) 4690793, Email: firstname.lastname@example.org, Out of Hours: (01) 2910943. Additional information will be requested during a Kadcyla-exposed pregnancy and the first year of the infant’s life. This will enable Roche to better understand the safety of Kadcyla and to provide appropriate information to Health Authorities, Healthcare Providers and patients.
REFERENCES 1. Kadcyla Summary of Product Characteristics 23 October 2014 2. Verma S et al. N Engl J Med 2012;367:1783-1791. 3. Dirix L et al. Expert Opin Biol Ther 2013; 13(4): 607-614. IE/KAD/0715/0017
Date of item: July 2015
Hospitals Publish Maternity Patient Safety Statements Maternity Patient Safety Statements have been published this month, for each of the country’s 19 maternity hospitals and units. From now on, each Hospital Group and Maternity Hospital will publish an updated statement each month. The objective in publishing these statements is to provide public assurance that maternity services are delivered in an environment that promotes open disclosure. It is intended that reporting in an honest and open way helps build trust and improves clinical performance and the culture of safety.
The Maternity Patient Safety Statement contains information on 17 metrics covering a range of clinical activities, major obstetric events, modes of delivery and clinical incidents. While all maternity hospitals collect a large range of information and data on an ongoing basis, these particular metrics have been selected on the basis that they are clinically robust, relevant and underpinned by standardised definitions. Welcoming the publication of the statements Professor Michael Turner National Clinical Lead,
HSE National Clinical Programme for Obstetrics and Gynaecology said, “As National Lead, I strongly welcome the publication of the first Maternity Safety Statements for all maternity units in the country. “I am delighted that Ireland is the world leader in publishing timely safety data which will assist local and national hospital managers in maintaining and improving the quality of care across the country's maternity services. The publication of this data should also provide welcome reassurance for women using our services.
“Like all performance measurements, the data should be interpreted with caution particularly when reporting low numbers which may vary naturally from month to month and are influenced by case complexity. I also expect that publishing these performance instruments will also lead over time to further improvements in the collection, analysis and presentation of a wider range of clinical outcomes.”
HRB funding for preclinical stroke studies A preclinical study aimed at establishing the potential of fingolimod as an acute stroke therapeutic agent was recently funded by the Health Research Board. Stroke is the third most common cause of death and the most common cause of acquired physical disability in Ireland. The only available drug, recombinant tissue plasminogen activator (tPA), can only be used in a small minority of patients. Thus, the need for an effective and easily administered treatment remains paramount.
Dr Waeber and others have found that fingolimod is effective in several rodent stroke models. Such findings and the fact that fingolimod is already licensed for another neurological indication (multiple sclerosis) suggest that fingolimod is one of the most compelling candidates ever characterized in stroke models. But hundreds of drugs effective in animals have failed to show efficacy in humans; this has greatly raised the bar to justify the considerable expenses and risks of a clinical trials. In his project, Dr Waeber therefore proposes
to implement recommendations issued stroke experts to decrease the gap between preclinical and clinical studies. The idea behind these studies is to better simulate the features of human stroke. For instance, while stroke is usually modelled in rodents by blocking blood supply to the brain with artificial filaments, Dr Waeber’s group will mimic stroke with actual blood clots. They will also use older rodents, which have additional diseases often found in stroke patients (diabetes, high blood pressure, high cholesterol levels).
2016 ISMO Fellowship meeting Pictured recently at the 2016 ISMO Fellowship meeting in the Mater Hospital are Ms Penny Donnelly, Bayer, Professor Liam Grogan, ISMO Vice President 2016 and Consultant Medical Oncologist, Beaumont Hospital, Dr Sarah Picardo (SPR) Beaumont Hospital, Dr Shereen Raffee (SPR) Cork University Hospital, Dr Deirdre O’Mahony, Consultant Medical Oncologist, Cork University Hospital and Dr Greg Leonard, Consultant Medical Oncologist, University Hospital Galway. Dr Picardo and Dr Raffee took part in the Bayer-sponsored ISMO-MSKCC Gastrointestinal Preceptorship at the Memorial Sloan Kettering Cancer Centre last month.
March 2016 • HPN
Because these diseases are usually managed with different drugs, this study will determine whether the presence of these drugs affects the efficacy of fingolimod, or increases the incidence of side-effects. If successful, Dr Waeber’s threeyear project should rapidly lead to clinical trials with a vastly increased likelihood of success, since will be one of the first potential stroke drugs to have undergone such an extensive preclinical characterisation.
CPD 19: Hospital based management of Pain Continuing Professional Development
CPD 60 Second Summary There is an increasing focus on rationalising pharmacological treatment of chronic nonmalignant pain (CNMP) in order improve patient treatment and appropriately utilise healthcare resources. The prevalence of CNMP places a large burden on society and recent studies in Europe highlight national and socioeconomic costs attributed to chronic pain represent 3–10% of gross domestic product. The aim of any treatment guideline should be to provide evidencebased treatment options for clinicians to work through while empowering them to manage therapeutic issues such as treatment initiation, disease monitoring and adherence. This provides a consistent framework for symptom management. Where the WHO pain ladder is followed, many patients require analgesia beyond that provided by regular codeine. Escalation of codeine to its maximum dose in appropriate patients (240mg/ day) provides a level of analgesia equivalent to that of approximately 24mg oral morphine. Development of a neuropathic treatment pathway, as with nociceptive pain, should focus on using evidence-based medicines while empowering non-specialist clinicians with information regarding treatment initiation and management. Improvements in access to treatment services should focus primarily on ensuring that patients are directed to appropriate resources at the earliest opportunity. This allows access to treatment suitable with the stage of care patients are in, and allows consistency in management. Of importance is that the implementation of any guidelines be undertaken using an active approach such as educational presentations and feedback sessions.
Gareth Tyrrell MPharmS, Clinical Lead Pharmacist – Surgery and Aseptic Services, Royal Glamorgan Hospital, Llantrisant, UK Local development and promotion of evidence-based treatment pathways for chronic pain can improve patient access to evidence-based medicines and avoid inappropriate use of healthcare resources
1. REFLECT - Before reading this module, consider the following: Will this clinical area be relevant to my practice. 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.
3. PLAN - If I have identified a knowledge gap - will this article satisfy those needs - or will more reading be required? 4. EVALUATE - Did this article meet my learning needs - and how has my practise changed as a result? Have I identified further learning needs? 5. WHAT NEXT - At this time you may like to record your learning for
future use or assessment. Follow the 4 previous steps, log and record your findings. Published by HPN, sponsored by MSD. Copies can be downloaded from www.irishpharmacytraining.ie Disclaimer: All material published is copyright, no part of this can be used in any other publication without permission of the publishers and author. MSD has no editorial oversight of the CPD programmes included in these modules.
Improving access to effective chronic pain treatment There is an increasing focus on rationalising pharmacological treatment of chronic non-malignant pain (CNMP) in order improve patient treatment and appropriately utilise healthcare resources. The prevalence of CNMP places a large burden on society and recent studies in Europe highlight national and socioeconomic costs attributed to chronic pain represent 3–10% of gross domestic product.1 In the US, the burden of chronic pain is greater than that of heart disease and diabetes.2 Due to the multitude of different therapeutic options and resources they demand, there are many barriers to provision of effective chronic pain treatment that have been well documented by the World Health Organization (WHO).3 While many are beyond the scope of the pharmacy profession, pharmacists can have an active role in improving knowledge and skills in the prescribing of chronic pain medications. Increasingly in the management of chronic conditions, the use of treatment pathways to standardise and guide practice is providing a consistent evidence-based approach. The management of
chronic pain is one such area where the use of treatment pathways, in conjunction with appropriate assessment tools, can provide non-specialist clinicians with the necessary information to treat patients effectively. Treatment of chronic pain remains difficult to treat pharmacologically, and there is no single analgesia that works for all conditions and underlying mechanisms. As such, the clinician must choose from a variety of drugs, all having different properties. The aims of any CNMP treatment pathway should be to provide a step-wise evidencebased approach to therapy. Development of a CNMP guideline The aim of any treatment guideline should be to provide evidencebased treatment options for clinicians to work through while empowering them to manage therapeutic issues such as treatment initiation, disease monitoring and adherence. This provides a consistent framework for symptom management. A successful therapeutic guideline for CNMP should:
• Provide advice on assessment of CNMP • Direct clinicians to evidencebased therapies for specific types of CNMP • Provide advice on treatment initiation, disease monitoring and review making therapy patient-centred • Guide clinicians to appropriate referral to specialist services Assessment of chronic pain Many non-specialist pain clinicians have neither the skills nor the time to provide appropriate musculoskeletal and neurological examinations when presented with CNMP. Improving the ability of non-specialist clinicians to differentiate between nociceptive and neuropathic pain will allow appropriate selection of pharmacological agents for treatment. In the absence of consensus agreement regarding diagnostic approaches to chronic pain, the most effective method of chronic pain assessment is via screening
Continuous Professional Development Modules are sponsored by MSD MSD has no editorial oversight of the CPD programmes included in these modules. HPN • March 2016
CPD 19: Hospital based management of Pain
cost without much added benefit. As with weak opioids, where use is regular, co-prescribing of laxatives is advocated to minimise opioid-induced constipation.8 Neuropathic CNMP treatment Development of a neuropathic treatment pathway, as with nociceptive pain, should focus on using evidence-based medicines while empowering non-specialist clinicians with information regarding treatment initiation and management. Unfortunately, because there are few direct comparisons between neuropathic agents, use of NNT and number needed to harm (NNH) allow a step-wise approach to neuropathic pain management.9 These treatment options provide effective therapy for a wide-ranging source of neuropathic pain disorders (generalised neuropathies). However where these treatment options become exhausted, either by treatment failure or tolerability, then referral to specialist services should be encouraged. tools.4 One such tool currently favoured by clinicians is the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) (Figure 1).5 Nociceptive CNMP treatment Nociceptive CNMP originates from continuous innervation of pain receptors by noxious stimuli. As such, pharmacological therapy should target the pathways that result in production of pain and inflammation. An appropriate treatment pathway should mirror the WHO pain ladder.6 The evidence of benefit for these drugs lie in the area of acute pain management; however, the effectiveness of these agents can be assumed to transcend the acute/chronic pain classification, and so may provide effective analgesia.
Use of opioids in chronic pain Where the WHO pain ladder is followed, many patients require analgesia beyond that provided by regular codeine. Escalation of codeine to its maximum dose in appropriate patients (240mg/ day) provides a level of analgesia equivalent to that of approximately 24mg oral morphine. Where regular maximum dose codeine is ineffective, and effectiveness should always be reviewed upon dosage increase, then clinicians should consider switching to modified-release opioid preparations. The documented number needed to treat (NNT) for opioids in chronic pain is around 2â€“4, making them effective tools for CNMP management. The concern for many clinicians is the long-term use of opioids in
a population where many patients can develop dependence, and side effects associated with long-term use. Good practice should recommend them as a third-line option in management of CNMP irrespective of nociceptive/ neuropathic origin.7 To avoid dependence-related issues, and ensure patients receive appropriate care, non-specialists should be advised on a maximum dose of opioids up to which they should prescribe. Where patients require further dose increases, referral into specialist services should be advocated. Clinicians should also be encouraged to utilise appropriate routes of administration where patients can take oral medications, because use of transdermal opioids comes at a much greater
The focus should be to empower non-specialist clinicians to manage these patients with evidencebased medicines as part of an overarching treatment plan. Guidelines, such as the one mentioned in this article, can serve to direct pharmacological treatment, advise on monitoring and review of medicines
Tricyclic antidepressants (TCAs) have been shown to be effective at treating a multitude of neuropathic pain conditions and, as such, should be considered first-line therapies (NNT 2.5). Clinicians should be aware of the incidence of anti-muscarinic side effects, particularly in the elderly (NNH 14.7) and low dose initiation and slow dose increases are advocated. Where sedation is a concern, use of secondary amine TCAs, such as nortriptyline, are recommended over tertiary amines, such as amitriptyline. Gabapentin has been studied in a variety of neuropathic pain conditions, and has been shown to be effective with a NNT of 5.4. The Scottish Intercollegiate Guideline Network (SIGN) guidelines for chronic pain suggest a high rate of adverse effects resulting in treatment withdrawal; however, this may be due to the rapid titration recommended over the first three days of therapy.10 Anecdotal evidence suggests that initial doses of 100â€“300mg daily titrated upwards in weekly intervals may improve patient tolerance. Pregabalin is another gabapentinoid used frequently for management of CNMP. While the NNT is comparable to that of gabapentin, there are issues
Continuous Professional Development Modules are sponsored by MSD MSD has no editorial oversight of the CPD programmes included in these modules. March 2016 â€˘ HPN
25 Chronic Pain Disorders
Neuropathic Pain Peripheral neuropathies (diabetes, HIV)
Migraine and chronic daily headache
Phantom limb pain
Central post-stroke pain
Complex regional pain syndrome
Spinal cord injury Neuropathic low back pain
Multiple sclerosis Low back pain Myofascial pain syndrome Skeletal muscle pain
Nociceptive Pain Mechanical low back pain Rheumatoid arthritis Osteoarthritis Chronic inflammatory conditions Somatoform pain disorder Postoperative pain Sickle cell crisis Sports/exercise injury
around tolerability in 18â€“28% of patients. Most common side effects are somnolence and dizziness. This is currently recommended for use after gabapentin therapy has failed due to costâ€“benefit comparison. Duloxetine has a favourable NNT of 6, making it effective for use in diabetic neuropathy. Advantages for its use are derived from the dual action as both a neuropathic analgesic and antidepressant. As the incidence of CNMP has a deleterious impact on patient quality of life, this is an added benefit in those suffering depression secondary to CNMP. Benefits of topical therapy for neuropathic pain are limited to localised neuropathies where oral medications have failed. Lidocaine 5% plasters are licensed in post-herpetic neuralgia; however, due to a questionable cost-benefit when compared with other medications, they are recommended only after more effective oral therapies have been used. Improving patient access to treatment services Improvements in access to treatment services should focus primarily on ensuring that patients
are directed to appropriate resources at the earliest opportunity. This allows access to treatment suitable with the stage of care patients are in, and allows consistency in management. Of importance is that the implementation of any guidelines be undertaken using an active approach such as educational
presentations and feedback sessions, rather than simple dissemination of the guideline. This ensures that clinicians are engaged in the process, and are aware of the appropriate use of referral pathways, which, in themselves, may avoid future referrals and so improve use of resources.
Several areas that may improve patient access are detailed below. Empowering treatment initiation Early in a diagnosis of CNMP non-specialist pain clinicians are commonly charged with managing the patients. There is a well documented lack of
Continuous Professional Development Modules are sponsored by MSD MSD has no editorial oversight of the CPD programmes included in these modules. HPN â€˘ March 2016
CPD 19: Hospital based management of Pain • Specified points for referral during the treatment pathway allow clinicians to utilise specialist services at appropriate stages in patient care. References 1. Breivik H, Eisenberg E. The individual and societal burden of chronic pain in Europe: the case for strategic prioritisation and action to improve knowledge and availability of appropriate care. BMC Public Health 2013;13:1229. 2. Gaskin DJ, Richard P. The economic costs of pain in the United States. J Pain 2012;13:715– 724. 3. World Medical Association. WMA Resolution in the Access to Adequate Pain Treatment. Adopted by the 62nd WMA General Assembly. Uruguay 2011. www.wma.net/ en/30publications/10policies/p2/ index.html (accessed 8 September 2014).
confidence in managing chronic pain conditions, and this can lead to referral to specialist services unnecessarily.11 The focus should be to empower non-specialist clinicians to manage these patients with evidence-based medicines as part of an overarching treatment plan. Guidelines, such as the one mentioned in this article, can serve to direct pharmacological treatment, advise on monitoring and review of medicines. Utilisation of such a guideline can ensure that the inexperienced clinician avoids specialist advice unless necessary. Improving patient understanding Use of visual diagnostic and treatment aids such as those displayed in Figures 1 and 2, allow the patient to understand their diagnosis and visualise the therapeutic path they are on. By sharing and discussing this step-wise approach, clinicians can provide patients with confidence in their treatment, vital in a condition that is difficult to treat. This can aid with patient adherence and, ultimately, treatment success. Specialist referral Any guideline for CNMP management should ensure that where the treatment options within the recommended pathways are
exhausted, there are clear points for specialist referral. This ensures only treatment-resistant patients, appropriate for specialist inputs are advanced towards such care, utilising resources effectively. This also allows direction in prescribing, promotes consistency in approach and when policed, reinforces the required patient progression to specialist services. Primary/secondary care interface Once specialist input into care commences, it is essential that clear and detailed information regarding changes to therapy are transferred efficiently. This will allow seamless changes to patient therapy to occur and avoid continuing treatment with ineffective/unsuitable medicines to ensure new therapy is started in a timely manner. Conclusions CNMP continues to remain a challenging condition to manage for patients and clinicians, and inconsistencies in practise result in inappropriate use of healthcare resources. Appropriate assessment of CNMP, and initiation of pharmacological therapies selected from evidencebased treatment guidelines remain the most effective way to
ensure patient receive successful therapy. Coupled with clear and regulated referral pathways to pain specialists, this approach can help to ensure pharmacological management of CNMP provides patients with safe and effective treatment while promoting responsible use of healthcare resources. Key points • Improving education and assessment skills during the patient consultation can direct prescribers to the most effective therapies. • Identification of nociceptive or neuropathic pain types is essential. • Opioids have a role in the management of chronic nonmalignant pain; however, referral to specialist services should occur before patients escalated to large doses to ensure appropriate management of potential opioid dependence. • Locally developed treatment pathways promoting costeffective evidence-based practice will ensure that patients receive the most effective therapies earlier in their care and ensure consistency in nonspecialist clinician approach.
4. Bennett MI. Using screening tools to identify neuropathic pain. Pain 2001;127:199–203. 5. Bennett MI. The LANSS Pain Scale: the Leeds assessment of neuropathic symptoms and signs. Pain 2001;92:147–57. 6. World Health Organization. www.who.int/cancer/palliative/ painladder/en/(accessed 8 September 2014). 7. British Pain Society. www. britishpainsociety.org/book_ opioid_main.pdf (accessed 8 September 2014). 8. Pappagallo M. Incidence, prevalence, and management of opioid bowel dysfunction. Am J Surg 2001;182:11S–8S. 9. Finnerup N, Otto M. Algorithm for neuropathic pain treatment: An evidence based proposal. Pain 2005; 118:289–305. 10. Scottish Intercollegiate Guidelines Network. www.sign. ac.uk/guidelines/fulltext/136/ (accessed 8 September 2014). 11. Johnson M, Collett B. The challenges of pain management in primary care: a pan-European study. J Pain Res 2013 6:393–401
Continuous Professional Development Modules are sponsored by MSD MSD has no editorial oversight of the CPD programmes included in these modules. March 2016 • HPN
Single Agent Once Daily Oral Therapy for R/R CLL and R/R MCL*
Discover how far therapy can go * Relapse/Refractory Chronic Lymphocytic Leukemia and Relapse/Refractory Mantle Cell Lymphoma.
IMBRUVICA® is indicated for the treatment of adult patients with: 1 • Relapsed or refractory mantle cell lymphoma • Chronic lymphocytic leukaemia who have received at least one prior therapy, or in ﬁrst line in the presence of 17p deletion or TP53 mutation in patients unsuitable for chemo-immunotherapy • Waldenström’s macroglobulinaemia who have received at least one prior therapy, or in ﬁrst-line treatment for patients unsuitable for chemo-immunotherapy IMBRUVICA® 140 mg Hard Capsules PRESCRIBING INFORMATION ACTIVE INGREDIENT: Ibrutinib. Please refer to Summary of Product Characteristics (SmPC) before prescribing. INDICATIONS: Treatment of adult patients with: relapsed or refractory mantle cell lymphoma (MCL); chronic lymphocytic leukaemia (CLL) who have received ≥ one prior therapy, or first line in presence of 17p deletion/TP53 mutation and are unsuitable for chemo-immunotherapy; Waldenström’s macroglobulinaemia (WM) who have received ≥ one prior therapy, or in first line in patients unsuitable for chemo-immunotherapy. DOSAGE & ADMINISTRATION: Adults: Orally, once daily, swallowed whole with water. MCL - 4 capsules. CLL & WM - 3 capsules. Concomitant moderate/strong CYP3A4 inhibitors – reduce to 1 capsule (or, with strong inhibitors, withhold IMBRUVICA for up to 7 days). Withhold IMBRUVICA therapy for any new onset/worsening grade ≥ 3 nonhaematological toxicity, grade ≥ 3 neutropenia with infection/fever, or grade 4 haematological toxicities. Re-initiate when toxicities resolved to grade 1 or baseline. If toxicities recur, reduce dose by 1-2 capsules. Discontinue IMBRUVICA if toxicities persist/recur following two dose reductions. Children: Safety/efficacy not established ≤ 18 years old. Elderly: No dose adjustment required. Renal impairment: Mild/moderate - no dose adjustment. Severe – no data; consider benefit/risk and monitor closely. No data with dialysis. Hepatic impairment: Mild (Child-Pugh class A) – 2 capsules daily; moderate (Child-Pugh class B) – 1 capsule daily; severe (Child-Pugh class C) – not recommended. Monitor for toxicities. Severe cardiac disease: No clinical data. CONTRAINDICATIONS: Hypersensitivity to active substance/excipients. St. John’s Wort preparations. SPECIAL WARNINGS & PRECAUTIONS: Bleeding-related events: Minor and major haemorrhagic events reported; caution with anticoagulant therapy – do not use concomitantly with warfarin or other vitamin K antagonists, avoid fish oil and vitamin E preparations. Withhold IMBRUVICA ≥ 3 to 7 days pre-/post-surgery. Leukostasis: Cases reported; consider temporary withhold of IMBRUVICA; monitor closely, give supportive care. Infections: Infections seen, some resulting in hospitalisation and death; monitor for fever, neutropenia and infections and give anti-infective therapy. Cytopenias: Treatment-emergent grade 3/4 cytopenias reported; monitor complete blood counts monthly. Atrial fibrillation/flutter: reported particularly in patients with cardiac risk factors/acute infections/previous history of atrial fibrillation; periodic clinical monitoring; consider ECG if arrhythmic symptoms or new
onset dyspnoea develop; consider alternative to IMBRUVICA when preexisting atrial fibrillation requiring anticoagulant therapy or high risk of thromboembolic disease; where no suitable alternatives to IMBRUVICA, consider tightly controlled treatment with anticoagulants. Tumour lysis syndrome: cases reported. Monitor at risk patients closely, take precautions. Effects on the QT interval: mild decrease in QTcF interval seen; use clinical judgement before prescribing for patients at risk from further shortening QTc duration. Drug-drug interactions: Strong/ moderate CYP3A4 inhibitors may increase ibrutinib exposure; CYP3A4 inducers may decrease ibrutinib exposure. Avoid where possible, if not monitor closely for toxicities/lack of efficacy. SIDE EFFECTS: Very common: Pneumonia, upper respiratory tract infection, urinary tract infection, sinusitis, skin infection, neutropenia, thrombocytopenia, anaemia, dizziness, headache, haemorrhage, epistaxis, bruising, petechiae, diarrhoea, vomiting, stomatitis, nausea, constipation, rash, arthralgia, musculoskeletal pain, pyrexia, oedema peripheral. Common: Sepsis, febrile neutropenia, leukocytosis, lymphocytosis, dehydration, hyperuricaemia, vision blurred, atrial fibrillation, subdural haematoma, dry mouth. Other side effects: Leukostasis, tumour lysis syndrome, angioedema. Refer to SmPC for other side effects. PREGNANCY: Women of child-bearing potential must use highly effective contraceptive measures during and for 3 months after stopping treatment; if using hormonal contraceptives, add barrier method. Not to be used during pregnancy. LACTATION: Discontinue breast-feeding during treatment. INTERACTIONS: CYP3A4 inhibitors: Strong: Avoid where possible or reduce dose (or withhold IMBRUVICA for ≤ 7 days) and monitor closely; e.g. ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, telithromycin, itraconazole, nefazadone, cobicistat. Moderate: Avoid where possible or reduce dose and monitor closely; e.g. diltiazem, voriconazole, erythromycin, amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ ritonavir, diltiazem, fluconazole, fosamprenavir, imatinib, verapamil, amiodarone, dronedarone. Avoid grapefruit and Seville oranges. Mild: No dose adjustment required; monitor closely. CYP3A inducers: Strong/moderate: Avoid or monitor closely for lack of efficacy; e.g. carbamazepine, rifampicin, phenytoin. Mild: may be used; monitor for lack of efficacy. Medicines that increase stomach pH (e.g. proton pump inhibitors) may decrease ibrutinib exposure. Potential interactions: Oral narrow therapeutic range P-gp or breast cancer resistance protein (BCRP) substrates (e.g. digoxin, methotrexate) should be taken ≥ 6 h
before/after IMBRUVICA. Ibrutinib may inhibit BCRP in the liver and so increase exposure of drugs undergoing BCRP-mediated hepatic efflux (e.g. rosuvastatin). Ibrutinib may inhibit intestinal CYP3A4 and thus increase exposure of some CYP3A4 substrates sensitive to gut CYP3A metabolism; caution with narrow therapeutic range oral CYP3A4 substrates (e.g. dihydroergotamine, ergotamine, fentanyl, cyclosporine, sirolimus, tacrolimus). Ibrutinib is a weak CYP2B6 inducer and may affect expression of other enzymes and transporters regulated via the constitutive androstane receptor (CAR),(e.g. CYP2C9, CYP2C19, UGT1A1, MRP2). Exposure to substrates of CYP2B6 (e.g. efavirenz, bupropion) and co -regulated enzymes may be reduced with ibrutinib. Refer to SmPC for full details of interactions. LEGAL CATEGORY: Prescription only medicine. PRESENTATIONS PACK SIZES Bottles Bottles
90 capsules 120 capsules
MARKETING AUTHORISATION HOLDER: Janssen-Cilag International NV, Turnhoutseweg 30, B-2340 Beerse, Belgium FURTHER INFORMATION IS AVAILABLE FROM: Janssen-Cilag Limited, 50-100 Holmers Farm Way, High Wycombe, Buckinghamshire, HP12 4EG UK. Prescribing information last revised: November 2015. Reference: 1. Imbruvica® Summary of Product Characteristics. Janssen Cilag International NV. 2015. Date of preparation: Feb 2016 PHIR/IBR/0216/0007 Adverse events should be reported. This medicinal product is subject to additional monitoring and it is therefore important to report any suspected adverse events related to this medicinal product. Healthcare professionals are asked to report any suspected adverse events via: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517, Website: www.hpra.ie, E-mail: email@example.com Adverse events should also be reported to Janssen-Cilag Limited on +44 1494 567447 or at firstname.lastname@example.org
IMBRUVICA® is co-developed with Pharmacyclics. Janssen-Cilag Limited is the marketing authorisation holder and responsible editor of this document.
@JanssenIE © Pharmacyclics LLC 2016
MARKETING AUTHORISATION NUMBER(S) EU/1/14/945/001 EU/1/14/945/002
© Janssen Cilag Limited 2016
Advances in Medical Oncology
Cancer is the second most common cause of death here. One in three people in Ireland will develop cancer during their lifetime and an average of 30,000 new cases of cancer are diagnosed each year. The number is expected to rise to over 40,000 per year by 2020. In addition, with care that aims to balance effectiveness of treatment alongside the importance of quality of life, more patients than ever are not just living longer but able to lead full lives. Yet, cancer accounts for over one-quarter of the annual death toll in Ireland. On a global level, cancer is now one of the world’s most pressing health challenges. Seven of every 10 cancer deaths occur in Africa, Asia, and Central and South America. By the year 2030, these cancer deaths could increase globally by as much as 80%, according to World Health Organisation estimates.
further research, and cumulative knowledge and progress result in tangible benefits for patients. This report, Clinical Cancer Advances 2016: Annual Report on Progress Against Cancer, reviews the recent top advances and emerging trends in clinical cancer research. These advances are based on discoveries in cancer biology that are leading to improved cancer treatments for patients. Now in its 11th year, this report also highlights policy issues and developments that will affect the future of cancer research and determine the pace of progress going forward. ADVANCE OF THE YEAR: CANCER IMMUNOTHERAPY
The scientific community is working hard to avert this grim projection. Clinical research is the bedrock of progress against cancer, and discoveries are moving from bench to bedside faster than ever. The best example of this in recent years is the explosion of immunotherapy approaches for a variety of cancers.
Just five years ago, the immunotherapy drug ipilimumab was hailed as the first treatment to improve the survival of people with advanced melanoma. Today, newer immunotherapies directed against programmed death-1 (PD1) and programmed death-ligand 1 (PD-L1) proteins seem to be as or even more effective, while causing fewer adverse effects. Additional studies have suggested that combining immunotherapy agents from these two different classes of drugs may provide even more benefit, although the combined regimens can be more toxic.
Overall, research progress from one year to the next is incremental, and true breakthroughs are rare. Nevertheless, knowledge gathered from any single study can inform
Research reported in 2015 showed that immunotherapies can improve outcomes for other difficult-totreat cancers. Within 3 months of approving the first PD-1 drug for
March 2016 • HPN
melanoma, the US Food and Drug Administration (FDA) expanded its use to treatment of advanced lung cancer. This advance has major implications for cancer care, because lung cancer is the most common and most deadly malignancy worldwide.
ever expanding understanding of tumour biology provides direction for the development of new therapies. Treatments like targeted therapy are increasingly being tailored to the key genetic mutations that drive the growth of particular cancers.
Last year, early reports indicated that the immunotherapy drugs that block PD-1 or PD-L1 proteins may play a role in the treatment of other cancers, including those that begin in the bladder, kidney, liver, and head and neck. These findings revealed potential new options for patients with advanced disease, especially those who had exhausted all standard therapy options.
In 2015, researchers reported marked gains in overcoming treatment resistance in several difficult-to-treat forms of blood, ovarian, lung, and breast cancers. New targeted treatments have been shown to keep cancer growth at bay for months to years. In each case, the success of newer treatments has stemmed from discoveries of the molecular underpinnings of cancer in general and of the mechanisms of drug resistance in particular.
Exciting early signs of success have also been reported with experimental immunotherapy strategies for certain blood cancers (acute lymphoblastic leukaemia [ALL] and diffuse large B-cell lymphoma [DLBCL]) and glioblastoma, the deadliest brain cancer in adults. This continued wave of success with immunotherapies, which has extended beyond just a few tumour types, promises to transform cancer care, thus making it ASCO’s Advance of the Year. Just as important, these achievements are sparking more innovation, such as the development of approaches that pair immunotherapy with traditional cancer treatments— chemotherapy, targeted therapy, and radiation therapy. The first clinical studies of such combinations are already under way. TREATMENT-RESISTANT CANCERS: PRECISION MEDICINE PUSHES AHEAD Drug resistance is a notorious and far too common problem in cancer therapy. Each time a cancer recurs or worsens, it becomes even more difficult to treat. Although most advanced-stage cancers cannot be cured, having more treatment options to choose from can improve both the length and quality of life. Precision medicine approaches have been making steady gains against cancers that are resistant to traditional cancer therapy. The
COMPETENCY FRAMEWORKS The role of pharmacists in the delivery of cancer care has changed significantly in Ireland over recent years. These changes are largely due to increases in the use of chemotherapy as a result of the aging population, and supportive therapy for the management of side effects and co-morbidities. In addition, there has been a significant increase in the use of oral anticancer medicines (OAM) which are dispensed to patients in the community. Consequently, the skill and knowledge requirement of pharmacists involved in the delivery of cancer care, in both hospitals and communities, has changed. This was recognised in the NCCP Oncology Medication Safety Review (1) which recommended the development of: “National competencies for all disciplines in relation to acute oncology in collaboration with the relevant colleges and professional bodies”. Competence assessment has evolved and been influenced by the learning taxonomy devised by Bloom (2). Bates & Bruno (3) define competence as “the overarching capacity of a person to perform”. Competencies are the “functional”, the “what” that are attached to competence and are defined as the knowledge, skills, attitudes and behaviours that an individual develops through
34.7 median OS1
MO N T H S
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® ▼ 250 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 (4 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 postdose). 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 (2 tablets) 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. 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, 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, flecanide, codeine, oxycodone and tramadol. Avoid strong inducers of CYP3A4 (e.g. phenytoin, carbamazepine, rifampicin, rifabutin, rifapentine, phenobarbital, St John’s wort). Zytiga is a CYP2C8 inhibitor (in vitro data). Examples of medicinal products metabolised by CYP2C8 incl paclitaxel, repaglinide. No clinical data are available on the use of Zytiga with CYP2C8 substrates. 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: Prescription only medicine. PRESENTATION, PACK SIZE & MARKETING AUTHORISATION NUMBER: PRESENTATION: 250 mg tablet. PACK SIZE: 120 tablets. MARKETING AUTHORISATION NUMBER: EU/1/11/714/001. MARKETING AUTHORISATION HOLDER: JANSSEN-CILAG INTERNATIONAL NV, Turnhoutseweg 30, B-2340 Beerse, Belgium. FURTHER INFORMATION IS AVAILABLE FROM: Janssen-Cilag Limited, 50-100 Holmers Farm Way, High Wycombe, Buckinghamshire, HP12 4EG, UK. © Janssen-Cilag Limited 2016 Adverse events should be reported. This medicinal product is subject to additional monitoring and it is therefore important to report any suspected adverse events related to this medicinal product. Healthcare professionals are asked to report any suspected adverse events via: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517, Website: www.hpra.ie, E-mail: medsafety@hpra. ie. Adverse events should also be reported to Janssen-Cilag Limited on +44 1494 567447. Prescribing information last revised: January 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), http://dx.doi.org/10.1016/j. eururo.2014.02.056. Date of Preparation: January 2016 | PHIR/ZYT/1014/0004(2)
30 Feature education, training, development and experience (3). To this end the National Cancer Programme recently established a National Competency Framework hopes to inform the development and provision of training for pharmacists working in cancer care. In addition, it will address the need to optimise medicine use, to improve the quality of care and to improve outcomes for cancer patients by illustrating the behaviours, skills and knowledge pharmacists require for working in cancer care. This competency framework can be used at an individual level to measure performance and to help pharmacists working in cancer care, through reflection, to identify gaps in their continuing professional development needs
(4). At a more strategic level, it can be used as a method to inform the development and provision of training and education for pharmacists working in cancer care (5,6). IMPROVING QUALITY OF LIFE Maintaining or improving quality of life for patients throughout the cancer continuum is an important component of overall cancer care. It is now recognised that maintaining or improving quality of life is particularly important for patients with advanced-stage disease; therefore, it is especially important to consider the balance of potential benefits and harms of various treatment options. Accumulating clinical trial evidence supports the long-held belief that proper selection of treatment for
an individual patient on the basis of his or her circumstances can help maximise quality of life. For example, recent research has shown that whole-brain irradiation for some patients with brain metastases exacerbates cognitive decline without extending survival. Meanwhile, another study identified a group of patients who nonetheless may benefit from this therapy.
Lenvatinib (LENVIMA®) January 2016 Trastuzumab Emtansine (Kadcyla®) August 2015
Between August and January of this year four new cancer drugs have been added to the National Cancer Programme Funded list.
Between October 2014 and October 2015, the FDA approved 10 new cancer treatments and expanded use for 12 previously approved therapies and one device. These approvals will help improve outcomes for people battling a range of difficult-to-treat cancers, including melanoma and ovarian, lung, breast, and blood cancers. A new vaccine for the prevention of the viral infections that cause cervical and certain other cancers was also approved in 2015.
New Drugs Funded
REFERENCES ON REQUEST
PATIENTS GAINED ACCESS TO NEW CANCER THERAPIES
Enzalutamide (Xtandi ) January 2016 ®
New scheme supports European Commission priorities The European Medicines Agency (EMA) has launched its new PRIME (PRIority MEdicines) scheme to strengthen support to medicines that target an unmet medical need. The scheme focuses on medicines that may offer a major therapeutic advantage over existing treatments, or benefit patients with no treatment options. These medicines are considered priority medicines within the European Union (EU). Through PRIME, EMA offers early, proactive and enhanced support to medicine developers to optimise the generation of robust data on a medicine’s benefits and risks and enable accelerated assessment of medicine applications. This will help patients to benefit as early as possible from therapies that may significantly improve their quality of life. By engaging with medicine developers early, PRIME aims to strengthen clinical trial designs to facilitate the generation of high quality data for the evaluation of an application for marketing authorisation. Early dialogue and scientific advice also ensure that patients participate in trials that are likely to provide the necessary data for an application for marketing authorisation, and help to make best use of limited resources. “The launch of PRIME is a major step forward for patients and their families that have long been hoping for earlier access to safe treatments for their unmet medical needs, such as rare cancers, Alzheimer’s disease and other dementias,” says Vytenis March 2016 • HPN
Andriukaitis, EU Commissioner for Health and Food Safety. “Through enhanced scientific support this scheme could also help, for example, to accelerate the development and authorisation of new classes of antibiotics or their alternatives in an era of increasing antimicrobial resistance.” The Commissioner also highlights that PRIME optimises the use of the current regulatory framework that can contribute to the European Commission's priorities in terms of boosting innovation, jobs, growth and competitiveness. “Our goal is to foster better planning of medicine development to help companies generate the high quality data we need to assess quality, safety and efficacy of medicines,” explains Professor Guido Rasi, EMA’s Executive Director. “Patients with no or insufficient treatments could then benefit from scientific progress and cutting edge medicines as soon as possible.” PRIME builds on the existing regulatory framework and available tools such as scientific advice and accelerated assessment. This means that a PRIME medicine is expected to benefit from accelerated assessment at the time of an application for marketing authorisation. “We want to ensure that breakthroughs in medicines reach patients quicker,” says Dr Tomas Salmonson, Chair of the Committee for Medicinal Products for Human Use (CHMP). “By strengthening collaboration between the scientific committees,
Professor Guido Rasi, EMA’s Executive Director
and by gaining and sharing knowledge on the medicine throughout the development, we will not only accelerate patients’ access but also ensure an efficient use of available resources.” To be accepted for PRIME, a medicine has to show its potential to benefit patients with unmet medical needs based on early clinical data. Once a candidate medicine has been selected for PRIME, the Agency: • appoints a rapporteur from EMA’s CHMP or from the Committee on Advanced Therapies (CAT) in the case of an advanced therapy, to provide continuous support and help to build knowledge ahead of a marketing authorisation application;
• organises a kick-off meeting with the CHMP/CAT rapporteur and a multidisciplinary group of experts from relevant EMA scientific committees and working parties, and provides guidance on the overall development plan and regulatory strategy; • assigns a dedicated EMA contact point; • provides scientific advice at key development milestones, involving additional stakeholders such as health technology assessment bodies to facilitate patients’ quicker access to the new medicine; • confirms potential for accelerated assessment at the time of an application for marketing authorisation.
XOFIGO® IS AN ALPHA PARTICLE-EMITTING PHARMACEUTICAL
that is indicated for the treatment of adults with castrationresistant prostate cancer (CRPC), symptomatic bone metastases and no known visceral metastases.1
Prolong life. Target bone metastases. The first agent to extend overall survival by targeting bone metastases in CRPC1,2 • Improved Overall Survival2 • Delayed time to first symptomatic skeletal event2 • 1-minute intravenous injection every 4 weeks for 6 injections1
▼ This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. Xofigo 1000 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, 1000 kBq/ml, corresponding to 0.53 ng radium-223 at the reference date). Each vial contains 6 mL of solution (6.0 MBq radium-223 dichloride at the reference date). Contains sodium. Indication: Treatment of adults with castrationresistant 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 50 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
© 2013 Bayer Pharma AG. November 2013
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 follow-up 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: November 2013. References: 1. Xofigo® (radium Ra 223 dichloride) solution for injection. Summary of Product Characteristics (SmPC), Bayer Pharma AG, 13342 Berlin, Germany, 2013. 2. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223.
radium Ra 223 dichloride SOLUTION FOR INJECTION
Overview and Treatment options for Hospital Based Management of Ovarian Cancer Ovarian cancer is the most common cause of cancer death from gynecologic tumors. Malignant lesions of the ovaries include primary lesions arising from normal structures within the ovary and secondary lesions from cancers arising elsewhere in the body. Primary lesions include epithelial ovarian carcinoma (70% of all ovarian malignancies), germ-cell tumors, sex-cord stromal tumours, and other more rare types. Metastases to the ovaries are relatively frequent, with the most common being from the endometrium, breast, colon, stomach, and cervix. Although many histologic types of ovarian tumours have been described, more than 90% of ovarian malignancies are epithelial tumours. The precise cause of ovarian cancer is unknown, but several risk and contributing factors (including both reproductive and genetic factors) have been identified. Around the world, more than 200,000 women are estimated to develop ovarian cancer every year and about 100,000 die from the disease. The lifetime risk of a woman developing epithelial ovarian cancer is 1 in 70. Most theories of the pathophysiology of ovarian cancer include the concept that it begins with the dedifferentiation of the cells overlying the ovary. During ovulation, these cells can be incorporated into the ovary, where they then proliferate. Ovarian cancer typically spreads to the peritoneal surfaces and omentum. Ovarian carcinoma can spread by local extension, lymphatic invasion, intraperitoneal implantation, hematogenous dissemination, and transdiaphragmatic passage. Intraperitoneal dissemination is the most common and recognized characteristic of ovarian cancer. Malignant cells can implant anywhere in the peritoneal cavity but are more likely to implant in sites of stasis along the peritoneal fluid circulation. As discussed later, these mechanisms of dissemination represent the rationale to conduct surgical staging, debulking surgery, and intraperitoneal administration of chemotherapy. In contrast, hematogenous spread is clinically unusual early on in the disease process, although it is
March 2016 • HPN
not infrequent in patients with advanced disease.
Clear cell (mesonephros)
EPITHELIAL OVARIAN CANCER
Some variation is observed in the patterns of spread and disease distribution within the various histologic subtypes.
Epithelial tumours represent the most common histology (90%) of ovarian tumours. Other histologies include the following: Sex-cord stromal tumours Germ cell tumours Primary peritoneal carcinoma Metastatic tumours of the ovary Epithelial ovarian cancer is thought to arise from epithelium covering the ovaries, which is derived from the coelomic epithelium in fetal development. This coelomic epithelium is also involved in formation of the Müllerian ducts, from which the Fallopian tubes, uterus, cervix, and upper vagina develop. Five main histologic subtypes, which are similar to carcinoma, arise in the epithelial lining of the cervix, uterus, and fallopian tube, as follows: Serous (from fallopian tube) Endometrioid (endometrium) Mucinous (cervix)
Epithelial tumors are found as partially cystic lesions with solid components. The surface may be smooth or covered in papillary projections (see the image below), and the cysts contain fluid ranging from straw-colored to opaque brown or hemorrhagic. Epithelial ovarian cancer most often spreads initially within the peritoneal cavity (see the image below). Metastatic disease often is found on the peritoneal surfaces, particularly on the undersurface of the diaphragms, the paracolic gutters, the bladder, and the cul-de-sac. Other common sites are the surface of the liver, the mesentery and serosa of the large and small bowel, in the omentum, the uterus, and para-aortic and pelvic lymph nodes. Outside the peritoneal cavity, epithelial ovarian cancer may spread to the pleural cavity, lungs, and groin lymph nodes. Presence of pleural effusion does not necessarily indicate disease
in the chest, and malignancy can be diagnosed only cytologically. Mucinous tumors tend to form large dominant masses, while papillary serous tumors have a more diffuse distribution and are more commonly bilateral. Endometrioid and clear-cell variants more commonly exhibit local invasion, retroperitoneal disease, and hepatic metastases. Li et al suggested a tubal origin of ovarian-serous cancers rather than through Müllerian metaplasia from ovarian surface epithelium. The precise cause of ovarian cancer is unknown, but several risk and contributing factors have been identified. Hippisley-Cox and Coupland developed an algorithm to determine risk of ovarian cancer in women with and without symptoms. In their cohort study, 10% of women with the highest predicted risk had 63% of all ovarian cancers diagnosed over the next 2 years. REPRODUCTIVE FACTORS Parity is an important risk factor. The risk of epithelial ovarian cancer is increased in women who have not had children and possibly those with early
Keep me in the picture Margaret
Avastin. Adding more time* in advanced ovarian cancer.1-3
ABRIDGED PRESCRIBING INFORMATION (For full prescribing information refer to the Summary of Product Characteristics [SmPC]) AVASTIN® (bevacizumab) 25mg/ml concentrate for solution for infusion Indications: (i) In combination with fluoropyrimidine-based chemotherapy for treatment of adult patients with metastatic carcinoma of the colon or rectum (mCRC). (ii) In combination with paclitaxel for first-line treatment of adult patients with mBC. (iii) In combination with capecitabine for first-line treatment of adult patients with metastatic breast cancer in whom treatment with other chemotherapy options including taxanes or anthracyclines is not considered appropriate. Patients who have received taxane and anthracycline-containing regimens in the adjuvant setting within the last 12 months should be excluded from treatment with Avastin in combination with capecitabine. (iv) In addition to platinum based chemotherapy for first line treatment of adult patients with unresectable advanced, metastatic or recurrent non-small cell lung cancer (NSCLC) other than predominantly squamous cell histology. (v) In combination with interferon alfa-2a for first line treatment of adult patients with advanced and/or metastatic renal cell cancer (mRCC). (vi) In combination with carboplatin and paclitaxel for front-line treatment of adult patients with advanced (FIGO stages IIIB, IIIC and IV) epithelial ovarian, fallopian tube or primary peritoneal cancer. (vii) in combination with carboplatin and gemcitabine, for the treatment of adult patients with first recurrence of platinum-sensitive epithelian ovarian, fallopian tube or primary peritoneal cancer who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor-targeted agents. (viii) In combination with paclitaxel, topotecan, or pegylated liposomal doxorubicin is indicated for the treatment of adult patients with platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who received no more than two prior chemotherapy regimens and who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor–targeted agents. (xi) Bevacizumab, in combination with paclitaxel and cisplatin or, alternatively, paclitaxel and topotecan in patients who cannot receive platinum therapy, is indicated for the treatment of adult patients with persistent, recurrent, or metastatic carcinoma of the cervix. Dosage and Administration: Physicians experienced in antineoplastic medicines should supervise administration of Avastin. Initial dose: 90 minute IV infusion; second dose: 60 minute IV infusion, if initial dose well tolerated; subsequent doses: 30 minute IV infusion, if 60 minute infusion well tolerated. It should not be administered as an IV push or bolus. Do not administer or mix with glucose solutions. Safety and efficacy has not been established in children and adolescents. No recommended paediatric posology. Avastin should not be used in children aged 3 to 18 years with recurrent or progressive high-grade glioma because of efficacy concerns. No dose adjustment is required in the elderly. No data in renal or hepatic impairment. Dose reduction for adverse reactions is not recommended. If indicated, therapy should either be permanently discontinued or temporarily suspended. For all indications it is recommended that the treatment be continued until progression or until unacceptable toxicity, refer to SmPC. mCRC: Recommended dose: 5mg/kg or 10mg/kg body weight given once every two weeks or 7.5mg/kg or 15mg/kg body weight given once every three weeks. mBC: 10mg/kg body weight once every two weeks or 15mg/kg body weight once every three weeks. NSCLC: Administer in addition to platinum based chemotherapy for up to 6 cycles of treatment followed by Avastin as a single agent until disease progression. Recommended dose: 7.5 mg/ kg or 15 mg/kg body weight once every three weeks. mRCC: Recommended dose: 10mg/kg body weight once every 2 weeks. Epithelial ovarian, fallopian tube and primary peritoneal cancer: Front Line: Administer in addition to carboplatin and paclitaxel for up to 6 cycles of treatment followed by continued use of Avastin as single agent. Recommended treatment dose of Avastin 15 mg/kg of body weight once every 3 weeks until disease progression or unacceptable toxicity or for a maximum of 15 months. Treatment of platinum-sensitive recurrent disease: Recommended dose of 15mg/kg of body weight once every 3 weeks in combination with carboplatin and gemcitabine for 6 cycles and up to 10 cycles followed by continued use of Avastin as single agent until disease progression. Treatment of platinum-resistant recurrent disease: Recommended dose of 10mg/kg of body weight once every 2 weeks in combination with one of the following agents-paclitaxel, weekly topotecan or pegylated liposomal doxorubicin. When Avastin is administered in combination with topotecan, the recommended dose of Avastin is 15mg/kg of body weight one every 3 weeks. Continue treatment until disease progression or unacceptable toxicity. Cervical Cancer: Avastin is administered in combination with either paclitaxel and cisplatin or paclitaxel and topotecan. The recommended dose of Avastin is 15 mg/kg of body weight given once every 3 weeks. It is recommended that treatment be continued until progression of the underlying disease or until unacceptable toxicity. Contraindications: Pregnancy. Hypersensitivity to bevacizumab, Chinese Hamster Ovary cell products, recombinant human or humanised antibodies or any excipients. Warnings and Precautions: In order to improve traceability the trade name of the administered biological medicinal product should be clearly recorded in the patient file. Increased risk of gastrointestinal (GI) perforation and gall bladder perforation when taking Avastin. Prior radiation is a risk factor for GI perforation in patients treated for persistent, recurrent or metastatic cervical cancer with Avastin and all patients with GI perforation had a history of prior radiation. Intra-abdominal inflammatory process may be a risk factor for GI perforations in patients with mCRC -permanently discontinue in patients developing GI perforation. GI-vaginal Fistulae in study GOG-0240: Patients treated for persistent, recurrent, or metastatic cervical cancer with Avastin are at increased risk of fistulae between the vagina and any part of the GI tract (GI-vaginal fistulae). Prior radiation is a major risk factor for the development of GI-vaginal fistulae and all patients with GI-vaginal fistulae in the GOG-0240 study had a history of prior radiation. Recurrence of cancer within the field of prior radiation is an additional important risk factor for the development of GI-vaginal fistulae. Permanently discontinue Avastin in patients with TE (tracheoesophageal) fistula or any Grade 4 fistula. Consider discontinuing Avastin in cases of internal fistula not arising in the GI tract. May affect wound healing, serious would healing complications including anastomotic complications with a fatal outcome have been reported. Do not initiate therapy for at least 28 days following major surgery or until surgical wound has healed. Withhold therapy for elective surgery and in patients experiencing wound healing complications during therapy until wound fully healed. Necrotising fasciitis including fatal cases have rarely been reported in patients treated with Avastin. Occurrence is usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Discontinue Avastin and promptly initiate appropriate treatment. Dose-dependent hypertension observed. Control pre-existing hypertension before starting Avastin. Diuretic therapies are not advised in patients on a cisplatin-based chemotherapy regimen. Permanently discontinue treatment in patients with medically significant hypertension that cannot be adequately controlled or in patients who develop hypertensive crisis or hypertensive encephalopathy. Monitor blood pressure during therapy. Risk of proteinuria, especially in patients with history of hypertension, may be dose-dependent; monitor patient before and during treatment, permanently discontinue if nephrotic syndrome occurs-refer to SmPC. Risk of arterial thromboembolic reactions including cerebrovascular accidents, transient ischaemic attacks and myocardial infarctions (especially if prior history of arterial thromboembolic reactions, diabetes or age over 65 years exercise caution with these patients). Permanently discontinue in patients developing arterial thromboembolic reactions. Increased risk of tumour associated haemorrhage; discontinue permanently if Grade 3/4 bleeding. Risk of CNS haemorrhage in patients with CNS metastases not prospectively evaluated in randomised clinical trials – monitor patients for signs and symptoms of CNS bleeding, discontinue treatment in cases of intracranial bleeding. Caution in patients with congenital bleeding diathesis, acquired coagulopathy or those taking full dose anticoagulants for thromboembolism prior to starting Avastin. Risk of serious and in some cases fatal pulmonary haemorrhage/haemoptysis in NSCLC patients. Do not treat patients with recent pulmonary haemorrhage/haemoptysis (> 2.5ml of red blood). Risk of developing venous thromboembolic reactions, including pulmonary embolism, discontinue in patients with life threatening (grade 4) thromboembolic reactions, patients with ≤ Grade 3 thromboembolic reactions need to be closely monitored. Exercise caution when treating patients with clinically significant cardiovascular disease such as pre-existing coronary artery disease, or congestive heart failure – refer to SmPC. In combination with some myelotoxic chemotherapy regimens mainly platinum or taxane-based therapies in treatment of NSCLC and mBC, increased rates of severe neutropenia, febrile neutropenia or infection with or without severe neutropenia (including some fatalities) observed. Rare reports of Avastin treated patients developing signs and symptoms of Posterior reversible encephalopathy syndrome (PRES), confirm by brain imaging, preferably MRI, treat symptoms including control of hypertension and discontinue Avastin. The safety of re-initiating Avastin in patients previously experiencing PRES is unknown. Risk of developing infusion/hypersensitivity reactions -closely observe patients during and after administration. If a reaction occurs the infusion should be discontinued and appropriate medical therapies should be administered, systemic premedication is not warranted. Cases of osteonecrosis of the jaw (ONJ) have been reported in cancer patients treated with Avastin, the majority had received prior or concomitant treatment with intravenous bisphosphonates, for which ONJ is an identified risk. Caution when Avastin and intravenous bisphosphonates are administered simultaneously or sequentially. Invasive dental procedures are an identified risk factor. Consider a dental examination and appropriate preventive dentistry prior to starting Avastin. Avoid, if possible, invasive dental procedures in patients who have previously received or are receiving intravenous bisphosphonates. Avastin is not formulated for intravitreal use. Individual cases and clusters of serious adverse reactions including infectious endophthalmitis, intraocular inflammation such as sterile endophthalmitis, uveitis and vitritis, retinal detachment, retinal pigment epithelial tear, intraocular pressure increased, intraocular haemorrhage such as vitreous haemorrhage or retinal haemorrhage and conjunctival haemorrhage have been reported from unapproved intravitreal use. Some events have resulted in various degrees of visual loss, including permanent blindness. A reduction in circulating VEGF concentrations has been demonstrated following intravitreal anti-VEGF therapy. Systemic adverse reactions including non-ocular haemorrhage and arterial thromboembolic reactions have been reported following intravitreal injection of VEGF inhibitors. Avastin may impair female fertility-discuss fertility preservation strategies with women of child-bearing potential prior to starting treatment. Drug Interactions: No clinically relevant pharmacokinetic interaction of co-administered chemotherapy on Avastin disposition observed. No difference in clearance of Avastin in patients receiving Avastin monotherapy compared to patients receiving Avastin in combination with Interferon alpha-2a or other chemotherapies (IFL, 5-FU/LV, carboplatin/paclitaxel, capecitabine, doxorubicin or cisplatin/gemcitabine). No significant effects of Avastin on pharmacokinetics of irinotecan and its active metabolite SN38, capecitabine and its metabolites, oxaliplatin, interferon alfa-2a and cisplatin. The impact of Avastin on gemcitabine pharmacokinetics is unknown. In two clinical studies of mRCC, microangiopathic haemolytic anaemia (MAHA) was reported in 7 of 19 patients treated with Avastin (10 mg/kg every two weeks) in combination with sunitinib malate (50 mg daily). Hypertension (including hypertensive crisis), elevated creatinine and neurological symptoms were observed in some of these patients reversible upon discontinuation of Avastin and sunitinib malate. Increased rates of severe neutropenia, febrile neutropenia or infection with or without severe neutropenia (including some fatalities) have been observed mainly in patients treated in combination with platinum or taxane-based therapies in treatment of NSCLC and mBC. The safety and efficacy of concomitant administration of radiotherapy and Avastin has not been established. EGFR monoclonal antibodies should not be administered for the treatment of mCRC in combination with bevacizumab containing chemotherapy. Concomitant administration of panitumumab and cetuximab is associated with decreased PFS/OS and with increased toxicity, compared with bevacizumab plus chemotherapy alone please refer to SmPC. Fertility, Pregnancy and Lactation: Contraindicated during pregnancy. No data on use in pregnant women. Animal studies have shown reproductive toxicity including malformations. May inhibit foetal angiogenesis and is suspected to cause serious birth defects if administered during pregnancy. Women of childbearing potential must use effective contraception during treatment and for six months after last dose. Discontinue breast-feeding during treatment and for at least six months after last dose as Avastin may harm infant growth and development. Animal repeat dose toxicity studies show possible adverse effect on female fertility. Refer to SmPC for Phase III human data. Effects on ability to drive and use machines: If patients are experiencing symptoms that affect their vision or concentration they should be advised not drive and use machines (dizziness), some somnolence and syncope have been reported with use. Side Effects and Adverse Reactions: Very Common (≥1/10): febrile neutropenia*, leucopenia*, neutropenia*, thrombocytopenia*, anorexia, peripheral sensory neuropathy*, dysarthria, headache*, dysgeusia, eye disorder, lacrimation increased, hypertension*, thromboembolism (venous)*, dyspnoea*, rhinitis, rectal haemorrhage, stomatitis*, constipation, diarrhoea*, nausea*, vomiting*, abdominal pain*, wound healing complications*, exfoliative dermatitis, dry skin, skin discoloration, arthralgia, proteiniuria*, ovarian failure, asthenia*, fatigue*, pyrexia, pain*, mucosal inflammation*, weight decreased. Common (≥1/100 to <1/10): Sepsis*, abscess*, cellulitis*, infection, urinary tract infection*, anaemia*, lymphopenia*, hypersensitivity infusion reactions, dehydration*, cerebrovascular accident*, syncope*, sommolence*, congestive heart failure*, supraventricular tachycardia*, thromboembolism (arterial)*, haemorrhage*, deep vein thrombosis*, pulmonary haemorrhage*, haemoptysis*, pulmonary embolism*, epistaxis*, hypoxia*, dysphonia, gastrointestinal perforation, intestinal perforation*, ileus intestional obstruction, recto-vaginal fistulae*, gastrointestinal disorder*, proctalgia*, palmar-plantar erythrodysaesthesia syndrome*, fistula*, myalgia*, muscular weakness*, back pain*, pelvic pain*, lethargy*. Adverse reactions of lesser frequency include: necrotising faciitis*, posterior reversible encephalopathy syndrome*, osteonecrosis of the jaw*. Reactions marked with an asterisk were considered as severe. 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 and Marketing Authorisation Numbers: EU/1/04/300/001 for 100mg/4ml (Pack size of one); EU/1/04/300/002 for 400mg/16ml (Pack size of one). Marketing Authorisation Holder: Roche Registration Limited, 6 Falcon Way, Shire Park,Welwyn Garden City, AL7 1TW, United Kingdom. Avastin 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: December 2015.
Reference: 1. Burger, R. et al. N Eng J Med 2011 2. Aghajanian et al. J Clin Oncol 2012 3. Pujade-Lauraine et al. J Clin Oncol 2014 Zinc Number: IE/AVAO/0915/0003(1) Date Of Item: February 2016 *progression-free survival.
34 Feature menarche or late menopause. Women who have been pregnant have a 50% decreased risk for developing ovarian cancer compared with nulliparous women. Multiple pregnancies offer an increasingly protective effect. Oral contraceptive use decreases the risk of ovarian cancer. These factors support the idea that risk for ovarian cancer is related to ovulation. Two theories regarding this relationship have been proposed. The incessant ovulation theory suggests that repeated ovarian epithelial trauma caused by follicular rupture and subsequent epithelial repair results in genetic alterations within the surface epithelium. The gonadotropin theory proposes that persistent stimulation of the ovaries by gonadotropins, coupled with local effects of endogenous hormones, increases surface epithelial proliferation and subsequent mitotic activity. Thus, the probability of ovarian cancer may be related to the number of ovulatory cycles, and conditions that suppress the ovulatory cycle may play a protective role. Ovulation suppression has been shown to decrease cancer incidence. Although treatment with agents that induce ovulation in women with infertility has been suggested to increase the incidence of epithelial ovarian cancer, this is unproven. GENETIC FACTORS Family history plays an important role in the risk of developing ovarian cancer. The lifetime risk for developing ovarian cancer is 1.6% in the general population. This compares with a 4-5% risk when 1 first-degree family member is affected, rising to 7% when 2 relatives are affected. From 5-10% of cases of ovarian cancer occur in an individual with a family history of the disease. Only a small percentage of these patients have an inherited genetic abnormality, and the risk of this occurrence increases with the strength of the family history. Hereditary epithelial ovarian cancer occurs at a younger age (approximately 10 years younger) than nonhereditary epithelial ovarian cancer, but the prognosis may be somewhat better. Integrated genomic analyses by the Cancer Genome Atlas Research Network have revealed high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumors. The findings also include the low prevalence but statistically recurrent somatic mutations in 9 further genes, including NF1, BRCA1, BRCA2, RB1, and CDK12,
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along with 113 significant focal DNA copy number aberrations and promoter methylation events involving 168 genes. Pathway analyses revealed defective homologous recombination in about half of all tumors, and that NOTCH and FOXM1 signaling are involved in serous ovarian cancer pathophysiology. Evidence from the Cancer Genome Atlas Network showed that serous ovarian tumors and breast basallike tumors shared a number of molecular characteristics such as the types and frequencies of genomic mutations, suggesting that ovarian and breast cancer may have a related etiology and potentially similar responsiveness tosomeofthesametherapies. At least 2 syndromes of hereditary ovarian cancer are clearly identified, involving either (1) disorders of the genes associated with breast cancer, BRCA1 and BRCA2, or (2) more rarely, genes within the Lynch II syndrome complex. Breast/ovarian cancer syndrome is associated with early onset of breast or ovarian cancer. Inheritance follows an autosomal dominant transmission. It can be inherited from either parent. Most cases are related to the BRCA1 gene mutation. BRCA1 is a tumor suppressor gene that inhibits cell growth when functioning properly; the inheritance of mutant alleles of BRCA1 leads to a considerable increase in risk for developing ovarian cancer. Approximately 1 person in 4000 in the general population carries a mutation of BRCA1. Some populations have a much higher rate of BRCA1 and BRCA2 mutations, especially Ashkenazi Jews. In families with 2 first-degree relatives (mother, sister, or daughter) with premenopausal epithelial ovarian cancer, the likelihood of a female relative having an affected BRCA1 or BRCA2 gene is as high as 40%. The probability is much lower when the disease occurs in relatives postmenopausally. Individuals with a BRCA1 gene mutation have a 50-85% lifetime risk of developing breast cancer and a 15-45% risk of developing epithelial ovarian cancer. Those with a BRCA2 gene mutation have a 50-85% lifetime risk of developing breast cancer and a 10-20% risk of developing epithelial ovarian cancer. Families with BRCA2 mutations are at risk for developing cancer of the prostate, larynx, pancreas, and male breast. Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers; however, in an investigation of a common genetic
variation at the 9p22.2 locus, a decreased risk of ovarian cancer was noted in carriers of a BRCA1 or BRCA2 mutation.
aggressive debulking surgery followed by chemotherapy.
Families with Lynch II syndrome or hereditary nonpolyposis colorectal cancer are characterized by a high risk for developing colorectal, endometrial, stomach, small bowel, breast, pancreas, and ovarian cancers. This syndrome is caused by mutations in the mismatch repair genes. Mutations have been demonstrated in mismatch repair genes MSH2, MLH1, PMS1, and PMS2.
Early ovarian cancer causes minimal, nonspecific, or no symptoms. The patient may feel an abdominal mass. Most cases are diagnosed in an advanced stage.
Women with a history of breast cancer have an increased risk of epithelial ovarian cancer. In a study by Rafner et al, whole-genome sequencing identified a rare mutation in BRIP1, which behaves like a classical tumor suppressor gene in ovarian cancer. This allele was also associated with breast cancer. PREVIOUS HORMONE THERAPY A nationwide prospective cohort study over 10 years that included all Danish women aged 50-79 years concluded that risk for ovarian cancer is increased with hormone therapy, regardless of duration of use, formulation, estrogen dose, regimen, progestin type, and administration route. Nearly 1 million women without hormone-sensitive cancer or bilateral oophorectomy were followed. In an average of 8 years of follow-up, 3068 ovarian cancers were detected, of which 2681 were epithelial cancers.
SIGNS AND SYMPTOMS
Epithelial ovarian cancer presents with a wide variety of vague and nonspecific symptoms, including the following: Bloating; abdominal distention or discomfort Pressure effects on the bladder and rectum Constipation Vaginal bleeding Indigestion and acid reflux Shortness of breath Tiredness Weight loss Early satiety Symptoms independently associated with the presence of ovarian cancer include pelvic and abdominal pain, increased abdominal size and bloating, and difficulty eating or feeling full. Symptoms associated with later-stage disease include gastrointestinal symptoms such as nausea and vomiting, constipation, and diarrhea. Presentation with swelling of a leg due to venous thrombosis is not uncommon. Paraneoplastic syndromes due to tumor-mediated factors lead to various presentations. DIAGNOSIS
Current users of hormones had incidence rate ratios for all ovarian cancers of 1.38 (95% confidence interval [CI], 11.261.51) compared with women who never took hormone therapy. Risk declined as years since last hormone use increased. Incidence rates in current and never users of hormones were 0.52 and 0.40 per 1000 years, respectively. This translates to approximately 1 extra ovarian cancer for approximately 8300 women taking hormone therapy each year.
Physical findings are uncommon in patients with early disease. Patients with more advanced disease may present with ovarian or pelvic mass, ascites, pleural effusion, or abdominal mass or bowel obstruction.
Lactose consumption and the use of talcum powder on the vulva and perineum may be associated with increased risk of epithelial ovarian cancer.
The National Cancer Institute (NCI) recommends that high-risk women seek advice from their physicians and consider having annual ultrasonographic examinations and annual CA125 testing, as well as consider oophorectomy or participation in a clinical trial.
Early disease causes minimal, nonspecific, or no symptoms. Therefore, most cases are diagnosed in an advanced stage. The prognosis of ovarian cancer is closely related to the stage at diagnosis; thus, overall, prognosis for these patients remains poor. Standard treatment involves
The presence of advanced ovarian cancer is often suspected on clinical grounds, but it can be confirmed only pathologically by removal of the ovaries or, when the disease is advanced, by sampling tissue or ascitic fluid.
LABORATORY TESTING No tumor marker (eg, CA125, betahuman chorionic gonadotropin, alpha-fetoprotein, lactate dehydrogenase) is completely specific; therefore, use diagnostic
35 immunohistochemistry testing in conjunction with morphologic and clinical findings. Also, obtain a urinalysis to exclude other possible causes of abdominal/pelvic pain, such as urinary tract infections or kidney stones.
STAGES OF OVARIAN CANCER
IMAGING STUDIES Routine imaging is not required in all patients in whom ovarian cancer is highly suggested. In cases in which the diagnosis is uncertain, consider the following imaging studies: Pelvic ultrasonography[4, 5]: Warranted Pelvic and abdominal computed tomography (CT) scanning[4, 5]: Warranted Pelvic and abdominal magnetic resonance imaging: Increases specificity of imaging when sonography findings are indeterminate Chest radiography: Routine imaging to exclude lung metastases Mammography: Part of preoperative workup for women older than 40 years who have not had one in the preceding 6-12 months; estrogen producing tumors may increase the risk of breast malignancies, and breast cancers can metastasize to the ovaries and are often bilateral In patients with diffuse carcinomatosis and GI symptoms, a GI tract workup may be indicated, including one of the following imaging studies: Upper and/or lower endoscopy Barium enema Upper GI series PROCEDURES Fine-needle aspiration (FNA) or percutaneous biopsy of an adnexal mass is not routinely recommended, as it may delay diagnosis and treatment of ovarian cancer. Instead, if a clinical suggestion of ovarian cancer is present, the patient should undergo a laparotomy for diagnosis and staging. An FNA or diagnostic paracentesis should be performed in patients with diffuse carcinomatosis or ascites without an obvious ovarian mass. MANAGEMENT Standard treatment for women with ovarian cancer involves aggressive debulking surgery followed by chemotherapy. The aim of cytoreductive surgery is to confirm the diagnosis, define the extent of disease, and resect all visible tumour. SURGERY The type of procedure depends
on whether or not disease is visible outside the ovaries. No disease should be visible outside the ovaries, and patients must be adequately surgically staged (including peritoneal cytology, multiple peritoneal biopsies, omentectomy, and pelvic and para-aortic lymph node sampling). Individualize surgery for patients with stage IV disease. The following are surgeries that may be performed in women with ovarian cancer: Surgical staging Cytoreductive surgery Interval debulking Laparoscopic surgery Secondary surgery CHEMOTHERAPY Postoperative chemotherapy is indicated in all patients with ovarian cancer except those who have surgical-pathologic stage I disease with low-risk characteristics. Standard postoperative chemotherapy for ovarian cancer is combination therapy with a platinum compound and a taxane (eg, carboplatin and paclitaxel). Additional agents for recurrent disease include liposomal doxorubicin, etoposide, topotecan,
gemcitabine, vinorelbine, ifosfamide, fluorouracil, melphalan, altretamine, bevacizumab, and olaparib. Adjunctive medications include the following: Cytoprotective agents (eg, mesna) Although the 5-year survival rate for ovarian cancer has improved significantly in the past 30 years, the prognosis for ovarian cancer remains poor overall, with a 46% 5-year survival rate. The prognosis of ovarian cancer is closely related to the stage at diagnosis,[16, 17] as determined according to the staging system developed by the International Federation of Gynecology and Obstetrics (FIGO). (See Staging.) Approximately 20%, 5%, 58%, and 17% of women present with stage I, II, III, and IV, respectively. The 5-year survival rates (rounded to the nearest whole number) for epithelial ovarian carcinoma by FIGO stage are as follows:
Stage IIB - 55% Stage IIC - 57% Stage IIIA - 41% Stage IIIB - 25% Stage IIIC - 23% Stage IV - 11% Overall survival rate – 46% Bakhru et al found poorer survival among patients with ovarian cancer and diabetes. Although the underlying reason for this association is unknown, further studies are needed. Among women with highgrade serous ovarian cancer, BRCA2 mutation but not BRCA1 deficiency was associated with improved survival, improved chemotherapy response, and genome instability compared with BRCA wild-type. A study by Bolton et al found improved 5-year overall survival among carriers of BRCA1 or BRCA2, with BRCA1 having the best prognosis.
Stage IA - 87%
• Antiemetics (eg, ondansetron, granisetron, palonosetron, dexamethasone)
Stage IB - 71%
REFERENCES ON REQUEST
Stage IC - 79% Stage IIA - 67%
HPN • March 2016
Starting antiretroviral treatment early improves outcomes for HIV-infected individuals NIH-funded trial results likely will impact global treatment guidelines.
Jens Lundgren, M.D., of the University of Copenhagen
A major international randomized clinical trial has found that HIV-infected individuals have a considerably lower risk of developing AIDS or other serious illnesses if they start taking antiretroviral drugs sooner, when their CD4+ T-cell count—a key measure of immune system health—is higher, instead of waiting until the CD4+ cell count drops to lower levels. Together with data from previous studies showing that antiretroviral treatment reduced the risk of HIV transmission to uninfected sexual partners, these findings support offering treatment to everyone with HIV. The new finding is from the Strategic Timing of AntiRetroviral Treatment (START) study, the first large-scale randomized clinical trial to establish that earlier antiretroviral treatment benefits all HIV-infected individuals. The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of
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Health, provided primary funding for the START trial. Though the study was expected to conclude at the end of 2016, an interim review of the study data by an independent data and safety monitoring board (DSMB) recommended that results be released early. “We now have clear-cut proof that it is of significantly greater health benefit to an HIV-infected person to start antiretroviral therapy sooner rather than later,” says NIAID Director Anthony S. Fauci, M.D. “Moreover, early therapy conveys a double benefit, not only improving the health of individuals but at the same time, by lowering their viral load, reducing the risk they will transmit HIV to others. These findings have global implications for the treatment of HIV.” “This is an important milestone in HIV research,” adds Jens Lundgren, M.D., of the University of Copenhagen and one of the co-chairs of the START study. “We now have strong evidence that early treatment is beneficial
to the HIV-positive person. These results support treating everyone irrespective of CD4+ T-cell count.” The START study, which opened widely in March 2011, was conducted by the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT) at 215 sites in 35 countries, including Ireland. The trial enrolled 4,685 HIVinfected men and women ages 18 and older, with a median age of 36. Participants had never taken antiretroviral therapy and were enrolled with CD4+ cell counts in the normal range — above 500 cells per cubic millimeter (cells/mm3). Approximately half of the study participants were randomized to initiate antiretroviral treatment immediately (early treatment), and the other half were randomized to defer treatment until their CD4+ cell count declined to 350 cells/mm3. On average, participants in the study were followed for three years.
The study measured a combination of outcomes that included serious AIDS events (such as AIDS-related cancer), serious non-AIDS events (major cardiovascular, renal and liver disease and cancer), and death. Based on data from March 2015, the DSMB found 41 instances of AIDS, serious non-AIDS events or death among those enrolled in the study’s early treatment group compared to 86 events in the deferred treatment group. The DSMB’s interim analysis found risk of developing serious illness or death was reduced by 53 percent among those in the early treatment group, compared to those in the deferred group. Rates of serious AIDS-related events and serious non-AIDSrelated events were both lower in the early treatment group than the deferred treatment group. The risk reduction was more pronounced for the AIDS-related events. Findings were consistent across geographic regions, and the benefits of early treatment were similar for participants from low- and middle-income
THE FIRST APPROVED
UNBOOSTED INTEGRASE INHIBITOR
ISENTRESS® (raltegravir) ABRIDGED PRODUCT INFORMATION Refer to Summary of Product Characteristics before prescribing. PRESENTATION 400 mg film-coated tablet containing 400 mg of raltegravir (as potassium). 25 mg chewable tablets containing 25 mg of raltegravir (as potassium). 100 mg chewable tablets containing 100 mg of raltegravir (as potassium). INDICATIONS For use in combination with other anti-retroviral medicinal products for the treatment of human immunodeficiency virus (HIV-1) infection in adults, adolescents, and children weighing at least 11 kg. DOSAGE AND ADMINISTRATION Therapy to be initiated by a physician experienced in the management of HIV infection. Posology For use in combination with other active anti-retroviral therapies (ARTs). Adults: 400 mg (one tablet) twice daily. Elderly: Limited information therefore use with caution. Children and adolescents: If at least 25 kg, the recommended dosage is 400 mg (one tablet) twice daily. Children at least 11 kg: weight based to maximum dose 300 mg chewable tablets, twice daily. Because the formulations are not bioequivalent, the chewable tablets should not be substituted for the 400 mg tablet. The chewable tablets have not been studied in HIV-infected adolescents or adults. Renal impairment: No dosage adjustment required. Hepatic impairment: No dosage adjustment required for mild to moderate hepatic impairment. Safety and efficacy not established in patients with severe underlying liver disorders. Use with caution in patients with severe hepatic impairment. Paediatric population: Safety and efficacy of raltegravir in infants below 4 weeks of age have not yet been established. No data are available. Method of administration Oral use. ISENTRESS can be administered with or without food. The 400mg tablets should not be chewed, crushed or split due to anticipated changes in the pharmacokinetic profile. The 100 mg chewable tablet can be divided into equal 50 mg doses. However, breaking the tablets should be avoided whenever possible. CONTRA-INDICATIONS Hypersensitivity. PRECAUTIONS AND WARNINGS Advise patients that current ART does not cure HIV and has not been proven to prevent the transmission of HIV to others through blood contact. While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines. Considerable interand intra-subject variability was observed in the pharmacokinetics of raltegravir. Raltegravir has a relatively low genetic barrier to resistance. Therefore, whenever possible, raltegravir should be administered with two other active ARTs to minimise the potential for virological failure and the development of resistance. In treatment naïve patients, the clinical study data on use of raltegravir are limited to use in combination with two nucleotide reverse transcriptase inhibitors (NRTIs) (emtricitabine and tenofovir disoproxil fumarate). Depression, including suicidal ideation and behaviours, has been reported, particularly in patients with a pre-existing history of depression or psychiatric illness. Caution should be used in patients with a pre-existing history of depression or psychiatric illness. Monitor patients with pre-existing liver dysfunction including chronic hepatitis as they have an increased frequency of liver function abnormalities during combination anti-retroviral therapy. Consider interruption or discontinuation if evidence of worsening liver disease exists. Patients with chronic hepatitis B or C and treated with combination anti-retroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions. Osteonecrosis: Although etiology is multifactorial, cases of osteonecrosis have been reported. Advise patients to seek medical advice if they experience joint effects or difficulty in movement. Immune reactivation syndrome: In HIV-infected patients with severe immune deficiency at the time of institution of combination anti-retroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise. Evaluate any inflammatory symptoms and institute treatment when necessary. Autoimmune disorders (such as Graves’ disease) have also been reported to occur in the setting of immune reactivation: however, the reported time to onset is more variable and these events can occur many months after initiation of treatment. Antacids Co-administration of ISENTRESS with aluminium and magnesium antacids resulted in reduced raltegravir plasma levels. Co-administration of ISENTRESS with aluminium and/or magnesium antacids is not recommended. Myopathy and rhabdomyolysis Myopathy and rhabdomyolysis have been reported. Use with caution in patients who have had myopathy or rhabdomyolysis in the past or have any predisposing issues including other drugs associated with these conditions. Severe skin and hypersensitivity reactions Severe, potentially life-threatening, and fatal skin reactions have been reported in patients taking ISENTRESS, in most cases concomitantly with other drugs associated with these reactions. These include cases of StevensJohnson syndrome and toxic epidermal necrolysis. Hypersensitivity reactions have also been reported and were characterized by rash, constitutional findings, and sometimes, organ dysfunction, including hepatic failure. Discontinue ISENTRESS and other suspect agents immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema). Clinical status including liver aminotransferases should be monitored and appropriate therapy initiated. Delay in stopping ISENTRESS treatment or other suspect agents after the onset of severe rash may result in a lifethreatening reaction. Rash occurred more commonly in treatment-experienced patients receiving regimens containing ISENTRESS + darunavir compared to patients receiving ISENTRESS without darunavir or darunavir without ISENTRESS. Lactose ISENTRESS filmcoated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. INTERACTIONS In vitro studies indicate that Raltegravir is not a substrate of cytochrome P450 (CYP) enzymes, does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A, does not induce CYP3A4 and does not inhibit P-glycoprotein-mediated transport. It is not expected to affect the pharmacokinetics of drugs that are substrates of these enzymes or P-glycoprotein. Raltegravir is eliminated mainly by metabolism via a UGT1A1-mediated glucuronidation pathway. Although in vitro studies indicated that raltegravir is not an inhibitor of the UDP glucuronosyltransferases (UGTs) 1A1 and 2B7, one clinical study has suggested that some inhibition of UGT1A1 may occur in vivo based on effects observed on bilirubin glucuronidation. However, the magnitude of the effect seems unlikely to result in clinically important drug-drug interactions. The following information is based on Geometric Mean values; the effect for an individual patient cannot be predicted precisely. Effect of raltegravir on the pharmacokinetics of other medicinal products: Raltegravir did not have a clinically meaningful effect on the pharmacokinetics of etravirine, maraviroc, tenofovir, hormonal contraceptives, methadone, midazolam, or boceprevir. In some studies, co-administration of ISENTRESS with darunavir resulted in a modest decrease in darunavir plasma concentrations; the mechanism for this effect is unknown. However, the effect of raltegravir on darunavir plasma concentrations does not appear to be clinically meaningful. Effect of other agents on the pharmacokinetics of raltegravir: Raltegravir is metabolised primarily via UGT1A1, therefore use caution when co-administering with strong inducers of UGT1A1 (e.g., rifampicin). Rifampicin reduces plasma levels of raltegravir; the impact on the efficacy of raltegravir is unknown. If co-administration with rifampicin is unavoidable, consider doubling the dose of ISENTRESS in adults. There are no data to guide co-administration of ISENTRESS with rifampicin in patients below 18 years of age. The impact of other strong inducers of drug metabolising enzymes, such as phenytoin and phenobarbital, on UGT1A1 is unknown. Less potent inducers (e.g., efavirenz, nevirapine, etravirine, rifabutin, glucocorticoids, St. John’s wort, pioglitazone) may be used. Coadministration with drugs known to be potent UGT1A1 inhibitors (e.g., atazanavir) may increase plasma levels of raltegravir. Less potent UGT1A1 inhibitors (e.g. indinavir, saquinavir) may also increase plasma levels of raltegravir, but to a lesser extent compared with atazanavir. Tenofovir may increase plasma levels of raltegravir too, but mechanism is unknown. The safety profile in patients who
used atazanavir and / or tenofovir in trials was similar to that of patients who did not use these agents. Therefore no dose adjustment is required. Co-administration of ISENTRESS with antacids containing divalent metal cations may reduce raltegravir absorption by chelation, resulting in a decrease of raltegravir plasma levels. Taking an aluminium and magnesium antacid within 6 hours of ISENTRESS administration significantly decreased raltegravir plasma levels. Therefore, co-administration of ISENTRESS with aluminium and/or magnesium containing antacids is not recommended. Co-administration of ISENTRESS with a calcium carbonate antacid decreased raltegravir plasma levels; however, this interaction is not considered clinically meaningful. Therefore, when ISENTRESS is co-administered with calcium carbonate containing antacids no dose adjustment is required. Co-administration of ISENTRESS with other agents that increase gastric pH (e.g., omeprazole and famotidine) may increase the rate of raltegravir absorption and result in increased plasma levels of raltegravir. Safety profiles in the subgroup of patients in Phase III trials taking proton pump inhibitors or H2 antagonists were comparable with those who were not taking these antacids. Therefore no dose adjustment is required with use of proton pump inhibitors or H2 antagonists. PREGNANCY AND LACTATION Do not use during pregnancy. An Anti-retroviral Pregnancy Registry has been established which physicians are encouraged to use. Breastfeeding is not recommended. SIDE EFFECTS Refer to Summary of Product Characteristics for complete information on side-effects. The safety profile was based on the pooled safety data from two Phase III clinical studies in treatment-experienced patients and one Phase III clinical study in treatment-naïve adult patients. The most frequently reported adverse reactions during treatment were headache and nausea, occurring at 5% or greater. The most frequently reported serious adverse reaction was immune reconstitution syndrome. In treatment-experienced patients, the two randomised clinical studies used the recommended dose of 400-mg twice daily in combination with OBT in 462 patients. In treatment-naïve patients, the multi-centre, randomised, double-blind, active-controlled clinical study used the recommended dose of 400 mg twice daily in combination with a fixed dose of emtricitabine 200 mg (+) tenofovir 245 mg in 281 patients, in comparison to 282 patients taking efavirenz (EFV) 600 mg (at bedtime) in combination with emtricitabine (+) tenofovir. In this pooled analysis of treatment-experienced patients, the rates of discontinuation of therapy due to adverse reactions were 3.9 % in patients receiving ISENTRESS + OBT and 4.6 % in patients receiving placebo + OBT. The rates of discontinuation of therapy in naïve patients due to adverse reactions were 5 % in patients receiving ISENTRESS + emtricitabine (+) tenofovir and 10% in patients receiving efavirenz + emtricitabine (+) tenofovir. Paediatric population Children and adolescents 2 to 18 years of age. Raltegravir has been studied in 126 antiretroviral treatment-experienced HIV-1 infected children and adolescents 2 to 18 years of age, in combination with other antiretroviral agents in IMPAACT P1066 (see sections 5.1 and 5.2). Of the 126 patients, 96 received the recommended dose of ISENTRESS. In these 96 children and adolescents, frequency, type and severity of drug related adverse reactions through Week 48 were comparable to those observed in adults. One patient experienced drug related clinical adverse reactions of Grade 3 psychomotor hyperactivity, abnormal behaviour and insomnia; one patient experienced a Grade 2 serious drug related allergic rash. One patient experienced drug related laboratory abnormalities, Grade 4 AST and Grade 3 ALT, which were considered serious. Clinical adverse reactions related to ISENTRESS (alone or in combination with other ART) are listed below. Any term that includes at least one serious adverse reaction is identified with a dagger (†). Adverse reactions identified from postmarketing experience are included in italics. Frequencies are defined as common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100) and not known (cannot be estimated from the available data). Common Decreased appetite, abnormal dreams, insomnia, nightmare, abnormal behaviour, depression, dizziness, headache, psychomotor hyperactivity, vertigo, abdominal distention, abdominal pain, diarrhoea, flatulence, nausea, vomiting, dyspepsia, rash, asthenia, fatigue, pyrexia, alanine aminotransferase increased, atypical lymphocytes, aspartate aminotransferase increased, blood triglycerides increased, lipase increased, blood pancreatic amylase increased. Uncommon genital herpes†, folliculitis, gastroenteritis, herpes simplex, herpes virus infection, herpes zoster, influenza, lymph node abscess, molluscum contagiosum, nasopharyngitis, upper respiratory tract infection, skin papilloma, anaemia†, iron deficiency anaemia, lymph node pain, lymphadenopathy, neutropenia, thrombocytopenia, immune reconstitution syndrome†,drug hypersensitivity, hypersensitivity, cachexia, diabetes mellitus, dyslipidaemia, hypercholesterolaemia, hyperglycaemia, hyperlipidaemia, hyperphagia, polydipsia, body fat disorder, mental disorder†, anxiety, suicide attempt†, confusional state, panic attack, suicidal ideation , suicidal behaviour (particularly in patients with a pre-existing history of psychiatric illness) ,amnesia, carpal tunnel syndrome, cognitive disorder, disturbance in attention,dysgeusia, hypersomnia, hypoaesthesia, memory impairment, migraine, neuropathy peripheral, paraesthesia, somnolence, tremor, poor quality sleep, visual impairment, tinnitus, sinus bradycardia, hot flush, hypertension, ventricular extrasystoles, dysphonia, epistaxis, nasal congestion, gastritis†, anorectal discomfort, constipation, epigastric discomfort, erosive duodenitis, eructation, gastrooesophageal reflux disease, gingivitis glossitis, pancreatitis acute, peptic ulcer, rectal haemorrahage, hepatic steatosis, hepatitis†, hepatitis alcoholic, hepatic failure, acne, alopecia, hyperhidrosis, lipoatrophy, dermatitis acneiforme, erythema, facial wasting, lipodystrophy acquired, lipohypertrophy, prurigo, pruritis, rash macular, rash maculopapular, rash pruritic, xeroderma, skin lesion, Stevens Johnson syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), urticaria, arthralgia, arthritis, neck pain, flank pain, osteopenia, tendonitis, rhabdomyolysis, renal failure†, nephritis, nephrolithiasis, nocturia, renal cyst, renal impairment, tubulointerstitial nephritis, erectile dysfunction, gynaecomastia, menopausal symptoms, chest discomfort, face oedema, submandibular mass, oedema peripheral, fat tissue increased. Cancers were reported in treatment-experienced and treatment-naïve patients who initiated ISENTRESS in conjunction with other antiretroviral agents. The risk of developing cancer in these studies was similar in the groups receiving ISENTRESS and in the groups receiving comparators. Grade 2-4 creatine kinase laboratory abnormalities were observed in subjects treated with ISENTRESS. Patients co-infected with hepatitis B and/or hepatitis C virus: The safety profile of ISENTRESS in patients with hepatitis B and/or hepatitis C virus co-infection was similar to that in patients without hepatitis B and/or hepatitis C virus co-infection, although the rates of AST and ALT abnormalities were somewhat higher in the subgroup with hepatitis B and/or hepatitis C virus co-infection for both treatment groups. PACKAGE QUANTITIES 60 tablets. Legal Category: POM. Marketing Authorisation number: EU/1/07/436/001. EU/1/07/436/003. EU/1/07/436/004. Marketing Authorisation holder: Merck Sharp & Dohme Limited, Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, UK. Date of revision: December 2014. © Merck Sharp & Dohme Ireland (Human Health) Limited, 2014. All rights reserved. Further information is available on request from: MSD, Red Oak North, South County Business Park, Leopardstown, Dublin 18 or from www.medicines.ie. Date of preparation: November 2015.
Adverse events should be reported. Reporting forms and information can be found at www.hpra.ie Adverse events should also be reported to MSD (Tel: 01-299 8700)
Red Oak North, South County Business Park, Leopardstown, Dublin 18, D18 X5K7 Ireland
ENVISION A PATH FORWARD
38 Feature countries and participants from high-income countries. “The study was rigorous and the results are clear,” said INSIGHT principal investigator James D. Neaton, Ph.D., a professor of biostatistics at the University of Minnesota, Minneapolis. “The definitive findings from a randomized trial like START are likely to influence how care is delivered to millions of HIV-positive individuals around the world.” The University of Minnesota served as the trial’s regulatory sponsor and statistical and data management center. Prior to the START trial, there was no randomized controlled trial evidence to guide initiating treatment for individuals with higher CD4+ cell counts. Previous evidence to support early treatment among HIVpositive people with CD4+ cell counts above 350 was limited to data from non-randomized trials or observational cohort studies, and on expert opinion. START is the first large-scale randomized clinical trial to offer concrete scientific evidence to support the current U.S. HIV treatment guidelines, which recommend that all asymptomatic HIV-infected individuals take antiretrovirals, regardless of CD4+ cell count. Current World Health Organization HIV treatment guidelines recommend that HIV-infected individuals begin antiretroviral therapy when CD4+ cell counts fall to 500 cells/mm3 or less. In light of the DSMB findings, study investigators are informing all participants of the interim results. Participants will be offered treatment if they are not already on antiretroviral therapy, and they will continue to be followed through 2016. The HIV medicines used in the trial are approved medications donated by AbbVie, Inc., BristolMyers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV Healthcare, Janssen Scientific Affairs, LLC, and Merck Sharp & Dohme Corp. In addition to NIAID, funding for the START trial came from other NIH entities, including the National Cancer Institute;
March 2016 • HPN
the National Heart, Lung and Blood Institute; the National Institute of Mental Health; the National Institute of Neurological Disorders and Stroke; the Eunice Kennedy Shriver National Institute of Child Health and Human Development; the NIH Clinical Centre; and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Funding was also provided by the National Agency for Research on AIDS and Viral Hepatitis (ANRS) in France, the Federal Ministry of Education and Research in Germany, the European AIDS Treatment Network and government organizations based in Australia, Denmark, and the United Kingdom.
Clinical Trials Unit, London; Fred Gordin, M.D., of the Veterans Affairs Medical Center, Washington, D.C.; and Jens Lundgren, M.D., D.M.Sc., of the Copenhagen HIV Program.
The Medical Research Council Clinical Trials Unit at University College London; the Copenhagen HIV Program at the Rigshospitalet, University of Copenhagen in Denmark; the Kirby Institute at the University of New South Wales in Sydney, Australia; and the Veterans Affairs Medical Centre affiliated with George Washington University in Washington, D.C. coordinated the work of the 215 START sites.
The START trial enrolled 4,685 HIV-infected men and women ages 18 years or older (median age of 36 years) who had CD4+ T-cell counts above 500 cells/ mm3, no symptoms of HIV infection, and had never taken antiretroviral therapy. Twentyseven percent of the participants are women, and approximately half are gay men.
The START (“Strategic Timing of AntiRetroviral Treatment”) study is a randomised, controlled clinical trial designed to more clearly define the optimal time for HIV- infected individuals to begin antiretroviral therapy. The trial enrolled healthy, asymptomatic, HIV-infected people whose level of CD4+ T cells—a measure of immune system health—exceeded 500 cells per cubic millimeter (mm3). The primary objective was to determine whether taking antiretroviral therapy immediately would lead to a lower risk of AIDS, other serious illnesses or death compared to waiting until a person’s CD4+ T-cell count fell to 350 cells/mm3. The study is conducted by the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT), which is led by principal investigator James D. Neaton, Ph.D., of the University of Minnesota. INSIGHT is funded by the National Institute of Allergy and Infectious Diseases (NIAID). The START protocol cochairs are Abdel Babiker, Ph.D., of the Medical Research Council
The START study was conducted at 215 sites in 35 countries: Argentina, Australia, Austria, Belgium, Brazil, Chile, the Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, India, Ireland, Israel, Italy, Luxembourg, Malaysia, Mali, Mexico, Morocco, Nigeria, Norway, Peru, Poland, Portugal, South Africa, Spain, Sweden, Switzerland, Thailand, Uganda, the United Kingdom and the United States (including Puerto Rico).
The first participant was enrolled in April 2009, during the study’s pilot phase. The main study began in March 2011 and was scheduled to end in December 2016. What are the results of the START study? Starting antiretroviral therapy early prevents a combination of outcomes that includes AIDS events (such as AIDS-related cancer) and serious non-AIDS events (major cardiovascular, renal and liver disease, nonAIDS cancer, and death not attributable to AIDS). According to a new analysis of data from the Strategic Timing of AntiRetroviral Treatment (START) study, the first largescale randomized clinical trial to establish that earlier antiretroviral treatment benefits all HIV-infected individuals, rates of both serious AIDS and serious non-AIDS events were significantly reduced with early therapy. Furthermore, other potentially life threatening events and unscheduled hospitalizations for reasons other than AIDS that were assessed to measure the safety of early treatment did not differ between
the immediate and deferred antiretroviral therapy groups. The study measured a combination of outcomes that included serious AIDS events, serious non-AIDS events, and death. Based on new data and analysis, the study now reports risk of developing serious AIDS, serious non-AIDS, or death was reduced by 57 percent among those in the early treatment group, compared to those in the deferred group. This reduction was seen regardless of age, sex, baseline CD4+ cell counts, geographic region or country income level. Although the median age of study participants was 36 – a relatively young group of participants – the most common events observed in the study were non-AIDS events that typically affect older individuals. The two most common individual serious non-AIDS events in the immediate and deferred groups were cardiovascular disease (12 and 14 participants with events, respectively) and non-AIDS-defining cancer (9 and 18 participants with events, respectively). Most of the tuberculosis occurred among participants at study sites in Africa (16 of 26 events), where both TB and HIV/AIDS are endemic. To evaluate the safety of early treatment, potentially lifethreatening symptomatic events not attributable to AIDS and unscheduled hospitalizations for reasons other than AIDS were assessed in both treatment groups. These events occurred more often than serious AIDS and serious AIDS-related events, and rates were similar in the two groups. When these events were combined with the serious AIDS and serious non-AIDS events, as an overall measure of clinical benefit for early treatment, the rate was 18 percent lower in the early treatment group, compared to the deferred treatment group.
Forr the treatment of HIV, choosee a One core agent. Many different patients. 1
dolutegravir/abacavir/ lamivudine Simplicity of dolutegravir in a single-pill regimen
Flexibility to build a tailored treatment regimen
www.dolutegravir.com TRIUMEQ is indicated for the treatment of HIV-infected adults and adolescents above 12 years of age weighing at least 40 kg. Triumeq is contraindicated: in patients with hypersensitivity to dolutegravir, abacavir or lamivudine or to any of the excipients, and with co-administration with dofetilide1. Before initiating treatment with abacavir-containing products, screening for carriage of the HLA-B*5701 allele should be performed in any HIV-infected patient, irrespective of racial origin. Abacavir should not be used in patients known to carry the HLA-B*5701 allele1. TIVICAY is indicated in combination with other antiretroviral medicinal products for the treatment of HIV-infected adults and adolescents above 12 years of age. Tivicay is contraindicated: in patients with hypersensitivity to dolutegravir, abacavir or lamivudine or to any of the excipients, and with co-administration with dofetilide2. 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 abacavircontaining 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. Caution with ribavirin. 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. POM Triumeq is a registered trademark of the ViiV Healthcare Group of Companies Date of approval: February 2016 Zinc code: UK/TRIM/0037/14(4)
Tivicay® dolutegravir 50 mg tablets See Summary of Product Characteristics before prescribing Indication: HIV in > 12 years and ≥ 40 kg as part of combination therapy. Dosing: 50 mg once daily with or without food if no proven/suspected integrase resistance. 50 mg 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: 50 mg 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. POM Date of approval: August 2015 Zinc code: UK/DLG/0055/13(7)
Adverse events should be reported. For the UK, reporting forms and information can be found at www.mhra.gov.uk/yellowcard. 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, email@example.com. Adverse events should also be reported to GlaxoSmithKline on 1800 244 255. References: 1. Triumeq SmPC 2. Tivicay SmPC
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.
TRIUMEQ and TIVICAY are registered trademarks of the ViiV Healthcare group of companies. ©2015 ViiV Healthcare group of companies All rights reserved.
February 2016 IE/572/0003/16
40 Feature Type 2 Diabetes and Insulin Therapy - Key Recommendations on Management of Type 2 Diabetes Individualise glycaemic targets and glucose-lowering therapies. Diet, exercise, and education remain the foundation of all type 2 diabetes treatment programmes. Metformin is the optimal firstline drug in the absence of contraindications. After metformin, it is reasonable to consider combination therapy with an additional 1-2 oral or injectable agents with the objective of minimising sideeffects where possible. For many patients insulin therapy alone or in combination with other agents will ultimately be required to maintain glucose control. All treatment decisions, where possible, should take into account the patient’s preferences, needs and values. A major focus of therapy must be comprehensive cardiovascular risk reduction. DIAGNOSIS OF TYPE 2 DIABETES Diabetes may be diagnosed based on HbA1c criteria or plasma glucose criteria, either the fasting plasma glucose (FPG) or the 2-h plasma glucose (2-h PG) value after a 75-g oral glucose tolerance test (OGTT). Diabetes may be identified in seemingly low risk individuals who happen to have glucose testing, in symptomatic patients, and in higher-risk individuals who are tested because of a suspicion of diabetes.
Table 1. Criteria for Diagnosis of Type 2 Diabetes HbA1c ≥6.5% Performed in lab using NGSP-certified method and standardised to DCCT assay* OR FPG ≥126 mg/dL (7.0mmol/L) Fasting is defined as no caloric intake for at least 8 h* OR 2h PG ≥200 mg/dl (11.1mmol/L) during an OGTT Perform as described by WHO, using a gluclose load containg the equivalent of 75g anhydrous gluclose dissolved in water* OR Random plasma gluclose ≥200 mg/dL (11.1 mmol/L) In patients with classic symptoms of hyperglycaemia or hyperglycaemic crisis * In the absence of uneqivocal hyperglycaemia, results should be confirmed by repeat testing. Women with polycystic ovary syndrome HbA1c ≥5.7%, IGT, or IFG on previous testing Other clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis nigricans) History of cardiovascular disease For all patients, particularly those who are overweight or obese, testing should begin at age 45 years. If results are normal, testing should be repeated at a minimum of 3 year intervals, with consideration of more frequent testing depending on initial results (e.g., those with prediabetes should be tested yearly) and risk status.
Table 1. Criteria for Diagnosis of Type 2 Diabetes
ASSESSMENT OF GLYCAEMIC CONTROL
TESTING FOR DIABETES OR PREDIABETES IN ASYMPTOMATIC ADULTS
Two primary techniques are available to assess the effectiveness of glycaemic control: Patient self-monitoring of blood glucose (SMBG) or interstitial glucose and A1C. Continuous glucose monitoring (CGM) may be a useful adjunct to SMBG in selected patients. SMBG results may help guide treatment decisions and/or selfmanagement for patients using less frequent insulin injections or noninsulin therapies. CGM may be a supplemental tool to SMBG in those with hypoglycaemia unawareness and/or frequent hypoglycaemic episodes.
Consider testing in all adults who are overweight (BMI≥25kg/m2 or ≥23 kg/m2 in Asian Americans) and have ≥1 risk factor: Physical inactivity First-degree relative with diabetes High-risk race/ethnicity Women who delivered a baby weighing >9lb or were diagnosed with gestational diabetes mellitus Hypertension (≥140/90mmHg or on therapy for hypertension) HDL cholesterol level <35mg/ dL (0.90mmol/L) and/or a triglyceride level >250mg/Dl (2.82mmol/L)
March 2016 • HPN
Patients on multiple-dose insulin or insulin pump therapy should perform SMBG prior to meals and snacks, occasionally postprandially, at bedtime, prior
to exercise, when they suspect low blood glucose, after treating low blood glucose until they are normoglycaemic, and prior to critical tasks such as driving. ANTIHYPERGLYCAEMIC THERAPY IN TYPE 2 DIABETES – GENERAL RECOMMENDATIONS Initial therapy: Most patients should begin with lifestyle changes – healthy eating, weight control, increased physical activity, and diabetes education. When lifestyle efforts alone have not achieved or maintained glycemic goals, metformin monotherapy should be added at, or soon after, diagnosis (in patients intolerant, or with contraindications for, metformin, select initial drug from other treatment options). Advancing to dual combination therapy: If the HbA1c target is not achieved after ~3 months with metformin, there are six drug choices including a second oral agent (sulfonylurea, TZD, DPP-4 inhibitor, or SGLT2 inhibitor), a GLP-1 receptor agonist, or basal insulin. The higher the HbA1c, the more likely insulin will be required. Shared decision making with the patient is important to help in the selection of therapeutic option. The choice is based on patient and drug characteristics, with the over-riding goal of improving glycaemic control while minimising side-effects. Consider beginning at this stage when HbA1c ≥9%. Advancing to triple combination therapy: Evidence suggests that there is some advantage in adding a third noninsulin agent to a twodrug combination not achieving the glycaemic target. However, the
most robust response will usually be with insulin. Since diabetes is associated with progressive beta-cell loss, many patients, especially those with longstanding disease, will ultimately need to be transitioned to insulin. Insulin should be preferred in circumstances where the degree of hyperglycaemia (e.g. ≥8.5%) makes it unlikely that another drug will be sufficiently effective. In using triple combinations the essential consideration is obviously to use agents with complementary mechanisms of action. Combination injectable therapy: If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables; (2) on GLP-1 RA, add basal insulin; or (3) on optimally titrated basal insulin, add GLP-1 RA or mealtime insulin. In refractory patients consider adding thiazolidinedione or SGLT2 inhibitor. Consider beginning at this stage when blood glucose is 16.7 – 19.4mmol/L and/or HbA1c ≥10 – 12%, especially if symptomatic or catabolic features are present. Abbreviations: HbA1c, glycated haemoglobin; FBG, fasting blood glucose; OGTT, oral glucose tolerance test; SMBG, self-monitoring of blood glucose; CGM, continuous glucose monitoring; TZD, thiazolidinedione; DPP-4, dipeptidyl peptidase-4; SGLT2, sodium glucose cotransporter 2; GLP-1-RA, glucagon-like peptide-1 receptor agonist; GLP-1 receptor agonist; hypo, hypoglycemia; PPG, postprandial glucose.
ANNOUNCING RESULTS FROM TECOS — A LONG-TERM CARDIOVASCULAR (CV) SAFETY TRIAL
TEC S TRIAL EVALUATING CARDIOVASCULAR
O U T C O M E S W I T H S I TA G L I P T I N LONGESTa CV SAFETY TRIAL WITH A DPP-4 INHIBITOR1
NOW EVEN MORE REASONS TO CHOOSE JANUVIA ® FIRST AS A PARTNER TO METFORMIN • No increased CV risk (primary end point) in a clinical trial of >14,000 patients with type 2 diabetes and CV disease1* • Met all secondary CV end points
TO COMPLEMENT YOUR PATIENTS’ EFFORTS TO ACHIEVE THEIR GOALS * When sitagliptin is added to usual care compared to placebo plus usual care
ing 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 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. DRUG 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. Sitagliptin with metformin: Common: hypoglycaemia, nausea, flatulence and vomiting; Uncommon: somnolence; upper abdominal pain, diarrhoea, and constipation. 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 and exfoliative skin conditions including Stevens-Johnson syndrome (see precautions); 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, 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. 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, Januvia 50 mg: EU/1/07/383/008, Januvia 100mg: EU/1/07/383/014. Janumet 50 mg/850 mg: EU/1/08/455/003, Janumet 50 mg/1000 mg: EU/1/08/455/010. Marketing Authorisation Holder Merck Sharp & Dohme Limited, Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, UK. Date of revision: March 2015. © Merck Sharp & Dohme Ireland (Human Health) Limited, 2015. All rights reserved. Further information is available on request from: MSD, Red Oak North, South County Business Park, Leopardstown, Dublin 18 or from www.medicines.ie. Date of preparation: June 2015.
Adverse events should be reported. Reporting forms and information can be found at www.hpra.ie Adverse events should also be reported to MSD (Tel: 01-299 8700) Median follow-up: 3 years. Reference: 1. Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes [published online ahead of print June 8, 2015]. N Engl J Med. 2015;1–11. doi:10.1056/NEJMoa1501352.
Red Oak North, South County Business Park, Leopardstown, Dublin 18, 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. Elderly ≥ 75 years: Exercise care as there are limited safety data in this population. 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 administer-
Urinary Incontinence Overview According to a survey carried out in the late 90’s, urinary incontinence is amongst the top three health problems which embarrass Irish people. In 2013, it was estimated that over 28% of the Irish population are affected by urinary incontinence at some stage in their lifetime. The reported incidence of urinary incontinence varies depending on the population in question. For example, in the UK a 9% incidence of UI was found in the adult population. However, a similar Irish study found the figure to be much higher, at 33%.What is known is that UI affects more women than men and that the prevalence of incontinence increases with age. The exact prevalence of FI is difficult to determine due to the under-reporting of its symptoms, the lack of a standard scoring scale and variations in populations. It is estimated to affect approximately 3% of the population over 65 years. Whatever the exact incidence or population affected, incontinence has devastating consequences on the individual and also burdens the carers of those who require personal care. However, 52% of Irish people believed urinary incontinence to be a natural part of the ageing process. This misconception obscures the fact that incontinence is reversible for the majority of patients. Urinary incontinence is the unintentional passing of urine and is an extremely common complaint in every part of the world. It is estimated that between three and six million people are affected by the condition in the UK alone. Urinary incontinence is not a condition itself but is a symptom from one or more underlying conditions. Effective treatment depends on a thorough assessment and compliance with treatment plan. Urinary incontinence can occur as a result of a number of
March 2016 • HPN
abnormalities of the function of the lower urinary tract or as a result of other illnesses, which tend to cause leakage in different situations. There are a number of different types of urinary incontinence• Stress urinary incontinence is involuntary urine leakage on effort or exertion or on sneezing or coughing. Causes include- pregnancy, childbirth, menopause, post hysterectomy, age and obesity. • Urge urinary incontinence is involuntary urine leakage accompanied or immediately preceded by urgency. Causes include- enlarged prostate, cystitis and neurological problems.
• Mixed urinary incontinence is involuntary urine leakage associated with both urgency and exertion, effort, sneezing or coughing. • Total incontinence is where urine is continually leaking, and is usually as a result of the sphincter muscle no longer functioning. Causes include a fistula, a spinal cord injury or an injury to the kidneys during birth. • Overflow incontinence - this type of urinary incontinence is more common in men with prostate gland problems, a damaged bladder, or a blocked urethra. The enlarged prostate gland obstructs the bladder; the person often only manages to urinate in
small trickles and has to go frequently. They may feel that his bladder is never really completely emptied, even after trying hard. Causes include constipation, urinary stones, an enlarged prostate and cancer of the bladder. • Functional incontinence is an inability to make it to the bathroom in time. It is often as a result of a physical barrier or immobility that causes a delay but lack of tone in the sphincter causes loss of urine suddenly. Functional incontinence is more prevalent among elderly people, and is common in nursing homes. Acute incontinence can be used by certain medicines- diuretics, antihypertensive drugs, sleeping
44 Feature tablets, sedatives, and muscle relaxant. It can also be caused by alcohol, certain foods and drinks, urinary tract infections and dehydration. Prior to any treatment it is essential that the urine is assessed to rule out any underlying infections or conditions. Reagent strip (‘dipstick’) urinalysis may detect infection, proteinuria, haematuria and glycosuria. Antimuscarinics are the drug of choice for patients with persistent urinary incontinence, despite lifestyle interventions. They act by blocking muscarinic receptors in the bladder wall. Muscarinic receptor antagonists are a treatment option in men with moderate to severe lower urinary tract symptoms that have predominantly bladder storage symptoms, independent of bladder outlet obstruction. This class of drugs decrease the ability of the bladder to contract by blocking the muscarinic receptors on the detrusor muscle, the muscle responsible for the passing of urine. Drugs within class • Fesoterodine fumarate • Oxybutynin HCL • Propiverine HCL
• Solifenacin succinate • Tolterodine tartrate This group of medicines are generally well tolerated with the side effect profile relating to the well-known peripheral anti-muscarinic adverse effects, such as dryness of the mouth, tachycardia and constipation. The antimuscarinic Oxybutynin is the mainstay of treatment for incontinence. This drug offers maximum dosage flexibility but carry a greater risk of side effects due to its higher plasma peak levels. Randomised, placebo-controlled trials demonstrated that tolterodine can significantly reduce urgency incontinence and daytime or 24-hour frequency compared to placebo. Desmopressin is indicated for the management of primary nocturnal enuresis. It is chemically similar to the antidiuretic hormone (ADH) which is found naturally in the body. It increases urine concentration and decreases urine production. Duloxetine- is used for the treatment of stress incontinence. It works by increasing intracellular serotonin and noradrenaline within the nerves increasing the strength of the pelvic floor muscles. This
increase in muscle tone helps control the flow of urine and prevent any involuntary loss.
• Discuss fluid intake and avoidance of drinking excess fluids too late in the evening.
The alpha-reductase inhibitors finasteride and dutasteride are also used to treat overflow incontinence secondary to BPH. Their mechanism of action is through inhibiting the conversion of testosterone to dihydrotestosterone, resulting in reduced androgenic prostate stimulation and leading to reduced gland size and improved urine outflow.
• Offer weight management advice to overweight patients.
Pharmacy teams can offer educational support to patients by questioning and monitoring the effectiveness and tolerability of the various pharmacotherapies. Taking time to get to know your patients in the ambulatory and clinical settings allows the opportunity to provide valuable education, intervention, and recommendations to improve patient care outcomes in the management of this complex disorder.
The study showed the superior efficacy of fesoterodine over tolterodine extended release (ER) in a placebo-controlled overactive bladder (OAB) trial with predefined treatment comparisons for both diary measures and patientreported outcomes.
• Inform women starting systemic oestrogen replacement therapy that it may cause urinary incontinence, or worsen current symptoms.
• Offer smoking cessation advice, as part of healthy living advice. One notable study demonstrated superior efficacy of fesoterodine over tolterodine extended release with rapid onset in a prospective, head-to-head, placebo-controlled trial.
In this randomised study, which was the largest to compare antimuscarinic efficacy performed to date, fesoterodine 8 mg was superior to tolterodine ER 4 mg for UUI episodes, micturitions and urgency episodes, as well as for self-reported patient assessments of bladder-related problems, urgency, symptom bother and health related quality of life.
• Advise patients to avoid any known precipitants that may contribute to their symptoms
News A new innovation for a burning issue It is estimated that up to 60% of the adult population in Ireland have experience of heartburn - most will consider it a passing inconvenience and very few will think about consulting their GP on the issue.
impedance Testing, Barium Swallow, and Endoscopy, to establish whether Reﬂux is the problem. All expensive, invasive, time consuming and unpleasant for the patient.”
However, frequent and consistent heartburn (more than once a week) may in fact be a symptom of something more serious, a chronic disease called gastro-oesophageal reflux disease or Gord (often called Gerd because of the Americanised spelling, esophagus) which affects an estimated 5-7% of the population.
And Professor Dettmar has developed Peptest to solve that problem.
Also known as acid reflux disease, Gord occurs when stomach acid used for digestion repeatedly backs up, or refluxes, into the oesophagus. Professor Peter Dettmar, Managing Director of RD Biomed Limited has spent many years studying reﬂux and the problems patients and doctors have in diagnosing it. He says, “Reﬂux diagnosis typically entails several tests, such as 24/48 hour pH monitoring, March 2016 • HPN
Peptest is a new, accurate, painless and inexpensive saliva test that tells sufferers conclusively if they have reﬂux. Peptest can be ordered by both doctors and patients direct. RD Biomed take samples of saliva and test them in their laboratory for Pepsin. If Pepsin is present the concentration in the sample is measured to show the severity of reﬂux and give a benchmark to assess the success or failure of any treatment. Retesting can be used at any future treatment point. He continues, “I've been working on reflux disease since 1981. In those days, histamine receptor antagonists such as cimetidine and ranitidine had been launched
and were the first acid suppression agents on the market. The proton pump inhibitors weren't even launched at that time, but a product called Gaviscon was available which I’d been involved with during the early stages of development. “We were trying to understand what reflux was and we all believed that acid was the cause of all the problems. It probably wasn’t until the beginning of the '90s that it occurred to us that the pepsin present in the gastric refluxate might be one of the causal factors of reflux disease symptoms and I did a lot of basic research into pepsin.” Peptest has been developed with two unique monoclonal pepsin antibodies which are owned by RD Biomed. They have developed them and so they are the only people in the world that have them. One of the antibodies they use to detect pepsin and the other is used to capture pepsin. Professor Peter Dettmar
Professor Dettmar believes this new test is the future of reflux disease. “We will be able to use Peptest to diagnose patients more quickly and more accurately than we are at the moment. Also, the patient comfort and non-invasiveness of the procedure is important. We've been involved in a study looking at how patients perceive their reflux disease and how they perceive the diagnosis and the treatment they get,” he adds. Visit www.rdbiomed.com, www.bodycare.ie and www.peptest.ie for more information.
Aims to develop a harmonised definition of medicines shortages
The European Medicines Agency (EMA) has called for the establishment of a harmonised definition of a medicine shortage after hosting a meeting of national regulatory authorities, the pharmaceutical industry, and other stakeholders such as EAHP, to discuss the development of proactive approaches to preventing shortages in supply. The formal report of the October 2015 meeting has now been published and provides insights to current intended direction of medicines agencies in Europe towards the shortages issue. PROBLEMS WITH DEFINING SHORTAGE As preparation for the meeting a survey was conducted which
revealed that most Member States do not have a definition for a shortage (18 out of 28 responses). The lack of a common definition was highlighted several times during the workshop as an obstacle for a common approach in dealing with shortages. The report of the meeting notes: "This lack of clarity about what a shortage is means that the conditions for reporting shortages differ from one country to another which makes benchmarking and comparisons very difficult." At the meeting, EAHP presented headline results from its 2014 survey of medicines shortages across Europe. The report of the survey revealed 86% of hospital pharmacists report that medicines shortages are a current problem in the hospital they work in, with 66% stating that shortages are affecting their hospital on a daily or weekly basis. Reported impacts for patients included delayed or interrupted chemotherapy treatment, additional side effects, heightened Clostridium difficile risk and deterioration in their condition. EAHP emphasized the need for greater international coordination of efforts to combat what is clearly a global problem. This should include a step change improvement in the information
made available to healthcare professionals about shortages, with available national best practices shared and taken up. Regulatory activity in the United States was pointed to as an example. RECOMMENDATIONS FROM THE WORKSHOP The recorded recommendations from the workshop are: • the need for a harmonised definition of a medicines shortage; • the requirement to identify at what point a manufacturing or quality issue becomes likely to lead to a meaningful disruption as well as when it should trigger a report to authorities; • national regulators should agree on common trigger points for notification as well as harmonised data requirements across the EU; • a European shortages communication network, similar to a rapid alert network, should be constructed; and, • the pharmaceutical industry should consider the value of stress tests to evaluate effectiveness of measures in place to prevent shortages.
The European Medicines Agency will update its implementation plan on this topic accordingly and further developments are awaited. Commenting on the published report of the meeting, EAHP Board Member Aida Batista, who is the Board lead on medicines shortages, said, "The headline recommendation of this meeting on the need for a harmonized definition on medicines shortages is absolutely right. However it is imperative that that definition is not of a highly restrictive nature. For example, some at the meeting advocated only defining a medicines shortage if it could be categorized as providing a "high risk". This will not do. Every medicines shortage causes problems for patients and healthcare professionals, with risks of error contained from substitution to alternatives. This problem must be dealt with holistically and in totality. "We also emphasised at the meeting the need for transparency in medicines shortage information. As the example of the USA and some countries in Europe show, when you make information on shortages public terrible events do not occur. Public debate and solution finding is certainly better informed however."
Government must prioritise legal reform Ahead of the General Election the Medical Protection Society (MPS) urged the new administration to prioritise legal and procedural reform to tackle the cost of clinical negligence. According to the indemnifier, these reforms should include, among others: the swift introduction of a
pre-action protocol following the inclusion of legislation to allow this in the Legal Services Regulation Act; limits on lawyers’ fees in smaller value cases; a debate on the merits of a limit on damages (special and general); and a tariff of general damages created in statute.
Legal and procedural reform could save public money, which would be better spent on patient care. Furthermore, reform would make the legal system quicker, fairer and more efficient for healthcare professionals and their patients. John Tiernan, Executive Director of Member Engagement at MPS,
said, “Because the cost of clinical negligence continues to be a challenge and is costing the public purse a significant amount of money, we believe that the new government must prioritise legal reform and support healthcare professionals so that they can do what they entered their profession to do – care for patients.”
Joint Working Group on Patient Safety Matters A working group with relevant members of the Medical Council and the Pharmaceutical Society of Ireland has been established to examine patient safety matters of mutual concern and particularly focusing on safe prescribing and dispensing.
The aim of this is to make sure that pharmacists, doctors and members of the public receive clear information on agreed best practice for both professions. This positive initiative aims to explore how the two regulators can work together to support the existing
collaborative practice between medical doctors and pharmacists, in the shared care of patients in the broader multidisciplinary team. Some of the areas being examined relate to the prescribing and dispensing of controlled drugs and
the care of patients in particular care settings. This work will be progressed on a phased basis throughout 2016, and both professions will continue to be updated.
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46 Clinical Profiles NEW EVIDENCE FROM REALWORLD PATIENTS REAFFIRMS POSITIVE EFFECTS ON BLOOD GLUCOSE LEVELS FOR JANSSEN’S INVOKANA®Q (CANAGLIFLOZIN) IN PATIENTS WITH TYPE 2 DIABETES MELLITUS [1,2] Janssen has announced data from three real-world studies showing significant and consistent improvements in HbA1c measurements after the initiation of its sodium glucose co-transporter 2 (SGLT2) inhibitor INVOKANA® (canagliflozin) in patients with Type 2 diabetes mellitus in routine clinical practice. The real world evidence also showed that when prescribed for patients already taking multiple blood-glucose-lowering medications, INVOKANA® is associated with further improved HbA1c control, and may lead to patients discontinuing additional blood glucose-lowering agents. In clinical trials, canagliflozin has been shown to improve glycaemic control as monotherapy, dual therapy and triple therapy in patients with T2DM. The three retrospective cohort analysis real world evidence studies, from registries with over 70,000 Type 2 diabetes patients, sought to determine changes in glycaemic control and treatment patterns following initiation with canagliflozin.[1,2,3] Results from the Optum and the Inovalon-MORE studies, as well as persistence data for the therapy, highlighted the significant improvements in glycaemic control achieved through use of canagliflozin in everyday clinical practice. Characteristics and short-term outcomes of patients with type 2 diabetes mellitus treated with canagliflozin in a real-world setting: This retrospective cohort study demonstrated that patients treated with canagliflozin when first available in the US typically had poorly controlled HbA1c levels at baseline and had received multiple prior antihyperglycaemic agents. Baseline was six months prior to treatment, while followup took place at three months after canagliflozin initiation; the data found that patients (n=826) had significant improvement in HbA1c levels and used fewer antihyperglycaemic agents. It was seen that mean HbA1c decreased from 8.54% at baseline to 7.76% at follow-up (p<0.001); while the proportion of patients with HbA1c 9.0% decreased by more than half (from 32.0% at baseline to 15.5% at follow-up, p<0.001). Almost all (94.8%) patients received at least one baseline antihyperglycaemic agent, of which 33.6% received two and March 2016 • HPN
41.5% received three or more agents. Compared to baseline, usage of antihyperglycaemic agents during follow-up was lower for metformin, sulfonylureas, insulin, DPP-4 inhibitors, GLP-1 receptor agonists and thiazolidinediones. An Observational Study of Glycaemic Control in Canagliflozin Treated Patients: This retrospective cohort analysis of adult patients with T2DM found that patients with T2DM had improved glycaemic control following their initial canagliflozin pharmacy claim as measured by HbA1c change and attainment of specific glycaemic control criteria. The study was conducted using 2013 medical, pharmacy and laboratory claims from the Inovalon MORE Registry. Among the 268 patients meeting the study criteria, mean HbA1c pre-index was 8.3% and post- index was 7.6%; the mean reduction in HbA1c prepost index was 0.7% (95% CI: 0.6%, 0.9%). The proportions of patients meeting the Healthcare Effectiveness Data and Information Set (HEDIS) glycaemic control measures (HbA1c <7%, <8% and poor control of >9%) improved and was significantly different pre- and post-index (all p<0.001). Visiting Dublin to discuss the real world data on canagliflozin, Professor Carol H. Wysham, MD, Clinical Associate Professor of Medicine at the University of Washington School of Medicine, Seattle, and Research Professor, College of Pharmacotherapy at Washington State University, Spokane, said: “Real-world evidence is increasingly important for physicians as it complements what we see in Phase III clinical trials. These data demonstrate the effectiveness of canagliflozin across a broader range of patients than included in the Phase III trials, showing consistent and significant improvements in HbA1c concentrations for those taking the medicine in the real world setting.” “It is also notable that the use of other antihyperglycaemic therapies decreased after patients began taking canagliflozin. These data gleaned from everyday clinical practice are extremely valuable for physicians and may assist them in making more informed treatment decisions in the management of their patients with Type 2 diabetes mellitus.” “The real-world evidence for canagliflozin demonstrates the important role of our SGLT-2 inhibitor in improving HbA1c control for people with Type 2 diabetes,” said Dr Leisha Daly, Country Director, Janssen Ireland. “Patients with Type 2 diabetes who are treated with canagliflozin may have a reduced need for
additional blood glucose-lowering agents following initiation, thereby reducing the polypharmacy burden.”
MSD WELCOMES THE APPROVAL OF NEW INDICATIONS MSD has welcomed the approval by the European Medicines Agency (EMA) of new indications for EZETROL (ezetimibe), INEGY (ezetimibe and simvastatin) and ATOZET (ezetimibe and atorvastatin). The updated Prescribing Information for these medicines now includes outcomes from the landmark IMPROVEIT trial, which demonstrated that ezetimibe was the first non-statin cholesterol-lowering medication to show additional benefit in decreasing the risk of cardiovascular (CV) events when added to a statin. EZETROL, administered in combination with an HMG CoA reductase inhibitor (statin), is indicated to reduce the risk of cardiovascular events in patients with coronary heart disease (CHD) and a history of acute coronary syndrome (ACS) when added to ongoing statin therapy or initiated concomitantly with a statin. INEGY, which contains ezetimibe, a cholesterol absorption inhibitor, and simvastatin, an HMG-CoA reductase inhibitor (statin), is indicated to reduce the risk of cardiovascular events in patients with CHD and a history of ACS, either previously treated with a statin or not. ATOZET, which contains ezetimibe, a cholesterol absorption inhibitor, and atorvastatin, an HMG-CoA reductase inhibitor (statin), is indicated to reduce the risk of cardiovascular events in patients with CHD and a history of ACS, either previously treated with a statin or not. Commenting on these new indications for EZETROL, INEGY and ATOZET, Dr Niall Colwell, Consultant Cardiologist, South Tipperary General Hospital said “Ezetimibe is the first non-statin agent with an evidence base in the IMPROVE IT trial. Ezetimibe use alone in Statin-intolerant patients and more especially in combination with a statin in high CVD risk patients may assist clinicians in getting these subjects to their LDL goal which currently is as low as 1.3 mmol/L.” Louise Houson Managing Director Human Health, MSD in Ireland added, “These new indications for EZETROL, INEGY, and ATOZET demonstrate the value of MSD’s continuing efforts in progressing cardiovascular care. Because many patients with coronary heart disease continue to have CV events, even when treated with statins, there is still a significant
medical need. The results of IMPROVE-IT demonstrate our commitment to improving the treatment of cardiovascular disease, and establish the benefits of ezetimibe in improving cardiovascular outcomes in appropriate patients.” Because high-risk patients treated with statins, including those on treatment with low levels of LDLcholesterol (LDL-C), continue to be at increased cardiovascular risk, IMPROVE-IT was designed to address whether lowering LDL-C to under 1.8mmol/L by adding ezetimibe (EZETROL) to a statin further reduced cardiovascular events. Among patients participating in IMPROVE-IT who had blood samples obtained at one year, the mean LDL-C levels achieved were 1.8 mmol/L, in the simvastatin alone group and 1.4 mmol/L in the ezetimibe and simvastatin group. This 0.4 mmol/L difference (P<0.001) represents a 24 percent further lowering of LDL-C by ezetimibe relative to the LDL-C on simvastatin alone. Over a median follow-up of 6 years, IMPROVE-IT demonstrated a 6.4 percent relative risk reduction in the primary composite endpoint of major cardiovascular events. The primary endpoint occurred in 32.7 percent in the ezetimibe and simvastatin group and 34.7 percent in the simvastatin group alone at 7 years (Hazard Ratio 0.936, 95% CI, 0.887-0.988; p=0.016). These efficacy results were driven by a 13 percent reduction in non-fatal myocardial infarction and a 20 percent reduction in non-fatal stroke. Entitled IMProved Reduction of Outcomes: VYTORIN Efficacy International Trial, IMPROVE-IT was led by the Thrombolysis In Myocardial Infarction (TIMI) Study Group of Brigham and Women’s Hospital and the Duke Clinical Research Institute (DCRI), and was sponsored by MSD. It was an international, multi-centre, randomised, double-blind active comparator trial of 18,144 patients presenting with high-risk acute coronary syndromes (ACS), including unstable angina (UA), non-ST-segment elevation acute myocardial infarction (NSTEMI), and ST-segment elevation acute myocardial infarction (STEMI). The study assessed the incidence of major CV events, as measured by a composite of CV death, non-fatal MI, non-fatal stroke, rehospitalisation for unstable angina, or coronary revascularisation (occurring 30 days or more after the initial event), in patients treated with ezetimibe and simvastatin (INEGY) compared with patients treated with simvastatin alone.
47 DAKLINZA APPROVAL BY EU Bristol-Myers Squibb Company announced that the European Commission has approved Daklinza for the treatment of chronic hepatitis C (HCV) in three new patient populations. The expanded label allows for the use of Daklinza in combination with sofosbuvir (with or without ribavirin, depending on the indication and HCV genotype) in HCV patients with decompensated cirrhosis, HIV-1 (human immunodeficiency virus) co-infection, and post-liver transplant recurrence of HCV in all 28 Member States of the European Union. “The European Commission’s approval of these new indications for Daklinza is an important step forward for a significant group of patients with chronic hepatitis C who are still in need of treatment options that can deliver high cure rates,” said Douglas Manion, MD, head of Specialty Development, Bristol-Myers Squibb. “The complex clinical considerations for physicians treating HCV/HIV coinfected patients and patients with cirrhosis, decompensated cirrhosis or post-transplant recurrence of HCV reinforces the vast diversity of this disease, and we have worked hard to continue to identify and address those patients who require additional solutions for cure.” Daklinza is contraindicated in combination with medicinal products that strongly induce CYP3A and P-glycoprotein transporter, as this may lead to lower exposure and loss of efficacy of Daklinza. Daklinza must not be administered as a monotherapy. Daklinza is already approved by the European Commission for use in combination with other medicinal products across genotypes 1, 2, 3 and 4 for the treatment of chronic HCV infection in adults, and the Daklinza + sofosbuvir regimen is the only approved 12-week, all-oral treatment for genotype 3 HCV patients without cirrhosis. The new indications are based on data from the ALLY-1 clinical trial (in posttransplant patients and patients with advanced cirrhosis) and ALLY2 clinical trial (in HIV co-infected patients).
IMBRUVICA® (IBRUTINIB) PHASE 3 RAY DATA SHOW SIGNIFICANT IMPROVEMENTS IN PROGRESSION-FREE SURVIVAL VERSUS TEMSIROLIMUS IN PATIENTS WITH RELAPSED OR REFRACTORY MANTLE CELL LYMPHOMA[i] Janssen Ireland have announced data from the Phase 3 RAY (MCL3001) study, an investigational clinical trial, which showed oral IMBRUVICA® (ibrutinib) significantly improved progression-free survival (PFS; the primary endpoint) versus
intravenous temsirolimus in patients with relapsed or refractory mantle cell lymphoma (MCL).1 Janssen announced Ibrutinib was associated with a 57 percent reduction in the risk of disease progression or death with a median follow-up of 20 months. The data was presented at the 2015 American Society of Haematology (ASH) meeting in Orlando, FL, U.S. and simultaneously published online in The Lancet.1 “The results of the Phase 3 RAY trial confirm that Ibrutinib is an effective and extremely well tolerated treatment for patients with relapsed mantle cell lymphoma whom historically have had very few treatment options,” said Professor Elisabeth Vandenberghe, Consultant Haematologist, Department of Haematology, St. James’s Hospital. “The arrival of Ibrutinib is one of the most important milestones in MCL treatment for a decade in my opinion.” RAY is a Janssen-sponsored, Phase 3, randomised, open-label trial that enrolled 280 patients with relapsed or refractory MCL who were randomised to receive either Ibrutinib (N=139) or temsirolimus (N=141). Patients were given either oral Ibrutinib 560 mg per the approved label or intravenous temsirolimus (175 mg on days one, eight and 15 of cycle one; 75 mg on days one, eight and 15 of all subsequent 21-day cycles) until disease progression or unacceptable toxicity. The primary endpoint of the study was PFS as assessed by the Independent Review Committee (IRC); secondary endpoints included overall response rate (ORR), overall survival (OS) and safety, among others.1 Ibrutinib significantly improved PFS as determined by the IRC compared with temsirolimus, reducing the risk of disease progression or death by 57 percent after a median follow-up of 20 months (HR 0.43; [95 percent CI, 0.32-0.58]; P<0.0001). The median PFS for patients who received Ibrutinib was 14.6 months, compared with 6.2 months for those who received temsirolimus. Notably, at two years, patients receiving Ibrutinib had a 41 percent PFS rate, compared with seven percent in those receiving temsirolimus.1 Ibrutinib demonstrated a significantly higher ORR versus temsirolimus (72 percent vs. 40 percent, respectively; difference 31.5 percent [95 percent CI, 20.5-42.5]; P<0.0001). Twenty-six patients who received Ibrutinib (19 percent) achieved a complete response (CR), while only two patients who received temsirolimus experienced a CR (one percent). These findings are consistent with
results from previous trials.1 Treatment with Ibrutinib significantly lengthened the time to a patient’s next treatment. The median time to next treatment was not reached with Ibrutinib, versus 11.6 months median time to next treatment with temsirolimus (P<0.0001). These data articulate that subsequent treatments were required more frequently following temsirolimus treatment compared to treatment with Ibrutinib. In addition, the median treatment duration was four times longer in patients taking Ibrutinib (14.4 months vs. 3.0 months, respectively). Median OS was not reached with Ibrutinib, as compared to 21.3 months with temsirolimus.1 “The positive data demonstrated by the Phase 3 RAY trial reinforce the earlier Phase 2 data that supported the European approval of Ibrutinib last year. It’s exciting to see such encouraging results while further evaluating this therapy against existing treatments for MCL.” said Dr Leisha Daly, Country Director, Janssen Ireland. “We continue to see positive results with Ibrutinib, and it was particularly exciting to see the extent of new data, demonstrating our commitment to exploring Ibrutinib use for patients with difficult to manage blood cancers, such as MCL, and our growing haematology offering.”
NEW DATA DEMONSTRATES MSD’S KEYTRUDA (PEMBROLIZUMAB) SIGNIFICANTLY IMPROVES SURVIVAL COMPARED TO CHEMOTHERAPY IN PREVIOUSLY-TREATED PATIENTS WITH NON-SMALL CELL LUNG CANCER MSD recently announced results from the pivotal KEYNOTE-010 study, the first study of its kind to evaluate the potential of an immunotherapy compared to chemotherapy based on prospective measurement of PD-L1 expression in patients with advanced non-small cell lung cancer (NSCLC). In the Phase 2/3 study, KEYTRUDA (pembrolizumab), MSD’s anti-PD-1 (programmed death receptor-1) therapy, significantly improved overall survival (OS) compared to chemotherapy in patients with any level of PD-L1 expression, as defined by a tumour proportion score (TPS) of 1 percent or more. The study, which was also published in The Lancet, included 1,034 patients with advanced NSCLC with PD-L1 expression. Among the patients who received the FDA-approved dose of KEYTRUDA (2 mg/kg every three weeks) (n=345) and an investigational dose of KEYTRUDA (10 mg/kg every three weeks) (n=346), a similar response was found. Both groups of patients
who received KEYTRUDA were compared to patients who received docetaxel (n=343). Based on findings from KEYNOTE-010, MSD has submitted a Marketing Authorisation Application to the European Medicines Agency for KEYTRUDA, following the submission of a supplemental Biologics License Application (sBLA) to the U.S. Food and Drug Administration. Commenting on the announcement, Louise Houson, Managing Director Human Health, MSD in Ireland, said “Lung cancer remains one of the most common and challenging cancers to treat, therefore understanding the role that KEYTRUDA can play in helping to improve survival and quality of life for people suffering from a wide range of cancers, including NSCLC, is essential. This data clearly demonstrates KEYTRUDA’s efficacy, and is another exciting milestone in our continued efforts to improve patient outcomes, and help a larger proportion of cancer sufferers to live well and for longer.” KEYTRUDA is a humanised monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. By binding to the PD-1 receptor and blocking the interaction with the receptor ligands, KEYTRUDA releases the PD-1 pathwaymediated inhibition of the immune response, including the anti-tumour immune response. KEYTRUDA was the first antiPD-1 therapy approved in the United States, and was approved by the U.S. Food and Drug Administration (FDA) in October 2015 for the treatment of patients with metastatic NSCLC. KEYTRUDA also received approval from the European Commission for the treatment of advanced (unresectable or metastatic) melanoma in adults in July 2015.
TEGRETOL RETARD 200 NAME CHANGE Novartis Ireland Ltd recently requested approval from the Health Products Regulatory Authority to change the name of the products from ‘Tegretol Retard 200 mg gastro-resistant tablets’and ‘Tegetrol Retard 400mg gastroresistant tablets’ to ‘Tegretol SR 200mg prolonged release tablets’ and ‘Tegretol SR 400mg prolonged release tablets’ respectively. We are delighted to announce that these changes have now been approved and have been implemented in the packaging (outer cartons and blisters) for Tegretol. There have been no other changes made to the product or the contents of the cartons.For the current version of prescribing information for Tegretol SR prolonged release tablets 200mg and 400mg please consult www.medicines.ie
HPN • March 2016
Published on May 6, 2016