Page 1

Issue 7

THE INDEPENDENT VOICE OF HOSPITAL PHARMACY IN THIS ISSUE: News: Local researchers discuss rates of Polypharmacy

Profile: Galway University Hospital maximise use of Lean technology

Report: In what direction is medicines pricing within Europe headed? Now using a validated diagnostic tool1,2, you can accurately identify specific patients who may benefit from targeted therapy3 in unresectable or metastatic melanoma.

CPD: Hospital acquired venous thromboembolism - a major health burden

In patients harbouring BRAFV600 mutations, Zelboraf significantly improves response rate and overall survival as compared with DTIC4.

ABRIDGED PRESCRIBING INFORMATION For full prescribing information refer to the Summary of Product Characteristics (SmPC) ZELBORAF® (vemurafenib) 240mg film-coated tablets. Indication: As monotherapy for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. Dosage and Administration: Confirm BRAF V600 mutation-positive tumour status by a validated test prior to treatment. Treat until disease progression or the development of unacceptable toxicity. Recommended dose is 960mg (4 tablets of 240mg) twice daily. The first dose is to be taken in the morning and the second approximately 12 hours later, in the same manner i.e. either with or without a meal. Swallow tablets whole with water. If a dose is missed, it can be taken up to 4 hours prior to the next dose to maintain the twice daily regimen. Both doses should not be taken at the same time. Vomiting – continue treatment as usual. Management of symptomatic adverse drug reactions or QTc prolongation may require dose reduction, temporary interruption and/or treatment discontinuation – refer to SmPC. Dose reduction for cutaneous squamous cell carcinoma (cuSCC) is not recommended. Adjustments to <480mg twice daily are not recommended. Contra-indications: Hypersensitivity to the active substance or to any of the excipients. Warnings and Precautions: CuSCC and new primary malignant melanoma: cuSCC (including keratoacanthoma or mixed keratoacanthoma subtype) and new primary malignant melanoma have been reported; no cases of non-cuSCC reported but remain vigilant. Evaluate prior to and monitor routinely while on therapy. Excise any suspicious skin lesions, and obtain dermatopathologic evaluation; treat as per local standard of care. Examine patient monthly during and for 6 months after treatment. In patients who develop cuSCC or new primary malignant melanoma, continue treatment without dose adjustment. Monitoring should continue for 6 months following discontinuation of vemurafenib or until initiation of another anti-neoplastic therapy. Patients should inform their physician upon the occurrence of any skin changes. Hypersensitivity reaction: Serious hypersensitivity reactions, including anaphylaxis have been reported. Vemurafenib treatment should be permanently discontinued if severe hypersensitivity reactions occur; these may include Stevens- Johnson syndrome, generalised rash, erythema or hypotension. Ophthalmologic reactions: Serious reactions have been reported; monitor patients routinely. QT prolongation: Exposure-dependent QT prolongation has been observed and may lead to an increased risk of ventricular arrhythmias including Torsade de Pointes. Treatment not recommended in patients with uncorrectable electrolyte abnormalities (including magnesium), long QT syndrome or who are taking medicines known to prolong the QT interval. ECG and electrolytes (including magnesium) should be monitored before treatment with vemurafenib, after one month of treatment and after dose modification. Further monitoring recommended (particularly in patients with moderate-severe hepatic impairment) monthly for first 3 months and then 3 monthly thereafter, more frequently if clinically indicated. Initiation of vemurafenib is not recommended in patients with QTc >500ms. If during treatment the QTc >500ms, temporarily interrupt vemurafenib and correct electrolyte abnormalities (including magnesium); control cardiac risk factors for QT prolongation (e.g. congestive heart failure, bradyarrythmias). Re-initiate treatment once the QTc <500ms, and at a lower dose as per SmPC. Permanently discontinue vemurafenib if the QTc increase is both >500ms and >60ms change from pre-treatment values. Liver injury: Monitor transaminases, alkaline phosphatase and bilirubin before initiation and monthly during treatment, or as clinically indicated. Hepatic impairment: No adjustment to starting dose needed. Patients with moderate to severe hepatic impairment may have increased exposure; monitor closely and be aware of accumulation. Renal impairment: Mild or moderate – no adjustment of starting dose needed. Severe impairment – use with caution and monitor closely. Photosensitivity: Has been reported; avoid sun exposure and protect against sunburn. Drug Interactions: Vemurafenib may increase plasma exposure of drugs metabolised by CYP1A2 and decrease that of those metabolised by CYP3A4. The efficacy of contraceptive pills metabolised by CYP3A4 used with vemurafenib might be decreased. Exercise caution when co-administered with warfarin (CYP2C9), or CYP2B6 substrates (e.g. bupropion). May affect pharmacokinetics of medicines transported by P-gp. A wash out period of ≥8 days is recommended between vemurafenib and initiation of a new therapy. Fertility/pregnancy/lactation: Women of childbearing potential should use effective contraception during treatment and for at least 6 months afterwards. Vemurafenib might decrease efficacy of hormonal contraceptives. No data in pregnant or lactating women. Side Effects and Adverse Reactions: See SmPC for full details. Very common(>1/10): arthralgia, myalgia, pain in extremity, musculoskeletal pain, back pain, fatigue, pyrexia, oedema, peripheral asthenia, pruritus, cuSCC, seborrheic keratosis, skin papilloma, decreased appetite, headache, dysgeusia, cough, nausea, diarrhoea, vomiting, constipation, rash, photosensitivity reaction, alopecia, actinic keratosis, rash maculo-papular, rash popular, hyperkeratosis, erythema, dry skin, sunburn, and GGT increase. Common(>1/100-<1/10): folliculitis, basal cell carcinoma, 7 th nerve paralysis, uveitis, palmar-plantar erythrodysaesthesia syndrome, erythema nodosum, keratosis pilaris, arthritis, ALT increase, phosphatase increase, bilirubin increase and weight decreased. Serious or potentially serious: Hypersensitivity reactions, including anaphylaxis and Stevens-Johnson syndrome. Legal category: Limited to sale and supply on prescription only. Presentations and MA Numbers: 56 film-coated tablets (Aluminium/Aluminium blisters). EU/1/12/751/001 MA holder: Roche Registration Ltd., 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, UK. 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: May 2012.

The power of personalisation

References: 1. Bloom J, et al. Molecular testing for BRAFV600 mutations in the BRIM-2 trial of the BRAF inhibitor vemurafenib (RG7204/PLX4032) in metastatic melanoma. Abstract #10523. ASCO Annual Meeting. 2011. 2. Anderson S, et al. Molecular testing for BRAFV600 mutations in clinical trials of the BRAF inhibitor vemurafenib (RG7204/PLX4032) in metastatic melanoma: clinical validation studies of the analytic performance of a companion diagnostic assay. Abstract #1403. ESMO Annual Meeting. 2011. 3. Bollag G, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAFmutant melanoma. Nature 2010; 467: 596-599. 4. Zelboraf Summary of Product Characteristics, Feb. 2012. P06/04/12 - May 2012

Feature: Generic immunosuppressant drugs in solid organ transplantation

Meeting: Coverage of the 6th All Ireland Pharmacy Conference in Ballymascanlon House


100 ml

Mercaptopurine oral suspension 20 mg/ml Xaluprine oral suspension offers your patients: n

Accuracy of dosing to 2 mg


Flexibility of dosage


Consistent absorption1


A palatable alternative to tablets

Abbreviated Prescribing Information for Xaluprine (mercaptopurine) 20 mg/ml oral suspension: Please refer to the full Summary of Product Characteristics and the treatment protocol when prescribing Xaluprine. Presentation: Oral suspension, each 1 ml contains 20 mg mercaptopurine (as monohydrate), 3 mg aspartame, 1 mg methyl hydroxyl benzoate, 0.15 mg propyl hydroxybenzoate and sucrose (trace). Indications: For the treatment of acute lymphoblastic leukaemia (ALL) in adults, adolescents and children. Dose and administration: Treatment should be supervised by a physician or other healthcare professional experienced in the management of patients with ALL. The dose is governed by cautiously monitored haematotoxicity and should be carefully adjusted to suit the individual patient. Starting or target doses vary between 25 - 75 mg/m2 body surface area per day, but should be lower in patients with reduced or absent Thiopurine Methyl Transferase (TPMT) activity. Elderly: Monitor renal and hepatic function and if there is any impairment, consider reducing the dose. Renal impairment: Consider reduced starting doses. Monitor patients for dose related adverse reactions. Hepatic impairment: Consider reduced starting doses. Monitor patients for dose related adverse reactions. Switching between tablet and oral suspension and vice versa: The oral suspension and tablet are not bioequivalent. Intensified haematological monitoring is advised on switching formulations. Administration: Redisperse by shaking vigorously at least for 30 seconds. Xaluprine should be taken in the evening and may be taken with food or on an empty stomach. Standardise the method of administration. Xaluprine should not be taken with milk or dairy products but it should be taken at least 1 hour before or 2 hours after milk or dairy products. Water should be taken after each dose. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Concomitant use with yellow fever vaccine. Special Warnings and Precautions for Use: Cytotoxicity and haematological monitoring: Monitor haematological parameters.

Interrupt treatment immediately at the first sign of abnormally large fall in leucocyte and platelet counts. Bone marrow suppression is reversible if 6–mercaptopurine is withdrawn early. Patients with little or no inherited TPMT activity are at increased risk for severe toxicity and require substantial dose reduction. TPMT testing cannot substitute for haematological monitoring. Immunosuppression: Immunisations with live organism vaccines are not recommended. Hepatotoxicity: Monitor liver function weekly. More frequent monitoring may be advisable in those with pre-existing liver disease or receiving other potentially hepatotoxic therapy. Discontinue Xaluprine if jaundice becomes apparent. Renal toxicity: Monitor uric acid levels in blood and urine during remission induction. Hydration and urine alkalinisation may minimize potential renal complications. Mutagenicity and carcinogenicity: 6–mercaptopurine is potentially carcinogenic and consideration should be given to the theoretical risk of carcinogenesis. Excipients: Aspartame may be harmful for people with phenylketonuria. Methyl parahydroxybenzoate and propyl parahydroxybenzoates may cause delayed allergic reaction. Safe handling of the suspension: Avoid Xaluprine contact with skin or mucous membrane. For contact with skin or mucosa, wash immediately and thoroughly with soap and water. Interactions: When allopurinol and 6–mercaptopurine are administered concomitantly only a quarter of the usual dose of 6–mercaptopurine must be given. Other xanthine oxidase inhibitors should be avoided. Reinforced monitoring of INR is recommended in patients co-administered anti-coagulants. Aminosalicylate derivatives inhibit TPMT enzyme and should be administered with caution. Pregnancy and Lactation: Do not use during pregnancy unless expected benefits outweigh any possible risk. Do not use whilst breast-feeding.

and thrombocytopenia is the most common adverse reaction. Anaemia, anorexia, stomatitis, diarrhoea, vomiting, nausea hepatic necrosis, biliary stasis and hepatotoxicity are common adverse reactions. The following adverse reactions have also been reported from uncommonly to very rarely: arthralgia, skin rash, drug fever, pancreatitis, oral ulceration, hepatic necrosis, facial oedema, alopecia, transient oligospermia, secondary leukaemia, myelodysplasia and intestinal ulceration. Overdose: There is no antidote to Xaluprine. Monitor the blood picture and if necessary provide general supportive measures together with appropriate blood transfusion. Activated charcoal or gastric lavage can be undertaken within 60 minutes of ingestion. Pack size: 1 glass bottle containing 100 ml Xaluprine (mercaptopurine) 20mg/ml oral suspension. Shelf-life/Storage: 1 year; 28 days after first opening. Do not store above 25ºC. Legal category: POM. Marketing authorisation number: EU/1/11/727/001. Marketing authorisation holder: Nova Laboratories Limited, Martin House, Gloucester Crescent, Wigston, Leicester, LE18 4YL, UK. Date of latest revision of brief prescribing information: April 2012. Further information including full prescribing information is available from: Nova Laboratories Limited, Martin House, Gloucester Crescent, Wigston, Leicester, LE18 4YL, UK. Tel: +44 (0)116 223 0100.

Contraception: Sexually active men and women should use effective methods of contraception during treatment and for at least three months after receiving the last dose. Undesirable effects: Refer to the SPC for full list. Bone marrow suppression leading to leucopenia

Reference: 1. Mulla H, Leary A, White P, Pandya H. A Step Toward More Accurate Dosing for Mercaptopurine in Childhood Acute Lymphoblastic Leukemia. Journal of Clinical Pharmacology 0091270011423663, first published on December 15, 2011

Adverse events should be reported. Reporting forms and information can be found at Adverse events should also be reported to: Nova Laboratories Limited, Martin House, Gloucester Crescent, Wigston, Leicester, LE18 4YL, UK. Tel: +44 (0)116 223 0100


Issue 7



Hospital pharmacists seek to address medication issue P4


Polypharmacy and the potential for cost savings examined locally P6 How Leans is benefiting more hospital pharmacists across the country P9 Pharmacy award prize winners presentation P11 EAHP's Richard Price gives HPN an exclusive overview of medicines pricing in Europe P14 Standardised systems needed at hospital pharmacy level P23 All-Ireland Pharmacy conference coverage P42

Regulars Medication Reconcilliation on Admission to Hospital P18 CPD - Hospital acquired venous thromboembolism constitutes a major health burden P25 Generic immunosuppressant drugs in solid organ transplantation P32 Childhood cancer survival rates in Ireland P38 Clinical Profiles P49

Hospital Pharmacy News is Circulated to all independent, multiple and hospital pharmacist, pre reg pharmacists, students pharmacy studentâ&#x20AC;&#x2122;s offi cial bodies, government officials and departments, Pharmacy Managers, Manufactures, Wholesalers. Buyers of pharmacy groups and healthcare outlets. Circulation is free to all pharmacists Subscription rate for Hospital Pharmacy News 60euro plus vat per year All rights reserved by Hospital Pharmacy News. All material published in Hospital Pharmacy News is copyright and no part of this magazine may be reproduced, stored in a retrieval system of transmitted in any form without written permission. Pharmacy Communication Ireland have taken every care in compiling the magazine to ensure that it is correct at the time of going to press, however the publishers assume no responsibility for any effects from omissions or errors.

PUBLISHER IPN Communications Ireland Ltd Carmichael House, Lower Baggot Street, Dublin 2 00353 (01) 6024715 MANAGING DIRECTOR Natalie Maginnis EDITOR Kelly Jo Eastwood ACCOUNTS Lorraine Moore

SALES MANAGER Debbie Graham CONTRIBUTORS Richard Price Kathryn Feeny Mairead Galvin Tamasine Grimes Prof James O'Donnell

Kelly Jo Eastwood Welcome to the first issue of Hospital Pharmacy News in 2013. This issue focuses on a variety of issues ranging from transparency and reference pricing to patient safety medications and the role of the hospital pharmacist. The economic recession continues to rampage relentless and no-one is immune from its touch, the pharmaceutical industry included. Spending restrictions in health and medicines reimbursement is rife and all professionals are feeling the pinch. As a result, solutions are being developed included risk-sharing between the payer and the provider of medicines. These can be grouped into Such two categories: risk-sharing based on cost, and risk-sharing based on outcomes delivered. Richard Price of the European Association of Hospital Pharmacists talks us through the process. In the race for innovative approaches to pricing, transparency may yet be a victim says Richard. Turn to page 14 for the full report. Meanwhile, the Pharmaceutical Group of the European Union and the European Association of Hospital Pharmacists are standing together to call for increased roles in patient use of medicines for pharmacists, both within the hospital and community settings. In addition, the two groups are asking for improvements in the systems supporting multi-professional care across Europe. Pharmacists are the medicines experts, this principle has been in force for a number of years now and as such it is vital they are the heart of national strategies. Our Continuing Professional Development series continues as Professor James O'Donnell of St Jame's Hospital gives his insights into the health burden posed by hospital acquired venous thromboembolism while Kathryn Feeny a pharmacist at St Vincent's University Hospital addresses the growing issue of generic immunosuppressant drugs in solid organ transplants. During the medication use process patient safety is key and hospital pharmacists are ideally placed and have the responsibility to optimise this. Medication errors are clinically significant and as such Tamasine Grimes and Mairead Galvin have looked at the clinical pharmacists contribution to medication reconciliation on admission to hospitals in Ireland. May I take this opportunity to wish you all a very happy and prosperous New Year!

ART DIRECTED BY Smart Page Design


4 News

Hospital pharmacists tackle medication issue Hospital pharmacists are asking patients to bring a list of medicines with them when being admitted to hospital, to help improve the accuracy of medicines prescribed to them while in hospital. A recent study conducted in one Irish hospital found that 67% of patients had at least one error in their medication history /prescription when admitted to hospital.* In response, the Hospital Pharmacists Association of Ireland (HPAI) has launched an information leaflet entitled “Your Hospital Pharmacist, Looking Out For You" which lists what details the patients should include on their list and how they can help to improve their own medication safety.

Speaking at the launch Ms Deirdre Lynch, (HPAI president and Chief Pharmacist at CUH) commented; “There are thousands of medications on the market, many of them with similar sounding names but perhaps used for very different purposes. It is very important that whoever is asking the patient about their current medication in hospital, whether it is the hospital pharmacist, doctor or nurse, can find out exactly what the patient is taking, the correct name and strength.” The patient information leaflet also aims to increase awareness of the role of the hospital pharmacist and describes ways that the hospital pharmacist can help patients, either behind the

scenes or at the bedside. "This survey revealed that almost 40% of people surveyed had never heard of a pharmacist working in a hospital and were unaware of what hospital pharmacists do to help patients, such as the supply function, medicines reconciliation, medication counselling and medication safety. We hope this new patient information leaflet will raise awareness of patient services provided by hospital pharmacists" said Anne Marie Cushen, Medication Safety Pharmacist, Beaumont Hospital.

Your hospital pharmacist looking out for you

Copies of “Your Hospital Pharmacist, Looking Out For You" are available by emailing

Community and hospital pharmacists come together The two organisations representing community and hospital pharmacists in Europe have come together to make a declaration on the development of the pharmacy profession. The joint statement by the Pharmaceutical Group of the European Union (PGEU) and

the European Association of Hospital Pharmacists (EAHP) represents a call to action to national governments to, firstly, enable pharmacists to increase their role in optimising patient use of medicines, and, secondly, to improve the systems supporting multi-professional

care across Europe. EAHP and PGEU believe that pharmacists, as experts in medicines, should be at the heart of national strategies to ensure best outcomes for patients. This includes pharmacists educating patients about the optimal use of their

medicines, and helping to ensure that potential polypharmacy problems, which can arise when a patient takes multiple medications, are satisfactorily resolved and reconciled. Turn to page 11 for the full report.

Strategic planning on the agenda Dr Marian Ivey, Associate Professor in Pharmacy Practice the University of Cincinnati, Ohio, will be one of the first of three keynote speakers at the European Association of Hospital Pharmacists 18th Congress being held in Paris from 13-15 March, 2013. Dr. Ivey teaches and consults in the areas of pharmacy leadership, strategic planning and clinical services, and operations management. She says: "Much of today’s Issue 7 • HPN

education of health care professionals recognises the contributions made by different disciplines who have different perspectives and knowledge to apply to the problem being considered. Today’s leaders of hospitals have also generally had training that includes discussing the benefits of a diverse approach to care. Many have had training that includes case studies in other disciplines such as air travel safety and space exploration. These case studies demonstrate that not listening to

all the team members has had disastrous results of morbidity and mortality very similar to what can happen in health care delivery. "The EAHP congresses are thoughtfully planned to be relevant to the practice of today’s hospital pharmacists. The meetings provide challenges and stimulation to deliver better care through presentations of examples from leading practitioners in Europe and elsewhere.

"The time spent together during breaks, looking at the exhibitors booths and in sharing social time together is a way to get new ideas in a refreshing change of pace from our everyday work life. "Finally the opportunity for experienced pharmacists to share their knowledge and enthusiasm with younger practitioners is a great way to increase involvement in hospital pharmacy organisations such as EAHP."


Cork pharmacists work together

Pictured at the recent All Ireland Pharmacy Conference are Marita Kinsella, Department of Health and Tom McGuinn, Irish Centre for Continuing Pharmaceutical Education

Interface between community and hospital pharmacy was the main focus of a recent evaluation carried out between University College Cork and Cloyne Pharmacy, Cork. Hospital intern pharmacist Kieran Walshe worked with community pharmacists in Cloyne to compare anticoagulation control between a primary and secondary anti-coagulant clinic and to evaluate anticoagulation management services in both clinics. The findings were part of the poster presentation section at the recently held 6th All Ireland

Pharmacy Conference, held on the 13th November 2012 at the Ballyscanlon House Hotel, Dundalk. The event was attended by over 150 pharmacists, pharmaceutical assistants and technicians from all over Ireland. Warfarin is currently the most commonly prescribed oral anticoagluant for the prevention of stroke in patients with atrial fibrillation and prosthetic heart valves. An estimated 1.5% of the Irish population are taking oral anticoagulation therapy and this is expected to increase by 10% year on year.

A retrospective analysis of all warfarin patients who had been assessed in Cloyne Pharmacy between February 2010 and January 2012 was carried out and the mean Therapeutic Time in Range per patient using Rosendaal's method was calculated. "It was found that anticoagulation control in Cloyne pharmacy was as effective as that in CUH and adheres to international standards" concluded the authors.

New script layout to enhance safety Hospital pharmacists at St Vincent’s University Hospital have introduced new format prescriptions for outpatients and discharges. It is anticipated that these changes will: a) improve patient safety by enhancing legibility and by highlighting patient allergies and sensitivities, b) reduce the number of

separate MDA prescriptions that prescribers need to write and c) enhance the management and security of prescriptions. St Vincent’s University Hospital also distributes some 40,000 blank medication cards to outpatients each year, for patients and their carers to record current medications, prior to scheduled appointments or admission. This facilitates the medication reconciliation process at the

community / hospital interface and helps reduce medication errors associated with discrepancies and omissions. SVUH welcomes feedback. If you would like to comment,

or if you would like additional information on either of the above topics, please contact Niamh O’Hanlon, SVUH Pharmacy Dept at n.ohanlon@

Pharmacist looks at potential universal flu vaccines Pharmacy specialist Dr Anne Moore has been looking at potential ‘universal’ flu vaccines that introduce a small amount of the flu virus into the host in order to encourage the host’s immune system to build up a memory of it. Her research study has worked out important elements of the manner in which a host

immune system responds to the two potential vaccines. It has also established expertise in universal flu virus development at UCC and has led to an EUfunded study on flu vaccine delivery. Every flu season a new flu vaccine is created, because

the predominant flu virus that is going around is likely to have changed, and vaccines from previous years will not give enough protection. If a pandemic flu breaks out, there is a global scramble to develop and distribute vaccines in time. Dr Moore's study is a Health

Research Board-funded one. “Instead of targeting the outer surface of the flu virus, which is the part that changes the most, we want to develop a vaccine that targets more hidden parts of the virus, which tend to change less,” explains Dr Anne Moore, School of Pharmacy, UCC.

HPN • Issue 7

6 News

Rates of polypharmacy discussed locally Researchers at The Irish Longitudinal Study on Ageing (TILDA) at Trinity College Dublin have published a new report on multiple medication use in adults aged over 50 in Ireland, examining rates of polypharmacy and opportunities for cost savings using generic and reference prices. The report was prepared using data from the first wave of The Irish Longitudinal Study on Ageing (TILDA). TILDA is a large-scale study of 8,175 people aged 50 and over and living in Ireland. Participants were first interviewed in 2010.

TILDA Assessment

Dr Kathleen Bennett

Polypharmacy, the regular use of five or more medicines, is very common in older people in Ireland (one in three aged over 65) and becomes more common with advancing years (table 1). Polypharmacy is important because it can put people, particularly older people, at risk of serious complications − such as falls, fractures and complications from drug interactions (confusion, delirium, strokes). The findings of this report highlight the need for frequent medications review in older adults. TILDA participants were all living in the community at the time of the report, it may be that polypharmacy is more common in older people in nursing home settings. The report’s authors were Kathryn Richardson, Patrick Moore, Jure Peklar, Kathleen Bennett and Rose Anne Kenny (all of Trinity College Dublin) and Rose Galvin (Royal College Surgeons in Ireland). High levels of concomitant food supplement (also known as dietary supplement) use were also reported in those with polypharmacy and were more common in women (44% in women, 27% in men). Food supplements can interact with other medicines and these interactions should be discussed by pharmacists and general practitioners. Prescribed medications can be made cheaper by prescribing generics (copies of the original medicine no longer protected by patent) or by using reference pricing (setting one price for groups of similar medicines).

Issue 7 • HPN

Over ¤0.3 billion is spent each year on medicines for adults on polypharmacy over 50 years. Only one in five prescribed medicines are generic, which compares poorly with other cultures such as the US and UK. Furthermore, generic prices of commonly used medicines in Ireland are several times more expensive than their UK counterparts. Current international guidelines recommend regular medication review and substitution for a cheaper medicine with the same therapeutic outcome where possible. One of the senior authors , Professor Kathleen Bennett, commented that “ the Irish prices were substantially higher than UK counterparts, for example 2 of the 10 most commonly prescribed medicines were 6 times more expensive in Ireland.” Because only one in five medicines used by those reporting polypharmacy was a generic, in 2010, €30 million per year could have been saved by increasing the use of generic medicines (Irish generic pricing). Based on 2010 prices, up to €152 million could have been saved annually using a system of reference pricing based on groups of similar drugs. For example, for commonly prescribed drugs such as statins for lowering cholesterol, the potential annual savings from increasing the use of generics would have been €1 million and from using reference pricing €40 million per year. Commenting on the results, the Principal Investigator for TILDA, Professor Rose Anne Kenny said: “This report highlights the extent of the medication burden in adults in Ireland and where considerable cost savings could be made. Polypharmacy is common and potentially puts the ageing population at risk of serious complications. Given that polypharmacy accounts for over half of the annual costs of prescribed medications in the entire population aged over 50 years, review of medications and generic substitution should offer opportunities for considerable savings”.

NEW oral anti-platelet treatment for a broad range of ACS patients

BRILIQUE saves more lives than clopidogrel as measured by CV deaths (PLATO study)1

BRILIQUETM 90MG FILM-COATED TABLETS (ticagrelor) Abridged Prescribing Information (For full details see Summary of Product Characteristics (SmPC)) Use: Adults aged 18 years and older, co-administered with acetylsalicylic acid (ASA) daily: for the prevention of atherothrombotic events in patients with acute coronary syndromes (unstable angina, non-ST-segment elevation myocardial infarction [NSTEMI] or ST-segment elevation myocardial infarction [STEMI]); including patients managed medically, and those who are managed with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). Presentation: 90mg ticagrelor film-coated tablets. Dosage and administration: Treatment should be initiated with a single 180mg loading dose (two tablets of 90mg) and then continued at 90mg twice daily. Following an initial dose of ASA, patients should also take a daily maintenance dose of 75-150mg of ASA with Brilique, unless ASA is specifically contraindicated. Treatment is recommended for up to 12 months unless discontinuation is clinically indicated. Premature discontinuation of treatment or lapses in therapy should be avoided. Patients treated with clopidogrel can be directly switched to Brilique. For oral use. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Active pathological bleeding. History of intracranial haemorrhage. Moderate-to-severe hepatic impairment. Co-administration with strong CYP3A4 inhibitors (e.g. ketoconazole). Precautions: Due to the increased risk of non-fatal or non-life threatening bleeding, use with caution in patients at an increased risk for bleeding (e.g. recent trauma or surgery, bleeding disorders or recent gastrointestinal bleeding) or those on concomitant medication that may increase bleeding risk (e.g. NSAIDs, anticoagulants) within 24 hours of taking Brilique. Brilique should be stopped 7 days prior to elective surgery if the antiplatelet effect is not desired. Use with caution in patients with an increased risk of bradycardic events (e.g. patients on digoxin), as asymptomatic ventricular pauses have been observed with Brilique, a history of asthma and/or COPD, a history of hyperuricaemia or gouty arthritis. Creatinine levels may increase during treatment with Brilique. Renal function should be checked after one month and thereafter according to routine medical practice, paying special attention to patients ≥ 75 years, patients with moderate-to-severe renal impairment and those receiving concomitant treatment with an ARB. Co administration of Brilique is not recommended with a high maintenance dose of ASA (> 300mg) or with doses of simvastatin > 40mg. Co administration of ticagrelor with strong CYP3A4 inducers is discouraged, as this may lead to a decrease in exposure and efficacy of ticagrelor. Co-administration with CYP3A4 substrates with narrow therapeutic indices is not recommended. Concomitant use of ticagrelor with doses of simvastatin or lovastatin > 40mg not recommended. Caution with concomitant use of P-gp inhibitors or P-gp substrates with narrow therapeutic indices e.g. verapamil, quinidine and cyclosporin. Caution with concomitant administration of SSRIs. Brilique is not recommended during pregnancy and breastfeeding. Undesirable effects: Common: Dyspnoea, epistaxis, gastrointestinal haemorrhage, subcutaneous or dermal bleeding, bruising and procedural site haemorrhage. Other undesirable effects include intracranial bleeding, elevations of serum creatinine and uric acid levels. Consult SmPC for a full list of undesirable effects. Legal category: POM. Marketing Authorisation Number: EU/1/10/655/004. Market Authorisation Holder: AstraZeneca AB, S 151 85, Södertälje, Sweden. Further information on request from: Freephone 1800 800 899 or contact AstraZeneca UK Limited, Horizon Place, 600 Capability Green, Luton, Bedfordshire, LU1 3LU, United Kingdom. Abridged prescribing information prepared: 04/12. BRILIQUE is a trade mark of the AstraZeneca group of companies. Reference 1: Brilique Summary of Product Characteristics. URN: 12/0266. Date of preparation: May 2012


NEW in Ireland

Treats acute uncomplicated UTIs with just one dose

the on

e dose

One Treatment. One Solution.

One-dose sachet dissolves in water

Fos fom ycin (a s Trom eta m ol)

Adult 3g

Name of mediciNal al Product: monuril 3g granules for oral solution. Each single-dose sachet contains 5.631g fosfomycin â&#x20AC;&#x201C; trometamol (1:1) equivalent to 3g fosfomycin. It is a white granular powder for oral solution with a characteristic odour and flavour of mandarin. TheraPeutic iNdicatioNs: Treatment of acute uncomplicated urinary tract infections due to sensitive organisms in adults. Posology aNd admiNistratioN: Adults only: A single dose of 3g taken on an empty stomach, preferably before bedtime, after bladder emptying. The contents of the sachet should be dissolved in water and the solution swallowed immediately. Elderly patients: Not recommended due to diminished urinary excretion. Paediatric population: It is not for use in children coNtraiNdicatioNs: Hypersensitivity to the active substance or to any of the excipients. Monuril should not be used in patients with impaired renal function (creatine-clearance <80 ml/min). WarNiNgs aNd sPecial PrecautioNs for use: Clostridium difficile associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents, including fosfomycin trometamol, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C.difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. this medicinal product contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine. Do not use more than one single dose of Monuril to treat a single episode of acute cystitis. Prolonged use of an anti-infective may result in the development of super infection due to organisms resistant to that anti-infective. iNteractioNs: When co-administered with fosfomycin, metoclopramide lowers the serum and urine concentrations of fosfomycin. Other drugs that increase gastrointestinal motility may produce similar effects. No information is available on the interaction between fosfomycin and oral contraceptives, nevertheless there is a potential for interaction between oral contraceptives and antibiotics. PregNaNcy aNd lactatioN: Pregnancy: Data on a limited number of exposed pregnancies indicate no adverse effects of fosfomycin on pregnancy or on the health of the foetus/new-born child. To date, no other relevant epidemiological data are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. Caution should be exercised when prescribing to pregnant women. Lactation: Due to lack of safety information, the use of fosfomycin during human lactation cannot be recommended usiNg moNuril With food & driNk: Take Monuril on an empty stomach (2-3 hrs after a meal) as food delays and reduces the absorption of fosfomycin trometamol, resulting in reduced blood and urinary concentrations. driviNg aNd usiNg machiNery: Monuril oral solution has no influence on the ability to drive and use machines. uNdesirable effects: commoN (1/100 to <1/10): Headache, Dizziness, Diarrhoea, Nausea, Vulvo-vaginitis, Dyspepsia and Asthenia uNkNoWN Anaphylactic shock, Allergic reaction, Asthma, Vomiting, Abdominal pain, Angioedema, Rash, Urticaria and Pruritus overdose: Symptoms: The following events have been observed in patients who have taken MONURIL 3g granules for oral solution in overdose: vestibular loss, impaired hearing, metallic taste, and general decline in taste perception. Treatment in the event of overdose: In the event of over dosage, treatment should be symptomatic and supportive. PharmacodyNamic ProPerties: Fosfomycin trometamol [mono (2-ammonium-2-hydroxymethil-1,3propandiol) (2R-cis) (3- methiloxyranil) phosphonate] is a broad spectrum antibiotic, derived from phosphonic acid, for the treatment of urinary tract infections. The antibacterial activity of fosfomycin is due to an inhibition of bacterial cell wall synthesis. Its particular mechanism of action, specific inhibition of enol pyruviltransferase, results in lack of cross resistance with other classes of antibiotic, and the possibility of synergism with other antibiotics (in vitro synergic effect with amoxicillin, cephalexin, pipedimic acid and aztrenam). Pharmacokinetic properties: Fosfomycin trometamol which is an orally well absorbed salt of fosfomycin, in which the formulation is completely soluble in water. Fosfomycin, unbound to the plasma proteins, is eliminated mainly unchanged through the kidneys and this results in very high urinary concentrations (about 3000mcg/ml) within 24 hours. Therapeutic concentrations of the active moiety in the urine are usually maintained for at least 36-48 hours. In patients with moderately reduced renal function (including elderly patients) the serum half-life of fosfomycin is slightly prolonged but urinary concentration remains therapeutically adequate. legal category: POM Package Quantities: Sachets are supplied in cardboard outer containing 1 sachet. date of last Pi revision: Nov 11. marketiNg authorisatioN holder: Zambon S.p.A. via Lillo del duca, 10 20091-Bresso, Milano. marketiNg authorisatioN Number: PA1441/2/2 distributor: Sinclair IS Pharma Ireland Ltd. marketed iN irelaNd by: faNNiN ltd, faNNiN house, leoPardstoWN, dubliN 18. for a copy of the smPc or further medical information, please contact adverse events should be reported to fannin ltd, Pharmacovigilance at 01 2907000 or fN2012-07-003. date of Preparation: August 2012



Galway Hospital Pharmacy Lean in The hospital pharmacy team at University Hospital Galway had a very different challenge last year thinking of new ways to improve pharmacy performance despite a recruitment embargo: HPN looks at their innovation in more detail. The pharmacy department with the strong support of the teaching hospital was under significant pressure to perform more work with less staff. A recruitment embargo and the absence of an assistant grade of staff in dispensing operations meant the pharmacy team must respond to acute and non-acute patient needs without having an optimal skills mix. The hospital pharmacy developed the capacity of the pharmacy team to solve problems and implement solutions within these constraints by using Lean thinking. “Several important process improvements have been identified and realised. We could not have done this without the Leading Edge Group consultant’s professionalism, intelligence and enthusiasm," says Peter Kidd, Chief 2 Pharmacist, Clinical Services. Prior experience with implementing Lean thinking had convinced the hospital’s Chief Pharmacist that introducing Lean tools and concepts to the pharmacy team would empower them to make ongoing improvements despite the constraints within which they work. A Leading Edge Group consultant was appointed to deliver a tailored programme of training and mentoring to 10-12 hospital pharmacy team members, primarily pharmacy technicians and pharmacists. Stepping out of the classroom The key outcomes achieved were empowered staff, improved customer focus, better stock management, better workflow

HPN • Issue 7

10 Profile

We were able to utilise our pharmacy space more effectively

and better space utilisation. Pharmacy team members have made process improvement an ongoing part of their routine work. The team members have also spoken to their customers to get a better understanding of the needs, expectations and experiences of both patients and hospital staff in other departments to ensure greater visibility of stock and almost eliminate stock- outs of key stock items. Work processes have been mapped and unnecessary movement of people and transportation of products have been eliminated. A re-organised, tidier and more visual work environment has created space savings of 25%. In addition, the team have developed the knowledge, skills and confidence to lead process improvement work on an ongoing basis and have a better understanding of the needs, expectations and experiences of both patients and hospital staff in other departments. Says Peter: "We can now manage stock more effectively, with greater visibility of stock and less stock-outs and have improved workflow by reducing the movement of staff and transportation of products.

techniques by implementing improvement projects in the hospital pharmacy. Walking the process Techniques used in the project included: • Prompting conversations about staff opinions and anxieties. • Implementing an ideas board and establishing daily ten minute improvement meetings. • Mapping key team processes. • Facilitating a site visit to another organisation to see Lean in action. • Mentoring team members as they planned and executed projects to achieve a tidier, safer work environment and better stock management. To contact Leading Edge Group visit

In addition we were able to utilise our pharmacy space more effectively." The project was characterised by: • Taking learning out of the classroom – relating Lean concepts to the everyday work of pharmacy team members. • Walking the process – going to where each step of a process happens and talking to “customers” about their experiences and needs. • Learning by doing – developing team knowledge of Lean

Issue 7 • HPN

The pharmacy team at Galway University Hospital


St Luke's get proactive with patient safety In January of this year, the pharmacy department within St Luke's Hospital in Kilkenny, headed by Sinead McCool, hospital pharmacist, decided to take a more proactive approach to the recording and review of medication safety incidents pharmacy staff come across and record. This initiative has resulted in an increase in the number of incidents reported, and a more timely transfer of information to the clinical risk officer, and the use and review of targeted follow-up has increased

the impact and effect of dissemination of information to medical and nursing staff. The paper - Re-engineering the recording and review of medication safety incidents in the pharmacy department in St Luke's Hospital, Kilkenny - was presented as a poster at the recent 6th All-Ireland Pharmacy Conference in Ballymascanlon House. She states: "As there is no dedicated medication safety officer in the hospital, it falls to the pharmacy department to manage the medication safety

element of patient safety within the hospital." In order to learn more from incidents a number of new approaches were taken including: > A database established to record headline information and follow-up for each recorded medication incident; > A review and grading of incidents, using the NCC MERP index for categorising medication errors algorithm as a monthly group exercise by all pharmacists within the

department, and; > Feedback to staff on the medication safety initiative, and its findings were fed-back to hospital staff via the Drugs and Therapeutics committee. "Medication safety is a multifaceted subject, and improving medication safety required a multi-faceted approach. This proactive pharmacy initiative has resulted in improved recording of incidents, and better dissemination of information and education to clinical and nursing staff within St Luke's Hospital," says the author.

Cork and Canada co-operation Research between Cork and Canada shows that the bacterial composition in the gut of infants treated with broad-spectrum antibiotics is still altered eight weeks after treatment. In the study, nine infants were treated with intravenous ampicillin/gentamicin within 48 hours of birth, and over the two month study period, their gastrointestinal flora was compared to that in nine infants who received no antibiotics. At four weeks, beneficial bacteria, including Bifidobacteria and Lactobacilli, were significantly reduced in the treated group, and although the numbers bounced back by the study's end, the species diversity did not. The researchers used advanced DNA sequencing to identify the species of gut flora, and to quantify their numbers. Eight weeks after antibiotic treatment of infants, the diversity of gastrointestinal flora remained diminished, although the number of individual bacteria was back to normal. Additionally, the potentially disease-causing Proteobacteria were now the

dominant population in the treated infants. It remains unclear whether the potentially harmful Proteobacteria predominate because their population has grown or because the other populations have shrunk, the researchers write. However, the data suggest the former, which jibes with previous research. "This is the first sequencingbased study to demonstrate the negative effects of shortterm antibiotic treatment on the beneficial gut bacteria populations in infants," says senior author Catherine Stanton of the Alimentary Pharmabiotic Centre based at Teagasc Food Research Centre, Fermoy, Co Cork. â&#x20AC;&#x153;By altering the gut microbiota, and thus the immune system very early in life, the antibiotics could negatively influence long-term health, particularly by increasing the risk of developing asthma, allergy, and obesity. This risk is heightened by the fact that the antibiotic-driven disruption of the microbiota comes at a time when this population is

Professor Tony Ryan and Dr Catherine Stanton

in rapid flux and can easily be unbalanced" The research was carried out by scientists in the Alimentary

Pharmabiotic Centre based in Teagasc, University College Cork, Cork University Maternity Hospital and The Hospital for Sick Children, Toronto, Canada.

HPN â&#x20AC;˘ Issue 7

12 Report

Can adaptive licensing bridge the gap? The prospect of a new model for drug approval based on ‘acknowledged uncertainty’ provided for a lively debate at the European Medicines Agency Review of the Year and Outlook for 2013, an annual meeting organised with TOPRA. The concept of adaptive licensing is not revolutionary, but rather a natural step in the evolution of drug approval, explained the EMA’s Senior Medical Officer, HansGeorg Eichler. Nonetheless, not all parties were in agreement.

Hans-Georg Eichler

face on a daily basis. The vision is to allow products onto the market sooner, but perhaps with a more restricted indication to begin with. Post-authorisation, the target population could be broadened when more real-life data became available. This might also be a way to bridge the gap between the evidentiary standards required by regulatory agencies and HTA bodies for assessing the benefits and risks of a therapy.

The idea of adaptive licensing (or staggered approval) was introduced in the EMA’s Road Map to 2015 as a possible solution for earlier approval of drugs to meet an unmet medical need, for those drugs not eligible for conditional marketing authorisations or marketing authorisations under exceptional circumstances.

Dr Eichler made it clear that it would be a prospectively planned approach to the regulation of drugs, through ‘iterative phases of evidence gathering followed by regulatory evaluation and licence adaptation’. He hastened to add that it was not without its challenges and would not be a one-size-fits-all solution to solve all the problems of the pharmaceutical industry.

It is seen as a possible way to address the constant ‘access vs evidence’ dilemma that regulators

Tomas Salmonson, Chair of the EMA’s CHMP, agreed that this was ‘not a way of rescuing drug

development programmes that have gone wrong’. He said that the time had come to pilot the idea and that everything was in place to do so. One of the main prerequisites for success, however, is to make sure all decision makers are on board, and this of course includes HTA bodies.

Innovation must focus on patient need Innovation in healthcare and the pharmaceutical industry in particular, needs to focus itself on the needs of patients, was the message at the Annual meeting of the Irish Pharmaceutical Healthcare Association (IPHA) which was held in the Radisson Blu St. Helen’s Hotel, Stillorgan, on Thursday 29th November.

Francis Lynch, IPHA President

Delegates heard the new IPHA President, Francis Lynch argue that despite health budgets across the world being slashed, the research based pharmaceutical industry must remain focused on the needs of patients. Austerity was an inevitable fact of life due to the economic crisis, however, the industry needed to be in a position to “bring to the market the cutting edge medicines and treatments of tomorrow”. Pointing to the recent negotiation of a new supply agreement that will bring savings of over €400 million to the State, Mr. Lynch said that this demonstrated how the industry was working

Issue 7 • HPN

with the State to allow for new and innovative medicines to be funded: “From the perspective of the patient, the agreement puts innovation on a far more secure footing and will ensure a timely access to new medicines”, he said. The meeting also heard from the Deputy Chief Executive Officer/ Director General Designate of the HSE, Mr Tony O’Brien who outlined that despite the enormous and continuing challenges facing the health services, particularly on the funding front, ongoing structural reform would lead to a better service for patients. Irish Cancer Society Chief Executive Mr John McCormack argued that too often the voice of patients was not heard in the debate on healthcare expenditure, particularly regarding the value of new medicines. In his view a more formal involvement by patients and their representatives needed be heard in considerations on how medicines are funded.

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14 Report

Medicines pricing in Europe: In which direction is it headed, and what does it mean for hospital pharmacists? The current economic crisis has impacted every industry in Europe in some form or other, and no less so for the pharmaceutical industry who are now increasingly feel the pain brought about by spending restrictions in public services, including in the field of health, and medicines reimbursement. This has produced, for example, recent large scale cuts in pricing across hundreds of medicines in Ireland, and unprecedented offers by industry to the Government in Greece, to impose a ceiling on the amount the Government pays for outpatient prescription drugs in return for a commitment to pay outstanding debts.

Richard Price

But such “crisis deals” with countries in relation to medicines prices have multiple implications, including, and perhaps most importantly, impacting the international reference price that countries with healthier public balance sheets, like Germany, use to calculate their reimbursement levels to industry. Clearly, a more sustainable and long-lasting mechanism for handling medicines cost must be found, particularly in view of the fact that ageing societies across Europe, combined with raised public expectations, were placing existing systems of medicines reimbursement under strain, even before the 2008 financial crisis. A particular response to the problem that has now developed in a number of countries is risksharing between the payer and the provider of medicines. Such schemes can be loosely divided in to two categories: risk-sharing based on cost, and risk-sharing based on outcomes delivered. Risk-sharing based on cost An example of cost-sharing is the many “price-volume” agreements that have been initiated in a number of European

Issue 7 • HPN

countries. In essence, a pricevolume agreement specifies a volume threshold value. The manufacturer has to give a rebate to the payer if the actual sales exceed this threshold. An example is in Portugal where an agreement is made on each individual product and includes the establishment of a maximum price and a maximum annual budget, based on the estimated population that will use the medicine. If the budget is exceeded, the marketing authorisation holder is required to pay back the difference. Such agreements typically last for 2 years, so are relatively short term in duration. In Italy, as another example, the provision by manufacturers of discounts on initial therapies has come in to relatively common use. An example are 3 year cost-sharing schemes that requires manufacturers to pay back 50% of the treatment cost for all eligible patients during the first treatment cycle (e.g. 6 weeks). Such arrangements are useful in cases where, at the time of marketing authorisation, there are not enough results to know the real value of the new treatment, advantages for patients are not clear enough, and prices are high. Another cost-sharing approach adopted in the UK has been “Utilisation Caps”, which places a limit on the overall cost to NHS of a new medicine at the average number of cycles received by patients in the trial. In the case of Revlimid, the NHS funds the once-a-day pill

ch to op a io o r id p p


a uni








Targin® tablets contain an opioid analgesic


Targin® (oxycodone hydrochloride/naloxone hydrochloride) 5mg/2.5mg, 10mg/5mg, 20mg/10mg and 40mg/20mg prolonged release tablets Prescribing Information Republic of Ireland Please read the Summary of Product Characteristics (SmPC) before prescribing. Indications: Severe pain, which can be adequately managed only with opioid analgesics. Naloxone is added to counteract opioidinduced constipation by blocking the action of oxycodone at opioid receptors locally in the gut. Dosage and administration: Adults over 18 years: Usual starting dose for opioid naïve patients: 10 mg/5 mg taken orally at 12hourly intervals. Patients already receiving opioids may be started on higher doses depending on their previous opioid experience. Targin® 5 mg/2.5 mg is intended for dose titration when initiating opioid therapy & individual dose adjustment. The dosage is dependent on the severity of the pain and the patient’s previous history of analgesic requirements. Maximum daily dose of Targin is 80 mg oxycodone hydrochloride & 40 mg naloxone hydrochloride. Targin is not intended for the treatment of breakthrough pain. Please refer to SmPC for further details. Targin must be swallowed whole & not be broken, chewed or crushed. Children under 18 years: Not recommended. Contra-indications: Hypersensitivity to active substances or excipients, any situation where opioids are contra-indicated, severe respiratory depression with hypoxia and/or hypercapnoea; severe COPD, cor pulmonale, severe bronchial asthma, non-opioid induced paralytic ileus, moderate to severe hepatic impairment. Precautions and warnings: Respiratory depression, elderly or infirm, opioid-induced paralytic ileus, severely impaired pulmonary function, myxoedema, hypothyroidism, adrenocortical insufficiency, toxic psychosis, cholelithiasis, prostate hypertrophy, alcoholism, delirium tremens, pancreatitis, hypo- or hyper-tension, pre-existing cardiovascular diseases, head injury, epileptic disorder, predisposition to convulsions, patients taking MAO inhibitors, history of alcohol/drug abuse, galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorption, renal impairment, mild hepatic impairment, pre-operative use or within the first 12 - 24 hours post-operatively. Not suitable for treatment of withdrawal symptoms. Not recommended in cancer associated with peritoneal carcinomatosis or sub-occlusive syndrome in advanced stages of digestive & pelvic cancers. Concomitant use of alcohol and Targin may increase the undesirable effects of Targin and should be avoided. Tolerance and dependence may occur. It may be advisable to taper dose when stopping treatment to prevent withdrawal symptoms. Interactions: Substances having a CNS-depressant effect (e.g. other opioids, sedatives, hypnotics, anti-depressants, sleeping aids, phenothiazines, neuroleptics, anti-histamines and antiemetics) may enhance CNS-depressant effect of Targin (e.g. respiratory depression). Alcohol may enhance the pharmacodynamic effects of Targin; concomitant use should be avoided. Interaction with coumarin

anticoagulants may increase/decrease INR. Pregnancy and lactation: Not recommended. Side-effects: Common: decreased/loss of appetite, restlessness, dizziness, headache, vertigo, decrease in blood pressure, abdominal pain, diarrhoea, dry mouth, constipation, flatulence, vomiting, nausea, dyspepsia, increased hepatic enzymes, hiccups, altered mood, personality change, decreased activity, psychomotor hyperactivity, agitation, dysuria, pruritus, skin reactions, hyperhidrosis, drug withdrawal syndrome, feeling hot & cold, chills, asthenic conditions. Uncommon but potentially serious: hypersensitivity, confusion, depression, euphoric mood, hallucinations, paraesthesia, speech disorder, convulsions, sedation, syncope, visual disturbances, palpitations, angina pectoris, tachycardia, increase in blood pressure, dyspnoea, respiratory depression, biliary colic, erectile dysfunction, urinary retention, peripheral oedema, tooth disorder, chest pain and injuries from accidents. Refer to SmPC for further details of other uncommon side-effects and oxycodone class-effects. Legal category: CD (Sch2) POM. Package quantities: Blisters of 56 tablets. Marketing Authorisation numbers: PA913/025/001-4. Marketing Authorisation holder: Napp Pharmaceuticals Limited, Cambridge Science Park, Milton Road, Cambridge CB4 0GW, UK. Member of the Napp Pharmaceutical Group. Further information is available from: Mundipharma Pharmaceuticals Limited, Millbank House, Arkle Road, Sandyford, Dublin 18, Tel: +353 (0)1 2063800. Date of preparation: August 2011. References: 1. Nadstawek J, et al. Int J Clin Pract, August 2008; 62 (8): 1159–1167. 2. Simpson K, Leyendecker P, Hopp M, et al. Fixed-ratio combination oxycodone/naloxone compared with oxycodone alone for the relief of opioid-induced constipation in moderate-tosevere noncancer pain. Curr Med Res Opin 2008;24(12):3503-3512. 11144TRG

Adverse events should be reported to Mundipharma Pharmaceuticals Limited on 1800 991830

® The Napp device (logo) is a Registered Trade Mark. ® Targin is a Registered Trade Mark. © 2011-2012 Napp Pharmaceuticals Limited.

­ educed­risk­of­ r opioid-induced­ constipation

➞ ➞

Targin® provides pain relief that is as effective as oxycodone alone2 Targin® reduces the risk of opioid-induced constipation when compared to oxycodone alone2 Targin® is indicated for severe pain, which can be adequately managed only with opioid analgesics. The opioid antagonist naloxone is added to counteract opioid-induced constipation by blocking the action of oxycodone at opioid receptors locally in the gut.

16 Report

regime for two years, after which the pharmaceutical company will cover any additional costs for as long the patient requires treatment. Such schemes, whilst useful in terms of short term budget control, do not offer effective direction or long term incentivisation to industry endeavour however, and contribute to a certain amount of uncertainty about the long term stability of approaches to new medicines access. Risk-sharing based on outcome Risk-sharing based on outcome, builds on both the principle of risk-sharing, as well as the now established processes of health technology assessment, and additionally, concepts of personalised and evidence based medicine. Early leaders in this area include Italy, France, Germany and the United Kingdom. In Italy, schemes exist where the manufacturer pays back 50% of the costs for non-responder patients. In France, outcome based payment methods are underlined using a system known as ASMR (l'amélioration du service médical rendu) which scores new medicines into 6 categories of relative therapeutic advance (I being “Major Therapeutic Advance” and VI being “Negative opinion – not reimbursed). Germany has used value based pricing effectively for existing products such as statins and Proton Pump Inhibitors. Meanwhile, in the UK, the introduction of a system of “value based pricing” was set out as an explicit commitment in the formation of the current coalition Government’s agreement of policies immediately following the 2010 General Election. In theory, value based pricing means the prices paid for medicinal products will better reflect the value they provide to patients, and indeed, to society more widely - taking in to consideration matters

Issue 7 • HPN

such as reduced carer need for the patient. The systems proposed are also intended to balance incentive in favour of new treatments for rare disease and builds on the existing and established NICE methodologies of health technology assessment such as quality-adjusted lifeyears (QALYs). If successful the scheme could even serve to reduce perceptions of unfair industry profit. However, as with any pioneering scheme in an established system, there remain uncertainties about how the theory will convert in to practice. Measuring Quality of Life remains controversial – both in technical terms and morally. Further clarity remains to be provided about the levels of administrative burden to be associated with such a pricing

Meanwhile, all of these more recent developments in medicines reimbursement across countries has left some existing European legislation in the area looking out of date. A 1989 Directive covering the transparency of approach by EU Member States towards pricing of medicines has not been reformed or amended since its original initiation, with no reference contained, for example, to health technology assessment as a key part of the pricing process. With little direct legal competence for the European institutions in national health systems, the Transparency Directive’s main intentions are to support the internal market in relation to medicines by creating a framework to prevent any country operating a system of pricing that favours or disfavours

One interesting element of the shift is the part it may play in further developing the hospital pharmacists' role

scheme, and the transparency of results. Nor does the scheme necessarily guarantee cost savings to the payer. One interesting, and potentially under-discussed, element of the shift towards outcomebased methods of medicines reimbursement is the part it may play in further developing the hospital pharmacist’s roles in tasks such as robust monitoring of the difference in outcomes delivered by new medicines, ensuring effective counselling of patients in the use of new medicines, and the potential for a generally raised profile of the hospital pharmacists in era of heightened emphasise on pharmacoeconomics within the health system. Pan-European dimensions on pricing and revision of the medicines “Transparency Directive”

manufacturers according to their country of origin. Key to this has been the construction of timescales by which national authorities must give decisions on pricing of a new medicine following application by the manufacturer.

Reviewing the 1989 Directive, the European Commission belives that the existing deadlines are too generous and hold back the bringing to market of new medicines. In proposals launched in March 2012, the Commission suggested imposing stricter time limits for such decisions including: • 60 days from receipt of application (allowance if more information required to 120 days) • If a Health Technology Assessment is required, this deadline is extended to 90 days (180 days if more information

required) • 15 days for a generic product, where the price of the reference product has already been approved (30 days if more information required) To give teeth to the proposals, the new Directive will also establish a new body to rule on, and award, penalties for breach of time limits. Member States are also required to be more transparent about the criteria they use to make pricing decisions about medicines. The proposed Directive is currently being scrutinised in the European Parliament. Whether it can successfully negotiated through the Council of Ministers (representatives of national governments) without major alteration remains to be seen. Whilst the generic manufacturing industry has suggested its support for the Directive, others within the pharmaceutical industry counsel that guidelines on timescales for pricing decisions would be a more wise approach than inflexible legal measures. Many Governments have already expressed their concern. Moreover, strict timelines for pricing decisions may not sit well in a policy context of increasingly novel and bespoke arrangements being created for medicines reimbursement. In this way, the debate over the Transparency Directive nicely sums up the present scenario in relation to medicines reimbursement in Europe. In the race for innovative approaches to pricing, transparency may yet be a victim. The Transparency Directive, and other European current legislative initiatives of relevance to hospital pharmacists will be the subject of a Policy Workshop at the 18th Congress of the EAHP in Paris from 13 to 15 March 2013. Any Hospital Pharmacist in Europe can register to attend via www.eahp. eu

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18 Medication safety

Clinical pharmacist’s contribution to medication reconciliation on admission to hospital in Ireland the Irish setting: on discharge, medication non-reconciliation was identified in 50% of patients7. Non-reconciliations originating at admission frequently occurred due to the omission of a pre-admission medication but also occurred due to lapses in communication or documentation about changes made to a patient’s longstanding pre-admission medication. A challenge to medication reconciliation is identifying which medication the patient was actually using before they were admitted to hospital, as opposed to those medications prescribed or dispensed for the patient. This list, known as the gold standard pre-admission medication list (GSPAML), takes time and effort to collate8.

Top Mairead Galvin Bottom: Tamasine Grimes

Introduction Pharmacists have a responsibility to optimise patient safety during the medication use process. The vulnerability of patients due to medication mismanagement at transfer of care is well acknowledged1-5. Transfer of care occurs when the main duty of care changes from one clinician to another, for example when a patient is admitted to or discharged from hospital. A systematic review identified that onethird of patients experienced a medication history error on admission and over half of these errors were clinically significant6. There is evidence that this problem also exists in

Issue 7 • HPN

Medication reconciliation is widely recognized and mandated nationally and internationally as a tool for the prevention of medication misuse and consequent patient harm at points of transfer of care9-11. In the UK, comprehensive guidance clearly describes the admission medication reconciliation process. A series of three steps are outlined; namely, collecting, checking and communicating12. Each of these steps is comprised of several tasks. Some of these can be time-consuming and resource intensive and all are yet to be formally standardized in the Irish setting. In the UK, it is also recommended that the role of providing admission medication reconciliation be assigned to the pharmacy profession11. This recommendation is supported by evidence of the competency of the clinical pharmacist to elicit the most accurate medication history on admission compared to other professionals (nurses, doctors, pharmaceutical technicians) who also routinely perform this function13-15; and the cost effectiveness of employing clinical pharmacists for this purpose16. There is also evidence that improved patient outcomes result when medication

reconciliation forms part of a standardized inpatient clinical pharmacy service. A randomized controlled trial in Sweden showed a reduction of 49% and 80% respectively in emergency department visits and drugrelated re-admission rates in the group of patients who had received a comprehensive clinical pharmacist service compared to those who had not17. A pharmacist led integrated medicines management service, including medication reconciliation at admission and discharge and inpatient monitoring and counseling, resulted in a significant improvement in the quality of prescribing and reduction in both length of stay and readmission rates18,19. In the Netherlands, undertaking patient counselling at discharge in a group of patients who had received medication reconciliation on admission and discharge increased the scope for pharmacist intervention20. In Ireland, the Commission on Patient Safety and Quality Assurance recommended as a priority that medication reconciliation be provided to all patients at all transfer of care stages and the national “Acute Medicines Programme” recommends that pharmacists should provide this service at admission to hospital 10,21. Definitions Gold-standard pre-admission medication list (GSPAML): The most accurate list of medication the patient was actually taking or using prior to admission, including the name, dose, frequency and route of administration of each medication. Over-the-counter, herbal and “as-required” medicines were included. This was constructed according to the study protocol using as many potential sources as were available including but not limited to patient or carer interview, patient’s own drugs or own list of drugs, community pharmacist and

general practitioner records. The construction of the GSPAML is described in detail in a recent publication.8 Discrepancy: Any difference between the GSPAML and the admission medication prescription2.This included intentional and unintentional differences. Endorsement: The clarification by the clinical pharmacist of an ambiguous or incomplete prescription through the provision of additional written information to facilitate continuity of supply or administration. For example, the clarification of inhaler formulation when there are two devices available. Intervention: An action taken to resolve an apparently unintentional medication reconciliation discrepancy; including endorsement as defined above; written and/ or verbal communications to the prescriber detailing the discrepancy. For example, recognising a medication omission and suggesting addition to the admission medication prescription. Unresolved Unintentional Discrepancy: A medication reconciliation discrepancy subject to a clinical pharmacist’s intervention which was unresolved at 48 hours into the patients admission and confirmed verbally by the physician at that time as not intentional. Resolved Unintentional Discrepancy: A medication reconciliation discrepancy subject to a clinical pharmacist’s intervention which was resolved at 48 hours into the patients admission by the prescribing of the medication as per GSPAML Omission: The absence of a medication from the admission medication prescription that the patient had been using prior to admission and which should have continued on admission (i.e. the medication was part of the GSPAML)

19 Commission: The inclusion of a medication on the admission medication prescription which the patient had not been using prior to admission (i.e. the medication was not part of the GSPAML)

nursing and pharmacy staff were unaware of the exact nature of the study or the data collection period23. The data collection process, undertaken by the clinical pharmacists, is presented in Figure 1.

Aim The aim of this paper is to describe the contribution of the accident and emergency (A&E) based clinical pharmacist to medication reconciliation for adult patients on admission to acute hospital in Ireland and identify ways to further improve the process.

The following lists the outcome measures:

Method This was a prospective observational study undertaken in two acute teaching hospitals of Trinity College Dublin: Naas General Hospital (NGH) is a 243-bed general hospital serving a predominantly rural community; the Adelaide and Meath Hospital, incorporating the National Childrens Hospital (AMNCH) is a 500-bed tertiary referral centre serving a predominately urban population. The annual volume of inpatient discharges are approximately 10,000 and 25,000 from each respective site [in-house data]. Adults over the age of 18 years were eligible for inclusion in the study if they were admitted via A&E from a non-acute setting and reported the use of at least three regular medications prior to admission22. The following exclusion criteria were employed: absence of the patient from the ward at the time of data collection and unavailability of an interpreter to interview non-English speaking patients. Patients were randomly selected from a list of new admissions each morning during the study period. Data were collected at each study site by clinical pharmacists involved in the delivery of admission medication reconciliation. Ethics Committee approval for the study to proceed was obtained from the relevant committee at each study site. In NGH, the committee required that verbal patient consent be obtained, following completion of the medication history interview, for use of the patient’s data in the study, whilst this was not required by the AMNCH committee. Patients in NGH who could not provide verbal consent were therefore excluded. Data were collected between February and April 2009. In order to minimise reactive bias, medical, surgical,

1. Frequency of clinical pharmacist’s activities (analysis was performed using two units of measure: per patient and per medication) 2. Frequency and nature of unresolved unintentional discrepancies at 48 hours post admission 3. Potential for harm averted by clinical pharmacist input and consequent to unintentional unresolved discrepancies at 48 hours post admission. Measurement of inter-rater agreement regarding the medications to be included on the gold-standard pre-admission medication list (GSPAML) was undertaken across the two study sites during the pilot phase of data collection. Assessment of clinical significance Two random samples of inpatient episodes were selected; the first included only patients affected by an unresolved unintentional discrepancy and the second included those where all initial discrepancies were completely resolved at 48 hours. The potential for patient harm was assessed using a reliable and validated tool, which employs a visual analog scale (0-10: 0 represents no harm;10 represents death) 24. Six assessors individually assessed and scored each case, and a mean score was then calculated. Assessors were all practising clinicians and included medical consultants, hospital clinical pharmacists, general practitioners and community pharmacists. The mean score was categorised as minor harm (<3), moderate harm (3-7) or severe harm (>7).

Fig 1: The data collection process for medication reconciliation


Age (median, y) Median number of pre-admission medications Median number of co-morbidities Male Medical Care Patients transferred to another consultant post admission Hospital Naas AMNCH Presenting complaint per body system Cardiovascular Infections Gastro-intestinal Central nervous system Respiratory system Others Pre-admission source Self-referral GP referral Other MEDICATIONS Most common medications prescribed per BNF Chapter Cardiovascular system Central nervous system Gastro-intestinal system Respiratory system Endocrine system Infections

n (%)

70 (18-92) 9 (4-23) 3 (1-10) 73 (56.5) 113 (84.3) 43 (32.1) n (%) 52 (38.8) 82 (61.2) n (%) 47 (35.1) 31 (23.1) 20 (14.9) 14 (10.4) 6 (4.6) 16 (11.9) n (%) 61 (45.5) 48 (35.8) 25 (18.7) n(%) 576 (37.1) 270 (17.4) 180 (11.6) 119 (7.6) 114 (7.3) 110 (7.1)

Table 1: Characteristics of the study populations

Data were inputted and analysed Study Populations Inter-rater Agreement Admission Medication Reconciliation  Patien using SPSS (version 16). A total of 134 patients were There was agreement in Within of admission Descriptive statistics were used24 hours recruited to the initial studydiscrepancies and and identify onmedication admission name, dose, 1 to represent process andCollect patientGSPAML data were collected for 1556or unintentional Determine whether discrepancy intentional 130 frequency, formulation and route outcome measures. Associations The majority of available that discrepancy intentional Reconciled medications. a discrepancy as documentation 106 for 99 out of the 110 medications between categorical variables patients received care a a discrepancy as clinicallyfrom rationalised byassessed pharmacist 68 ( were examined using theReconciled chi(90%). Based on this, rather surgical Reconciled amedical discrepancy asthan resolved by pharmacistthe endorsement 12 square test. An a priori level of kappa co-efficient (ĸ=0.52) consultant, were self referred to Intervention to resolve an apparently unintentional discrepancy 122 significance of 0.05 was chosen. indicated moderate inter-rater A&E and just over half were male -A discrepancy also verbally communicated to physician 24 ( Results (Table 1). agreement. Within 48 hours of admission A discrepancy resolved by prescribing as per GSPAML A discrepancy resolved as physician documented change intentional Unresolved unintentional discrepancy

HPN • Issue 7

40 (2 2( 61 (

Central nervous system Gastro-intestinal system Respiratory system Endocrine system Infections

20 Medication safety

270 (17.4) 180 (11.6) 119 (7.6) 114 (7.3) 110 (7.1)

Admission Medication Reconciliation 

Patient n (%)* 

Medication n (%) 

Within 24 hours of admission Collect GSPAML and identify initial discrepancies on admission 134 Determine whether discrepancy intentional or unintentional 130 (97%) Reconciled a discrepancy as documentation available that discrepancy intentional 106 (79%) Reconciled a discrepancy as clinically rationalised by pharmacist 68 (51%) Reconciled a discrepancy as resolved by pharmacist endorsement 12 (9%) Intervention to resolve an apparently unintentional discrepancy 122 (91%) -A discrepancy also verbally communicated to physician 24 (19%) Within 48 hours of admission A discrepancy resolved by prescribing as per GSPAML 40 (29.8%) A discrepancy resolved as physician documented change intentional 2 (1%) Unresolved unintentional discrepancy 61 (46%) DENOMINATOR 134 * Patients could experience more than one discrepancy; have documentation relating to only one discrepancy etc.

Clinical pharmacist activity

Table 2: Admission Medication Reconciliation per Patient and per Medication   Identifying discrepancies   between GSPAML and admission medication

The medications prescribed on admission for   four of the 134 patients surveyed were identical to their GSPAML, whilst for the remainder (97%) at least one initial discrepancy was identified. The range of initial discrepancies was 0-24. Determining whether the discrepancy was intentional or unintentional For the majority of patients (81.5%), the prescriber documented in the healthcare record that at least one medication change was intentional. Documentation supporting a discrepancy was more likely when the change in therapy related to a medication indicated for the management of the presenting complaint (chisquare (1)=3.193 p<0.05) than for medications used to manage other conditions. Documentation justifying all initial discrepancies was made in the healthcare record for five (3.8%) patients of the 134 surveyed. The majority of patients (n=115; 85.8%) experienced at least one change to their GSPAML which could not be rationalized by the clinical pharmacist. For nine patients (6.7%) involving eleven medications (0.7%) the changes were documented by the team but were not regarded as rational and so necessitated clinical pharmacist intervention. Most related to medication management issues for example use of antibiotics outside the hospital’s empiric antibiotic guidelines and inappropriate prescription of low molecular weight heparins.

Issue 7 • HPN

Resolving apparently unintentional discrepancies The remaining discrepancies (n=467) were judged to be unintentional and merited clinical pharmacist intervention, as follows. Endorsement A minority of the interventions (n=20; 1% of meds involving 9% of patients) took the form of endorsement of the admission prescription. Over three-quarters of endorsements related to the clarification of active ingredients of combination products or formulation type including extended release and enteric coated preparations. Communication of apparently unintentional discrepancies to the team to facilitate resolution For the majority (91%) of patients surveyed, there was no explanation in the patient’s healthcare record for the discrepancies identified between the GSPAML and the medications prescribed on admission. These discrepancies were apparently neither intentional nor rational, thus necessitating clinical pharmacist intervention. In total, there were 447 (29% of meds surveyed) interventions, a mean of 3.3 per patient surveyed. The majority related to medication omission (65.3%), incorrect dose or frequency (22.5%) or medication commission (8.9%). In all cases, the intervention was conveyed to the prescriber by documentation in the patient’s healthcare record detailing the nature of the identified discrepancy with a request for appropriate remedial action to resolve the discrepancy. The discrepancy was also verbally communicated to the team, particularly where it was considered to have the potential to cause serious patient harm. In less urgent cases, verbal communication

1, 556 916 (59%) 323 (21%) 154 (9.9%) 20 (1.2%) 447 (29%) 305 (20%) 237 (15.2%) 8 (0.5%) 152 (9.7%) 1, 556

was opportunistically made to the prescriber if present at the time the discrepancy was identified. Verbal communication occurred for over a quarter (n=105) of the apparently unintentional discrepancies. Discrepancies resolved at 48 hours Over half (54% n=244) of the clinical pharmacists’ interventions were accepted at 48 hours, thereby resolving the discrepancy. In the majority of cases resolution was by means of the admission medication prescription reverting to the original pre-admission regimen. Of the 52 patients who experienced a clinical pharmacist intervention, two had discrepancies resolved at 48 hours by the prescriber documenting that the change was intentional. Apparently unintentional discrepancies were more likely to be resolved when also verbally communicated to the team at the time of identification compared to those discrepancies which were not also verbally communicated to the team (chi-square (1)=30.029 p<0.05) Nature and number of nonreconciliations at 48 hours Less than half of patients (46%) surveyed experienced an unresolved unintentional discrepancy at 48 hours into admission. For most of these (89%), the medication involved was not indicated for nor used in the management of the patient’s presenting complaint. Medication omission accounted for almost two-thirds (62.5%) of these, followed by dose/ frequency errors (24.3%) and commissions (9.9%). The remaining unresolved unintentional discrepancies comprised of route issues and substitution or formulary issues. A statistically significant correlation between the number

Table 2: Admission Medication Reconciliation per Patient and per Medication

of pre-admission medications the patient used and the number of unintentional discrepancies was identified (rho (134)= 0.224; r2=5% p<0.05) Clinical significance The majority of the unresolved unintentional discrepancies that were assessed for clinical significance (n=22) were judged to have the potential to cause minor harm (54.5%). The remaining cases were judged to have the potential to result in moderate harm (45.5%). The clinical significance of the resolved unintentional discrepancies (n=20) were judged to risk the patient experiencing moderate harm (70%) and minor harm (30%) had these unintentional discrepancies not been resolved. Discussion This study demonstrates the potential contribution that clinical pharmacists can make to medication management on admission to acute hospital care in Ireland, consistent with international literature25,26. Furthermore it provides a measure of the demand for such a service: almost all of the patients surveyed experienced a change to their GSPAML. In some instances, discrepancies were immediately resolved once identified by the clinical pharmacist. However, the majority of pharmacist interventions involved communication about and discussion with the physician regarding apparently unintentional discrepancies. The most common type of discrepancy was omission of a pre-admission medication, followed by dose & frequency issues and commissions, consistent with research in other settings8,27. The clinical significance of most unresolved unintentional discrepancies was assessed as low. This measure has not been routinely reported. This is the first published study in the Irish setting that details how a clinical pharmacist can contribute to medication management on admission to hospital, including provision of a medication reconciliation

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22 Medication safety service. Data were collected in two Irish hospitals to enhance the external validity of the findings therefore the results are likely generalisable to hospitals providing acute care for adult surgical and medical admissions in Ireland. The findings provide evidence to support clinical pharmacist involvement in medication management on admission. Future research can now build on this foundation. A limitation of the study is the exclusion of patients without the capacity to give consent from the NGH cohort (n=4). This removed a potentially vulnerable group of patients from the population, as such patients have been identified as susceptible to medication reconciliation errors11. It is important that Ethics Committees balance the benefits of obtaining consent for the use of non-identifiable patient data in research against the cost of excluding a group of vulnerable patients from a study which might uncover ways to improve their safety. However, inclusion of such patients within the AMNCH sample allowed representation of this group in the overall sample. The rigorous methodology employed strengthened the study: Firstly, there was moderate agreement between the investigators at each site compiling the GSPAML. This ensured that the process undertaken at each site was consistent and the two investigators were following a consistent method of developing the GSPAML. This formed the first step of medication reconciliation and ensures a reliable process to be employed by other clinical pharmacists undertaking this role in the future. Secondly, the exact purpose of this study was not disclosed to medical, surgical, pharmacy and nursing staff, thereby minimizing reactive bias. Thirdly, the intentional status of unresolved discrepancies was confirmed by the physician at 48-hours, as recommended in previous medication reconciliation studies6. The finding that almost half of the patients surveyed continued to experience an unintentional discrepancy 24 hours after the clinical pharmacistâ&#x20AC;&#x2122;s intervention indicates the need to review the process of medication management on admission. The majority of the unresolved

Issue 7 â&#x20AC;˘ HPN

unintentional discrepancies were judged to be of low clinical significance and were unrelated to the presenting complaint. The resolved unintentional discrepancies were assessed as having greater potential to result in harm, which is suggestive that the involvement of the clinical pharmacist in admission medication management may be an effective barrier to medication related morbidity and this should be investigated using a comparative study. For the less clinically significant discrepancies, future studies should investigate the benefit of the pharmacist resolving the discrepancy and communicating the change to the prescriber, rather than relying solely on the prescriber to implement the suggested change. Furthermore as the mode of communication (verbal or written) appeared to influence whether a discrepancy was resolved or not, consideration should be given to testing this as a means to improviwng outcomes in the overall medicines management process. Pharmacist participation in post-admission ward rounds may provide a forum for communication with physicians which facilitates timely resolution of medicationrelated issues. Ultimately, medication reconciliation is a resource intensive process and research to establish how best to deliver this with limited resources is warranted. Conclusion Clinical pharmacists contribute positively to medication reconciliation on admission to hospital in Ireland and they should be engaged to deliver this service within 24 hours of admission. Funding

References 1. Pippins JR, Gandhi TK, Hamann C, Ndumele CD, Labonville SA, Diedrichsen EK et al. Classifying and predicting errors of inpatient medication reconciliation. J Gen Intern Med. 2008;23(9):1414-22 2. Cornish PL, Knowles SR, Marchesano R, Tam V, Shadowitz S, Juurlink DN et al. Unintended medication discrepancies at the time of hospital admission. Arch Intern Med. 2005;165:424-429 3. Vira T, Colquhoun M, Etchells E. Reconcilable differences: correcting medication errors at hospital admission and discharge. Qual. Saf. Health Care; 2006;15:122-126 4. Rees S, Thomas P, Shetty A, Makinde K . Drug history errors in the acute medical assessment unit quantified by use of the NPSA classification. Pharm J. 2007;279:469-471 5. Wong JD, Bajcar JM, Wong GG, Alibhai SMH, Huh J-H, Cesta A et al. Medication reconciliation at hospital discharge: evaluating discrepancies. Ann Pharmacother 2008;42:1373-9 6. Tam VC, Knowles SR, Cornish PL, Fine N, Marchesano R, Etchells EE. Frequency, type and clinical importance of medication history errors at admission to hospital: a systematic review. CMAJ. 2005;173(5):510-5 7. Grimes TC, Duggan CA, Delaney TP, Graham IM, Conlon KC, Deasy E at al. Medication details documented on hospital discharge: cross sectional observational study of factors associated with medication non-reconciliation. Br J Clin Pharmacol 2011;71(3):449-457 8. Fitzsimons M, Grimes T, and Galvin M. Sources of pre-admission medication information: observational study of accuracy and availability. International Journal of Pharmacy Practice. 2011;19(6):408-416 9. Institute for Healthcare Improvement. Accuracy at Every Step: the Challenge of Medication Reconciliation. Cambridge MA: Institute of Healthcare Improvement, 2006 10. Madden D. Building a Culture of Patient Safety. Report of the Commission on Patient Safety and Quality Assurance (IE). Department of Health, Ireland. 2008 11. National Institute for Health and Clinical Excellence/National Patient Safety Agency. Technical patient safety solutions for medicines reconciliation on admission of adults to hospitals. PSG001 December 2007 12. National Prescribing Centre (UK). Medicines Reconciliation: A Guide to Implementation. Good practice guide, 5 min guides, March 2008 13. Campbell F, Karnon J, Czoski C, Jones R. A systematic review of the effectiveness and cost-effectiveness of interventions aimed at preventing medication errors (medicines reconciliation) at hospital admission. The University of Sheffield, School of Health and Related Research. (ScHARR), 2007. 14. de Winter S, Spriet R, Indevuyst C, Vanbrabant P, Desruelles D, Sabbe M et al. Pharmacist-versus-physician-acquired medication history: a prospective study at the emergency department. Qual Saf Health Care 2010; 19(5):371-5 15. Nester TM, Hale LS. Effectiveness of a pharmacist-acquired medication history in promoting patient safety. Am J Health Syst Pharm 2002;59:2221-2225 16. Karnon J, Campbell F, Czoski C. Model-based cost-effectiveness analysis of interventions aimed at preventing medication error at hospital admission (medicines reconciliation). J Eval Clin Pract. 2009;15:299-306 17. Gillespie U, Alassaad A, Henrohn D, et al. A comprehensive pharmacist intervention to reduce morbidity in patients 80 years or older: a randomised controlled trial. Arch Intern Med 2009; 169:894-900 18. Burnett KM, Scott M, Fleming GF, Clark CM, McElnay JC. Effects of an integrated medicines management program on medication appropriateness in hospitalised patients. Am J Health Syst Pharm. 2009;66:854-9 19. Scullin C, Scott MG, Hogg A et al. An innovative approach to integrated medicines management. J Eval Clin Pract 2007;13:781-8 20. Karapinar-Carkit F, Borgsteede S, Zoer J et al. Effect of medication reconciliation with and without patient counselling on the number of pharmaceutical interventions among patients discharged from the hospital. Ann Pharmacother 2009;43:1001-10


21. Royal College of Physicians of Ireland/ Irish Association of Directors of Nursing and Midwifery/ Therapy Professions Committee/ Quality and Clinical Care Directorate, Health Service Executive. Report of the National Acute Medicine Programme 2010 [internet] accessed 5th October 2011 services/Publications/services/Hospitals/AMP.pdf


22. Bolas H, Brookes K, Scott M et al. Evaluation of a hospital-based community liaison pharmacy service in Northern Ireland. Pharm World Sci. 2004;26(2):114-120

None Conflict of Interest

The work of all the healthcare professionals who undertook the clinical significance testing is greatly appreciated.

23. Bowling A. Research Methods in Health: Investigating Health and Health Services. 2002. 2nd Ed. Buckingham. Open University Press. 24. Dean BS, Barber ND. A validated reliable method of scoring the severity of medication errors. Am J Health-Syst Pharm. 1999;56:57-62 25. Vasileff HM, Whitten LE, Pink JA et al. The effect on medication errors of pharmacists charting medication in an emergency department. Pharm World Sci 2009;31:373-9 26. Cohen V, Jellinek SP, Hatch A, Motov S. Effect of clinical pharmacists on care in the emergency department: a systematic review. Am J Health Syst Pharm 2009;66(15):1353-61 27. Bracey G, Miller G, Dean B et al. The contribution of a pharmacy admissions service to patient care. Clin Med. 2008;8(1):53-7


Changes in medication management are key, hospital pharmacists hear at Dublin conference The future of hospital pharmacy in Ireland was the topic of a recent conference held in the Royal College of Physicians, Dublin. Issues on the agenda included the significant issues facing pharmacists right across Europe in complying with variation in regulations and co-ordinated approaches to medication management. The conference was held in conjunction with the Hospital Pharmacists Association of Ireland and Baxter Healthcare. “Benchmarking Hospital Pharmacy” Prof. Fitzpatrick - Clinical Director of Pharmacy Royal Wolverhampton Hospitals NHS Trust & Professor of Pharmacy Wolverhampton University Professor Fitzpatrick showcased a benchmarking approach for comparison of staffing and medicines use across NHS Hospitals. This powerful approach showed significant variation in practice across hospital Trusts. Prof. Fitzpatrick emphasised that standardised systems across Pharmacy at Hospital level allows extremely powerful comparison and benchmarking of practice between Hospitals. • Last 3 years Hospital medicines spend increased 12%, Primary Care medicines spend increased 1.8% • Hospital medicines now represent 31% of NHS medicine bill – £12.5Bn • The number of medicines per head of population in primary care has risen year on year since the early nineties particularly in >60’s • A study of Hospital Pharmacy staffing levels undertaken a few years ago showed significant regional variation even after taking into account activity in individual hospitals. • Mental Health Trusts have much higher proportion of Pharmacist/admission (patient length of stay longer) • There are difficulties in obtaining accurate up to

Professor Raymond Fitzpatrick

date information on hospital medicines use since hospital pharmacies as use different IT systems and the varying size, activity and case mix of hospitals. • Where usage data can be obtained it can be extremely powerful in changing practice, for example encouraging all hospitals to use a generic PPI rather than a branded version which had been ‘loss led’ into the hospital. • Using retrospective data he investigated the use of short acting inhaled anaesthetics across hospitals in England.

As these are more expensive than Isoflurane they should be reserved for short cases if they are to be used cost effectively. However, his analysis demonstrated a huge variation in use across hospitals and no correlation between use and day case activity. • He described the development of a new software system ‘Define’ which pulls data from hospital pharmacy computer systems and posts this to a central NHS server to create a live NHS database of hospitals medicines use. • He showed examples of using

this database in practice including how one colleague had dramatically changed their use of short acting inhaled anaesthetics as a result of having this comparative data. He was also able to reassure his Trust that they were effectively managing the use of quinolone antibiotics which are known to predispose patient to Clostridium Difficle. • Once the software is used in a large number of hospitals the emphasis will be to develop good metrics to compare hospitals usage and help standardise practice or at least change practice for outliers

HPN • Issue 7

24 News “Lean working in Pharmacy” Michelle Rowe – Aseptics/ Clinical Trial Manager, Christie Hospital NHS Trust Ms. Rowe highlighted how implementation of a LEAN approach from the automotive industry enabled the successful implementation of a robotic dispensing system in Pharmacy in the Christie Hospital. This resulted in greater satisfaction with work practices for the Pharmacy team but more importantly for patients too, as the ‘script dispensing times have been dramatically reduced. • Largest Phase 1 Clinical Trial Unit in the EU – 3.2m population • 40k patients per year for Hospital • 12.5k new patients per year • Have focused on implementing

a “lean” methodology towards process redesign in Pharmacy activity – dispensing in particular • Managers went to Toyota to see this in action • Patients could not be sure how long ‘script dispensing would take, however there is a Trust maximum 20 mins. waiting time for patients, but large complex‘scripts could take a long time • Simple ‘scripts weren’t always accelerated and could queue behind more complicated ones for long time • Big frustration for patients and staff

Michelle Rowe

• Introduced an automated queuing system for script dispensing

• New system involved automated robot picking and dispensing and the dispensary process flow was changed to be streamlined

• Previously manual system process flow was utterly chaotic

A co-ordinated approach to improving medication safety Tim Delaney National programme lead – Medication Safety, Quality and Clinical Care Directorate, HSE

Tim Delaney

“The European perspective on developing compounding solutions” Richard Dickson – Marketing Manager Pharmacy Services, Baxter EMEA Richard gave a broad ranging talk which highlighted the significant issues facing Pharmacists across Europe in complying with the substantial

Issue 7 • HPN

Given current ways of working with paper-based prescribing and only telepohic communications to confirm medication profiles, I calculated it would take almost 400 pharmacists to carry out medication reconcilation at admission and dischage from the acute hospitals. This is not efficient which is why we need to change how we manage medications in the following ways:.

variation in regulations surrounding Compounding. Medicine safety as a topic is the focus of intense research currently and all of the papers Richard referred to were published within the 3 months preceding the meeting. On a closing note Richard put forward the view that the Compounding and Manufacturing regulations are likely to harmonise in the coming years as practice is

• Reduced script waiting times

• By implementing computerised prescribing at discharge from hospitals with prescription databases that can be viewed by health professionals who have permission, we can facilitate efficient medication reocncilation. Even then we will need more pharmacists, but as I pointed out based on extrapolating the evidence from the Cork STOPP/START studies, halving medicationrelated admissions in the elderly would save €30 million per year, far more than the cost of additional pharmacists. • Right now we have a large national database of patient medication profiles derived from the returns community pharmacies make to the Primary Care Reimbursement

standardised and improved across Europe.

Richard Dickson

enabled the 20 mins. target to be met. • Overall targets set were exceeded in a short timeframe • Dec. 2012 moving to 3rd party dispensing service by Boots

Service under the various schemes (PCRS, LTI, DPS). However at the moment this database is used only for reimbursement when it has potential to be used to make medication reconcilation more efficient. Before this could be done, we needed to evauate the database for accuracy compared to other sources of information. [We have done this and in a paper that has been accepted for publication in the Journal of Clinical Pharmacy and Therapeutics we conclude that "The HSE-PCRS database is a relatively accurate, available and contemporaneous source of medication history information and could support acute hospital medication reconciliation."

CPD 2: Venous Thromboembolism

Prof James O’Donnell

Biography - Prof James O’Donnell PhD, MD, FRCPI, PRCPath, Professor of Haematology and Director Haemostasis Research Group, National Centre for Coagulation Disorders, Trinity College Dublin, Ireland James O’Donnell obtained his MB from Trinity College Dublin, and completed his clinical haematology training in the Hammersmith and Royal Free Hospitals in London. He obtained a prestigious Medical Research Council Training Fellowship in 1998, and was awarded his PhD by Imperial College London in 2001. Prior to returning to Dublin, James spent three years as a Senior Lecturer and Principal Investigator in Imperial College, during which time he was funded through a Clinician Scientist award from the British Heart Foundation. His principal research interests include the role of carbohydrate structures in determining the biological activity of coagulation proteins; the molecular mechanisms through which coagulation is regulated at the feto-maternal interface; and the molecular basis of constitutional thrombophilia. Following his return to Ireland in 2005, he has since became the first clinician scientist to receive the prestigious Science Foundation Ireland President of Ireland Young Investigator award. In addition, he is Director of the large Haemostasis Research group in the Institute of Molecular Medicine in Trinity College. This group has already been successful in obtaining in excess of €5M in peer-reviewed grant awards over the past five years. Prof O’Donnell has more than 70 peerreviewed publications in high impact journals, (including 5 papers in Blood and 3 papers in the Journal of Biological Chemistry) and has given a series of invited presentations at leading international meetings including the American Society for Hematology and the ISTH congresses.

60 Second Summary

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

Population studies suggest that the annual incidence of VTE (deep vein thrombosis (DVT) and/or pulmonary embolism (PE)) is in the order of one in 1000 (0.1%) of the adult population [1]. It is well recognised that VTE is associated with significant mortality. Indeed previous studies have estimated that at least 25,000 deaths per annum are attributable to PE in the UK alone [2].

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.

The therapeutic options available for the prevention of hospital-acquired VTE have developed rapidly in recent years. In particular, a number of novel oral anticoagulants (NOACs) have been developed. A number of inherited and acquired risk factors for the development of hospitalacquired VTE have been defined. These include constitutional thrombophilias, pregnancy, malignancy and surgery. In particular, it is well recognised that major orthopaedic surgery is associated with a marked increased risk of VTE. With the emergence of the NOACs, major changes in clinical practise are likely to emerge in the coming years. Both direct thrombin and factor Xa inhibitors show great promise. However it is critical to appreciate that the different commercial products have significant differences with respect to their individual pharmacokinetic and pharmacodynamics properties.

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 Pfizer Healthcare Ireland. Copies can be downloaded from www. Disclaimer: All material published is copyright, no part of this can be used in any other publication without permission of the publishers and author. Pfizer Healthcare Ireland has no editorial oversight of the CPD programmes included in these modules.

Hospital acquired venous thromboembolism constitutes a major health burden Venous thromboembolism (VTE) constitutes a major health problem and is associated with significant mortality and morbidity. Population studies suggest that the annual incidence of VTE (deep vein thrombosis (DVT) and/or pulmonary embolism (PE)) is in the order of one in 1000 (0.1%) of the adult population [1]. It is well recognised that VTE is associated with significant mortality. Indeed previous studies have estimated that at least 25,000 deaths per annum are attributable to PE in the UK alone [2]. Consequently, overall deaths due to VTE are approximately five times greater than the combined total of deaths from breast cancer, acquired immunodeficiency syndrome and road traffic accidents. Approximately half

of all fatal PE cases occur in hospital [3]. Moreover, postmortem analyses have shown that in-patient PE is directly responsible for 10% of all hospital deaths [4]. Furthermore, PE also represents the commonest cause of maternal death during pregnancy in the developed world. In addition to this significant mortality, VTE is also associated with significant long-term morbidity in the form of post-thrombotic or postphlebitic syndrome. Despite the significant mortality and morbidity associated with hospital-acquired VTE, audits have consistently found that the use of thromboprophylaxis in hospital in-patients remains sub-optimal [5]. This important issue was highlighted in a

systematic review by the US Agency for Healthcare Quality and Research that ranked PE as the most common preventable cause of hospital death [6]. For many years, anticoagulation with heparin and/or warfarin have been established as the treatment of choice for the prevention of VTE. Unfractionated heparin (UFH) and low molecular weight heparins (LMWH) require parenteral administration and exert their anticoagulant effect indirectly by enhancing plasma antithrombin. In contrast, warfarin and other coumarin anticoagulants function as vitamin K antagonists. Although warfarin therapy is administered orally, it has a number of clinically important limitations. In particular, a clinically significant anticoagulant effect

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CPD 2: Venous Thromboembolism

New oral anticoagulants XI



VIIIa Pl Ca 2+

Factor Xa inhibitors - Rivaroxaban - Apixaban

Factor Xa





Direct thrombin inhibitors - Dabigatran


Figure 1

is not observed until several days following the initiation of warfarin therapy. Consequently, combined administration of both LMWH and warfarin is necessary until the INR has reached the target therapeutic range (INR≥2 for two consecutive days).

pharmacodynamics properties of each of the different commercial available NOACs is beyond the scope of this brief review, some of the important properties are outlined below.

Novel oral anticoagulant therapies and VTE prophylaxis

Apixaban is a new oral anticoagulant that specifically inhibits procoagulant factor Xa. Clinical studies have shown that apixaban is rapidly absorbed with an absolute bioavailability of approximately 50%. Absorption is not influenced by food intake, and peak plasma anticoagulant effects are reached 3-4 hours after oral administration. Unlike warfarin, clinical studies have demonstrated that apixaban has predictable pharmacokinetic and pharmacodynamic profiles. Consequently, apixaban can be given at fixed doses without the need for regular coagulation monitoring in most patients. In terms of clearance, apixaban has multiple routes of elimination plasma and has a plasma half-life of approximately 12-14 hours. It is metabolised in the liver in a cytochrome P450-dependent manner. In addition, 27% of the drug is eliminated unchanged by the kidneys. Consequently, apixiban therapy is not recommended

The therapeutic options available for the prevention of hospital-acquired VTE have developed rapidly in recent years. In particular, a number of novel oral anticoagulants (NOACs) have been developed. These include the direct factor Xa inhibitors (e.g. Rivaroxiban and Apixiban) and direct thrombin inhibitors (e.g. Dabigatran) (Figure 1). Unlike warfarin, these NOACs have predictable pharmacokinetics so that routine monitoring is not required. In addition, these agents are fast-acting so that overlapping cover with LMWH at initiation is not necessary. Nevertheless, it is important to emphasise that there a number of important differences between the NOACs that have direct importance in relation to their use in clinical practise. Although a comprehensive review of the pharmacokinetic and

Apixaban (Eliquis )

in patients with severe hepatic impairment, or in patients with creatinine clearance < 15ml/ min. Moreover, apixiban is not recommended in patients receiving concomitant treatment with inhibitors of cytochrome P450 and P-glycoprotein (e.g. keatconazole, itraconazole, voriconazole, ritonavir). Rivaroxaban (Xarelto®) Rivaroxaban is another oral anticoagulant that is a highly selective direct factor Xa inhibitor. Like apixaban, rivaroxaban is well absorbed, with bioavailability of 60-80% and reaches peak plasma concentrations within 2-4 hours following oral administration. Rivaroxaban also demonstrates predictable pharmacokinetic and pharmacodynamic properties, and therefore can be administered at fixed doses without the need for regular coagulation monitoring in most patients. With respect to clearance, one third of rivaroxaban is eliminated unchanged by the kidneys. The remaining two thirds is metabolised mainly by cytochrome P450-mediated metabolism within the liver. The terminal half-life of rivaroxaban

is approximately 5-9 hours in young individuals with normal renal and hepatic function. However some anticoagulant effect remains detectable for up to 24 hours, so that oncedaily dosing is feasible. Similar to apixaban, rivaroxaban is not recommended in patients with creatinine clearance < 15ml/min, and should be used with caution in patients with creatinine clearance 15 – 29ml/min. Furthermore, again in keeping with apixaban, concomitant use of potent inhibitors of cytochrome P450 and P-glycoprotein (e.g. keatconazole, itraconazole, voriconazole, ritonavir) should be avoided as these agents significantly increase plasma rivaroxaban levels and consequent bleeding risk. Dabigatran etexilate (Pradaxa®) Dabigatran etexilate is an orally available synthetic small molecule direct thrombin inhibitor. It is a prodrug that is rapidly converted into the active metabolite dabigatran which has a high affinity for thrombin. The bioavailability of dabigatran is low (approximately 6.5%). Moreover, dabigatran absorption is markedly influenced by pH. Consequently, the low bioavailability is further reduced in the presence of proton pump inhibitors. Peak plasma dabigatran concentrations are achieved within 2-3 hours after oral administration, and the plasma half-life has been estimated as ranging between 12-14 hours, which enables once-daily dosing. Dabigatran clearance is primarily mediated via the kidneys, with 85% being excreted unchanged in the urine. Consequently, dabigatran treatment is contraindicated in patients with creatinine clearance < 30ml/min. Moreover, phase I studies suggested that the exposure (area under

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CPD 2: Venous Thromboembolism

curve or AUC) following the oral administration of dabigatran was approximately 2.7-fold higher in individuals with even moderate renal insufficiency (creatinine clearance 30-50ml/min). NOACs and orthopaedic surgery A number of inherited and acquired risk factors for the development of hospitalacquired VTE have been defined. These include constitutional thrombophilias, pregnancy, malignancy and surgery. In particular, it is well recognised that major orthopaedic surgery is associated with a marked increased risk of VTE. For example, post-operative VTE has been reported in 50-70% of patients undergoing elective hip- replacement (THR) or total knee replacement (TKR) who do not receive appropriate thromboprophylaxis. As a result, international consensus guidelines recommend that thromboprophylaxis be used routinely in this cohort of patients. Until recently, subcutaneous LMWH (e.g. enoxaparin or tinzaparin) has been used widely regarded as constituting optimal thrombopropyhylaxis following elective major orthopaedic surgery. Importantly however, emerging data from a number of large prospective randomised studies has suggested that the oral administration of the NOACs may also have a role to play in this context. In particular, use of oral direct anti-Xa inhibitors has been reported to offer a number of therapeutic benefits. Given the fact that extended duration thromboprophylaxis treatment is recommended after both TKR and THR (typically 2 weeks and 5 weeks respectively), the potential benefits to the patient from using an oral rather than subcutaneous treatment regimen are readily apparent.

[1] Apixaban in major elective orthopaedic surgery The efficacy and safety of apixaban thromboprophylaxis following major elective orthopaedic surgery has been investigated in a number of large randomised prospective trials. In the ADVANCE-1 and ADVANCE-2 trials, apixaban treatment was compared to standard enoxaparin thromboprophylaxis regimens. In ADVANCE-2, 3057 patients undergoing elective TKR were randomised to receive oral apixaban 2.5mg twice daily or subcutaneous enoxaparin 40mg once daily [7]. Apixaban therapy was initiated 12-24 hours after wound closure, whilst the enoxaparin was started 12 hours before surgery. Both treatment regimens were continued for 10-14 days post-operatively. The primary outcome measure was the composite of asymptomatic and symptomatic DVT, non-fatal PE, and all-cause death during treatment. This primary outcome was recorded in 15% of patients on apixiban compared to 24% of those on enoxaparin, suggesting that the apixaban regimen

was more efficacious (relative risk 0.62; 95% CI 0.51-0.74; p<0.0001). Moreover, the risk of bleeding was similar in both patient cohorts, with major bleeding observed in 4% of patients on apixaban compared to 5% of those on enoxaparin. Similarly, in the ADVANCE-3 trial, 5407 patients undergoing elective THR were randomised to receive either apixaban (2.5mg orally twice daily commenced 12 to 24 hours after closure of the surgical wound) or enoxaparin (40mg subcutaneously once daily initiated 12 hours before surgery) [8]. Both prophylaxis regimens were continued for 35 days after surgery. A total of 1949 patients in the apixaban group and 1917 patients in the enoxaparin group were evaluated for the same primary outcome measure as in ADVANCE-2. The primary efficacy outcome occurred in 1.4% of patients in the apixaban group compared to 3.9% of patients in the enoxaparin cohort (relative risk 0.36; 95% CI 0.22-0.54; p<0.001). These data suggest that apixaban thromboprophylaxis

is associated with a statistically significant lower rate of VTE compared to standard enoxaparin therapy. In addition, similar rates of major and clinically significant bleeding complications were observed in both the apixaban and enoxaparin cohorts (4.8% versus 5.0% respectively). Cumulatively, a total of four randomised controlled trials involving more than 14,000 patients have addressed the question regarding the clinical efficacy of oral apixaban thromboprophylaxis for elective major orthopaedic surgery. On the basis of these data, a recent meta-analysis concluded that apixaban was both more effective, and had a similar safety profile, compared to the standard enoxaparin regimen for thrombopropylaxis following THR and TKR [9]. [2] Rivaroxaban in major elective orthopaedic surgery The efficacy and safety of rivaroxaban treatment compared to LMWH thromboprophylaxis

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CPD 2: Venous Thromboembolism REFERENCES [1] White RH. The epidemiology of venous thromboembolism. Circulation. 2003 Jun 17;107(23 Suppl 1):I4-8. [2] Hunt BJ. The prevention of hospital-acquired venous thromboembolism in the United Kingdom. Br J Haematol. 2009 Mar;144(5):642-52. [3] Spencer FA, Lessard D, Emery C, Reed G, Goldberg RJ. Venous thromboembolism in the outpatient setting. Arch Intern Med. 2007 Jul 23;167(14):1471-5. [4] Stein PD, Henry JW. Prevalence of acute pulmonary embolism among patients in a general hospital and at autopsy. Chest. 1995 Oct;108(4):978-81. [5] Hunt BJ. Awareness and politics of venous thromboembolism in the United kingdom. Arterioscler Thromb Vasc Biol. 2008 Mar;28(3):398-9.

has also been assessed in patients undergoing major orthopaedic surgery. Once again, the cumulative data suggest that rivaroxaban is either superior, or at least certainly non-inferior, to LMWH thromboprophylaxis in this setting. For example, in the RECORD1 trial, 3153 patients undergoing total hip arthroplasty were randomised to receive either oral rivaroxaban (10mg once daily beginning 6-8 hours after wound closure) or subcutaneous enoxaparin (40mg once daily initiated 12 hours before surgery and restarted 6-8 hours after wound closure) [10]. Thromboprophylaxis was continued for 35 days postoperatively in all patients. The primary outcome measure was again the composite of DVT (either symptomatic or asymptomatic detected by bilateral venography), nonfatal PE, or death from any cause at 36 days. This primary efficacy outcome occurred in 1.1% in the rivaroxaban group compared to 3.7% in the enoxaparin group (absolute risk reduction 2.6%; 95% CI 1.5 to 3.7; p<0.001), suggesting that the rivaroxaban regimen was more effective for extended thromboprophylaxis than a once-daily 40mg subcutaneous dose of enoxaparin in patients undergoing elective THR. Moreover, major VTE was significantly reduced in the rivaroxaban group compared to the enoxaparin group (0.2%

versus 2%; p<0.001). Despite the improved efficacy of oncedaily oral rivaroxaban compared to subcutaneous enoxparin, the risk of major bleeding was not significantly different between the two patient groups, with major bleeding observed in 0.3% of patients on rivaroxaban compared to 0.1% of those on enoxaparin (p=0.18). Similarly, the RECORD3 trial compared rivaroxaban to enoxparin thromboprophylaxis in 2531 patients undergoing elective knee arthroplasty [11]. Once again, the risk of major VTE was significantly reduced in the patients randomised to receive rivaroxaban rather than enoxaparin (1% versus 2.6%; p=0.01). Based upon the three RECORD studies, together with six other randomised controlled trials (including a total of more than 15,000 patients), a recent systematic review concluded that oral rivaroxaban 10mg once-daily is superior to subcutaneous enoxaparin in VTE prophylaxis for patients undergoing either THR or TKR [12].

years. Both direct thrombin and factor Xa inhibitors show great promise. However it is critical to appreciate that the different commercial products have significant differences with respect to their individual pharmacokinetic and pharmacodynamics properties. Furthermore, it remains unclear whether the effectiveness of these novel agents demonstrated in the published clinical trials will also apply in real-world clinical practise. Clearly trial participants are often younger, more motivated, and less likely to have multiple significant co-morbidities such as renal impairment. In addition, patients in the setting of a trial are more likely to be compliant with their daily dosing regimens. Consequently, the importance of close postmarketing surveillance will be of particular significance with respect to optimising the use of the NOACs in general clinical practise. Nevertheless, the novel anticoagulants certainly constitute a major therapeutic advance and provide a unique opportunity to significantly enhance patient care.

Conclusion Alternative anticoagulant therapies to warfarin have been long awaited. With the emergence of the NOACs, major changes in clinical practise are likely to emerge in the coming

[6] Shojania KG, Duncan BW, McDonald KM, Wachter RM, Markowitz AJ. Making health care safer: a critical analysis of patient safety practices. Evid Rep Technol Assess (Summ). 2001;(43):i-x, 1-668. [7] Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P; ADVANCE-2 investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010 Mar 6;375(9717):80715. [8] Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM; ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010 Dec 23;363(26):2487-98. [9] Li XM, Sun SG, Zhang WD. Apixaban versus enoxaparin for thromboprophylaxis after total hip or knee arthroplasty: a metaanalysis of randomized controlled trials. Chin Med J (Engl). 2012 Jul;125(13):2339-45. [10] Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, Bandel TJ, Beckmann H, Muehlhofer E, Misselwitz F, Geerts W; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2765-75. [11] Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, Misselwitz F, Turpie AG; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2776-86. [12] Turun S, Banghua L, Yuan Y, Zhenhui L, Ying N, Jin C. A systematic review of rivaroxaban versus enoxaparin in the prevention of venous thromboembolism after hip or knee replacement. Thromb Res. 2011;127(6)525-34.

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INCIVO®, in combination with peginterferon alfa & ribavirin, for treatment of genotype 1 chronic hepatitis C in adult patients with compensated liver disease (including cirrhosis)1: n who are treatment‑naïve; n who have previously been treated with interferon alfa (pegylated or non‑pegylated) alone or in combination with ribavirin, including relapsers, partial responders and null responders INCIVO® is the only PI to prospectively demonstrate superior SVR rates vs standard therapy for all Genotype 1 patient types2,3,4


INCIVO® 375mg film-coated tablets ACTIVE INGREDIENT(S): Telaprevir Please refer to Summary of Product Characteristics (SmPC) before prescribing. INDICATION(S): Only in combination with peginterferon alfa and ribavirin, for treatment of genotype 1 chronic hepatitis C in adult patients with compensated liver disease (including cirrhosis): treatment naïve or previously treated with interferon alfa (pegylated or nonpegylated) alone or combination with ribavirin, including relapsers, partial and null responders. DOSAGE & ADMINISTRATION: Adults: Two 375 mg tablets, orally every 8 hours with food, swallowed whole (total daily dose: 6 tablets) for 12 weeks, in combination with peginterferon alfa-2a or -2b and ribavirin. Refer to peginterferon alfa and ribavirin SmPC for specific dosage instructions. Total treatment duration of peginterferon alfa and ribavirin either 24 or 48 weeks refer to INCIVO SmPC All patients: Patients with HCV RNA > 1,000 IU/ml at week 4 or 12 should discontinue all therapy. In case of 48 weeks treatment, discontinue peginterferon alfa and ribavirin if HCV RNA detectable at week 24 or 36. Do not reduce or interrupt INCIVO treatment. Do not restart INCIVO treatment if discontinued for ADRs or insufficient virologic response. Missed dose can be taken within 4 hours; otherwise skip dose. Children: <18 years old - no data available. Elderly: Limited data ≥ 65 years old. Renal impairment: No dose adjustment . No data on moderate/severe renal impairment (CrCl < 50 ml/min) or haemodialysis. Hepatic impairment: Dose modifications not required in mild hepatic impairment (Child-Pugh A, score 5-6). Not recommended in moderate to severe impairment (Child-Pugh B or C, score ≥ 7) or decompensated liver disease. Peginterferon alfa and ribavirin are contraindicated in Child Pugh score ≥ 6. CONTRAINDICATIONS: Hypersensitivity to INCIVO tablets. Combinations with strong inducers of CYP3A and active substances highly dependent on CYP3A for clearance where resulting elevated plasma concentrations associated with serious and/or life-threatening events. Do not use with medicines such as: alfuzosin, amiodarone, bepridil, quinidine, astemizole, terfenadine, cisapride, pimozide, ergot derivatives, lovastatin, simvastatin, atorvastatin, sildenafil or tadalafil (only when used for treatment of pulmonary arterial hypertension), oral midazolam and triazolam, rifampicin, St. John’s wort, carbamazepine, phenytoin, phenobarbital. Concomitant Class Ia or III antiarrhythmics, except IV lidocaine. Refer to SmPCs for peginterferon alfa and ribavirin for their contraindications SPECIAL WARNINGS & PRECAUTIONS: Rashes: Severe rashes reported with INCIVO combination treatment; inform patients. Monitor all rashes for progression. Consider consultation with dermatology specialist for moderate rash (< 50% of body surface area). If rash severe (> 50% of body surface area), discontinue INCIVO immediately; consult dermatology

specialist; peginterferon alfa and ribavirin may need to be discontinued. Discontinue INCIVO, peginterferon alfa and ribavirin if generalised bullous eruption, Drug Rash with Eosinophilia and Systemic Symptoms (DRESS), Stevens-Johnson syndrome/toxic epidermal necrolysis, acute generalised exanthematous pustulosis, erythema multiforme suspected/ diagnosed; consult dermatology specialist. Do not restart INCIVO if discontinued. Anaemia: Incidence and severity of anaemia increased with INCIVO combination treatment. Regularly monitor haemoglobin prior to and during treatment. Management of anaemia, see SmPC for ribavirin. If ribavirin permanently discontinued, INCIVO must also be permanently discontinued. If INCIVO discontinued for anaemia, may continue treatment with peginterferon alfa and ribavirin. Do not reduce dose of INCIVO or restart if discontinued. Pregnancy and contraception: see ‘Pregnancy’ below, see also SmPC for ribavirin. Cardiovascular: Significance of modest increase in QTcF interval uncertain. Use with caution with Class Ic antiarrhythmics propafenone and flecainide and other QT prolonging medicines. Avoid in patients with congenital QT prolongation, or family history of congenital QT prolongation or sudden death. Caution in patients with: history of acquired QT prolongation; persistent heart rate < 50 bpm; history of heart failure with reduced left-ventricular ejection fraction; with medicinal products known to prolong QT interval. Clinical and ECG monitoring required. Monitor and correct electrolyte disturbances. Laboratory tests: Monitor HCV RNA levels at least at weeks 4 and 12. Prior to treatment, monitor complete blood count with white blood cell differential counts, electrolytes, serum creatinine, liver function tests, TSH, uric acid and at least at weeks 2, 4, 8 and 12. Combination with peginterferon alfa-2b: No clinical data on treatment-experienced patients and limited data in treatment-naïve patients. Thyroid disease: Risk of increased TSH. Monitor TSH levels before and during treatment. Possible dose adjustment of thyroid replacement therapy. No clinical data on retreating patients who have failed HCV NS3-4A protease inhibitor-based therapy; in pre/peri/post-liver or other transplants; with HCV/HBV coinfection. Limited data in HIV/HCV co-infection. Tablets contain sodium. SIDE EFFECTS: Very common (> 1/10): anaemia, nausea, diarrhoea, vomiting, haemorrhoids, proctalgia, pruritus, rash. Common (> 1/100 to < 1/10): oral candidiasis, thrombocytopenia, lymphopenia, hypothyroidism, hyperuricaemia, hypokalameia, dysgeusia, syncope, anal pruritus, rectal haemorrhage, anal fissure, hyperbilrubinaemia, eczema, swelling face, exfoliative rash, oedema peripheral, product taste abnormal. Serious side effects: DRESS, Stevens-Johnson syndrome, retinopathy. Refer to INCIVO SmPC for other side effects. Refer to peginterferon alfa and ribavarin SmPC for associated side effects. PREGNANCY: Not recommended. Males and females (of childbearing potential) and their partners must use 2 effective non-hormonal contraceptives during treatment and for 2 months after INCIVO

treatment ended. Refer to peginterferon alfa and ribavirin SmPC. LACTATION: Discontinue breast-feeding prior to therapy. INTERACTIONS: Co-administration with CYP3A and/or P-gp inducers may decrease telaprevir plasma concentrations; avoid use with mild/ moderate CYP3A inducers. CYP3A and/or P-gp inhibitors may increase telaprevir plasma concentrations. INCIVO may increase systemic exposure to substrates of CYP3A or P-gp. Refer to C/Is. Avoid domperidone. Rifabutin, darunavir/ritonavir, fosamprenavir/ritonavir, lopinavir/ritonavir, salmeterol, vardenafil not recommended. Inhaled/ nasal fluticasone/budesonide not recommended unless benefit/risk positive. Avoid colchicine in renal or hepatic impairment. Caution with: Class Ic antiarrhythmics propafenone and flecainide, IV lidocaine, digoxin, clarithromycin, erythromycin, telithromycin, troleandomycin, warfarin, dabigatran, trazodone, ketoconazole, itraconazole, posaconazole, voriconazole, parenteral midazolam, amlodipine, diltiazem, felodipine, nicardipine, nifedipine, nisoldipine, verapamil, systemic dexamethasone, bosentan, atazanavir/ritonavir, tenofovir disoproxil fumarate, abacavir, zidovudine, ethinylestradiol/norethindrone, cyclosporine, tacrolimus, sirolimus, methadone, tadalafil (for erectile dysfunction). Use telaprevir 1,125 mg q8h with efavirenz. Clinical relevance of changes unknown for alprazolam, escitalopram, zolpidem. LEGAL CATEGORY: Prescription only medicine. PRESENTATIONS, PACK SIZES, PRODUCT LICENCE NUMBERS- 375mg film coated tablets; pack of 42 tablets (1 week) EU/1/11/720/002 MARKETING AUTHORISATION HOLDER: JANSSENCILAG INTERNATIONAL NV, Turnhoutseweg 30, B-2340 Beerse, Belgium. FURTHER INFORMATION IS AVAILABLE FROM: Janssen-Cilag Ltd, 50100 Holmers Farm Way, High Wycombe, Buckinghamshire HP12 4EG UK. © Janssen-Cilag Ltd 2011 Prescribing information last revised: October 2011 PIVER1011 References 1. INCIVO® Summary of Product Characteristics. 2. Jacobson IM et al. ADVANCE Study team. Telaprevir for previously untreated chronic hepatitis C infection. N Engl J Med 2011; 364 (25): 2405-2416. 3. Sherman et al. ILLUMINATE study team. N Engl J Med. 2011; 365: 1014-24. 4. Zeuzem et al, REALIZE Study team, N Engl J Med. 2011;364(25)2417-2429. Date of preparation: March 2012. IRE/TPV/2012/0055

30 News

The role of the pharmacist in optimising patient use of medication PGEU Joint statement As experts in medicines, pharmacists, in both the community and hospital sectors, are central to helping patients better manage their medicines and therefore make a unique contribution to improved patient outcomes. The core of pharmacy practice is effective management of patient care and ensuring that optimal therapeutic outcomes are achieved when medicines are prescribed and dispensed. For example, pharmacists are uniquely placed to assist patients with any issues connected to multiple medications they may be taking (polypharmacy). This can include helping to manage the risk of medication errors due to the complexity of treatment or investigating any potential medicine interaction problems. Clinical interventions by pharmacists can also make notable impacts on improving adherence to prescribed treatments. The pharmacist can then give evidence-based and experienced advice on potential improvements to a patient’s treatment plan in light of these discussions. Additionally, one of the major challenges we face in Europe is ensuring proper reconciliation of medication regimes between the primary and secondary setting, an area where both hospital and community pharmacists have an essential contribution to make. Consequently, any policies across Europe designed to improve patient outcomes with medicines should recognise the pharmacist’s clinical role and exploit the full potential of pharmacist-led interventions. Policy Needs > Greater recognition of medicines adherence and polypharmacy as health system challenges that require a strategic response; > Consequent commitments from national and regional Governments to support and

Issue 7 • HPN

extend the pharmacist’s role in optimising patient use of medication as a health policy priority; > The inclusion within health strategies and action plans of pharmacist-led programmes to optimise patient use of medication; and, > Support for the development of the pharmacy workforce in their efforts to maintain and upgrade their professional competence through the provision of appropriate education and professional development opportunities. Multi-professional care Multi-professional care requires bringing together professionals from different disciplines and in different practice settings to ensure appropriate transfer of information and utilisation of professional skills in order to gain the best outcomes for a patient or group of patients. The pharmacist’s particular contribution in this regard is often knowledge, experience and assistance to the patient pathway in respect of optimising use of medication. In the ideal multi-professional care scenario, relevant communication and key data should follow a patient through the patient pathway, and health professionals should work together in a way that maximises the competence and contribution of each professional involved.The barriers often presented to closer cooperation between settings and disciplines in the health sector include:

Isabelle Adenot • insufficient commitment to the goal of multi-professional care from health service management and national/ regional policy makers which often leaves patient needs unmet; • lack of existing interventions that support and promote professional trust and collaboration between different professionals involved in patient care. Policy Needs > A better understanding by policy makers of the benefits of multi-professional care; > Commitment from national and regional governments to achieving multi professional care; > Awareness by policy makers of the desirability of interoperable systems between health sectors and professional groups (e.g. eHealth solutions such as read and write access to the patient record by all professionals involved in care); > Integration of the multiprofessional team concept within health professional education curriculums;

> Better understanding of the potential of continuity of pharmaceutical care, with the active participation of the pharmacist during the patient’s transition between acute care settings and home to deliver better care and system efficiency. Joint Commitment EAHP and PGEU commit to co-ordinated advocacy to develop the pharmacist’s role in optimising patient use of medication. EAHP and PGEU commit to working together to improve the understanding of European policy makers about the benefits of multi-professional care, and the role of community and hospital pharmacists within that. In so doing, EAHP and PGEU will work closely with partner organisations in the pharmacy and health sector.


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32 Immunosuppressants

Generic immunosuppressant drugs in solid organ transplantation In July of last year, the Health (Pricing and Supply of Medical Goods) Act 2012 Bill was published and will shortly be enacted by the Oireachtas. This bill will allow pharmacists to substitute generic medicinal products in place of branded products, without informing the prescriber. This has raised concerns among transplant specialists, as uncontrolled generic substitution of immunosuppressant drugs could prove catastrophic for patients. This article will explore the issues surrounding generic substitution of immunosuppressant drugs in solid organ transplant recipients and provide guidance on their safe use.

Written by Kathryn Feeley, Senior Pharmacist (Hepatology), St. Vincent's University Hospital, Elm Park, Dublin 4

Issue 7 • HPN

Generic drugs are currently assessed by the European Medicines Agency (EMA) using bioequivalence studies. There is however considerable controversy as to whether these studies are sufficient to prove therapeutic equivalence of immunosuppressant drugs in the organ transplant population. To be considered bioequivalent, a generic product must contain the same molar quantity of active ingredient as the originator brand, and the rate and extent to which the active ingredient becomes available at the site of drug action in the body should be comparable. To demonstrate this, the 90% confidence interval for both the Area Under the Curve (AUC(0-t)) and the maximum plasma concentration (Cmax) mean ratio must fall within the limits of 80 – 125%. Narrow therapeutic index drugs are assessed individually by the EMA, and may need to adhere to tighter limits of 90 – 111%. Bioequivalence studies are typically single dose assessments carried out in small numbers of healthy individuals. Organ transplant patients, however, may demonstrate markedly different pharmacokinetics due to co-morbidities, function of the transplanted organ and concomitant drug use. There is also no requirement to validate therapeutic drug monitoring of generic products. In clinical practice, trough levels are used to guide dosing of immunosuppressant drugs, not Cmax, and it is unknown if a generic with an acceptable AUC and Cmax will give an equivalent trough level to the originator brand.

What worries transplant specialists is that even small changes in exposure to some anti-rejection medications may cause potentially devastating graft rejection or toxic effects (Borra et al. 2010;PollockBarziv et al. 2010). Despite the tighter bioequivalence criteria for tacrolimus, a recent study examining effect of generic substitution, showed that 41.7% of patients required a dose adjustment, (either up or down), when switched from the branded product (Momper et al. 2011). A critical lesson about the potential inadequacy of the current bioequivalence criteria came to light with a generic ciclosporin product in the US, which was permanently withdrawn from the market when it was found not to be bioequivalent when taken with apple juice (Federal Register Notice, December 4, 2000). This underlines the crucial importance of trough level measurement, monitoring of clinical effect and vigilance for signs of toxicity by a specialist transplant centre, following generic substitution of tacrolimus and other narrow therapeutic immunosuppressant drugs. Under-dosing may lead to rejection, graft failure and death. Over-dosing may lead to nephrotoxicity, infection, malignancy or other toxicities. Although generic products must each demonstrate bioequivalence to the originator brand, they do not have to demonstrate bioequivalence to each other. This means that the difference between two generic products may be even greater than the difference between an individual generic

and the originator brand. For this reason, it is recommended that only branded generics should be used, and only if started by a transplant specialist and that patients should stick to a single generic product and avoid sequential switching. There are also differences between the criticality of the various immunosuppressant drugs used in transplantation. Tacrolimus and ciclosporin require very close monitoring and individualised dosing, whereas mycophenolate is more amenable to standard dosing and sirolimus is somewhere in between. Thus the suitability of each drug for generic substitution must be considered separately. The management of immunosuppression exhibits intra-patient variability, with some patients considered to be easily stabilised and others considered “brittle”, in whom appropriate trough levels, achievement of therapeutic effects and avoidance of toxicity, can be difficult to manage. Add to this the way in which immunosuppressant drugs are used in different types of transplantation, kidney, liver, heart, lung, etc. and the complexity of the picture becomes apparent. The reason most often cited for the generic switch is the potential for cost savings. The question is how can the potential savings be realised without increasing morbidity and mortality: what is the potential cost to the patient? The answer lies in managing the switch closely for individual patients. There are also shortterm hidden costs associated


with additional therapeutic drug monitoring, blood tests and clinic visits. Targeted patient education in transplant centres is needed so that patients are aware of different generic products and are counselled to remain on the product prescribed for them in the hospital. Medication reconciliation on transfer between primary and secondary care will have an added layer of complexity, as now the correct product will need to be identified, as well as the drug and dose. Both hospital and community pharmacies will have to stock multiple generic and branded products of immunosuppressant drugs, bringing an additional burden in terms of storage and stockholding cost , a new potential for dispensing errors and, in hospitals, administration errors. Generic substitution may reduce patient compliance. Poor compliance can result in increased morbidity and mortality. The Irish College of General Practitioners

(ICGP) has expressed concern that generic substitution confuses patients, and adversely affects compliance. Studies have shown that generic substitutes that are new or unfamiliar may result in medication errors such as consumption of both products simultaneously (Gabbay et al. 2012;Hakonsen et al. 2009). If a patient is unfamiliar with a dispensed medication, they may delay taking it or even not take it at all. There is a danger that a different generic may be sequentially dispensed in community pharmacies at each visit, based on the current lowest list or reimbursed price. This practice is encouraged by the new bill where reimbursement is based on a reference price and the lowest cost generic may change from month to month as drug companies vie for market share.

drugs such as tacrolimus or ciclosporin could occur in the community, either by accident or by design. Such switches could occur without prescriber knowledge, and pose a considerable risk to patients (Harrison et al. 2012). Although the use of generic tacrolimus has been adopted by many international transplant centres, it has been done in a highly controlled manner, using one branded generic, with close monitoring and patient counselling. Some centres have adopted measures to safely manage medication supply. In the UK, hospital dispensing with home delivery is being considered in some centres. In the US, some centres ask patients to attend named community pharmacies who are aware of the issues surrounding generic immunosuppressant substitution.

The great fear among transplant experts is that unmonitored and unintentional switching of narrow therapeutic immunosuppressant

Following significant concern over the proliferation of generic immunosuppressant medications in the EU over the last number


The Irish College of General Practitioners (ICGP) has expressed concern that generic substitution confuses patients


HPN â&#x20AC;˘ Issue 7

34 Immunosuppressants

of years, the European Society for Organ Transplantation (ESOT) convened a specialist committee to examine the issue in 2011 and came up with a number of recommendations (van Gelder, 2011): 1. Switching from a branded immunosuppressant drug should only be done by a transplant physician with appropriate monitoring. 2. Each switch needs to be followed closely to ensure correct therapeutic levels and effect are achieved and toxicity avoided. 3. Repetitive consecutive substitutions to other generic formulations should be avoided. To avoid this, a selected branded generic should be prescribed. 4. Patients should be informed about generic substitution and educated to identify the different formulations. They should alert the physician if uncontrolled substitutions are made. 5. Generic formulations that do not fulfil stricter bioequivalence criteria should not be used. In summary, the use of generic immunosuppressant drugs is complex and, for drugs with a narrow therapeutic window, current EU bioequivalence studies are not sufficiently robust to allow uncontrolled switching. Uncontrolled switching or poor management of a generic switch can have significant adverse effects on patient care and outcome. Pharmacists in both primary and secondary care must be aware of the dangers of uncontrolled generic substitution in transplant patients, particularly when generic tacrolimus becomes available. Transplant centres must decide whether they will use generic immunosuppressant drugs and if yes, which ones. Robust planning of the switch will be required. Even if generic switching does not occur, additional patient education will now be necessary, in the context of multiple generic products, to ensure that patient safety is not compromised.

Issue 7 • HPN

References Borra, L. C., Roodnat, J. I., Kal, J. A., Mathot, R. A., Weimar, W., & van, G. T. 2010, “High within-patient variability in the clearance of tacrolimus is a risk factor for poor long-term outcome after kidney transplantation”, Nephrol.Dial. Transplant, vol. 25, no. 8, pp. 27572763. Gabbay, U., Yosef, N., FederKrengel, N., & Meyerovitch, J. 2012, “Therapeutic equivalent substitute that is new or unfamiliar to the chronic patient may result in medication error”, Int.J Health Care Qual.Assur., vol. 25, no. 6, pp. 509-518. Hakonsen, H., Eilertsen, M., Borge, H., & Toverud, E. L. 2009, “Generic

substitution: additional challenge for adherence in hypertensive patients?”, Curr.Med Res.Opin., vol. 25, no. 10, pp. 2515-2521. Harrison, J. J., Schiff, J. R., Coursol, C. J., Daley, C. J., Dipchand, A. I., Heywood, N. M., Keough-Ryan, T. M., Keown, P. A., Levy, G. A., Lien, D. C., Wichart, J. R., & Cantarovich, M. 2012, “Generic immunosuppression in solid organ transplantation: a Canadian perspective”, Transplantation, vol. 93, no. 7, pp. 657-665. Momper, J. D., Ridenour, T. A., Schonder, K. S., Shapiro, R., Humar, A., & Venkataramanan, R. 2011, “The impact of conversion from prograf to generic tacrolimus in liver and kidney

transplant recipients with stable graft function”, Am J Transplant, vol. 11, no. 9, pp. 1861-1867. Pollock-Barziv, S. M., Finkelstein, Y., Manlhiot, C., Dipchand, A. I., Hebert, D., Ng, V. L., Solomon, M., McCrindle, B. W., & Grant, D. 2010, “Variability in tacrolimus blood levels increases the risk of late rejection and graft loss after solid organ transplantation in older children”, Pediatr.Transplant, vol. 14, no. 8, pp. 968-975. van, G. T. 2011, “European Society for Organ Transplantation Advisory Committee recommendations on generic substitution of immunosuppressive drugs”, Transpl Int., vol. 24, no. 12, pp. 1135-1141.




Superior efficacy vs. enoxaparin 40mg OD1,2 No increase in bleeding vs. enoxaparin 40mg OD1,2 Convenient oral administration3 A 12–24 hour post-surgery initiation window* No dose adjustments required in elderly† or patients with mild or moderate renal impairment ELIQUIS® alone or in combination with acetylsalicylic acid should be used with caution in patients with severe renal impairment (CrCl 15–29ml/min) because of a potentially higher bleeding risk; ELIQUIS® is not recommended for use in patients with CrCl <15ml/min or undergoing dialysis

No dose adjustments required in patients with mild to moderate hepatic impairment (Child Pugh A or B), but use with caution in these patients Not recommended for use in severe hepatic impairment * Physicians may consider the potential benefi ts of earlier anticoagulation for VTE prophylaxis as well as the risks of post-surgical bleeding in deciding on the time of administration within this time window. † There is limited clinical experience in elderly patients co-administered ELIQUIS® with acetylsalicylic acid. This combination should be used cautiously because of a potentially higher bleeding risk.

For the prevention of venous thromboembolic events (VTE) in adult patients who have undergone elective hip or knee replacement surgery 3 ELIQUIS® (apixaban) 2.5 mg FILM-COATED TABLETS PRESCRIBING INFORMATION. See summary of product characteristics prior to prescribing and for full list of adverse events. PRESENTATION: Film coated tablets; 2.5mg (apixaban); each film-coated tablet contains 51.43 mg lactose INDICATION: Prevention of venous thromboembolic events (VTE) in adult patients who have undergone elective hip or knee replacement surgery. DOSAGE AND ADMINISTRATION: Oral. The recommended dose is 2.5mg taken twice a day, with or without food. The initial dose should be taken 12 to 24 hours after surgery. Physicians may consider the potential benefits of earlier anticoagulation for VTE prophylaxis as well as the risks of post-surgical bleeding in deciding on the time of administration within this time window. Patients undergoing hip replacement: recommended duration of treatment is 32 to 38 days. Patients undergoing knee replacement surgery: recommended duration of treatment is 10 to 14 days. If a dose is missed, Eliquis should be taken immediately and then continue with twice daily dose as before. Switching treatment from parenteral anticoagulants to apixaban (and vice versa) can be done at the next scheduled dose. Eliquis is not recommended in children below the age of 18. CONTRAINDICATIONS: Hypersensitivity to any ingredients, active bleeding or hepatic disease associated with coagulopathy or risk of bleeding. SPECIAL WARNINGS AND PRECAUTIONS: Haemorrhage risk: Use with caution in patients with increased risk of haemorrhage such as congenital or acquired bleeding disorders, active ulcerative gastrointestinal disease, bacterial endocarditis, thrombocytopenia, platelet disorders, history of haemorrhagic stroke, severe uncontrolled hypertension and recent brain, spinal or ophthalmological surgery. Eliquis administration should be discontinued if severe haemorrhage occurs. Renal impairment: Eliquis is not recommended in patients with creatinine clearance <15ml/min or in patients undergoing dialysis. Eliquis alone or in combination with acetylsalicylic acid should be used with caution in patients with severe renal impairment (creatinine clearance 15-29 ml/min). No dose adjustment is required in patients with mild or moderate renal impairment. Eliquis is not recommended in patients receiving concomitant strong inhibitors of both

CYP3A4 and P-gp or in the presence of additional factors such as severe renal impairment. Hepatic impairment: Eliquis is contra-indicated in patients with hepatic disease associated with coagulopathy or risk of bleeding. Eliquis is not recommended in patients with severe hepatic impairment. It should be used with caution in patients with mild to moderate hepatic impairment. No dose adjustment is required for patients with mild or moderate hepatic impairment. Eliquis should be used with caution in patients with elevated liver enzymes ALT/AST >2 x ULN or total bilirubin ≥ 1.5 X ULN. ALT should be measured as part of the standard pre-op evaluation. Epidural or intrathecal Catheters: must be removed at least 5 hours prior to first dose of Eliquis. Patients who have undergone spinal or epidural anaesthesia should be monitored frequently. Hip fracture: not recommended in these patients, as Eliquis has not been studied in this patient group. Patients with galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Eliquis. DRUG INTERACTIONS: Eliquis is not recommended in patients receiving the following agents; CYP3A4 and P-gp inhibitors such as azole-antimycotics (e.g., ketaconazole, itraconazole, voriconazole and posaconazole), HIV protease inhibitors (e.g. ritonavir). Eliquis should be used with caution in patients taking CYP3A4 and P-gp inducers such as rifampicin, phenytoin, carbamazepine, phenobarbital or St. John’s Wort. Eliquis should be used with caution in patients co-administered with NSAIDs including acetylsalicylic acid. Other platelet aggregation inhibitors or other antithrombotic agents associated with serious bleeding are not recommended concomitantly. PREGNANCY: Not recommended. Breastfeeding: Discontinue breast feeding or discontinue Eliquis therapy. UNDESIRABLE EFFECTS: Common (≥ 1/100 to < 1/10): anaemia (including postoperative and haemorrhagic anaemia), haemorrhage (including haematoma, and vaginal and urethral haemorrhage), nausea, contusion. Uncommon (≥ 1/1,000 to < 1/100): thrombocytopenia (including platelet count decreases), hypotension (including procedural hypotension), epistaxis, gastrointestinal haemorrhage (including haematemesis and melaena), haematochezia, transaminases increased (including alanine aminotransferase increased and alanine aminotransferase abnormal), aspartate aminotransferase

increased, gamma-glutamyltransferase increased, liver function test abnormal, blood alkaline phosphatase increased, blood bilirubin increased, haematuria (including respective laboratory parameters), post procedural haemorrhage (including post procedural haematoma, wound haemorrhage, vessel puncture site haematoma and catheter site haemorrhage) wound secretion, incision site haemorrhage (including incision site haematoma), operative haemorrhage. Rare (≥ 1/10,000 to < 1/1,000): hypersensitivity, ocular haemorrhage (including conjunctival haemorrhage), haemoptysis, rectal haemorrhage, gingival bleeding, muscle haemorrhage. LEGAL STATUS: S1B. PACKAGE QUANTITIES: Carton of 10 film coated tablets 2.5mg, 20 film coated tablets 2.5mg, 60 film coated tablets 2.5mg. MARKETING AUTHORISATION NUMBERS: EU/1/11/691/001 - EU/1/11/691/003. Not all pack sizes may be marketed. MARKETING AUTHORISATION HOLDER: BristolMyers Squibb/Pfizer EEIG, BMS House, Uxbridge Business Park, Sanderson Road, Uxbridge, Middlesex. UB8 1DH. Telephone: 0800-731-1736. ADDITIONAL INFORMATION AVAILABLE ON REQUEST FROM: Bristol-Myers Squibb Pharmaceuticals, South County Business Park, Leopardstown, Dublin 18. Tel: 1-800-749-749. DATE OF PI PREPARATION: July 2011. 432IE11PM001(2). EL 1_0 IRE. References: 1. Lassen MR et al. N Engl J Med 2010; 363:2487 2498. 2. Lassen MR et al. Lancet 2010; 375:807-815. 3. ELIQUIS® (apixaban) Summary of Product Characteristics. Date of preparation: August 2012 Job code: EUAPI069a ELI/2012/005

Oral anticoagulation that delivers on both levels1,2


Hospital pharmacy winners presentation Roche Pharmaceuticals Sales and Marketing Director Frances Galvin recently met up with two of the 2012 Irish Pharmacy Award hospital winners to present them with their coveted framed presentation certificates. Hospital pharmacy winner team lead Muireann Ní Shúilleabháin told us: "The Irish Pharmacy Awards ceremony was a very positive experience for us. Hospital pharmacists are generally modest about their achievements. There are many hospital pharmacies doing challenging and innovative work throughout the country and I would encourage hospital pharmacy teams to partake in the award process in the future. The participation process has boosted morale in our department and raised our profile in the hospital. "We would like to thank Roche Pharmaceuticals for sponsorship of this Hospital Pharmacy Award.” Tim Delaney walked off on

the night with the prestigious Hospital Pharmacist of the Year Awards. He told us: "However I would like to dedicate this award to the first pharmacist I recruited when I became a Chief Pharmacist. Denise Ward Molloy worked with me for twelve years in the Adelaide and Tallaght Hospital. She played a key role in the forging of one team from three as we moved from our three small city centre hospitals to one large one. Her untimely death, just one week before this ceremony, leaving her husband David and two boys bereft, reminds us of how precious and unpredictable life is. I dedicate this award to her memory."

The team at Our Lady's Hospice with Frances Galvin of Roche Pharmaceuticals

Pharmacy helps develop new strategies in HD A new and innovative strategy has been developed to deliver a therapy that successfully silences a gene responsible for the neurodegenerative condition known as Huntington’s Disease (HD). Brain disorders affect approximately 30% of the Irish population annually with

immense personal, social and economic costs. There are two major challenges in developing therapeutic strategies for the brain. Firstly, the blood brain barrier keeps most medicines out of the brain, secondly brain cells (neurons) themselves are very difficult to penetrate in a safe manner.

Professor Caitriona O'Driscoll, Professor John Cryan and PhD student Bruno Godinho

Issue 7 • HPN

In tackling this later problem scientists at the School of Pharmacy and Department of Anatomy and Neuroscience at UCC have come up with an innovative strategy to deliver a therapy that successfully silences a gene responsible for the neurodegenerative disease Huntington’s Disease (HD). Professor Caitriona O’Driscoll (Pharmacodelivery group in School of Pharmacy, UCC) and her long standing collaborator Dr Raphael Darcy (University College Dublin) have developed sugar-based carriers called cyclodextrins which are able to encapsulate and transport molecules which silence the expression of toxic genes. In collaboration with neuroscientist Professor John F Cryan (Department of Anatomy and Neuroscience, UCC) and through the efforts of PhD student Bruno Godinho the application of this novel technology to brain

disorders was made possible. They have shown that these sugar-based carriers effectively deliver silencing molecules (siRNAs) into nerve cells reducing the levels of the toxic HTT protein. Furthermore, the results obtained in cell-based models also translated to mice. Reducing the HTT messages by direct administration into the brain of a mouse model of HD resulted in alleviation of some of the motor deficits. “This is a very encouraging breakthrough for disorders where there is often very little hope,” says Professor Cryan. “We now have an effective and non-toxic carrier which could be applied to many brain disorders especially those with genetic basis. However”, he cautions “whilst these experiments in cells and model systems are encouraging, we are still a long way from transferring this technology to human use.”

Job code: XIA/2011/014

Date of preparation: August 2011

Dissolve the frustration of Dupuytren’s contracture

Introducing XIAPEX, an innovative injectable treatment for Dupuytren’s contracture XIAPEX is the first pharmaceutical treatment indicated for Dupuytren’s contracture.1,2 It is a minimally invasive, outpatient procedure, which improves joint contractures and helps restore hand function.1,2 To find out more about XIAPEX and how you can incorporate it into your treatment protocol for Dupuytren’s contracture, please visit or contact your local Pfizer representative today.

Transforming treatment XIAPEX® Abbreviated Prescribing Information: (See Xiapex Summary of Product characteristics for full Prescribing Information) Presentation: Powder and solvent for solution for injection for intralesional use. The vial of powder contains 0.9mg collagenase clostridium histolyticum. The powder is a white lyophilised powder and the solvent is a clear colourless solution. Indications: Treatment of Dupuytren’s contracture in adult patients with a palpable cord. Dosage: Xiapex must be administered by a physician appropriately trained in the correct administration of the product and experienced in the diagnosis and management of Dupuytren’s disease. The recommended dose of Xiapex is 0.58mg per injection into a palpable Dupuytren’s cord. For an MP joint, each dose is administered in an injection volume of 0.25ml (requiring 0.39ml solvent for reconstitution). For a PIP joint, each dose is administered in an injection volume of 0.20ml (requiring 0.31ml solvent for reconstitution). Approximately 24 hours after injection, a finger extension procedure may be performed to facilitate cord disruption. If a satisfactory response has not been achieved, injections and finger extension procedures may be repeated up to 3 times per cord at approximately 4-week intervals. Only one cord must be treated at a time. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Warnings and Precautions: Allergic reactions - 17% of Xiapex-treated patients in phase 3 placebo-controlled clinical studies had mild allergic reactions (i.e. pruritus). Physicians must be prepared to address any severe local or systemic allergic reactions including the

potential for anaphylaxis following injection, including the potential for such reactions following repeated use. Whilst there is no evidence from the clinical data of an increased risk of serious allergic reactions upon repeated injections, the potential for such reactions following repeated use cannot be excluded. Tendon rupture or other serious injury to the injected extremity – Injection of Xiapex into collagen containing structures of the hand other than the Dupuytren’s cord may result in damage to those structures including possible tendon rupture or ligament damage. Injections into cords affecting the PIP joint of the 5th finger must not be more than 2 to 3 mm in depth and nor more than 4mm distal to the palmar digital crease. Patients should be instructed to contact their physician in case of symptoms of tendon rupture. Use in patients with coagulation disorders – Xiapex must be used in caution in patients with coagulation disorders or those taking anticoagulants. Use of Xiapex in patients who have received anticoagulants (with the exception of up to 150mg acetylsalicylic acid daily) within 7 days prior to receiving an injection of Xiapex is not recommended. Immunogenicity As with any non-human protein medicinal product, patients may develop antibodies to the therapeutic protein. Since the enzymes in Xiapex have some sequence homology with human matrix metalloproteinases (MMPs), anti-drug antibodies could theoretically interfere with human MMPs. No safety concerns related to the inhibition of endogenous MMPs have been observed, in particular no adverse events indicating the development or exacerbation of autoimmune diseases or the development of a musculoskeletal syndrome

but the potential for it to occur cannot be excluded. If this syndrome were to develop, it would occur progressively and is characterized by one or more of the following signs and symptoms: arthralgia, myalgia, joint stiffness, stiffness of the shoulders, hand oedema, palmar fibrosis and thickening or nodules forming in the tendons. Long-term safety - Longterm safety of Xiapex is not fully characterised. The impact of treatment with Xiapex on subsequent surgery, if needed, is not known. Drug Interactions: Use of Xiapex in patients who have received tetracycline antibiotics e.g. doxycycline, within 14 days prior to receiving an injection of Xiapex is not recommended. Pregnancy & Lactation: Not recommended in pregnancy. Xiapex can be used during breast feeding. Driving and operating machinery: Xiapex may have a major influence on the ability to drive and use machines due to swelling and pain in the treated hand. Other minor influences include dizziness, paraesthesia, hypoesthesia, and headache, see side effects. Patients must be instructed to avoid potentially hazardous tasks such as driving or using machines until it is safe to do so or as advised by the physician. Side Effects: In clinical trials, the most frequently reported adverse reactions during the Xiapex were local injection site reactions such as oedema peripheral (local to the injection site), contusion (including ecchymosis), injection site haemorrhage and injection site pain. Injection site reactions were very common, occurring in the vast majority of patients, were mostly mild to moderate in severity and generally subsided within 1-2 weeks post injection. Serious adverse reactions of tendon rupture, tendonitis, other ligament injury and

complex regional pain syndrome related to the medicinal product were reported. Very commonly reported adverse reactions include lymphadenopathy, pruritus, ecchymosis, pain in extremity, oedema peripheral (including injection site oedema and oedema), injection site haemorrhage, injection site pain, injection site swelling, tenderness, contusion. Commonly reported adverse reactions include lymph node pain, paresthesia, hypoesthesia, burning sensation, dizziness, headache, nausea, blood blister, blister, rash, erythema, hyperhidrosis, arthralgia, joint swelling, myalgia, axillary pain, inflammation, injection site inflammation, swelling, injection site erythema, injection site pruritus, injection site warmth, injection site vesicles, skin laceration. Overdose: Overdose is expected to be associated with increased local injection site reactions. Provide routine supportive care and treat symptomatically. Legal Category: S1C Marketing authorisation holder: Pfizer Ltd, Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK. Package quantities, Marketing Authorisation numbers: XIAPEX 0.9mg powder and solvent for solution for injection, EU/1/11/671/001 Further information is available on request from: Pfizer Healthcare Ireland, Pfizer Building, 9, Riverwalk, National Digital Park, Citywest Business Campus, Dublin 24. Date of Preparation: August 2011. Company reference: XP2_0 References 1. XIAPEX Summary of Product Characteristics. February 2011. 2. Hurst LC, Badalamente MA, Hentz VR et al. N Engl J Med. 2009;361: 968-79.

38 Clinical Focus

Childhood cancer survival in Ireland: temporal, regional and deprivation-related patterns Paul M. Walsha,*, Julianne Byrneb, Michael Caprac, Harry Combera aNational Cancer Registry, Building 6800, Cork Airport Business Park, Kinsale Road, Cork, Ireland bBoyne Research Institute, Drogheda, Ireland cNational Paediatric Haematology/Oncology Centre (NPHOC), Our Lady’s Hospital, Crumlin, Dublin, Ireland

In Ireland, five-year survival after childhood cancers diagnosed during 1994-2000 was almost 80% for both males and females.1 This compared favourably with survival figures from Europe and the United States. Childhood cancer survival is steadily increasing in Europe.2-4 However, significant disparities in cancer survival, both for adults and for children, have been noted between eastern and western Europe. For childhood cancer, the ACCIS study reported average five-year survival of 64% for eastern Europe compared with 75% in the west.3 The EUROCARE-3 study reported five-year survival ranging 45-66% for individual eastern European countries compared with 71-90% (mainly 71-81%) for western European countries based on 1990-1994 cases. 2 Such geographical differences in survival after childhood cancer across Europe have been attributed to the need for more coordination, systematization and standardization in diagnosis, referral and treatment. Also, within regions, a number of studies have noted significant and persistent survival disparities related to socioeconomic status for cancers among adults. 5-9 Possible explanations or mechanisms involve factors relating to the tumour (e.g. stage), the patient, and access to healthcare, and interactions between these.7 In contrast to adults, studies of children have shown only limited or no evidence of a survivaldisparity related to deprivation.5,10-13 Survival disparities after childhood cancer may exist within Ireland, but have not been evaluated previously. We

Issue 7 • HPN

developed two hypotheses regarding regional or deprivation-based influences on survival after childhood cancer here. First, cancer services are centralized in the east of the country, in Dublin, so children from more distant regions might be expected to have less favourable survival. A second hypothesis was that relative deprivation would influence survival rates. To test our hypotheses we used data from the Irish National Cancer Registry to assess variation in survival between larger geographic regions and between area-based deprivation strata. We also assessed time-trends in survival trends, updating an earlier analysis.1 Our primary focus was on the three most common diagnostic groups – leukaemias, lymphomas and related neoplasms, and central nervous system (CNS) or intracranial neoplasms. Cases and incidence National data on the incidence and treatment of childhood and adult cancers in Ireland are registered by National Cancer Registry (NCR) staff from patients‟ records, pathology reports and other sources provided by hospitals or clinics, supplemented by death certificate registrations for some cases. Analyses presented here are based on the third edition of the International Classification of Childhood Cancer (ICCC),14 covering neoplasms in children below age 15. Neoplasms that are explicitly excluded from the ICCC were excluded from analysis (principally tumours of benign or uncertain behaviour).

However, for intracranial and intraspinal sites, benign tumours and tumours of uncertain behaviour fall within the ICCC and were included in analyses. Case numbers and incidence rates reported here excluded neoplasms flagged as duplicates by the IARCcrgTools program ( iarccrgtools.htm) i.e. if second or subsequent neoplasms were considered sufficiently „similar‟ by the program. Otherwise, individuals with more than one primary cancer may have been included once for each new primary neoplasm of a different type (but only the first neoplasm was included in survival analyses). Incidence rates were standardized to the traditional World standard,15 using age-groups 0-4, 5-9 and 10-14. Irish population data for each year 1994-2005 were from derived from census data for 1991, 1996, 2002 and 2006, and official interpolations for intermediate years, provided by Central Statistics Office Ireland (CSO) ( Trends in age-standardized incidence rates were assessed using the Joinpoint program (srab.cancer. gov/joinpoint).16 Region of residence and region of treatment Patients were assigned to one of four regions of residence, based on the Health Service Executive (HSE) administrative areas - Dublin / North-East, Dublin / Mid-Leinster, South and West - and this region was used both in descriptive analyses and in Cox regression (section 2.4). To summarize the extent to which treatment may have been centralized, regions where each patient was treated were also identified. We allocated

39 Table 2 – Percentage distribution by deprivation category (area of residence) of childhood cancer cases included in survival analyses, Ireland, 1994-2005, in relation to baseline population percentages for the same period. Patients from unknown deprivation category (11% of cases) are not tabulated.

all recorded tumour-directed treatments (aimed at removing or destroying tumour) within one year of diagnosis to the region where the hospital or other treatment centre was located. Some patients received treatment (usually of different modalities) in more than one region, or multiple treatments in the same region, and we counted each region once per patient for (a) all relevant treatments combined and also separately for (b) surgery, (c) radiotherapy and (d) medical oncology treatments. A small number of first-course treatments initiated later than six months after diagnosis may have been underrecorded, particularly for earlier diagnosis years, but the broad geographic patterns of treatment should be unaffected. Deprivation: the SAHRU index The standard measure of areabased deprivation currently used in Ireland is the SAHRU (Small Area Health Research Unit) Deprivation Index, derived from socioeconomic data collected for c3400 Electoral Divisions (EDs) as part of the 2002 Census of Ireland.17 The census variables used in the index cover unemployment, social class, type of housing tenure, car ownership and overcrowding.18 The index is similar in design to the Carstairs and Townsends indices widely used in the UK.19-20 The SAHRU index was available for 89% of all childhood cancer cases during 1994-2005, those for whom address data were precise enough to allow assignment of EDs. The ten-point index (1-10) was re-grouped for analysis into five broader categories (1-2 to

SAHRU deprivation All cancers index

Leukaemias & related

Lymphomas & related

CNS & related

Population (ages 0-14)

1-2 (least deprived)
























9-10 (most deprived)






9-10). The index is known to be strongly correlated with the incidence of cancers among Irish adults, with clear associations between higher deprivation and higher risk of lung and stomach cancers and between lower deprivation and higher risk of breast cancer and melanoma.18 Survival Follow-up of Irish cancer cases by the NCR was based on matching of personal details against national death certificate data n provided by the CSO and the General Registrar‟s Office and updated four times each year. Clinical data on deaths were also used where available. Observed survival is presented, as the standard approach for children in western populations, and has been estimated by life-table methods using the strs command in Stata (www. stata_colon/). Cohort estimates of fiveyear and ten-year survival are presented for 1994-2005, and five year survival for the diagnosis periods 1994-99 and 2000-2005, based on follow-up to the end of 2006. "Hybrid" estimates are also presented for the period 2000-2005, based on all cases diagnosed during those years and longer-term follow-up of cases diagnosed in earlier years supplemented by one-year follow-up of cases diagnosed in 1999. This approach and related "period‟ approaches provide an empirically validated basis for more up-to-date assessment of longer-term survival.21-22 Estimates were not standardized for age (but model-based comparisons were adjusted for

age – see below). Conditional survival (e.g. survival to five years assuming survival through the first year) was also examined, by diagnosis period and deprivation category, to allow assessment of possible late influences on survival (details presented in Appendices 2-3). Possible regional variations in survival were examined by area of residence, and fuller address data was also used to assign patients to Electoral Divisions (ED), allowing assignment of ED-based deprivation. Formal comparisons of survival between diagnosis cohorts, areas of residence or deprivation categories were made by Cox regression, adjusted for sex, five-year age-group and casemix. For regional and deprivationcategory analyses (included in a single model), diagnosis period – 1994-1999 or 2000-2005 – was also adjusted for. For all cancers combined, the case-mix categories used were (following EUROCARE-4):4 lymphoid leukaemias (ICCC Ia); acute myeloid leukaemias (Ib); Hodgkin lymphomas (IIa); non-Hodgkin lymphomas (IIb); CNS tumours (III); kidney (ICD10 C64-C65); eye and orbit (C69); bone (C40-C41); soft tissues (C49); and other sites. Within groups IIII, categories Ia-e, IIa-e and IIIa-f were used, respectively. Proportionality of hazards was assessed by testing the effect of including interactions between covariates and follow-up time in the Cox model ( faq/test_proportionality. htm). If there was significant interaction the final model used was stratified by the relevant

covariate(s) (mainly case-mix and age). Results Patient characteristics and data quality indicators Data on 1452 newly diagnosed cases of childhood cancer (within the ICCC groups I-XII) in Ireland during 1994-2005, an average of 121 per year, are summarized in Table 1. The percentage of cases microscopically verified and the percentage of cases assigned to non-specific tumour morphologies were broadly similar to recent figures for Europe as a whole.4 After excluding second malignancies and cases with same diagnosis and death date, 1440 patients were included in survival analyses. All patients diagnosed during 1994-1996 (24% of total) had potential follow-up of a full ten years to the end of 2006, while those diagnosed during 1994-2001 (65%) had potential follow-up of five years. The remainder had between one and five years of follow-up, but no patients were known to have been lost to follow-up. Of all cancer patients, 30% were resident in areas of highest deprivation (category 9-10), similar to the distribution of the childhood population at risk (Table 2). The distribution of patients by deprivation category within specific diagnostic groups was also broadly similar to the overall distribution. Region of treatment in relation to region of residence Regardless of region of residence, a high proportion of patients had tumour-directed

HPN • Issue 7

40 News

World age-standardized rates (per million children per year) Description & ICCC group













All childhood cancers (ICCC groups I-XII)










I. Leukaemias, myeloproliferative diseases, & myelodysplastic diseases










II. Lymphomas & reticuloendothelial neoplasms










III. CNS & miscellaneous intracranial & intraspinal neoplasms










Table 3 - Childhood cancer incidence rates, Ireland, by broad diagnosis period, 1994-2005

treatment (within a year of diagnosis) in the Dublin / MidLeinster (DML) region: 72% overall, ranging from 61% of patients resident in the Southern region to 79% of those resident in DML (Appendix 1). For leukaemias, lymphomas and related neoplasms, in particular, 85% of patients had treatment (mainly chemotherapy) in DML. Treatment of CNS tumours was more evenly split between DML (39% of patients, mainly for radiotherapy and medical oncology) and Dublin / NorthEast (48%, mainly surgery). Incidence by diagnostic group and diagnosis period Overall, the rate of childhood cancer increased from 137 per million during 1994-97 to 158 per million during 2002-2005, with an average percentage increase of 1.5% each year (Table 3). Leukaemia rates increased from 43 per million to 50, and lymphoma rates from 13 to 16, over the same period. Rates of tumours of the CNS showed little change from 40 per million during 1994-1997 to 39 during 2002-2005. However, trends during 1994-2005 as a whole were not statistically significant for any group or overall (Figure 2).

Issue 7 â&#x20AC;˘ HPN

Survival estimates and timetrends in survival Five-year survival for all cancers of childhood averaged 79% for 1994-2005 as a whole, and varied little over time (79% for 1994-1999, 80% for 20002005). Leukaemias and related neoplasms also showed little change in survival between diagnosis periods (overall figure 77%), as did tumours of the central nervous system (73%). Average five-year survival for lymphoma patients did show an apparent increase, from 87% in 1994-1999 to 96% in 2000-2005 (overall 91%). However, model-based comparisons, adjusted for age, sex and case-mix, found no significant changes in survival between the diagnosis periods 1994-99 and 2000-05, either overall or for any of the 12 specific diagnostic groups within the International Classification of Childhood Cancer. Lymphomas showed the strongest indications of improvement (hazard ratio 0.35, 95% CI 0.09-1.31, P=0.119). Conditional survival after the first year following diagnosis was high, as most deaths occurred in the first year. As with total

five-year survival, there was little evidence of an upward trend in conditional five-year survival. Estimates of ten-year survival were, in general, only slightly lower than the fiveyear estimates. Conditional ten-year survival (for children who survived five years) was very high - 96% for all cancers combined and for leukaemias and related neoplasms, 99% for lymphomas and related neoplasms, and 95% for CNS, intracranial and intraspinal neoplasms. With cancer incidence data now available comprehensively for Irish children back to 1994, there is increasing potential for detection of factors influencing late mortality. The present analysis did not find strong evidence of disparities in childhood cancer survival within Ireland, and mediumterm survival figures are quite high in a European context. However, in the absence of precise information that can only be obtained by personal contact, it may not be possible to detect subtle influences of socio-economic status on longterm survival. Nevertheless, as the National Cancer Registry matures and years of long-term

follow-up accrue, we will be able to produce useful information to inform policy and service provision for this growing population of patients.

Symbicort® Turbohaler® (budesonide/formoterol)

the ived Rece Design Good Japan rd Awa 10* 20


Easy to use


ot Patients do n their need to hold halation breath after in

High lung deposition se)² (25-40% of delivered do

Peak Inspiratory Flow3 from around 30 L/min

Symbicort® Turbohaler® – For Asthma and severe COPD


Consult SmPC for full information

PRESCRIBING INFORMATION. Refer to full Summary of Product Characteristics (SmPC) before prescribing Symbicort® Turbohaler® 100/6; 200/6; 400/12; Inhalation Powder (budesonide/formoterol fumarate dihydrate) Presentations: Inhalation powder. Symbicort Turbohaler 100/6: Each metered dose contains 100mcg budesonide/inhalation and 6mcg formoterol fumarate dihydrate/inhalation. Symbicort Turbohaler 200/6: Each metered dose contains 200mcg budesonide/inhalation and 6mcg formoterol fumarate dihydrate/inhalation. Symbicort Turbohaler 400/12: Each metered dose contains 400mcg budesonide/inhalation and 12mcg formoterol fumarate dehydrate/ inhalation. Uses: Asthma: Treatment of asthma where the use of a combination (inhaled corticosteroid and long acting β2 adrenoceptor agonist) is appropriate. Symbicort 100/6 is not appropriate for patients with severe asthma. COPD (Symbicort 200/6; 400/12): Symptomatic treatment of patients with severe COPD (FEV1 <50% predicted normal) and a history of repeated exacerbations, who have significant symptoms despite regular therapy with long-acting bronchodilators. Dosage and Administration: Asthma (Symbicort maintenance therapy – regular maintenance treatment with a separate rescue medication): Adults (including elderly) 100/6 and 200/6: 1-2 inhalations twice daily. Some patients may require up to a maximum of 4 inhalations twice daily; 400/12: 1 inhalation twice daily. Some patients may require up to a maximum of 2 inhalations twice daily Adolescents (12-17 years) 100/6 and 200/6: 1-2 inhalations twice daily; 400/12: 1 inhalation twice daily. Children 6 years and older 100/6 only: 2 inhalations twice daily. Symbicort is not recommended for children under 6 years. Symbicort 400/12 is not recommended for children under 12 years. Not intended for the initial management of asthma. Dose should be individualised. If an individual patient requires dosages outside recommended regimen, appropriate doses of β2 adrenoceptor agonist and/or corticosteroid should be prescribed. When long-term symptoms are controlled, titrate to the lowest effective dose, which could include a once daily dosage. Asthma (Symbicort maintenance and reliever therapy – regular maintenance treatment and as needed in response to symptoms) for Symbicort 100/6 and 200/6 only (NOT recommended with 400/12 strength): especially consider for (i) patients with inadequate asthma control and in frequent need of reliever medication (ii) patients with asthma exacerbations in the past requiring medical intervention. Close monitoring for dose-related adverse effects is needed in patients who frequently take high numbers of Symbicort asneeded inhalations. Adults (including elderly) 100/6 & 200/6: 1 inhalation twice daily or as 2 inhalations once daily. For some patients a dose of 2 inhalations twice daily may be appropriate (200/6 strength only). Patients should take 1 additional inhalation as needed in response to symptoms. If symptoms persist after a few minutes, an additional inhalation should be taken. Not more than 6 inhalations should be taken on any single occasion. A total daily dose of more than 8 inhalations is not normally needed; however, up to 12 inhalations a day could be used for a limited period. Patients using more than 8 inhalations daily should be strongly recommended to seek medical advice and should be reassessed; their maintenance therapy should be reconsidered. Patients should be advised to always have Symbicort for reliever use. Children and adolescents under 18 years of age: not recommended. COPD (200/6): Adults: 2 inhalations twice daily. (400/12): 1 inhalation twice daily. Contraindications, Warnings and Precautions etc.: Contraindications: Hypersensitivity (allergy) to budesonide, formoterol or lactose (which contains small amounts of milk proteins). Warnings and Precautions: If treatment is ineffective, or there is a worsening of the underlying condition, therapy should be reassessed. Sudden and progressive deterioration in control requires urgent medical assessment. Patients should have their appropriate rescue medication available at all times, i.e. either Symbicort or a separate reliever. If needed for prophylactic use (e.g. before exercise) a separate reliever should be used. Therapy should not be initiated during an exacerbation. Serious asthma-related adverse events and exacerbations may occur and patients should continue treatment but seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation of Symbicort. Paradoxical bronchospasm may occur, with an immediate increase in wheezing and shortness of breath after dosing. This responds to a rapid-acting inhaled bronchodilator and should be treated straightaway. As with any inhaled corticosteroid, systemic effects may occur, particularly at high doses prescribed for long periods. These may include Cushing’s syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, cataract and glaucoma and more rarely a range of psychological or behavioral effects. Potential effects on bone should be considered especially in patients on high doses for prolonged periods that have co-existing risk factors for osteoporosis. Prolonged treatment with high doses of inhaled corticosteroids, particularly higher than recommended doses, may also result in clinically significant adrenal suppression. Therefore additional systemic corticosteroid cover should be considered during periods of stress such as severe infections or elective surgery. Treatment with supplementary systemic steroids or inhaled budesonide should not be stopped abruptly. During transfer from oral steroid therapy to Symbicort, a generally lower systemic steroid action will be experienced which may result in the appearance of allergic or arthritic symptoms which will need treatment. In rare cases, symptoms such as tiredness, headache, nausea and vomiting can occur due to insufficient glucocorticosteroid effect and temporary increase in the dose of oral glucocorticosteroids is sometimes necessary. Observe caution in patients with thyrotoxicosis, phaeochromocytoma, diabetes mellitus, untreated hypokalaemia, or severe cardiovascular disorders. As with other β2 adrenoceptor agonists, hypokalaemia may occur at high doses. Particular caution recommended in unstable or acute severe asthma as this effect may be potentiated by xanthine-derivatives, steroids, diuretics and hypoxia. Monitor serum potassium levels. Hypokalaemia may increase the disposition towards arrhythmias in patients taking digitalis glycosides. In diabetic patients, consider additional blood glucose monitoring. Symbicort contains lactose monohydrate, as with other lactose containing products the small amounts of milk proteins present may cause allergic reactions. Interactions: Concomitant treatment with potent CYP3A4 inhibitors should be avoided. If this is not possible the time interval between administration should be as long as possible. Symbicort maintenance and reliever therapy is not recommended in patients using potent CYP3A4 inhibitors. Not to be given with beta adrenergic blockers (including eye drops) unless there are compelling reasons. Concomitant administration with quinidine, disopyramide, procainamide, phenothiazines, antihistamines (terfenadine), MAOIs and TCAs can prolong the QTc-interval and increase the risk of ventricular arrhythmias. L-Dopa, L-thyroxine, oxytocin and alcohol can impair cardiac tolerance. Concomitant administration with MAOIs, including agents with similar properties such as furazolidone and procarbazine, may precipitate hypertension. Risk of arrhythmias in patients receiving anaesthesia with halogenated hydrocarbons. Concomitant use of other beta adrenergic drugs or anticholinergic drugs can have a potentially additive bronchodilating effect. Pregnancy and Lactation: Should only be used when the benefits outweigh the potential risks. Budesonide is excreted in breast milk, however at therapeutic doses no effects on the child are anticipated. Undesirable effects: Common: headache, palpitations, tremor, candida infections in the oropharynx, coughing, mild irritation in the throat, hoarseness. Uncommon: tachycardia, nausea, dizziness, bruises, aggression, psychomotor hyperactivity, anxiety, sleep disorders. Rare: hypokalaemia, cardiac arrhythmias including atrial fibrillation, supraventricular tachycardia and extrasystoles, bronchospasm and immediate and delayed hypersensitivity reactions including exanthema, urticaria, pruritus, dermatitis, angioedema and anaphylactic reaction. Very Rare: psychiatric disorders including depression, behavioural changes (predominantly in children), angina pectoris, prolongation of QTc-interval, hyperglycaemia, taste disturbance, Cushing’s syndrome, adrenal suppression, growth retardation, decrease in bone mineral density, cataract and glaucoma and variations in blood pressure. As with other inhalation therapy, paradoxical bronchospasm may occur in very rare cases. Package Quantities: Each Symbicort Turbohaler 100/6 or 200/6 contains 120 inhalations. Each Symbicort Turbohaler 400/12 contains 60 inhalations. Legal Category: Prescription Only Medicine (POM). Marketing Authorisation Number(s): PA 970/28/1-3. Marketing Authorisation Holder (MAH): AstraZeneca UK Limited, 600 Capability Green, Luton, LU1 3LU, UK. Further product information available on request from: The MAH (address above), Freephone -1800 800 899. Abridged Prescribing Information prepared: 04/12. Symbicort and Turbohaler are Trade Marks of the AstraZeneca group of companies.URN: 12/0447 Date of Preparation: October 2012. Reference: 1. Adelphi Respiratory Disease Specific Programme 2009. 2. Olof Selroos et al. Treat Respir Med 2006; 5 (5): 305-315. 3. Engel et al. Br J Clin Pharmacol 1992; 33(4): 439-44. *JIDPO (Japan Industrial Design Promotion Organisation) Good Design Award Japan 2010: 687&sheet=outline&lang=en

42 Report

All-Ireland Pharmacy Conference The 6th All Ireland Pharmacy Conference was held on the 13th November 2012 at the Ballyscanlon House Hotel, Dundalk. It was attended by over 150 hospital and community pharmacists, pharmaceutical assistants and technicians from all over Ireland. This Conference is held every two years and is funded by the Northern Ireland Centre for Pharmacy Learning and Development (NICPLD) and by the Irish Centre for Continuing Pharmaceutical Education (ICCPE). As part of this Conference, there was a most

successful Poster exhibition which attracted over 80 poster presentations on a large variety of topics of significant interest to the practice of pharmacy. Its focus is to share good practice in pharmaceutical care across the primary and

secondary care sectors and is an important forum that enables the exhange of ideas for pharmaceutical service development in both the North and in the Republic of Ireland. The theme for this year's Conference was "Optimising

care in an age of austerity". The keynote address was delivered by Professor Christine Bond, Professor of Primary Care (Pharmacy) and Head of the Centre of Academic Primary Care at the University of Aberdeen.

Medicines in Pregnancy Consideration should be given to publishing new information relating to medicines in pregnancy focusing on those medicines generating the most common type of enquiries. These were the findings of an analysis of pregnancy enquiries made to the National Medicines Information Centre (NMC) for 2011. The NMC in 2006 published a series of bulletins on frequently asked questions on the use of medicines in pregnancy for healthcare professionals. The accounts for approximately 7%


of enquiries each year. The aim of this study was to investigate the number and type of pregnancy-related enquiries and to identifty the most common classes of medicines/therapeutic areas which are the subject of enquiries. "Enquiries relating to the safety of anti-depressants in pregnancy rate high in prevalence and with information in this area changing frequently, there would appear to be a need for continual advice. An up-to-date bulletin on medicines in pregnancy is timely," concludes the authors.



1: Peter McKee, PSNI pre-reg lead; Laura O'Loan, Northern Ireland Centre for Pharmacy Learning & Development; and Michelle McCorry, PSNI pre-reg lead 2: Cris Ryan, Queens University Belfast and Carole Parsons, Queens University Belfast 3: Niamh McMahon, Trinity College Dublin/St James's and Sinead McCool, Irish Centre for Continuing Pharmaceutical Education

Issue 7 â&#x20AC;˘ HPN


Poster Presentations A pharmaceutical care audit on bone health medication in long-term care for people with intellectual disability was carried out by Bernadette Flood, Senior Pharmacist at St Joseph's Centre, Daughters of Charity in Consilla. The purpose of the health care audit is to monitor to what degree standards for any given healthcare activity are met, identify reasons why they are not met and indentify and implement changes to practice to meet those standards. To ensure that PWAID have optimal access to bone health medication the pharmacist undertook an audit of medication dispensed in the

centre, providing a targeted medication report after each reported fall. The author reports: "Harm from falls can be dramatically reduced with appropriate interventions and a pharmaceutical service that is responsive o each individuals differing risk factors, needs and preferences.


"Pharmacists must be willing to participate in safety culture change by providing professional interventions, such as targeted pharmaceutical care, to achieve results that will help ensure quality care and quality of life years for those ageing with intellectual disability in long-term care."


Six Sigma Methadology The pharmacy team at Tallaght Hospital Dublin looked at a review of the dispensary process using the Six Sigma methadology. "Multiple order types and poor appreciation of workflow concepts had resulted in well meaning but inefficient practices, wide variation in turn around times and a perception among nurses that the dispensary process was slow and cumbersome," say the authors. "We used Six Sigma process improvement methodology to define what was critical to quality, identify key measureable out puts and generate solutions which would reduce the overall variation within our dispensary process." The aim of the study was

to streamline and clarify the process for dispensing of inpatient non-stock medication. The project used the Define, Measure, Analyse, Improve, Control (DMAIC) method and a project team was formed comprising of managers, team leaders and staff working on the dispensary floor.


"Use of the Six Sigma process improvement methodology in the dispensary has resulted in a positive change to our processes. The time taken to dispense and check each item has reduced and standard process instructions are available at each work station. "Time saved in the dispensary has been used to extend our Ward Based Technician service to an additional medical ward."


4: Leona McCallion, Whitehouse Pharmacy, Derry; Sandra Cooke, Whitehouse Pharmacy, Derry; and Michelle Anderson, Health Service Executive 5: Cris Ryan, Queens University Belfast and Dr Norman Morrow, Chief Pharmaceutical Officer with the Northern Ireland Department of Health, 6: Deirdre Quinn, Health & Social Care Board of Northern Ireland, Mark Timoney, Department of Health, Social Services & Public Safety; and Anita Hogg, Northern Health & Social Care Trust Social Services and Public Safety 7: Aoife Fleming, University College Cork and Jane Strong, Tallaght Hospital HPN â&#x20AC;˘ Issue 7

44 News

IPHA Annual Meeting The IPHA recently held their annual meeting. Discussions included: Neurologist and TCD academic, Prof Orla Hardiman in her contribution outlined how there was a strong link between innovation and better health outcomes, while the Director of the National Cancer Control Programme, Dr. Susan O’Reilly explained the challenges of bringing innovative cancer treatments to patients. The meeting also heard from the Director General of Science Foundation Ireland and Chief Scientific Advisor to the Government, Prof Mark Ferguson on how despite the current fiscal challenges, support for innovation and research and development in

Issue 7 • HPN

particular, was a key aspect of Government policy on economic growth. Professor Charles Normand, Edward Kennedy Professor of Policy Management at TCD, contended that the economic crisis provided the health

services with an opportunity to restructure itself and that better services to patients could be delivered at a lower cost.

1) Left to right, Prof. Mark Ferguson, Director General, SFI and Chief Scientific Advisor to the Government; John McCormack, Chief Executive, Irish Cancer Society; Francis Lynch, IPHA President 3) Francis Lynch, Anne Nolan, IPHA Chief Executive, John McCormack 4) John McCormack, Prof Orla Hardiman, Consultant Neurologist, Dr. Susan O’Reilly, Director NCCP 5) Francis Lynch, Anne Nolan, Tony O’Brien



BuTrans Patches ®

…effective analgesia helping 2,4 to improve quality of life

Butrans® patches contain an opioid analgesic BuTrans® 5 µg/h, 10 µg/h and 20 µg/h vasodilatation, dyspnoea, constipation, dry Transdermal Patch. Prescribing mouth, nausea, vomiting, abdominal pain, Information. Republic of Ireland. Please diarrhoea, dyspepsia, sweating, tiredness, read the Summary of Product pain, peripheral oedema, application site Characteristics before prescribing. pruritus, application site reaction, application Presentation: BuTrans 5 µg/h, 10 µg/h, 20 site erythema, application site rash, chest pain, µg/h. Transdermal beige patches containing pruritus, erythema, rash, exanthema, asthenia. buprenorphine. Indications: Treatment of Uncommon but potentially serious (≤ 1/100): non-malignant pain of moderate intensity anaphylactic reaction, anaphylactoid reaction, when an opioid is necessary for obtaining restlessness, agitation, depersonalisation, adequate analgesia. BuTrans is not suitable for euphoric mood, affect lability, hallucinations, the treatment of acute pain. Dosage and psychotic disorder, decreased libido, drug Administration: BuTrans should be admin- dependence, mood swings, sedation, istered every 7 days. Elderly and adults over 18 migraine, balance disorder, speech disorder, years only: Use the 5 µg/h patch for at least blurred vision, visual disturbance, eyelid the first 3 days of treatment, before increasing oedema, vertigo, angina pectoris, palpitations, the dose if necessary. Do not use more than tachycardia, hypotension, circulatory collapse, two patches at a time. Contra-indications: hypertension, asthma aggravated, hypoxia, Known buprenorphine or excipient wheezing, hyperventilation, respiratory hypersensitivity, opioid dependent patients, depression, respiratory failure, diverticulitis, use for narcotic withdrawal treatment, dysphagia, ileus, biliary colic, muscular respiratory depression, use of MAO inhibitors weakness, urinary retention, erectile within the past 2 weeks, myasthenia gravis, dysfunction, sexual dysfunction, oedema, delirium tremens. Precautions and drug withdrawal syndrome, alanine aminoWarnings: Convulsive disorders, head injury, transeferase increased, accidental injury, fall. shock, reduced consciousness of uncertain Please consult the SPC for details of other sideorigin, intracranial lesions or increased effects. Legal category: CD (Sch2) POM intracranial pressure, severe hepatic Package quantities: 5 µg/h transdermal impairment, history of drug abuse. Not patch: 2 individually sealed patches 10 µg/h recommended immediately postoperatively or transdermal patch: 4 individually sealed for situations characterised by a narrow patches 20 µg/h transdermal patch: 4 therapeutic index or for rapidly varying individually sealed patches. Marketing analgesic require-ments. May affect ability to Authorisation numbers: PA 913/24/1-3. drive or use machinery. As with all opioids, Marketing Authorisation holder: chronic use may result in the development of Mundipharma Pharmaceuticals Limited, physical dependence. Interactions: Mono- Millbank House, Arkle Road, Sandyford, amine oxidase inhibitors (MAOIs), CNS Dublin 18. Tel: +353 (0)1 2063800. One of depressants (e.g. benzodiazepines, opioid the Mundipharma / Napp independent derivatives, antidepressants, sedatives, associated companies. Date of preparation: alcohol, anxiolytics, neuroleptics, clonidine). August 2011 (UK/BUTR-11033). References: CYP 3A4 inhibitors and inducers, products 1. Butrans® SPC. 2. James IGV, O'Brien CM reducing hepatic blood flow (e.g. halothane). and McDonald CJ. J Pain Sympt Manage Pregnancy and lactation: BuTrans should not 2010; 40(2):266-278. 3. MIMS Ireland. 4. be used during pregnancy or in women of Karlsson M. et al: Efficacy and Safety of Low childbearing potential who are not using dose Transdermal Buprenorphine Patches effective contraception. The use of BuTrans (5,10 & 20ug/h) versus prolonged release during lactation should be avoided. Side tramadol tablets (75, 100, 150 and 200mgs) Effects: Very common (≥ 1/10) or common in patients with chronic osteoarthritis pain: a (≥ 1/100) side-effects: anorexia, confusion, twelve week, randomized open label, depression, insomnia, nervousness, headache, controlled, parallel-group non inferior study. dizziness, somnolence, paraesthesia, Clinical Therapeutics /Vol 31 No3, 2009. Adverse events should be reported to Mundipharma Pharmaceuticals Limited on 1800 991830 ® BuTrans and the Mundipharma device (logo) are Registered Trade Marks. © 2011 Mundipharma Pharmaceuticals Limited. IRE/BU-12001a. Date of Item: April 2012

BuTrans® 5mg: 7 days continuous pain relief 1 The lowest dose opioid analgesic patch 3 available in Ireland Reduces the burden of daily tablet use 2

A joint effort… good news for your patients and good news for you

46 LK Shields

Masters of pharmacy join the profession Approximately 134 students have been conferred with Degrees of Masters in pharmacy from the Royal College of Surgeons of Ireland. In total 835 students were conferred, marking the largest number of

students to graduate from the College in one day. Professor Cathal Kelly, CEO/ Registrar, RCSI said: "The variety and number of awards being presented here today reinforces RCSI's key role as a

leading provider in healthcare education in Ireland. This marks a celebration and recognition of the graduate's accomplishments which they have achieved through outstanding ability, diligent application, sacrifice,

excellent teaching and, in particular the support of family and friends. I would like to congratulate everyone here on their achievements and wish them success in their careers."

1) Pictured (l-r) is Paul Fahey, Helen O'Donnell, Lorraine Horgan, Ciara McGoldrick and Prof. Paul Gallagher, Head of School of Pharmacy, RCSI. 2) Pictured (l-r) are Maria McCarra, Muiriosa Healy, Shelia O'Loughlin, Béibhinn O'Leary and Maria O'Donovan who all graduated with a Degree of Master in Pharmacy 3) Pictured (l-r) are Orla Cunningham, Eamonn Cronin and Fiona Treacy who all graduated with a BSc in Pharmacy. 4) Pictured is Dr. Tom Patton, Prof. Kevin Nolan and Dr. Ben Ryan with students who graduated with an MSC in Industrial Pharmaceutical Science.

New journey to address disease On January 2nd 2013, almost 400 Staff in Ireland have started working for AbbVie – the world’s newest Biopharmaceutical company. AbbVie is the new biopharmaceutical company created by the separation of Abbott into two listed public companies. Almost 400 AbbVie staff in Ireland start on a new and exciting journey working for a company developing therapies to address some of the world’s most complex diseases. AbbVie will have manufacturing operations in Cork and Sligo,

Issue 7 • HPN

with its commercial offices based in Liffey Valley, Co.Dublin. The Sligo plant manufactures a number of commercial medicines and supports the company’s efforts in developing a strong pipeline of new therapies and medications. Among the products manufactured at AbbVie’s Cork facility in Carrigtwohill are medicines that are prescribed to reduce cholesterol levels in patients at risk of heart disease.

Ryan Quigley, General Manager, AbbVie Ireland, which employs almost 400 people in Cork, Sligo and Dublin following AbbVie’s global launch today as it separates from Abbott. Ireland is one of AbbVie’s key manufacturing locations hosting 3 of the company’s 14 global manufacturing and R&D sites.


Getting scientific with the Science Circle Pfizer (Ireland) has announced that is to join the ‘Science Circle’ at Trinity College Dublin’s Science Gallery. The ‘Science Circle’ is a group of companies who commit to an ongoing philanthropic relationship with the Science Gallery over a number of years and Pfizer will be joining other leading global companies in supporting the Gallery’s yearly programmes and fostering the development of science in Ireland.

Aoibhinn Ni Shuilleabhain and Dr. Paul Duffy, Vice-President, Pfizer at the Science Circle at the Science Gallery, Trinity College Dublin

Topra and IMB annual symspoium The Irish Medicines Board (IMB) and The Organisation for Professionals in Regulatory Affairs (TOPRA) recently cohosting the Annual Symposium in Dublin. This was the key annual European regulatory forum for all those involved in the pharmaceutical sector, both human and veterinary, and in medical devices and aimed to provide all the latest information and, importantly, what is coming over the horizon for all professionals in healthcare regulatory affairs. This Symposium was intended for all those involved in regulatory affairs and brings

together representatives of industry, the regulatory agencies and the European Commission to discuss and understand today’s regulatory issues and debate the future plans for regulation.

Pat O’Mahony, Chief Executive, IMB and Craig McCarthy, Chair of the 2012 Symposium Working Party, TOPRA

HPN • Issue 7

The evoluTion of Generics The evolution of Generics

Gemcitabine 100 mg/ml concentrate for solution for infusion Accord has developed a ready to use formulation of Gemcitabine: Gemcitabine 100 mg/ml Concentrate for Solution for Infusion which allows to calculate a more precise total volume of concentrate required to prepare a given dose, as shown in the table:

Dosage required

100 mg/ml formulation (Accord)

1800 mg

18 ml

2250 mg

22.5 ml

Aware of the higher concentration of the product before the preparation of solution for infusion (concentration 100 mg/ml as compared to 38 mg/ml after the preparation of solution for infusion in the originator) warning texts have been included in product cartons and labels to avoid any potential confusion by personnel dispensing, handling and preparing Gemcitabine concentrate for solution for infusion.

100 mg/ml

”: Concentration must be noticed

100 mg/ml

Warning text “caution, new concentration overdose may occur.

Text “Must be diluted before use”: Gemcitabine concentrate for solution for infusion must be diluted. The total quantity of the Gemcitabine concentrate for solution for infusion required for an individual patient should be diluted into at least 500 ml of sterile sodium chloride 9 mg/ml (0.9%) solution to a final concentration of 0.1 to 5 mg/ml.

100 mg/ml highlighted: 100 mg/ml concentration is highlighted by a coloured box on both main faces of carton, on top flap and on product label. This is highlighted across the different product presentations.

or life-threatening

1000 mg/10 ml

“Must be diluted before use” This text has been made more prominent on the main face of the carton and on label. Bold text has been applied.

“100 mg/ml” coloured box “caution, notice new concentration (100 mg/ml)” This text has been included in carton and label, right below the name of the product and it’s repeated on both main faces of the carton. Bolded text has been applied.


100 mg/ml

Concentrate for Solution for Infusion is available in different presentations:

Each presentation is differentiated by: •

including horizontal running lines: one line represents the lowest fill volume and for each next fill volume there is one additional bolded line.

each presentation has a different colour strip alongside the product name box, matching with the same colour of boxed text also included. Accord Gemcitabine Solution SPC available on IMB database

Accord Healthcare Ireland Ltd, 24-26 Bullford Business Campus, Kilcoole, County Wicklow, Ireland. Tel. +353 (0)1 2592020

healthcare Ltd.

1500 mg/15 ml 2000 mg/20 ml 200 mg/2 ml


Clinical Profiles New Product Launch – ZinforoTM (ceftaroline fosamil) in Ireland

AstraZeneca Pharmaceuticals (Ireland) Ltd. is pleased to announce the launch of ZINFOROTM, a new intravenous anti-MRSA cephalosporin for the treatment of complicated Skin and Soft Tissue Infections (cSSTI) and Community Acquired Pneumonia (CAP) in patients with additional concern, referred to the Infection Specialist. Mechanism of Action: In vitro studies have shown that ZinforoTM is bactericidal and able to inhibit bacterial cell wall synthesis in MRSA and penicillin non-susceptible Streptococcus pneumoniae (PNSP) due to its affinity for the altered penicillinbinding proteins (PBPs) found in these organisms1 Spectrum of Activity: ZinforoTM has demonstrated activity against multidrug-resistant Streptococcus pneumoniae and

Mirabegron Receives Positive Chmp Opinion For Treatment Of Overactive Bladder Symptoms

ELIQUIS® (apixaban) Launched in Ireland for Preventing Venous Thromboembolism after Elective Hip or Knee Replacement

ASTELLAS PHARMA EUROPE Ltd. have announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion, recommending the granting of a marketing authorisation for BETMIGATM (mirabegron) for the symptomatic treatment of urgency, increased micturition frequency and/or urgency incontinence as may occur in adult patients with overactive bladder (OAB) syndrome.

Staphylococcus aureus, including methicillin-resistant, vancomycinintermediate, linezolid-resistant, and daptomycin-non-susceptible strains.2 Indications and Administration: ZinforoTM is indicated in adults for the treatment of complicated Skin and Soft Tissue Infections (cSSTI) and Community Acquired Pneumonia (CAP). For the treatment of cSSTI and CAP in adults (>18 years old), the recommended dose is 600mg administered every 12 hours by IV infusion over 60 minutes. Recommended treatment duration for cSSTI is 5 to 14 days and recommended duration for CAP is 5 to 7 days.1 Safety and Tolerability: In four pivotal clinical trials, 1305 adult patients were treated with ZinforoTM

within the next 74-90 days. When approved, mirabegron will be the first in a new class of OAB treatment, offering healthcare professionals an alternative option to antimuscarinics (currently the only licensed oral treatment option) when treating patients with OAB.

The opinion now needs ratification by decision of the European Commission which is expected

Mirabegron is a once daily oral β3-adrenoceptor agonist with a distinct mechanism of action compared to antimuscarinics, the current treatment standard. Antimuscarinics work by binding to muscarinic receptors in the bladder and inhibiting involuntary bladder contractions. Mirabegron works by stimulating the β3

Eliquis® 2.5mg has been recently launched in Ireland for the prevention of venous thromboembolic events (VTE) in adult patients who have undergone elective hip or knee replacement surgery. This is the first approved indication for ELIQUIS®, a new oral direct Factor Xa inhibitor developed by the alliance of Bristol-Myers Squibb and Pfizer Inc.

ELIQUIS® is the only oral anticoagulant with a 12- to 24-hour post surgery initiation window, which may help physicians to observe and stabilize postsurgical patients before beginning treatment. ELIQUIS® is dosed 2.5 mg twice daily, requires no routine platelet or liver monitoring, other than measurement of ALT as part of standard preoperative assessment, and requires no dose adjustment in

The most common adverse reactions occurring in ≥ 3% of patients treated with ZinforoTM were diarrhoea, headache, nausea, and pruritus, and were generally mild or moderate in severity.1 Should you require further information please refer to the ZinforoTM Summary of Product Characteristics (SmPC), available on or contact AstraZeneca on FreePhone: 1800 800 899 URN: 12/0606; Date of Preparation: December 2012 References: 1. Zinforo SmPC 2. Saravolatz LD, Stein GE & Johnson LB (2011) ceftaroline: A Novel Cephalosporin with Activity against Methicillin resistant Staphylococcus aureus. Clinical Infectious Diseases 52 (9): 1156-1163.doi: 10.1093/cid/ cir147

receptors in the detrusor muscle of the bladder causing relaxation of the bladder muscle during the storage phase of the micturition cycle. This improves the storage capacity of the bladder without inhibiting bladder voiding. The positive opinion was reached after the CHMP reviewed comprehensive clinical trial evidence from 7 phase II / III studies in which over 5,000 patients received mirabegron, including three Phase III doubleblind, randomised controlled trials conducted in the US and EuropeAustralia.

indicated patients. In patients undergoing hip replacement surgery, the recommended duration of treatment is 32 to 38 days. In patients undergoing knee replacement surgery, the recommended duration of treatment is 10 to 14 days. The approval of ELIQUIS® was based on the ADVANCE-2 and ADVANCE-3 clinical trials, part of the EXPANSE clinical trial program.

HPN • Issue 7

50 Clinical Profiles Authorisation granted for bortezomib

The European Commission has granted marketing authorisation for the subcutaneous administration of bortezomib in the European Union, pharmaceutical company Janssen announced. Bortezomib is already indicated for the treatment of multiple myeloma. This new authorisation is based on data from a Phase III study demonstrating that subcutaneous administration of bortezomib is equally effective as intravenous bortezomib but is associated with a reduction in the frequency and severity of side effects. It also offers greater convenience for patients and physicians as

Daiichi Sankyo Completes Enrolment in Hokusai – VTE, investi-gating oncedaily Edoxaban in the Largest Single Phase 3 Study for the Treatment and Prevention of Recurrence of VTE

Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) announced that it has completed patient enrolment in the global Hokusai-VTE phase 3 study investigating the oncedaily oral factor Xa inhibitor edoxaban for the treatment and prevention of recurrence of venous thromboembolism (VTE) in patients who have had an acute symptomatic deep vein thrombosis (DVT), pulmonary embolism (PE), or both.


Actavis Ireland is delighted to announce the addition of Osbonelle (Ibandronic Acid) 150 mg X 1 film-coated tablets to its growing portfolio of products. Osbonelle is indicated for the treatment of osteoporosis in post menopausal women at increased risk of fracture.

Hokusai-VTE is the largest single phase 3 clinical study in

The Osbonelle launch adds another competitively-priced product to Actavis portfolio and further underlines the Company’s position as the fastest growing pharmaceutical company on the Irish market¹. Osbonelle is GMS reimbursable from November 1st and has a trade price of €16.31. It is subject to medical prescription. Osbonelle

Issue 7 • HPN

concluded by Moreau et al. Welcoming the approval Dr Peter O'Gorman MB FRCPI FRC Path PhD, Consultant Haematologist, Mater University Hospital, Dublin, said: “The introduction of Bortezomib SC will mean a new and convenient way to deliver Bortezomib with improved peripheral neuropathy rates which will ultimately lead to improved patient safety." The marketing authorisation is based on the results of the MMY3021 Phase III trial, published in The Lancet Oncology in 2011. The trial compared subcutaneous (SC) and intravenous (IV) administration

the treatment and prevention of recurrence of VTE. More than 8,250 patients have been enrolled in the trial from more than 400 clinical sites across 38 countries worldwide The Hokusai-VTE clinical study has been designed to reflect clinical practice, using a standard hepa-rin lead-in, and providing a flexible treatment duration of three, six or 12 months. Edoxaban 60mg once-daily will be compared to warfarin control therapy (target INR 2-3).2 This study design is allow-ing investigators to evaluate

is available from wholesalers with immediate effect. For further information on the Actavis portfolio please contact Actavis Ireland on

of bortezomib in relapsed multiple myeloma patients. Results from the trial showed that the efficacy of SC bortezomib was similar to that of IV bortezomib, but that the frequency and severity of side effects were reduced in the SC, compared to the IV group. The incidence of grade 3 or higher adverse events was significantly lower in SC compared to IV administration. Of particular note is that peripheral neuropathy was observed in 38% of patients who received SC bortezomib compared with 53% receiving IV bortezomib and grade 3 or higher peripheral neuropathy events were reduced from 16% with IV to 6% with SC.

patients with a broad range of risks, including patients with moderate or severe conditions of PE and DVT. Edoxaban is an investigational once-daily, novel oral anticoagulant that specifically, reversibly and directly inhibits factor Xa, which is an important factor in the coagulation system that leads to blood clotting

1890 33 32 31 or email on

Treatment for Pulmonary Arterial Hypertension classified as WHO functional class III, to improve exercise capacity.

Treatment should only be initiated and monitored by a physician experienced in the treatment of pulmonary arterial hypertension. In case of clinical deterioration in spite of Revatio treatment, alternative therapies should be considered. Please consult the Summary of Product Characteristics before treatment, particulary in relation to side-effects, precautions and contraindications. Further information is available on request from Pfizer Healthcare Ireland, 9 Riverwalk, National Digital Park, Citywest Business Campus, Dublin 24, Ireland. PH: 01 467 6500. Legal Category: S1A. Marketing Authorisation holder: Pfizer Limited, Sandwich, Kent CT13 9NJ, United Kingdom REV/2012/001

Renewed Renewed Hope Hope AAbreakthrough breakthrough oral medication oral medication for patients with metastatic castration-resistant prostate cancer

for patients with metastatic castration-resistant prostate cancer

ZYTIGA® 250mg Tablets PRESCRIBING INFORMATION ZYTIGA® 250mg Tablets PRESCRIBING INFORMATION ACTIVE INGREDIENT(S): Abiraterone acetate. Please refer Summary Product ACTIVE INGREDIENT(S): Abiraterone acetate. Please refer to to Summary of of Product Characteristics (SmPC) before prescribing. INDICATION(S): Taken with prednisone Characteristics (SmPC) before prescribing. INDICATION(S): Taken with prednisone or prednisolone for the treatment of metastatic castration resistant prostate cancer or prednisolone for the treatment of metastatic castration resistant prostate cancer in in whose disease progressed on after or after a docetaxel-based chemotherapy adultadult menmen whose disease has has progressed on or a docetaxel-based chemotherapy regimen. DOSAGE & ADMINISTRATION: Adults: 1000 mg (4 tablets) single daily regimen. DOSAGE & ADMINISTRATION: Adults: 1000 mg (4 tablets) single daily dose. food as this increases systemic exposure (take dose at least dose. NotNot withwith food as this increases thethe systemic exposure (take dose at least twotwo hours eating; no food forleast at least hour post-dose). Swallow whole with water. hours afterafter eating; no food for at oneone hour post-dose). Swallow whole with water. recommended of prednisone or prednisolone of mg 10 mg daily. Children: TakeTake withwith recommended dosedose of prednisone or prednisolone of 10 daily. Children: relevant Renal impairment: dose adjustment, however experience No No relevant use.use. Renal impairment: No No dose adjustment, however no no experience in patients prostate cancer severe renal impairment; caution advised. in patients withwith prostate cancer andand severe renal impairment; caution advised. Hepatotoxicity: If hepatotoxicity develops upper of normal - ULN), stop Hepatotoxicity: If hepatotoxicity develops (ALT(ALT >5x >5x upper limitlimit of normal - ULN), stop treatment immediately function returns to baseline; restart Zytiga at 500 treatment immediately untiluntil liverliver function returns to baseline; restart Zytiga at 500 mgmg (2 tablets) once daily and monitor serum transaminases at least every 2 weeks for (2 tablets) once daily and monitor serum transaminases at least every 2 weeks for 3 3 months monthly thereafter Special warnings & precautions). If hepatotoxicity months and and monthly thereafter (see(see Special warnings & precautions). If hepatotoxicity recurs on reduced dose, treatment. If severe hepatotoxicity develops (ALT 20xULN), recurs on reduced dose, stopstop treatment. If severe hepatotoxicity develops (ALT 20xULN), discontinue Zytiga and do not restart. Hepatic impairment: Mild (Child-Pugh class discontinue Zytiga and do not restart. Hepatic impairment: Mild (Child-Pugh class A) -A) no dose adjustment. Moderate (Child-Pugh class - approximately 4x increased systemic no dose adjustment. Moderate (Child-Pugh class B) -B) approximately 4x increased systemic exposure single doses of 1,000 Moderate/Severe (Child-Pugh class or C) exposure afterafter single oraloral doses of 1,000 Moderate/Severe (Child-Pugh class B orB C) no clinical for multiple doses; avoid Zytiga. CONTRAINDICATIONS: Pregnancy – no– clinical datadata for multiple doses; avoid Zytiga. CONTRAINDICATIONS: Pregnancy or potential to pregnant. be pregnant. Hypersensitivity to active substance excipients. or potential to be Hypersensitivity to active substance or or anyany excipients. SPECIAL WARNINGS & PRECAUTIONS: Cardiovascular: Caution in patients with history SPECIAL WARNINGS & PRECAUTIONS: Cardiovascular: Caution in patients with history of cardiovascular disease. Safety established in patients ventricular ejection of cardiovascular disease. Safety notnot established in patients withwith leftleft ventricular ejection fraction < 50% or NYHA Class orheart IV heart failure. Control hypertension correct fraction < 50% or NYHA Class III orIII IV failure. Control hypertension andand correct hypokalaemia pre-treatment. Caution in patients whose medical conditions might hypokalaemia pre-treatment. Caution in patients whose medical conditions might be be

compromised hypertension, hypokalaemia fluid retention e.g.heart heartfailure, failure,severe severe compromised byby hypertension, hypokalaemia oror fluid retention e.g. unstable angina pectoris,recent recentmyocardial myocardialinfarction infarctionororventricular ventriculararrhythmia, arrhythmia, or or unstable angina pectoris, severe renal impairment. Monitor blood pressure, serum potassiumand andfluid fluidretention retention severe renal impairment. Monitor blood pressure, serum potassium before treatmentand andat atleast leastmonthly monthlythereafter. thereafter.Hepatotoxicity: Hepatotoxicity:Measure Measureserum serum before treatment transaminases pre-treatment and every two weeks first three months,then thenmonthly. monthly. transaminases pre-treatment and every two weeks forfor first three months, If symptoms/signs suggest hepatotoxicity, immediatelymeasure measureserum serumtransaminases, transaminases, If symptoms/signs suggest hepatotoxicity, immediately particularly serum ALT. If ALT> 5x > 5xULN, ULN,stop stoptreatment treatmentand andmonitor monitorliver liverfunction. function. particularly serum ALT. If ALT Restart treatment after liver function returns baseline; use reduceddose dose(see (seeabove). above). Restart treatment after liver function returns toto baseline; use reduced clinical data patients with activeororsymptomatic symptomaticviral viralhepatitis. hepatitis.Corticosteroid Corticosteroid NoNo clinical data in in patients with active withdrawal: Monitor adrenocorticalinsufficiency insufficiencyif ifprednisone prednisoneororprednisolone prednisoloneisis withdrawal: Monitor forfor adrenocortical withdrawn. Monitor mineralocorticoid excess if Zytiga continued after corticosteroids withdrawn. Monitor forfor mineralocorticoid excess if Zytiga continued after corticosteroids withdrawn. Bone density: Decreased bone density may accentuatedbybyZYTIGA ZYTIGAplus plus withdrawn. Bone density: Decreased bone density may bebeaccentuated glucocorticoid. Prior use of ketoconazole: Lower response rates may occur patients glucocorticoid. Prior use of ketoconazole: Lower response rates may occur ininpatients previously treated with ketoconazole prostate cancer. Intolerancetotoexcipients: excipients:Not Not previously treated with ketoconazole forfor prostate cancer. Intolerance taken patients with galactose intolerance, Lapplactase lactasedeficiency deficiencyororglucoseglucoseto to bebe taken byby patients with galactose intolerance, Lapp galactose malabsorption. Take sodium content into account for those on controlled galactose malabsorption. Take sodium content into account for those on controlled sodium diet. SIDEEFFECTS: EFFECTS:Very Verycommon: common:urinary urinarytract tractinfection, infection,hypokalaemia, hypokalaemia, sodium diet. SIDE hypertension,peripheral peripheraloedema oedemaCommon: Common:hypertriglyceridaemia, hypertriglyceridaemia,cardiac cardiacfailure failure hypertension, (including congestive heart failure, left ventricular dysfunction and decreased ejection (including congestive heart failure, left ventricular dysfunction and decreased ejection fraction), angina pectoris, arrhythmia, atrialfibrillation, fibrillation,tachycardia, tachycardia,increased increasedalanine alanine fraction), angina pectoris, arrhythmia, atrial aminotransferase, fractures (includesallallfractures fractureswith withthe theexception exceptionofofpathological pathological aminotransferase, fractures (includes fracture). Uncommon: adrenal insufficiency.Refer RefertotoSmPC SmPCfor forother otherside sideeffects. effects. fracture). Uncommon: adrenal insufficiency. FERTILITY/ PREGNANCY/ LACTATION: Notforforuse useininwomen. women.Not Notknown knownwhether whether FERTILITY/ PREGNANCY/ LACTATION: Not abiraterone or its metabolites are present in semen. A condom is required if the patient 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 thepatient patientis isengaged engagedininsexual sexual is engaged in sexual activity with a pregnant woman. If the

activitywith withaawoman womanofofchildbearing childbearingpotential, potential,aacondom condomisisrequired requiredalong alongwith with another activity effectivecontraceptive contraceptivemethod. method.No No fertility fertility data data available. available. ItIt isis not not known known if either effective abirateroneacetate acetateororitsitsmetabolites metabolitesare are excreted excreted inin human human milk. milk. INTERACTIONS: INTERACTIONS: abiraterone Cautionwith withdrugs drugsactivated activatedby byor ormetabolised metabolisedby by CYP2D6 CYP2D6 particularly particularly when when there is Caution narrowtherapeutic therapeuticindex index e.g. e.g. metoprolol, metoprolol, propranolol, propranolol, desipramine, desipramine, venlafaxine, venlafaxine, a anarrow haloperidol,risperidone, risperidone,propafenone, propafenone,flecanide, flecanide, codeine, codeine, oxycodone oxycodone and and tramadol. tramadol. haloperidol, Zytigaisisa aCYP3A4 CYP3A4substrate substrate(in (invitro vitrodata); data);avoid avoidor oruse usewith withcaution cautionwith with strong strong CYP3A4 Zytiga inhibitors (e.g. ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, inhibitors (e.g. ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir,telithromycin, telithromycin,ritonavir, ritonavir,indinavir, indinavir,nelfinavir, nelfinavir, voriconazole) voriconazole) or or inducers inducers (e.g. (e.g. saquinavir, phenytoin,carbamazepine, carbamazepine, rifampicin, rifampicin, rifabutin, rifabutin, rifapentine, rifapentine, phenobarbital). phenobarbital). Zytiga Zytiga phenytoin, is a CYP2C8 inhibitor (in vitro data). Examples of medicinal products metabolised by is a CYP2C8 inhibitor (in vitro data). Examples of medicinal products metabolised by CYP2C8incl inclpaclitaxel, paclitaxel,repaglinide. repaglinide.No Noclinical clinicaldata dataavailable available on on the the use use of of Zytiga Zytiga with with CYP2C8 CYP2C8 substrates. Food (see Dosage & Administration) above). PRESENTATIONS, CYP2C8 substrates. Food (see Dosage & Administration) above). PRESENTATIONS, PACKSIZES, SIZES, PRODUCT PRODUCT LICENCE LICENCE NUMBERS: NUMBERS: One One bottle bottle containing containing 120 120 tablets tablets PACK EU/1/11/714/001.MARKETING MARKETINGAUTHORISATION AUTHORISATIONHOLDER: HOLDER:Janssen-Cilag Janssen-Cilag International International EU/1/11/714/001. NV, Turnhoutseweg 30, B-2340 Beerse, Belgium. FURTHER INFORMATION IS NV, Turnhoutseweg 30, B-2340 Beerse, Belgium. FURTHER INFORMATION IS AVAILABLEFROM: FROM:Janssen-Cilag Janssen-Cilag AVAILABLE Ltd, 50-100 50-100 Holmers Holmers Farm Farm Way, Way, Ltd, HighWycombe, Wycombe,Buckinghamshire, Buckinghamshire, High HP124EG, 4EG,UK UK©©Janssen-Cilag Janssen-CilagLtd Ltd HP12 2012. Prescribing Prescribing information information 2012. last revised: 04 September last revised: 04 September 2012. PIVER04092012. PIVER04092012. PHIR/ PHIR/ 2012. ZYT/1112/0120. Item Item prepared: prepared: ZYT/1112/0120. November 2012. November 2012.


IN THIS ISSUE: News: Local researchers discuss rates of Polypharmacy Profile: Galway University Hospital maximise use of Lean technology - R...