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Issue 2


Nova Laboratories is one of the UK’s leading independent suppliers of both ‘Specials’ and clinical trial medicines to healthcare professionals Our state of the art facilities allow us to provide virtually any pharmaceutical dosage form, including non-sterile cytotoxic formulations. With a highly experienced and responsive team, we are able to offer excellent value for money and routinely despatch both stock items and individually compounded patient medication within 24 hours of order receipt*.

For further information, please contact us at: Martin House, Gloucester Crescent Wigston, Leicester, LE18 4YL t: f: e: w:

0116 223 0099 0116 223 0120

Report: Antibodies detected to block onset of Alzheimers Feature: Pharmaceutical Aspects of Parkinsons Disease News: Multi Million Euro Biosciences Institute opens at Trinity Report: The emergence of the Biosimilars market in Ireland Meeting: Convergence Ireland Congress spotlights medical devices industry Profile: Professor Marek Radomski gives his insights into the Pharmacy Profession

*subject to ingredient availability

Issue 2 When sequencing agents for advanced renal cell carcinoma (RCC)*...

Extended Survival Is Within Reach




Traithlon Gold for Galway Hospital Pharmacist Miriam P5

Contributing Editor Kelly Jo Eastwood

New status for Hospital Pharmacists Association P6 Profile with Professor Marek Radomski, School of Pharmacy, Trinity College P8 Pharmaceutical Group of European Union hosts Annual Meeting in Berlin P16 Biomedical Sciences Institute opens its doors P18 New President for Hospital Pharmacist Technicians Association P26 MSD Brinny invests heavily in Irish plant P32

*Nexavar ® is indicated for the treatment of patients with advanced renal cell carcinoma who have failed prior interferon-alpha or interleukin-2 based therapy or are considered unsuitable for such therapy.

Regulars Pharmaceutical interventions in the treatment of Parkinsons Disease P20 Administering medicines to Dysphagia patients P28

Nexavar is also indicated for the treatment of hepatocellular carcinoma. ®

Hospital based pharmacy services in Cancer Treatment P35 Report on the market development of Biosimilars P36 Clinical Profiles P46 Appointments P50

Hospital Pharmacy News is Circulated to all independent, multiple and hospital pharmacist, pre reg pharmacists, students pharmacy student’s offi cial bodies, government officials and departments, Pharmacy Managers, Manufactures, Wholesalers. Buyers of pharmacy groups and healthcare outlets. Circulation is free to all pharmacists Subscription rate for Hospital Pharmacy News 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 L.SM.10.2011.0238

Nexavar® 200 mg film-coated tablets (Sorafenib, as tosylate) See full Summary of Product Characteristics (SmPC) before prescribing. Qualitative and quantitative composition: 200mg sorafenib (as tosylate) Indication: 1. Treatment of hepatocellular carcinoma. 2. Treatment of patients with advanced renal cell carcinoma who have failed prior interferon-alpha or interleukin-2 based therapy or are considered unsuitable for such therapy. Dosage/Use: Treatment should be supervised by a physician experienced in the use of anticancer therapies. Adults: 400 mg twice daily with water, without food or with a low/moderate fat meal. To be taken at least 1 hour before or 2 hours after a high fat meal. Treatment should be continued as long as a clinical benefit is observed or until unacceptable toxicity occurs. Adverse drug reactions may necessitate temporary dose interruption, reduction or discontinuation, depending on severity. When dose reduction is necessary, reduce to 400mg once daily. The safety and efficacy of Nexavar in children and adolescents (<18 years) has not yet been established. No dose adjustment in the elderly or in mild, moderate or severe renal impairment. No data available in patients requiring dialysis. Monitoring of fluid balance in patients at risk of renal dysfunction is advised. No dose adjustment in Child Pugh A and B (mild to moderate) hepatic impairment. No data available on patients with Child Pugh C (severe) hepatic impairment. Contraindications: Hypersensitivity to sorafenib or to any of the excipients. Warnings and Precautions: Hand-foot skin reaction and rash, usually CTC grade 1 and 2. Increased incidence of arterial hypertension (usually mild to moderate, early in the course of treatment). Blood pressure should be monitored regularly and treated as appropriate. Increased risk of bleeding. Increased incidence of cardiac ischaemia/infarction. Use sorafenib with caution in patients who may have, or may develop prolongation of QTc, and consider periodic monitoring (on-treatment electrocardiograms, electrolytes). Gastrointestinal perforation in less than 1%; sorafenib to be discontinued. Levels of sorafenib may be increased in patients with severe hepatic impairment. Infrequent bleeding events or elevations in INR have been reported in some patients taking warfarin concomitantly. Patients on such therapy should be monitored. No formal studies on wound healing have been conducted. Temporary interruption of sorafenib therapy is recommended in patients undergoing major surgical procedures. Experience of use in the elderly is limited and cases of renal failure have been reported. High risk patients according to MSKCC prognostic group were not included in the phase III study in renal cell carcinoma and benefit-risk has not been evaluated in these patients. Higher mortality has been reported in patients with squamous cell carcinoma of the lung treated with sorafenib in combination with platinum-based chemotherapies. Interactions: Caution is recommended when administering sorafenib with compounds that are metabolised/eliminated predominantly by the UGT1A1 (e.g. irinotecan) or UGT1A9 pathways. Caution is recommended when sorafenib is co-administered with docetaxel and other anti-neoplastic agents. The risk of reduced plasma concentrations of sorafenib should be considered before starting a treatment course with antibiotics. See SmPC. Pregnancy and lactation: No data on use in pregnant women. Animal studies show reproductive toxicity including malformations and impairment of male and female fertility. Do not use during pregnancy unless clearly necessary, after careful consideration of the needs of the mother and risk to foetus. Effective contraception must be used during treatment in women of childbearing potential. Women must not breast-feed during treatment (risk of harm to infant growth and development). Effects on ability to drive and operate machinery: No studies have been performed. Undesirable effects: Very common: lymphopenia, hypo-phosphataemia, haemorrhage (including gastrointestinal, respiratory tract, cerebral), hypertension, diarrhoea, nausea, vomiting, rash, alopecia, hand-foot syndrome (palmar plantar erythrodysaesthesia syndrome), erythema, pruritus, fatigue, pain (mouth, abdominal, bone, tumour, headache), increased amylase and lipase. Common: leucopenia, neutropenia, anaemia, thrombocytopenia, anorexia, depression, peripheral sensory neuropathy, tinnitus, congestive heart failure, myocardial ischemia and infarction, hoarseness, constipation, stomatitis (including dry mouth and glossodynia), dyspepsia, dysphagia, dry skin, dermatitis exfoliative, acne, skin desquamation, arthralgia, myalgia, renal failure, erectile dysfunction, asthenia, fever, influenza like illness, weight decrease, transient increase in transaminases. Uncommon: folliculitis, infection, hypersensitivity reactions (including skin reactions and urticaria), hypothyroidism, hyperthyroidism, hyponatraemia, dehydration, reversible posterior leukoencephalopathy, hypertensive crisis, rhinorrhoea, interstitial lung disease-like events (pneumonitis, radiation pneumonitis, acute respiratory distress, etc), gastro oesophageal reflux disease, pancreatitis, gastritis, gastrointestinal perforations, increase in bilirubin and jaundice, cholecystitis, cholangitis, eczema, erythema multiforme, keratoacanthoma/squamous cell cancer of the skin, gynaecomastia, increase in alkaline phosphatase, INR abnormality, prothrombin level abnormality. Rare: Angioedema, anaphylactic reaction, QT prolongation, drug induced hepatitis, radiation recall dermatitis, Stevens-Johnson syndrome. Prescription only medicine. Marketing Authorisation Holder: Bayer Pharma AG, 13342 Berlin, Germany. MA Number: EU/1/06/342/001. Additional information is available from: Bayer Ltd., The Atrium, Blackthorn Road, Dublin 18. Tel: 01 2999313. Date of preparation: October 2011. Reference: * Kirchner, H, Strumberg, D, Bhal, A, Overkamp, F Expert Rev. Anticancer Ther. 10(4), 585–596 (2010)

ACCOUNTS Susan McBride SALES AND EVENTS ORGANISER Cliona Dudgeon 004428 90801195


Much like the abrupt winter spell now facing the country, economic relations remain decidedly frosty. The second issue of Hospital Pharmacy News features an exclusive interview with Trinity College's School of Pharmacy Head, Professor Marek Radomski. He echoes our sentiments, revealing a challenge faced by everyone within pharmacy in Ireland, how to maintain standards whilst facing financial cuts. Lessons are to be learned from Trinity, which is heading for a deficit for the first time in the College's history. They have restructured their budget and spending plans and are focused on ensuring they continue to provide the highest levels of education and training for the pharmacists of tomorrow. As Professor Marek says: "Everyone within the profession has to do all they can; we have grown and we are ambitious but we need a concentrated effort." This year's European Association of Hospital Pharmacists annual General Assembly, held in Dublin, set a milestone in its history, as the legal status of EAHP was changed to an International not-forprofit organisation (AISBL). The assembly was hosted this year by the Hospital Pharmacists Association of Ireland and it was key for delegates to hear of the important projects currently being undertaken in hospital pharmacy. The EAHP Pharmine Group has created a document on competencies within hospital pharmacy, intended to 'provide direction for those entering the hospital sector'. Future opportunities include the establishment of centres for excellence in hospital pharmacy, thus highlighting yet again that the future is firmly rooted in standards, education and e-learning. Meanwhile, HPN provides a comprehensive range of clinical features in this issue, including a special report on the development of the Biosimilars market. This area has courted controversy over the last few years, none more so than now when their emergence onto the pharmaceutical market is nearing a peak. As numerous drugs are taken off patent this year, including Pfizer's Lipitor, it remains to be seen how these new generation drugs will settle into the market. As with everything else in Ireland, and indeed the rest of Europe, it may be the money that proves the obstacle.

Elaine Conyard Professor David Wright Rebecca White Caroline Whiriskey Alejandro Forner Marı´a E. Reig Carlos Rodriguez de Lope Jordi Bruix ART DIRECTED Smart Page Design


HPN • Issue 2

4 News


Olympics on horizon for Miriam!

Joan steps up to HPAI Presidency Joan Peppard has been appointed as President of the Hospital Pharmacists Association of Ireland. Joan, Chief Pharmacist at Midlands Regional Hospital in Tullamore, takes over from outgoing President Elaine Conyard. Meanwhile, it has been revealed the National Association of Hospital Pharmacy Technicians Ireland are currently campaigning for the pharmacy technician’s role to move into a statutory regulated position, with the same responsibilities and accountabilities to the public as other regulated healthcare professionals. President Yvonne Sheehan comments: "We believe that regulation is necessary to assure clear standards and competence in the interest of the public and improved patient outcomes." Through statutory regulation they aim to:

• Develop our role in a structured way • Develop education programmes to support learning needs • Increase pride in our profession • Increase accountability for our work • Commit to self improvement. The NAHPI are currently in talks with the PSI in relation to their campaign and collaborating with the IACPT to ensure that the needs of pharmacy technicians in both the public and private sector are met.

• Standardise and protect the use of the title ‘pharmacy technician’

Joan Peppard , President of the Hospital Pharmacists Association of Ireland

Hospital deficits continue to grow The HSE's financial results for April show a total expenditure of €4.197 billion against a year-to-date budget of €4.014 billion, reflecting a reported variance of €183.7 million. In particular, year-to-date expenditure in hospitals was €1.32 billion compared with a budget of €1.220 billion — leading to an adverse variance of €99 million. “Hospital deficits have grown again in April 2011 to €99 million,” the HSE stated. “There is still no sign of expenditure reversing and the deficit continues to grow in the month. “Major actions will now be necessary to bring hospital expenditure into line with budgets,” the Executive also warned. Some hospitals, it said,

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are running up very big deficits in 2011 and considerable local action is required to bring them back to financial stability. Among hospitals with the biggest deficits are Limerick Regional Hospital Dooradoyle, which has an annual budget of €130 million (26 per cent over budget), Our Lady

of Lourdes Hospital in Drogheda with an annual budget of €111 million (12 per cent over budget), Waterford Regional with a budget of €133 million (10 per cent over budget), and Letterkenny, which has an annual budget of €95 million (some 12 per cent over budget).

The HSE pointed out that the impact of these savings was being reduced by an underlying pay growth. “This is an issue which requires considerable focus by local budget holders along with agency costs, which are up €24 million year-on-year using April data,” it stated.

Hospital Pharmacist and mother of three Miriam Wall showed she had the 'coping' strategy recently as she scooped Gold in the Cope Traithlon event held in Galway. The Pharmacist takes time out from her busy schedule within University College's Pharmacy Department to spend six days a week training for these marathon event. Despite neglecting her running career this year to work on her cycling, including a very recent successful Malin to Mizen trip on the June bank holiday, Athenry AC member Miriam Wall took gold in the Cope Triathlon (sprint distance 750m/ 20km/ 5km) held in Salthill. Miriam had a strong swim in very rough conditions to set up a good lead on last year's winner and had a great cycle in wet and windy conditions building on the 700km in her legs from the previous weekend's Malin to Mizen spin

and held off the competition on the run to take her first ever gold on the podium in triathlon.

Traithlon Gold Medal winner Miriam Wall (left).

UCD Professors elected to Royal Irish Academy In recognition of their outstanding achievements, six UCD professors have been elected to the Royal Irish Academy. This is the highest academic honour in Ireland and membership is awarded to those who have achieved distinction in education and research. The Royal Irish Academy (RIA) is Ireland’s premier learned body and vigorously promotes excellence in scholarship, recognises achievements in learning, direct research programmes and undertakes its own research projects, particularly in areas relating to Ireland and its heritage. One of those honoured is Professor Catherine Godson, Professor of Molecular Medicine at University College Dublin, where she leads a group of investigators focused on the mechanisms underlying the initiation, progression and potential regression of kidney disease. She is internationally recognised for her expertise in diabetic complications. Professor Godson’s work has provided important insights into the regulation of inflammatory processes in health and disease.

Pictured at the RIA announcement is Professor Catherine Godson (front row far right) along with five colleagues elected to the Royal Irish Academy.

HPN • Issue 2


6 News


Group picture EAHP GA 2011

This year's European Association of Hospital Pharmacists annual General Assembly set a milestone in its history, as the legal status of EAHP was changed to an International not-for-profit organisation (AISBL). The assembly was hosted this year by the Hospital Pharmacists Association of Ireland and held in Dublin. 60 representatives from 24 member countries of the EAHP gathered to discuss relevant issues related to the further development of hospital pharmacy in Europe.

Representing local views During the two-day long assembly, chaired by EAHP's President, Roberto Frontini, EAHP’s board members and delegates of each member country discussed the hot topics in health systems in Europe. The group also covered EAHP’s active role in European projects and working groups, as well as the association’s educational activities. Joan Peppard, HPAI President and Elaine Conyard, HPAI Immediate Past President, represented the

Issue 2 • HPN

views of Irish Hospital Pharmacists at the AGM. The “new” EAHP AISBL consists of 31 member associations of hospital pharmacists from different European countries, sharing the same goals of developing and establishing a common hospital pharmacy policy in Europe. The delegates approved the Statements on Patient Safety and Hospital Pharmacist Specialisation, which both serve as a fundamental point of reference for promoting a common hospital pharmacy policy across Europe. Tajda Miharija Gala and Juraj Sykora, both of whom are EAHP Directors of Professional Development, presented the EAHP Survey 2010 preliminary results, which will be officially presented to the public at the next 17th Congress of the association to be held in Milano, Italy, March 21-23, 2012. The survey results will reveal how hospital pharmacy is practiced in different European countries and show the trend of development of the services across Europe.

working group met several times in 2010 and 2011 with the aim to promote specialisation in hospital pharmacy. As well as the approved statement on Hospital Pharmacist Specialisation, the group also created a comprehensive document on competencies in hospital pharmacy. The competencies listed in the document are built upon the foundation level for early year practitioners and are intended to provide direction for those practitioners entering into the hospital sector or those who wish to demonstrate evidence for a period of workplace learning and training in a hospital setting. Future activities of the PHARMINE group will involve the establishment of centres of excellence in hospital pharmacy, the promotion of e-learning programmes, and the creation of an accredited pan-European specialisation framework in Hospital Pharmacy.

2. PHIS (Pharmaceutical Health Information System) Elfriede Dolinar, EAHP Vice President, introduced the work carried out by the participating stakeholders to the project, which took place from September 2008 to April 2011 with the aim of increasing knowledge and exchanging information on pharmaceutical policies. Of particular interest was pricing and reimbursement in the EU Member States, covering both the outpatient and the in-patient sector. The working group compiled a

a a uni qu e

3. EDQM (European Directorate of the Quality of Medicines and Healthcare)


EAHP is involved in a number of projects at European level:

glossary of terms, a database of pricing and reimbursement information from member states as well as some case studies from individual hospitals


European Projects


Report written by Elaine Conyard, HPAI


New legal status for Hospital Pharmacists Association

ch to op a io o r id p p

Vagn Handlos, EAHP Director of Education Science and Research, presented some of the issues that the newly-estalished EDQM working group will be focussing on. The formation of this working group follows on from the publication of a recommendation from from the Council of Europe regarding manufacturing in hospital pharmacy. This working group will seek to provide a practice-based interpretation of the resolution for all member countries of EAHP. EAHP has approved the establishment of another new working group to focus on information technology in the frame of the Integrating the Healthcare Enterprise (IHE) project, Connectathon, where last April 2011 in Pisa, Italy, thirteen member states of the European Union exchanged patient information to prepare for a large-scale crossborder pilot program. While the schedule at the General Assembly was intense, HPAI organised some cultural entertainment for delegates while in Dublin. Indeed, many extended their stay in order to travel outside the capital and sample the Irish countryside. The European Association of Hospital Pharmacists was founded on 6 March 1972 and membership is open to hospital pharmacists in countries belonging to the Council of Europe. EAHP’s headquarters are located in Brussels, Belgium, from where the EAHP fosters its efforts at EU level. For further information and/or material, please visit EAHP website at: ""

Powerful­on­Pain ­reduced­risk­of­ opioid-induced­ constipation

Targin® tablets contain an opioid analgesic TARGIN® 5mg/2.5mg, 10mg/5mg, 20mg/10mg and 40mg/20mg prolonged release tablets Prescribing Information Republic of Ireland Presentation: Film-coated, oblong, prolonged release tablets containing oxycodone hydrochloride and naloxone hydrochloride, marked OXN on one side and the oxycodone strength on the other. Colours: Blue - 5mg (oxycodone hydrochloride)/2.5mg (naloxone hydrochloride), white - 10mg (oxycodone hydrochloride)/5mg (naloxone hydrochloride), pink - 20mg (oxycodone hydrochloride)/10mg (naloxone hydrochloride) and yellow - 40mg (oxycodone hydrochloride)/20mg (naloxone hydrochloride). Indications: 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. Dosage and administration: Adults over 18 years: Usual starting dose for opioid naïve patients is Targin® 10mg/5mg, taken orally at 12-hourly intervals. Patients requiring a higher dose are recommended Targin 20mg/10mg tablets. Targin 5mg/2.5mg is intended for dose titration when initiating opioid therapy and individual dose adjustment. The dosage is dependent on the severity of the pain and the patient’s previous history of analgesic requirements. Patients already receiving opioids may be started on higher doses of Targin depending on their previous opioid experience. The maximum daily dose of Targin is 80mg oxycodone hydrochloride and 40mg naloxone hydrochloride. Targin tablets are not intended for the treatment of breakthrough pain. For the treatment of breakthrough pain, a single dose of “rescue medication” should amount to one sixth of the equivalent daily dose of oxycodone hydrochloride. Please refer to the SmPC for further details on dose titration. Targin tablets must be swallowed whole and not broken, chewed or crushed which leads to a rapid release and absorption of a potentially fatal dose of oxycodone. Children under 18 years: Not recommended. Contraindications: Hypersensitivity to the active substances or excipients, any situation where opioids are contraindicated, severe respiratory depression with hypoxia and/or hypercapnoea; severe chronic obstructive pulmonary disease, 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, hypothyroidism, adrenocortical insufficiency, toxic psychosis, cholelithiasis, prostate hypertrophy, alcoholism, delirium tremens, history of alcohol and drug abuse, pancreatitis, hypotension, hypertension, galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption, pre-existing cardiovascular diseases, head injury (due to risk of raised intracranial pressure), epileptic disorder or predisposition to convulsions, patients taking MAO inhibitors, renal impairment, mild hepatic

impairment, pre-operative use or within the first 12 – 24 hours post–operatively. Not suitable for the treatment of withdrawal symptoms. Not recommended in cancer associated with peritoneal carcinomatosis or sub-occlusive syndrome in advanced stages of digestive and pelvic cancers. Interactions: Substances having a CNSdepressant effect (e.g. alcohol, other opioids, sedatives, hypnotics, anti-depressants, sleeping aids, phenothiazines, neuroleptics, anti-histamines and anti-emetics) may enhance the CNS-depressant effect of Targin (e.g. respiratory depression). Interaction with coumarin anticoagulants may increase or decrease INR. Pregnancy and lactation: Not recommended. Side-effects: Common adverse drug reactions are decreased/loss of appetite, restlessness, headache, vertigo, decrease in blood pressure, abdominal pain, diarrhoea, dry mouth, constipation, flatulence, vomiting, nausea, dyspepsia, increased hepatic enzymes, hiccups, altered mood, decreased activity, psychomotor hyperactivity, agitation, dysuria, pruritus, skin reactions, hyperhidrosis, dizziness, drug withdrawal syndrome, feeling hot and cold, chills, asthenic conditions. Some side-effects which are uncommon but could be serious are hypersensitivity, confusion, depression, halluc-inations, disturbance in attention, somnolence, speech disorder, convulsions, syncope, visual disturbances, palpitations, angina pectoris, tachycardia, increase in blood pressure, dyspnoea, respiratory depression, biliary colic, erectile dysfunction, urinary retention, peripheral oedema, abdominal distension and chest pain. Please refer to the SPC for further details of other uncommon side-effects and oxycodone class-effects. Tolerance and dependence may occur. It may be advisable to taper the dose when stopping treatment to prevent withdrawal symptoms. 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: April 2011. (UK/UNA-11115). References: 1. 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-to-severe 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. © 2010-2011 Napp Pharmaceuticals Limited.

➞ ➞ ➞

Targin® provides pain relief that is as effective as oxycodone alone1 Targin® reduces the risk of opioid-induced constipation when compared to oxycodone alone1 Targin® is GMS re-imbursable 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.

8 Professor Marek Radomski


Facing adversity 'Head' on!

For the first time in the history of Trinity College we are heading towards a huge deficit.

HPN talks pharmacy, money and education with Professor Marek Radomski, Head of School of Pharmacy, Trinity From Poland Onwards Professor Radomski is a Polish-born pharmacologist, the majority of his professional life however has been spent outside Poland. He has worked both in academia and the pharmaceutical industry in Poland, UK, Canada, Spain and USA. He was recruited to the Chair of Pharmacology (1979) in 2006. He served as Director of Research in the School of Pharmacy at Trinity before his appointed as Head of School. He is also one of PIs in the Institute of Molecular Medicine and CRANN. Born in Bochnia, Poland, Professor Radomski is a medical graduate of College of Medicine Jagiellonski University in Krakow, Poland. A highly-cited pharmacologist

he has 16,700 citations to date and he has worked both in academia and pharmaceutical industry in Poland (Jagiellonski University in Krakow and Polish Academy of Sciences in Warsaw), UK (Wellcome Research Laboratories in Beckenham), Spain (Lacer SA in Barcelona), Canada (University of Alberta in Edmonton) and USA (University of Texas in Houston. He joined School of Pharmacy and Pharmaceutical Sciences Trinity College Dublin in 2006 as Professor and Chair of Pharmacology. He served as Director of Research in School of Pharmacy and currently serves as Head of School and ProDean Faculty of Health Sciences Trinity College Dublin. He contributed to undergraduate teaching of medical,dentistry, nursing and pharmacy students

in Europe, Canada and USA. He has mentored many MSc, PhD students, as well as postdoctoral researchers. When at Trinity he graduated four PhD students and presently is supervising three PhD students.

Kent, where I was responsible for drug development and research. Four Nobel Prize winners have worked at the Wellcome Trust, it was a fascinating time of insights in my career."

In 2009 Professor Radomski was conferred with an honorary doctorate (Doctor Honoris Causa) from the Complutense University Madrid in Spain which is among the oldest universities in the world. The award was given in recognition of his research work on nitric oxide, matrix metalloproteinases and, more recently, nanopharmacology and nanotoxicology.

Once the children 'flew the nest' Professor Radomski and his wife decided to return to Europe from America to, in his words, 'complete the loop.' "I came across the Chair of Pharmacology post at Trinity and from there we entered a challenging time of deciding whether or not to go but I could not have turned down a role at such a prestigious School and, thus, here we are."

Money, Money, Money "I thoroughly enjoyed my time spent at the Wellcome Trust in

Three years ago Professor Radomski accepted the role of Head of School and he freely

Professor Marek Radomski is one busy man. As the current Head of the School of Pharmacy at Trinity College, Dublin, Professor Radomski is one of two of the most cited biomedical scientists working in Ireland. He is involved in no less than five pharmacology organisations and is instrumental in helping shape the future of pharmacy education and training. He exclusively tells HPN: "This is an extraordinarily busy time, now more so than ever as the country goes through such difficult times. Of course the current financial climate as adversely affected the College and the School of Pharmacy so I have a huge number of problems to take care of." "Everyone within the College, and the profession, has to do all they can; we have grown and we are ambitious but we need a concentrated effort."

Issue 2 • HPN

HPN • Issue 2

10 Professor Marek Radomski admits: "I love my research and I love my students," he tells HPN endearingly, "but I did not realise what I would be getting myself into, simply because of the crisis Ireland has now faced. My scientific set-up where I first joined Trinity was phenomenal. I graduated 5 Phd students but the challenge here now is in increasing the profile of the school. Quite simply, it is all money, money, money. "My budget has reduced by some 30-45% having had Euro 4.5m three years ago and Euro 3.1m today. For the first time in the history of Trinity College we are heading towards a huge deficit. Trinity is 80-90% Exchequer dependent so we have somewhat converted the School strategy. This is a huge challenge, maintaining standards with cutting costs. "I remain optimistic, I want to do as much as I can so that we can secure what we have already achieved. Our research is exciting, particularly our work looking at drug development and novel drug systems, the generation of new drugs, anti-cancer drugs and anti-inflammatory drugs for example." The School has witnessed some exciting recent developments, such as the establishment of the Boots Teaching Lab. Professor Radomski continues: "The students are extremely happy with this lab and for the last five years we have worked towards the opening of Trinity;s new Biomedical Sciences Institute." The Trinity Biomedical Sciences Institute was officially opened at the end of June by Taoiseach, Enda Kenny. The Trinity Biomedical Sciences Institute is the University’s most ambitious capital project to date and represents the second phase of TCD’s Pearse Corridor Development. It reflects the degree of research prioritisation that has taken place in Trinity over recent years from building up world class staff to creating scale of an internationally competitive dimension. It is continuing the expansion of its research and education capacity outside its historic walls as Trinity works with government and with industry to restore

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Ireland's economic potential.

Thanks to the relocation of some of the services currently undertaken at the School to the new Institute, this has allowed Professor Radomski to streamline all teaching under one roof.

But this move requires at least an additional 20% in monies. How are we going to fund it, where will the money come from?

The Furthering Education Debate

Referring to the new changes in pharmacy education and the new five year curriculum, Professor Radomski voices some serious concerns. "In theory I have no problem with the arguments for this system," he says. "But this move requires at least an additional 20% in monies. How are we going to fund it, where will the money come from? No-one can answer this question." Professor Radomski is keen to highlight the ongoing work of excellence being undertaken at Trinity in the face of adversity. "We have an excellent self financing Masters Programme, one of which is the Hospital Pharmacy Masters. We are very happy with the way the course has developed; we have an extremely high quality of students, it's viable and it's bringing in money." Turning his attention to the area of hospital pharmacy, he continues: "We work very closely with hospital pharmacists here. Tamasine Grimes who is based here works in tandem with Tallaght Hospital and indeed she was with them recently looking at ways we can best work together. "Currently we are examining different research projects that we would envisage hospital pharmacists becoming involved in. We would definitely like to make our links stronger. "I have an outstanding group of academics here at the School, our development with Boots is amazing and unique and McLernons as well. We will need more kindness and investment to be part of the help effort within pharmacy in Ireland!"

“We will need more kindness and investment to be part of the help effort within pharmacy in Ireland!"

HPN • Issue 2

12 News


Galway get into the drivers seat

New therapy for lung cancer

Given that the health service in Ireland is such a big organisation some might think the long waiting times and appointments that run late are unavoidable. But are these annoyances due to lack of resources or poor management and bad organisation?

Eli Lilly and Company have announced that the European Commission has granted approval for the use of ALIMTA® (pemetrexed for injection) as a single agent for continuation maintenance therapy in patients with advanced nonsquamous non-small cell lung cancer (NSCLC). Latest figures from the National Cancer Registry of Ireland show that there were a total of 1,784 cases of lung and bronchus cancer in 2009.


smooth the journey, remove all the barriers and interruptions to delivering value, while minimising waste and being flexible and open to change. It is not an expensive or necessarily radical overhaul of the way a business operates. It works by finding common sense solutions and exploiting the expertise that exists within the workforce. Julie O'Neill, IBEC deputy president and Gilead Sciences General Manager

The team at Galway University Hospital's pharmacy department have shown their commitment to quality improvement with the adoption of the increasingly popular 'Lean' technique; designed to change healthcare culture. The Lean management ethos means making small sustained changes in order to reduce waste, increase flow and

improve value in the eyes of the customer. Lean is an approach designed to improve flow and eliminate waste which was originally developed in the motor manufacturing industry, but is now being introduced into many other industries and sectors including the health sector. Lean is simply about flow, to

"Our department is also committed to quality improvement. To this end all staff have undergone training in “Lean” – a method used by Toyota to streamline processes which can be applied in healthcare settings. "Recent applications of the “Lean” process in the pharmacy include a review of the use of medicines returned from the wards and a change to the way we answer queries at the pharmacy hatch," says Mental Health Pharmacist Allison Dunne.

Galway University Hospital is spread across two sites but the pharmacy department is managed as one team. The hospital has capacity for 997 beds and is a busy teaching hospital with links to the National University of Ireland, Galway. The pharmacy team consists of 22 pharmacists, 13 technicians, two student technicians and one pharmacy intern. Amongst the team are pharmacists who are specialists in oncology, intensive care medicine, antimicrobial treatment, medicines safety, mental health, paediatrics and healthcare management. Pharmacy technicians are given the opportunity to specialise in aseptic preparation, HIV medicine, mental health and purchasing. Continuing professional development is high on the agenda, with the majority of pharmacists undertaking a clinical diploma or masters degree.

Respiratory Prize, Dublin Sanjay Chotirmall was awarded the Respiratory Medicine Prize at the Royal Academy of Medicine in Ireland Doctor Awards, at a reception in the Royal College of Physicians in Ireland in Kildare Street. He was awarded the prize for his paper entitled "17Beta-estradiol inhibits IL-8 in cystic fibrosis

by up-regulating secretory leucoprotease inhibitor. This paper was published in the American Journal of Respiratory and Critical Care Medicine. Dr. Chotirmall is a clinical-scientist funded by Molecular Medicine Ireland. He is jointly supervised by Catherine Greene, Brian Harvey and Noel G. McElvaney.

The approval is based on clinical trial results showing an improvement in progression-free survival, as well as a preliminary analysis showing a strong trend toward better overall survival, for NSCLC patients treated first with pemetrexed plus cisplatin and then continue treatment with pemetrexed alone in the maintenance setting. Pemetrexed is the first chemotherapy agent to be approved in Europe for continuation maintenance therapy. In this setting, patients whose disease has not progressed immediately following first-line treatment with pemetrexed plus cisplatin can continue maintenance treatment with pemetrexed alone and potentially achieve additional benefit.

Continuation maintenance therapy with pemetrexed is specifically tailored to potentially benefit the group of patients with a particular type of NSCLC, called nonsquamous, and who have shown a positive response or disease stabilisation after treatment with first-line pemetrexed plus cisplatin. Although other maintenance regimens are currently available for NSCLC, they involve using different medicines in the maintenance phase of treatment than were used in the first-line setting. “Lung cancer is one of the most difficult cancers to treat and new therapy options are much needed,” said Allen Melemed, M.D. M.B.A., medical director with Lilly Oncology. “Pemetrexed is

the first tailored treatment option that can potentially extend lives beginning in first line treatment and continuing through maintenance in

advanced nonsquamous non-small cell lung cancer.”

Podhaler launched in Dublin Novartis Ireland have launched the TOBI® Podhaler®, a fast and simple therapy that helps reduce the treatment burden for cystic fibrosis patients. Professor Charles Gallagher of St Vincent’s University Hospital and University College Dublin stated that “Ireland has the highest incidence of Cystic Fibrosis in the world and we also have more severe Cystic Fibrosis than in other countries.

Podhaler were from L-R: Jason Davies, Product Manager, Novartis; Dr Greg Hays, Medical Director, Novartis; Professor Charles Gallagher of St Vincent’s University Hospital and University College Dublin; Mr Philip Watt, CEO of the Cystic Fibrosis Association of Ireland and Tómas Thompson, CF advocate and patient.

People with Cystic Fibrosis battle bravely with CF every day of their lives and most spend at least 2 hours a day taking treatment." Pictured at the launch of the TOBI

Sanjay Chotirmall

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14 News


Scientists identify natural defence cells that impede chemotherapy treatment As part of the body’s front-line defences against infection, white blood cells called macrophages often infiltrate tumours in great numbers. However, according to new research published in the scientific journal Cancer Discovery, these cells can make tumours more resistant to chemotherapy treatment. The international team of scientists involved in the discovery have shown that a depletion of macrophages (TAM) in progressing breast tumours improved the antitumour effectiveness of paclitaxel, a chemotherapeutic agent. When the team treated TAMdepleted tumours (which also had fewer blood vessels, greater numbers of cytotoxic T cells and more signs of tumour destruction) with paclitaxel they witnessed a greater reduction in the size of the tumour.

Professor William Gallagher, UCD.

“Our findings offer a new approach to improving the efficacy of established chemotherapy agents,” said Dr Donal Brennan from the UCD Conway Institute, who, along with his colleague Professor William Gallagher, UCD School of Biomolecular &

Biomedical Science and UCD Conway Institute, was part of the international team led by Professor Lisa Coussens from the University of California San Francisco. “In addition to identifying a novel therapeutic agent, we have also developed a predicitive inflammatory signature which will identify patients likely to respond to anti-CSF1R therapy,” said Dr Brennan. “The inflammatory signature will hopefully allow us to run biomarker driven clinical trials, which should allow for rapid translation of these findings into breast cancer clinics over the next few years.” Commenting on the significance of the findings, a news article in the leading scientific journal Nature said: these results “add weight

to an emerging compelling case for deciphering the complexity of leukocyte infiltrates in breast cancer.” And, “this may provide clinically relevant indications of the likely response to chemotherapy and thus patient survival.” The predicitive signature developed during this research project took advantage of a novel image analysis approach, IHCMARK, developed by Professor Gallagher’s team at the UCD Conway Institute, to quantify inflammatory cell density in cancer tissues. The method is currently being in-licenced to the spin-out company, OncoMark Limited, which is utilising such automated image analysis approaches for development of companion diagnostics.

NAPT attends European Association of Pharmacy Technicians meeting in Cardiff This year the National Association of Pharmacy Technicians (NAPT) was represented at the annual meeting in Cardiff of the European Association of Pharmacy Technicians by its President Yvonne Sheehan. The Committee of European Pharmacy Technicians (CEPT) which organised the meeting was formed in 1989 and Ireland has been a member since 2001. The meeting ran over two days when delegates discussed the statutes and internal rules of the Association, the principle aims of which are:

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 To promote and develop the profession and role of pharmacy technicians  To promote patient safety within pharmacy practice  To promote, influence and negotiate European policies on issues relevant to the pharmacy technician profession.  To collaborate with other organisations with similar objectives.  To organise a European Congress Sheehan, told IPN that she hopes

the 2013 meeting will be held in Dublin. Next year’s Annual Meeting

of the EAPT will be held in May 2012.

New treatment option for Dupuytren Contracture XIAPEX® (collagenase clostridium histolyticum), a new treatment option for Dupuytren’s contracture in adult patients with a palpable cord, is now available in Ireland. Collagenase clostridium histolyticum is the first injectable treatment to be approved in Ireland for the treatment of Dupuytren's contracture. Dupuytren’s disease affects approximately 13% of the European population. It is a slowly progressive condition affecting the layer of connective tissue in the palm of the hand and the fingers (the palmar fascia). Dupuytren’s disease starts in the palm of the hand with the appearance of a number of nodules, made of cells that can produce collagen. As the disease progresses, excess collagen continues to build up and may eventually form into a rope-like cord under the skin. The cord extends from the palm into the finger and can gradually contract the finger permanently toward the palm; this is known as Dupuytren’s contracture. "As well as impacting on aspects of everyday life such as shaking hands, using cutlery and washing, Dupuytren's contracture can also affect patients' livelihoods due to the difficulties caused by decreased hand function. As it is a progressive condition, early intervention is advisable. The introduction of a new, less invasive treatment for Dupuytren's contracture is good news for those with the condition," said Mr Kieran O’Shea, Orthopaedic Surgeon, St James’ Hospital, Dublin. Collagenase clostridium histolyticum has been the subject of two pivotal studies, Collagenase Option for Reduction of Dupuytren’s (CORD I and CORD II). The primary endpoint of CORD I was the percentage of patients achieving a reduction in contracture of the selected primary joint to 5° or less, approximately 30 days after the last injection of that joint. Results showed that 64% of primary joints treated with collagenase clostridium histolyticum met the primary endpoint, compared with 6.8% of those injected with placebo (P <0.001). In CORD II, primary endpoint was the percentage of patients

Pictured at the recent launch of a new treatment for Dupuytren’s Contracture, Xiapex® (Collagenase Clostridium Histolyticum) at the Morrison Hotel, Dublin are (L-R): Dr Stephen Beldner, Attending Orthopaedic Surgeon, Beth Israel Medical Centre, New York; Anne Daly, Customer Marketing Manager, Pfizer Ireland; Mr Kieran O’Shea, Orthopaedic Surgeon, St James’s Hospital, Dublin; and Alistair Mc Bride, Medical Advisor, Pfizer Ireland.

achieving a reduction in contracture of their primary treated joint to 5° or less, approximately 30 days after the last injection. Statistically significantly more cords injected with collagenase than placebo met the primary end point (44.4% vs 4.8%; P <0.001). In addition, patient satisfaction and physician ratings of improvement after treatment with collagenase clostridium histolyticum were significantly higher than with placebo treatment.

“The discovery of collagenase clostridium histolyticum is an important step forward in the search for a pharmacological option for Dupuytren’s contracture”, said Dr Alistair McBride, Medical Advisor, Pfizer Ireland. “It is therefore good news for patients and physicians alike that this treatment for Dupuytren’s contracture is now available in Ireland”

histolyticum is administered by local injection directly into the Dupuytren’s cord, a procedure which can be carried out in an outpatient setting and it breaks down the structure of the cord. 24 hours after injection, a finger extension procedure can be carried out as necessary to break the cord and allow extension of the finger.

Collagenase clostridium

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16 News

New opportunities afoot says PGEU The Pharmaceutical Group of the European Union has hosted in Berlin its Annual Symposium dedicated to ‘New Opportunities in Primary Care: Maximizing Pharmacists' Contribution via Interdisciplinary Collaboration.’ Delegates from Ireland included IPU's Seamus Feely and Darragh O'Loughlin. The Symposium brought together examples of innovative pharmacy practice in primary care in Europe, including medicines management, pharmacist prescribing, systematic collaboration with physicians, and pharmacy based electronic medication records. Contributions came from pharmacists from Germany, the UK, Portugal, France and the Netherlands.

Irish delegates included Darragh O'Loughlin, Seamus Feely and Liz Hoctor.

The event provided a picture from different perspectives of how the pharmacist’s role has developed in the primary care setting. Particular emphasis was given to collaboration in the primary care team, and emerging opportunities for pharmacists to increase their contribution to patient safety and the overall quality of care.

The Symposium also addressed the new opportunities for pharmacists to report adverse drug reactions created by the new European Directive on Pharmacovigilance. The Symposium, attended by over 120 national representatives from the pharmacy profession in Europe, was opened by Thomas Ilka, Parliamentary State Secretary at the Federal Ministry of Health, who addressed the

new opportunities for pharmacists presented by, among other things, the new European Directives on Pharmacovigilance and Falsified Medicines. Mr John Chave, PGEU’s Secretary General and moderator of the event said: “It is essential for both the better health of European citizens and the sustainability of health systems, that primary care evolves to better meet growing problems such as poor adherence to medication, and adverse drug reactions. Our Symposium has shown that pharmacy practice in Europe is addressing these issues head on through new forms of practice. In particular, the meeting demonstrated that more systematic collaboration between health professionals and pharmacists improves patient care and saves money for the health system.”

Masters in Hospital Pharmacy Degree Trinity College Dublin are now offering a new course for Hospital Pharmacists. This two-year, part-time course leads to a Masters Degree in Hospital Pharmacy and commences in January, 2012. The course covers all aspects relating to the practice of hospital pharmacy including clinical pharmacy, aseptic services, medicines information, dispensary services, health services management and pharmacoeconomics. The programme consists of lectures, workshops, tutorials, practice-

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based learning and a research thesis. Students are released from their base hospital one afternoon per week to attend teaching sessions. All students have an onsite tutor to provide tuition and support. Applicants must hold a first or second class honours degree in

pharmacy, and have experience working in hospital pharmacy. Successful candidates will be assigned to a training post in one of the participating hospitals. Applicants must also be registered with the Pharmaceutical Society of Ireland, prior to commencement of the course in January 2012.

Further information about the course may be also be obtained from the Course Coordinator: Ms. Niamh Mc Mahon, St. James’s Hospital, James’s Street, Dublin 8. Phone: 416 2586 / 416 2467 E-mail:

18 News

€131m Institute creates corridor of academic activity to support these industries and underpin job creation. Corridor of Activity Built around the areas of immunology, cancer and medical devices and linked directly to both medical education and industrial collaboration, the Institute will contribute to the improvement of the physical health of Irish society. Through a combination of innovation and regeneration it will also underpin the longerterm economic health of the Irish economy.

TCD Dean of Research, Dr David Lloyd, the Taoiseach, Enda Kenny, TD and TCD Provost, Dr John Hegarty.

“Trinity researchers have led world-class research in biomedical sciences from developing the nicotine patch to identifying new genes for childhood eczema and increasing our understanding of major diseases such as Alzheimer’s disease, cancer and arthritis. The University’s international rankings show its outputs are amongst the best in the world in immunology, neuroscience, microbiology and many other key fields. Building on this impressive foundation, the Trinity Biomedical Sciences Institute will drive 21st century scientific research for the benefit of improved healthcare – ensuring the relevance of our research translates not only to patient benefit but to the creation of new ventures and enterprise in Ireland,” said TCD Dean of Research, Dr David Lloyd at the opening of The Trinity Biomedical Sciences Institute. The Trinity Biomedical Sciences Institute was officially opened at the end of June by Taoiseach, Enda Kenny. EU Commissioner for Research, Innovation and Science, Máire Geoghegan-Quinn, also attended the opening and delivered the keynote address. The Trinity Biomedical Sciences Institute is the university’s most ambitious capital project to date and represents the second

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phase of TCD’s Pearse Corridor Development. It reflects the degree of research prioritisation that has taken place in Trinity over recent years from building up world class staff to creating scale of an internationally competitive dimension. It is continuing the expansion of its research and education capacity outside its historic walls as Trinity works with government and with industry to restore Ireland's economic potential. Ireland is home to nine of the top ten global companies in this sector and approximately 47,000 people are employed in indigenous and multinational companies in this area. Irish research in this domain is among the world’s best, with Trinity College Dublin researchers to the fore in key areas such as immunology and infection. The new facility will bring over 700 researchers together in one building with the common goal of addressing major challenges in health and disease through leading edge scientific research. The Trinity Biomedical Sciences Institute is a state-of-the-art research facility which redefines the scientific landscape in Ireland and will allow the country to take an international lead in the delivery of quality pharmaceutical and biotechnological programmes

The €131 million eleven storey development (35,000m2) creates a corridor of academic activity and public interaction along Pearse Street in Dublin's city centre, providing new social spaces, commercial areas, and improved access to public transport. The facility received €80 million in state funding under the Higher Education Authority Programme for Research in Third Level Institutions (PRTLI), co-financed by the ERDF, and National Development Plan 2007-13 medical education funding, with the balance financed by the College. On the occasion of the official opening, Taoiseach Enda Kenny welcomed it, stating: “This Institute will help sustain Ireland’s position as an international leader in biomedical research. I am highly impressed by the enormous contribution Trinity’s bioscience researchers have already made to the improvement of human health and I am certain that this Institute will be at the heart of further groundbreaking discoveries, with national and global impacts.” The new facility will consolidate and integrate pre-clinical bioscience research from across five schools: Medicine; Biochemistry and Immunology; Pharmacy and Pharmaceutical Science; Chemistry and Engineering. The Trinity Biomedical Sciences Institute is structured around three interlinked research centres, the Centre for Study of Immunology; Centre for Cancer Drug Discovery and Centre for Medical Device Technologies.

Pushing the Boundaries Trinity’s scientists will collaborate in this multidisciplinary environment to push the boundaries of discovery, enabling the translation of this research into new products, innovation and enterprise. In a departure from the traditional university model, the TCD researchers will also work alongside industry through provision of dedicated industry-academic collaborative and commercial laboratory space. The building includes 3,000m2 of dedicated post-incubation wet laboratory as recommended by the Innovation Taskforce, providing the research-ready infrastructure necessary to facilitate the growth of both the indigenous biotechnology sector and the attraction of new foreign direct investment in this field. “The scale of this development is unlike anything undertaken in the history of Trinity or indeed in Ireland. It is a bold statement of Trinity’s confidence in the calibre of its academic staff in this area, and their capacity to build up a critical mass sufficient to compete with the best in the world and to help transform healthcare, education, and job creation. It has innovation at its core and I predict that it will generate enormous dividends to Irish society in terms of health, wealth and wisdom,” concluded Provost, Dr John Hegarty. International Rankings: Trinity’s biomedical sciences outputs are amongst the best in the world as is illustrated by the following international rankings: • In neuroscience research Trinity College Dublin is in the top 0.01% internationally • Immunology research carried out by TCD has placed Ireland third in the world • In the field of microbiology TCD ranks within the top 20 institutions internationally • In the field of molecular biology and genetics TCD ranks within the top 50 institutions in the world.



OF GORD Choose NEPRAMEL to help heal and soothe the symptoms of GORD ABBREVIATED PRESCRIBING INFORMATION Nepramel 20 and 40 mg gastro-resistant capsules, hard Nepramel 20 mg Capsules: Each capsule contains 20 mg of esomeprazole (as magnesium dihydrate). Nepramel 40 mg Capsules: Each capsule contains 40 mg of esomeprazole (as magnesium dihydrate). Presentation: Nepramel 20 mg Capsules: Capsule with an opaque yellow cap and an opaque white body imprinted in black with “20 mg”. Nepramel 40 mg Capsules: Capsule with an opaque yellow cap and an opaque yellow body imprinted in black with “40 mg”. Indications: Gastro-oesophageal Reflux Disease (GORD): treatment of erosive reflux oesophagitis, longterm management of patients with healed oesophagitis to prevent relapse, symptomatic treatment of GORD. In combination with appropriate antibacterial therapeutic regimens for the eradication of Helicobacter pylori, healing of H. pylori associated duodenal ulcer and prevention of relapse of peptic ulcers in patients with H. pylori associated ulcers. Patients requiring continued NSAID therapy: healing of gastric ulcers associated with NSAID therapy, prevention of gastric and duodenal ulcers associated with NSAID therapy, in patients at risk. Prolonged treatment after i.v. induced prevention of rebleeding of peptic ulcers. Treatment of Zollinger Ellison Syndrome. Dosage: The capsules should be swallowed whole with liquid. The capsules should not be chewed or crushed. Adults and adolescents from the age of 12 years: Gastro-oesophageal Reflux Disease (GORD): Treatment of erosive reflux oesophagitis: 40 mg once daily for 4 weeks. An additional 4 weeks treatment is recommended for patients in whom oesophagitis has not healed or who have persistent symptoms. Long-term management of patients with healed oesophagitis to prevent relapse: 20 mg once daily. Symptomatic treatment of gastro-oesophageal reflux disease (GORD): 20 mg once daily in patients without oesophagitis. If symptom control has not been achieved after 4 weeks, the patient should be further investigated. Once symptoms have resolved, subsequent symptom control can be achieved using 20 mg once daily. Please refer to Summary of Product Characteristics. Children below the age of 12 years: Not recommended. Impaired renal function: Dose adjustment is not required in patients with impaired renal function. Treat patients with severe renal insufficiency with caution. Impaired hepatic function: Dose adjustment is not required in patients with mild to moderate liver impairment. For patients with severe liver impairment, a maximum dose of 20 mg should not be exceeded. Elderly: Dose adjustment is not required. Contraindications: Known hypersensitivity to esomeprazole, substituted benzimidazoles or any other constituents of the formulation. Esomeprazole should not be used concomitantly with nelfinavir. Warnings and precautions: In the presence of any alarm symptom (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis or melaena) and when gastric ulcer is suspected or present, malignancy should be excluded. Patients on long-term treatment should be kept under regular surveillance. Patients on on-demand treatment should be instructed to contact their physician if their symptoms change in character. When prescribing esomeprazole for eradication of Helicobacter pylori possible drug interactions for all components in the triple therapy should be considered. Contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine. Contains parahydroxybenzoates, which may cause allergic reactions (possibly delayed). Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections. Interactions: Esomeprazole is metabolised by CYP2C19 and CYP3A4 and inhibits CYP2C19. Ketoconazole, itraconazole, atazanavir, nelfinavir, saquinavir, diazepam, citalopram, imipramine, clomipramine, phenytoin, voriconazole, cisapride, warfarin, clarithromycin. Pregnancy and lactation: For esomeprazole clinical data on exposed pregnancies are insufficient. Caution should be exercised when prescribing to pregnant women. Nepramel should not be used during breast-feeding. Undesirable effects: Headache, abdominal pain, constipation, diarrhoea, flatulence, nausea/vomiting, peripheral oedema, insomnia, dizziness, paraesthesia, somnolence, vertigo, dry mouth, increased liver enzymes, dermatitis, pruritis, rash, urticaria. Refer to Summary of Product Characteristics for other adverse effects. Pack size: 28 capsules. Marketing authorisation holder: Clonmel Healthcare Ltd., Clonmel, Co. Tipperary. Marketing authorisation number: PA 126/208/1-2. Full prescribing information is available on request, or go to Medicinal product subject to medical prescription. Date last revised: January 2011. Ref 1: Nepramel Summary of Product Characteristics 2011/ADV/NEP/018

Nepramel is indicated for Gastro-oesophageal Reflux Disease (GORD) Nepramel is indicated in combination with appropriate antibacterial therapeutic regimens for the eradication of Helicobacter pylori. Nepramel is also indicated for patients requiring continued NSAID therapy1




20 Parkinson's Disease

Parkinson's Disease


The Pharmacology of Parkinson's Disease Written by Dr Gavin Davey, School of Pharmacy, Trinity College Dublin.

Selective loss of dopaminergic neurons in the brain leads to the characteristic motor symptoms of Parkinson’s disease such as bradykinesis, rigidity and tremors. Dopamine replacement therapies are extremely successful in treating these symptoms however new strategies are urgently required to control non-motor symptoms and also to reverse neurodegeneration and provide neuroprotection in the brain. The following is up-to-date information on some relevant clinical trials in the Parkinsons field and efforts in Trinity College Dublin to identify neurodegenerative mechanisms and develop new drugs that reverse the disease progress. Parkinson's disease is a common chronic neurodegenerative disorder in which progressive loss of dopaminergic neurons in the substantia nigra pars compacta takes place in the brain. Decreased release of dopamine to the striatum causes the classical motor symptoms of bradykinesia, rigidity and resting tremors. The dopamine precursor, Levodopa (L-DOPA) is the classic dopamine replacement drug that crosses the blood brain barrier and replenishes dopamine levels following metabolism by the enzyme aromatic acid decarboxylase. As the disease progresses, patienttreatment is often complicated by the onset of motor fluctuations such as dyskinesia which leads to alternating periods of reduced mobility and abnormal involuntary movements. Subcutaneous delivery of dopamine receptor agonists such as apomorphine or intraduodenal delivery of L-DOPA, as well as surgical strategies such as deep brain stimulation (DBS) are partially effective in reducing severe motor fluctuations. However, PD pathogenesis is further complicated as other neurotransmitters such as noradrenergic, serotonergic and cholinergic systems are also affected, resulting in non-motor symptoms such as depression, dementia, sleep disturbance and autonomic failure. These symptoms often dominate the later

Dr Gavin Davey

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stages of PD and viable treatments remain a largely unmet clinical need. Some of the commonly marketed drugs that target the dopaminergic system include pergolide, benserazide, cabergoline, entacapone, bromocriptine, piribedil, deprenyl, tolcapone and rotigotine. Non-ergolinic dopamine receptor agonists such as ropinirole, pramipexole, rotigotine and apomorphine are devoid of fibrillation complications. There is some evidence that the monoamine oxidase B (MAO B) inhibitors deprenyl and rasagiline may be slightly neuroprotective, however they may protect through non MAO B-inhibitory related mechanisms. In terms of current drug company activity in the PD area, there is a lot of research and development in re-formulations, especially extended release formulation of existing drugs already approved for PD. Re-positioning of compounds already approved for other indications and development of novel small-molecule based approaches are also busy areas. However, while there is a focus on improving motor control, fluctuations and dyskinesias, there is limited activity in preventing non-motor symptoms or reversing neurodegeneration.

increase during the off-period and decrease during the onperiod. A range of drugs designed to delay the metabolism of dopaminergic drugs or act on non-dopaminergic targets are currently under development to target the 'wearing-off' phenomenon. Epidemiological studies have correlated low incidence of PD in smokers and coffee drinkers and with use of NSAIDS, leading to clinical trials that target adenosine and nicotine receptors, respectively. The adenosine 2A receptor is an interesting target and antagonists such as istradefyline, preladenant, and SYN-115 reduce the offtime. However, nicotine receptor agonist and NSAID trials have proved ineffective in preventing neurodegeneration.

Aside from deep brain stimulation and continuous infusion of apomorphine or L-DOPA, current treatment options for L-DOPA induced dyskinesias are limited. Only amantadine has achieved an efficacious designation as determined by the Movement Disorder Society Evidence-Based Medical Review. Other agents such as the 5-HT 1A receptor agonist and partial D2 receptor agonist, sarizotan, have failed large, double-blind placebocontrolled trials. Non-motor symptoms include neuropsychiatric symptoms, autonomic failure and sleep abnormalities, and they dominate the clinical, caregiver and financial burden in advanced stages of PD. Impulse control

disorders that include pathological gambling, compulsive shopping, hypersexuality and binge eating are also present in approximately 15% of patients with PD and are associated with the use of dopamine agonists, L-DOPA and higher doses of L-DOPA. Obviously, future clinical studies must address underlying mechanisms and potential treatments for these disorders. The majority of patients have sporadic PD, which is characterized by mitochondrial dysfunction as well as oxidative and nitrosative stress. Complex I of the mitochondrial electron transport chain is selectively dysfunctional in dopaminergic neurons in sporadic PD. Several other mechanisms, such as

Dopaminergic neurons grown from pluripotent cells

Safinamide is an interesting multifunctional drug that inhibits MAO B activity, glutamate release and dopamine reuptake. Emerging results from phase III clinical trials suggest it may reduce motor symptoms and increase the ON – time during which L-DOPA is effective. Of major interest will be the presence of any safinamiderelated neuroprotective properties. Common motor fluctuations include the wearing-off phenomenon as well as on/off fluctuations when symptoms Figure 1

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e ements

22 Parkinson's Disease

neuroinflammation, glutamatergic excitotoxicity, decreased levels of neurotrophic factors and environmental factors are also thought to contribute to PD. Recent studies in our neurodegeneration laboratory in Trinity have shown that the mitochondria which are located in the business-end of neurons, the nerve terminals, have an inherent weakness in their complex I activities. This is especially relevant to neurodegeneration as most of the ATP in the brain is made by mitochondria and is utilized to control ion gradients across neurons and synapses. Having reducing complex I activities in the nerve terminal region may initiate neuronal death at this location which then spreads

in a retrograde fashion to the rest of the neuron. This scenario fits with PD pathology, where dopamine nerve terminals initially die-off in the striatal region and then along the nigrostriatal tract and finally in the substantia nigra pars compacta. Such experiments have created the opportunity to target the mitochondria in the nerve terminal region and try and boost complex I function. Our experiments have shown that by using ubiquinone (coenzyme Q)-like compounds we are able to dramatically increase the capacity for ATP production in the nerve terminal region and make them more resistant to neurodegenerative processes. Such ‘super-charging’ of mitochondria may not only have

benefit in treating PD patients but also for other neurodegenerative conditions such as Alzheimer’s disease and motor neuron disease. Neurotoxins such as 1-methly-4phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine are extensively used as in vitro and in vivo models of PD. MPTP was discovered over 30 years ago when some chemistry students in California tried synthesizing pethidine analogues for illegal drug usage. The synthesized batches were contaminated with MPTP and following injection into the blood stream was rapidly metabolized to the protoxin MPP+. We now know that MPP+ is specifically recognized by the dopamine transporter and quickly accumulates inside neurons to

There is a lot of research and development in re-formulations, especially extended release formulation of existing drugs

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We provide a full procurement service of all Exempt Medicinal Products and operate in line with IMB regulations and HSE reimbursement. We provide a Specialty Ordering Service where we will source, price, supply and deliver unusual and once-off products.

For further details contact: United Drug Telesales Dublin - 01 463 2300 /2307 /2311 Limerick - 061 315 411 Ballina - 096 72 555

© Trinity College Dublin

Figure 2

Leonora Kinsella Customer Services Development Manager Telephone 01 463 2308 Mobile 087 251 3021 Fax 01-463 2525

24 Parkinson's Disease



JF Pharmacy students get suited up inhibit mitochondrial function, resulting in cell death and ablation of the nigrostriatal pathway in a similar manner to idiopathic PD. MPTP may be a potent neurotoxin but how it works provides us with valuable information for overcoming problems with developing new PD drugs. Because a major problem in PD-related drug development is lack of specificity and targeting, we decided to use some of the properties of MPP+ as a starting point for designing new drugs. For these experiments we built a computational or in silico model of the dopamine transporter and studied how it selectively recognizes MPP+ and transports it into dopamine neurons. Then we removed the toxic part of MPP+ and replaced it with functional groups that we know to be neuroprotective. In doing so, we have generated a series of novel compounds that are selectively accumulated only by dopamine neurons and will subsequently protect these cells from neurodegeneration. Of course these only predictions, but we are now at the stage of chemically synthesizing the drugs and testing them on experimental models.

Recent studies in our neurodegeneration laboratory in Trinity have shown that the mitochondria which are located in the business-end of neurons, the nerve terminals, have an inherent weakness in their complex I activities

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While selective neurotoxins are very useful to researchers a major problem in the PD field has been the lack of experimental models that accurately reflect the disease pathogenesis. However, one of the most astounding discoveries in recent years has been the development of cell reprogramming. Japanese scientists discovered that adult skin cells can be reprogrammed so that they revert to something very similar to the embryonic stem (ES) cell. The reprogrammed cells are called induced pluripotent stem (iPS) cells and have many of the pluripotent properties of ES cells and can differentiate into all the tissue types in the body. In the case of PD, these technologies have enabled fibroblasts obtained from patients

to be reprogrammed to stem cells and then redifferentiated to form neuronal tissue. Using such an induced pluripotent stem (iPS) cell line, it is now possible to generate dopaminergic neurons in vitro and test their viability. The advantage of this technique is that we can study the dopamine cells to figure out why they might be more likely to die under certain conditions and how we can stop such events from occurring. It also means that we have a non invasive system for screening new drugs that might be protective for dopamine cells (see Figure 1). Generating dopamine neurons in sufficient numbers to carry out further experiments is difficult and improving differentiation protocols to produce enriched dopamine neurons is something we have spent considerable effort (see Figure 2). Pharmaceutical companies are now heavily investing in iPS cell technologies as a screening tool for chemical libraries. A major problem is producing iPS cell based assays that are robust and likely to result in lead compounds but the potential for using patientspecific cells for drug discovery is enormous and many countries have established infrastructure and ethical frameworks for dealing with iPS cells and ES cells. International peer review and high research standards require human ES cells to be used as control cell lines when dealing with iPS cells however the complete lack of legislative framework in Ireland and the refusal of Irish funding agencies to support such research have effectively ruled out Ireland as a country in which to do such research. Interestingly, the Irish government has committed funds to the EU research Framework Programme for such research but will not allow Irish researchers to access it. Such a stance severely restricts the use of these technologies in Irish research and development and ultimately slows down the discovery rate for new drugs that might be effect in treatment of Parkinson’s disease.

Brona Staunton, Kate Mulligan, Amy Giles, Hannah-May Morrissey, James Fahey.

The School of Pharmacy at Trinity's incoming Junior Freshman students were measured up for their lab coats recently, sponsored by United Drug. The students were measured up for their coats on the morning of their Orientation Session on

21st September and presented with their coats the following Wednesday in time for their first Pharmaceutical Chemistry laboratory class. Professor Meegan was dazzled by the pristine array of white coats in the lab! Let’s hope they are as pristine by the end of the year.

Leukaemia medicine 'step closer' to European market John Seaton, Financial and Commercial Director for Nova Laboratories

Nova Laboratories are heading for 'exciting times' as it has been revealed their oral suspension of leukaemia medicine mercaptopurine has moved a key step closer to the European pharmaceutical market. The European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use

(CHMP) has adopted a positive opinion, for the orphan medicine Mercaptopurine Nova Laboratories (mercaptopurine monohydrate). It is intended for the treatment of acute lymphoblastic leukaemia in all adults, adolescents and children. Leicester-based Nova Laboratories has formulated the medicine as a suspension,which

provides improved accuracy and – especially when used in small children – ease of administration and more flexible and consistent dosing.

exciting time for the company and he was absolutely delighted that its novel medicine development and manufacturing expertise has been recognised.

Development of ageappropriate formulation to treat this disease was identified as a priority research area by the EMA’s Paediatric Committee, and Nova has spent more than two years on the project.

“This is a very important development in the treatment of leukaemia, especially for the benefits it will bring to young children, so we will make it our number one priority over the next few months that the medicine is available across Europe,” he said.

The CHMP, on the basis of quality, safety and efficacy data submitted, considered there was a favourable benefit to risk balance for Mercaptopurine Nova Laboratories and therefore recommended the granting of a Europe-wide licence, subject to final ratification. John Seaton, Financial and Commercial Director for Nova Laboratories, said it was an

“We are committed to developing childrens’ and adult medicines and this will be the first of many that Nova brings to market.” For all enquiries please contact: or call Matt Jelley, Head of Business Development, on T: (0044) 116 246 3768 M: (0044) 755 752 7112.

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26 News


Fran hands over the reigns Hospital Pharmacist Technician's Association President Fran Glyn has handed over the reigns to Yvonne Sheehan after two years in office.Commenting on the important work carried out by the Association in Ireland, Fran commented: "I do realise that a lot of us are working in an environment that has become more pressurised, with less staff doing more work. This can often cause people to become demotivated. This is all the more reason to attend our education days and conferences."

A New Filgrastim Biosimilar in Ireland

Pictured are the Hospital Pharmacist Technicians Association Committee: Back row: Jenny O Meara, Rebekeh Corrigan, Eglina Corrigan, Marie McLaughlin. Front row: Yvonne Sheehan, Fran Glynn, Laura Lyons

Meanwhile, July 1st marks an important milestone for Pharmacy Technicians. The journey, started by founder Katherine Miles, in 1952, aimed to bring together likeminded ‘pharmacy technicians’ to promote their work and recognition through the ultimate goal of professional registration. 59 years later, with the introduction of statutory registration,July 1st is being recognised as a day for celebration and reflection; for remembering the work done by so many dedicated pharmacy technicians. Whilst the temporary grand parenting route to the GPhC register has now closed there is still so much more to be done. Statutory registration and regulation of Pharmacy Technicians is finally here and the

move of Pharmacy Technician from occupation to profession truly begins. APTUK President Steve Acres said: “We bring our old values to the new challenges ahead as we begin the next stage of

the journey to developing our profession. As we celebrate, all pharmacy technicians should personally reflect on the road ahead. Being a professional brings responsibility and accountability and it is incumbent on all pharmacy technicians to rise to

this challenge. In doing so, they will send out a clear message that they are ready to be regarded as true professionals and are willing to respond appropriately to the trust placed in them.”

Data presented at ERS Congress Novartis has presented new Phase III data at the European Respiratory Society (ERS) congress demonstrating the potential for its portfolio of oncedaily inhaled therapies to help patients with chronic obstructive pulmonary disease (COPD) to maintain more active and productive lives.

lung function compared to placebo with a fast onset of action at first dose, as well as improving exercise endurance. NVA237 is a new drug in the long-acting antimuscarinic (LAMA) class which has recently been submitted for approval in the European Union under the brand-name Seebri® Breezhaler®.

The GLOW1 and GLOW3 studies show that investigational NVA237 (glycopyrronium bromide) significantly increased patients'

"These results illustrate the potential benefits of NVA237 for COPD patients and are especially encouraging as we move ahead

with plans to develop a fixeddose combination with Onbrez® Breezhaler®, our once-daily therapy in the LABA class," said David Epstein, Division Head of Novartis Pharmaceuticals. "This investigational combination of two bronchodilators with complementary modes of action is designed to give COPD patients access to the two leading classes of therapy in a single inhaler for the first time."

The studies, presented at the ERS congress in Amsterdam, The Netherlands, underscore the company's commitment to developing innovative medicines to treat this life-threatening disease. Although COPD is often thought of as a disease of the elderly, 50% of patients are estimated to be below the age of 65, and are likely to be at the peak of their earning power and family responsibilities.


(filgrastim) A new era in G-CSF therapy

FREEPHONE 1800 201700 Teva Pharmaceuticals Ireland, Unit 1, The Business Centre, Blackthorn Business Park, Coe’s Rd., Dundalk, Co. Louth Ph: 042 9395892 Fax: 042 9395898 P02/05/11

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28 Dysphagia



Administering medicines to patients with dysphagia David Wright, Professor in Pharmacy Practice, School of Pharmacy, University of East Anglia Rebecca White, Specialist Pharmacist for Nutrition, Oxford Radcliffe Hospitals NHS Trust formulations of medicines via these tubes, combined with poor flushing techniques can result in tube blockage which can cause rehospitalisation to have a new tube sited.

Professor David Wright How to administer medicines to patients with dysphagia is one of the most common medicines information enquiries from nurses and pharmacists within the UK where it has recently been shown that such patients are three times more likely to suffer medication administration errors as a result of their condition.1 The identified errors were largely as a result of inappropriate decisions made by nurses when faced with patients who either can’t easily swallow the formulations which they have been prescribed or when expected to place solid dose form medicines down enteral tubes. Extensive training in formulation science and awareness of the availability of different formulations makes the pharmacist the most suitable healthcare professional to provide advice in such situations. The aim of this article is therefore to enable pharmacists to identify the diseases most commonly associated with swallowing difficulties, to list and critique the alternative approaches available to pharmacists when asked to provide advice on the administration of medicines to patients with dysphagia and increase pharmacist awareness of the risks of formulation tampering, which, in certain circumstances, maybe the only option available.

Cause and types of dysphagia Swallowing difficulties can arise from either a psychological aversion to swallowing tablets, which can occur in any age group, or from dysphagia which is a physical impairment in the

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With the relatively high prevalence of dysphagia in the older person, its presence in patients who have experienced stroke and other chronic and ultimately disabling conditions it is not surprising that the extent of dysphagia has been found to be approximately 15% in general care homes for the older person and up to 30% in hospices.3

Where it is deemed no longer safe to administer medicines to patients orally, enteral tubes which bypass the oral route may be inserted. Enteral tubes, which are primarily designed for the administration of foods and liquids, provide an additional and significant barrier for the administration of medicines due to both their potential length and internal diameter. Administration of inappropriate

The two main concerns with dysphagia are aspiration and choking. In the first instance the patient is unable to effectively synchronise the closure of the epiglottis when swallowing foods or liquids. [Figure 1] If the epiglottis is not fully closed when the food or liquid bolus passes then there is an increased likelihood of unwanted materials passing into the lungs which have minimal defence systems against ingested bacteria and viruses. Regular aspiration of unsterile boluses is believed to be associated with pneumonia and therefore in patients where aspiration is a problem, thicker liquids which hold together when swallowed are preferred to ‘thin’ liquids which should be avoided. Choking occurs when either the tongue has lost the ability to create an appropriate size bolus prior to swallowing and/or the throat muscles are too weak to propel boluses into the oesophagus. In such patients the texture and size of boluses is important and thinner liquids may actually be more appropriate in this instance.

If dysphagia is not identified in a patient or an inappropriate formulation is prescribed then this may affect patient ability or willingness to take their medicine and therefore a patient’s ability to swallow oral medicines should always be ascertained. Where a swallowing difficulty is identified this should be explored further through medical referral and if necessary by a speech and language therapist.

Helping patients with swallowing difficulties Figure 1

Where patients are able to use the oral route then the pharmacist has three main options available to them: • Determine whether the medicine is still required or whether it can be safely discontinued

Extent of dysphagia swallowing process. Dysphagia can be acute in patients with a sore throat or those with an exacerbation of gastrooesophageal reflux disease (GORD) or chronic in patients who have experienced a stroke, patients with Parkinson’s disease, Dementia, Huntingdon’s Chorea, Polio and those patients with muscular dystrophy. Some form of swallowing difficulty is believed to be found in between 70-90% of older people and this can result from a reduction in the production of saliva and weakening of the muscles involved in the swallowing process.2

whether the oral route is appropriate and if so what the optimal texture of administered foods and medicines should be.

• Identify a suitable formulation which can be swallowed • Identify an alternative route of administration

Figure 2

Determining the extent or reason for the dysphagia is therefore important and should inform any pharmacist recommendations. Speech and language therapists are usually the most appropriate professionals to assess the swallowing process and this can be by a brief bedside assessment or more invasive procedures such as via a naso-gastric camera (Fibre Optic Endoscopic Examination or FEES) or an X-ray of the swallow of a radio opaque liquid material (Videofluoroscopy). The assessment should determine

In reviewing the ongoing need for the medicine the pharmacist, together with the prescriber should determine if the medicine is effective and if so, whether the benefits outweigh any risks. Additionally if the dysphagia is likely to be acute, as seen immediately post cerebrovascular accident, then medicines may be temporarily stopped until the swallow reappears. Liquid medicines are the most obvious alternative to tablets and capsules in patients with swallowing difficulties and are recommended as first choice in patients where a swallow via the oral route is still available.4Due to the complexity of developing a product with a reasonable shelf life and a taste and texture which is acceptable to patients, licensed liquid medicines are however only

available for a limited number of drugs. Furthermore the texture of the liquid medicines does require due consideration, with thick gloopy formulations frequently more desirable in patients with potential for aspiration and thinner liquids for those with concerns regarding choking. Alternative formulations of medicines which avoid the need to swallow are increasingly being made available e.g. patches, suppositories, orodispersible and buccal formulations (fast tabs, melts etc) however due to the relatively small size of the market the range of such options is still limited. Unlicensed liquid medicines are available for many drugs, however the quality of the product, patient acceptability, shelf life and cost can vary considerably. If unlicensed liquid medicines (specials) are to be used It is preferable to always source the same product for the patient and if possible to obtain ‘batch produced’ specials, with a ’Certificate of analysis’, rather than ‘bespoke’ specials with a ‘Certificate of conformity’. The former being exposed to greater levels of quality assurance testing than the latter. When sourcing and supplying unlicensed medicines pharmacists need to aware of the increased liability which they shoulder. Where licensed medicines are used within the terms of their licence, liability for any subsequent patient harms falls with the manufacturer. If however a patient is harmed on receipt of an unlicensed medicine the liability is shared between the prescriber and supplier with the actions of both being carefully considered in any subsequent legal action. When receiving prescriptions for unlicensed liquid medicines it is therefore recommended that these are discussed with the prescriber to ensure that they are aware of the implications of such prescriptions.

If a liquid medicine is unavailable then the only remaining option is to consider manipulating tablets and capsules prior to administration. Whilst, in many cases formulation tampering in the form of tablet crushing or dispersing may be unlikely to cause any significant harm to patients there is a significant risk of inaccurate dosing5, although scientific evidence supporting this is currently limited. There are certain formulations where it would generally be considered unwise to tamper with the formulation prior to administration and pharmacists need to be aware of these when their advice is sought. Firstly it is unsafe to recommend that cytotoxic or hormonal products e.g. finasteride, tamoxifen, methotrexate are tampered with prior to administration. Hormonal and cytotoxic products can be aerosolised or absorbed through the skin and therefore the administrator can receive a dose, however small, which may be unsafe. Similarly products which can cause contact sensitisation such as chlorpromazine should also not be crushed prior to administration. Consequently when considering the appropriateness of tablet crushing or dispersing any potential danger to the administrator should always be considered. Film coats are placed on medicines for a variety of reasons which may include providing protection against moisture in the environment, making the medicine easier to swallow, masking the taste of the drug within the medicine or preventing contact sensitisation when handling the medicine. In some cases damaging the film coat immediately prior to administration may not adversely affect patient care. Removing a film coat which is there to mask the flavour then a crushed or dispersed tablet may be unpalatable, whilst film coats which protect against

contact sensitisation should not be disrupted. Enteric coats are placed on tablets to either protect the stomach from the medicine, the medicine from the gastric acid or to release the active drug beyond the stomach in the GI tract. Whilst the evidence for the effectiveness of enteric coats for protecting the stomach is limited, coating to protect ingredients such as omeprazole and lansoprazole from stomach acid is known to be effective. Furthermore products such as mesalazine which are prescribed for Crohn’s disease are designed to be absorbed at the site of action and therefore it is reasonably appropriate to never recommend tampering with enteric coated formulations. Modified release products generally contain a larger dose of the drug than would be recommended as a single standard release bolus and consequently anything which damages the release mechanism could increase the likelihood of adverse events in the patient. Additionally quicker release may result in faster metabolism and consequently a time period between doses when levels are sub-therapeutic. (Figure 2) Although as a general rule of thumb pharmacists should therefore not be recommending formulation tampering of modified release products, it is incorrect to state that it is always inappropriate. There are capsules which contain modified release contain pellets which can be safely released from the outer shell of the capsule and providing they are not tampered with, this will not affect their release properties e.g. Modified release morphine capsules such as MXL capsules are allowed to be opened and the contents sprinkled on food. Medicines which have small therapeutic windows can switch from effectiveness to creating adverse events just by minimal changes to bioavailability. Crushing or dispersing digoxin

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30 Dysphagia



Irish Pharma companies streamline healthcare tablets which have a bioavailability of 70% could in theory increase this to 100% and effectively almost increase the dose received in the patient by 50%. Unlike modified release products, it would be inappropriate to never allow formulation tampering in medicines with small therapeutic windows however in such instances the effects of formulation tampering should be monitored for in the patient. The final point to consider when being asked for advice on how best to administer medicines to a patient who can’t swallow is whether your registration status allows you to authorise unlicensed use of medicines. If it does not and you are considering recommending formulation tampering then the prescriber should ultimately authorise such activity and this should be in writing, preferably as a direction on any prescription.

Administering medicines via enteral feed tubes Advice for administration of medicines via this route is specialised and two publications designed specifically for this purpose are currently available in the UK.6,7 If a pharmacist is asked to provide advice on the administration of medicines via such routes and does not have access to these publications it is strongly recommended that they contact their regional medicines information centre for advice. The administration of medicines via enteral tubes is usually unlicensed as most medicines have not been tested for administration via this route. Consequently the routine recommendation within both textbooks to crush or disperse tablets or open capsules prior to administration does not significantly increase the liability associated with this, although this should be considered a last resort and all reasonable steps should be taken to obtain an appropriate formulation, or change to an alternative medication available

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in an appropriate formulation. Although the taste of dispersed or crushed mixtures is theoretically of less concern, patients with enteral tubes do report tasting medicines administered via this route. Enteral feeding tubes are commonly used to maintain or supplement nutritional and fluid intake in patients with significant dysphagia. Within acute care the nasogastric tube is most frequently used, the internal diameter usually being within 1.5 to 2.5mm. Within the community permanent gastrostomy devices are most commonly used as these have minimal risk of displacement, these tubes are usually slightly wider. Increasingly jejunal tubes are being used in patients who also have delayed gastric emptying, gastroparesis or pancreatic disease. Several factors need to be considered when choosing a medicine and formulation for administration via an enteral feeding tube. The size of the tube, the exit site, the excipients in the formulation and any interaction with the enteral feed. For enteral tube administration a non-granular liquid formulation, preferably a solution is preferred. This will flush via the tube without resistance or blockage. Liquids with a high viscosity can be diluted immediately prior to administration to facilitate administration. Due to the small internal diameter of these tubes the risk of tube blockage from the administration of inappropriate formulation is high, this is not just inappropriately crushed tablets but also granular liquids such as Ciproxin ® or dispersible tablets with a large particle size i.e. Pentasa ®. The exit site of the tube can potentially influence the bioavailability and tolerability of the medication. Medication delivered directly to the jejunum may be incompletely absorbed or result in a rapid peak depending on the site of absorption of the medication. In addition liquid formulations with a high osmolarity, such as syrup

based formulations8, can have an osmotic laxative effect if delivered undiluted into the jejunum.

not available then formulation tampering may have to be considered.

Consideration should be given to the excipients in the formulation used. For liquid preparations sorbitol and alcohol content should be considered, a sorbitol dose exceeding 15g/day can result in bloating, flatulence and diarrhoea9. If using dispersible formulations the sodium content may be clinically important, for example 4g daily of soluble paracetamol can provide up to 160mmol of sodium a day.

The reasons for special coatings on tablets or capsule ingredients should always be considered before recommending altering them prior to administration. The prescriber should always be involved in any decisions to supply unlicensed medicines or recommend administration outside of the license.

There are many clinically important interactions between enteral feeds and medication10. They are usually the result of the medication binding to the protein or electrolytes in the feed or competition with amino acids for absorption. Significant interactions occur with phenytoin, theophylline, warfarin, l-dopa, quinolones, tetracyclines and rifampicin. Specific guidance should be given when supplying these medications to minimise the effect of the interaction. This is usually achieved through administering the medication during a break in the feeding regimen.

Summary When presented with a patient who has difficulties in swallowing solid dose formulations the pharmacist should firstly determine whether they are aspirating or not and what exactly the patient can swallow with respect to the texture of any medicine they are subsequently given. Thin liquids are generally not appropriate for patients who are aspirating, whereas thick viscous liquids may be less suitable for patients who are at risk of choking. The pharmacist should consider with the medical practitioner the need for the medicine and then whether alternative formulations are available. Licensed medicines should generally be recommended before considering unlicensed alternatives. Where licensed or unlicensed medicines are

Ireland is uniquely positioned to become a world leader in developing convergent technologies. Healthcare practitioners are increasingly looking for efficiencies in every stage of patient care, and Irish companies are putting the foundations in place now to integrate many technologies to streamline healthcare processes. are attractive to a worldwide healthcare market will not only help to drive Ireland's export-led recovery, but will also cement Ireland as a location of choice for this type of innovation. The critical importance to the Irish economy of convergence and collaboration between Ireland’s pharmaceutical and medical technology sectors was highlighted at the ‘Convergence Ireland’ conference earlier this month, where over 200 people participated.

References 1) Kelly J, Wright D, Wood J. Medicine administration errors in patients with dysphagia in secondary care: a multi-centre observational study. Journalof Advanced Nursing 2011 doi: 10.1111/j.13652648.2011.05700.x 2) Murry T, Carrau R. Clinical Management of Swallowing Disorders, Plural Publishing, Oxford 2006. 3) Wright D. Medication administration in nursing homes. Nursing Standard2002;16(42):33-8. 4) Wright D, Chapman N, Foundling-Miah M, Greenwall R, Griffith R, Guyon A, Merriman H. Consensus guideline on the medication management of adults with swallowing difficulties London: Connect Medical 2006.

Julie O'Neill, IBEC deputy president and Gilead Sciences General Manager Julie o’Neill, IBEC Deputy President and Gilead Sciences General Manager made the comments at a recent conference held in Dublin. With nine of the top-ten global pharmaceutical companies located in Ireland, and eleven of the top-twelve global

medical technology companies having a manufacturing base here, cross-sectoral collaboration across the LifeSciences arena has the potential to give Ireland a competitive advantage internationally. The creation of new ‘combination’ products that

Julie added: “The Convergence Council, in particular, is bringing together medical technology, pharmaceutical, ICT, financial services, Clean Tech and food and drink companies with State agencies to build the regulatory framework to allow Ireland to take advantage of this emerging world market. However, the Government and Business must work to create the right conditions for this type of investment-heavy R&D and

exporting activity. We would like to see continued improvement of the R&D tax credit and the intellectual property taxation regime and rapid implementation of those innovation taskforce recommendations that will drive the climate for innovation. Although Ireland's competitive position has improved substantially over the past two to three years, more remains to be done and must be a priority area for Government.” Hosted by the Convergence Council, the conference’s theme was ‘ Harnessing Ireland's unique potential for the commercialisation of drug, device and biologic combination products’. Industry participating in the event included Johnson and Johnson, Elan Drug Technologies, Nypro Healthcare, Merrion Pharma, Merck and Medtronic Cardiovascular together with researchers from University Collage Dublin, Tyndall National Institute, NUI Galway, University of Limerick, Royal College of Surgeons, and Trinity College Dublin.

5) Powers JE, Cascella PJ Comparison of methods used to prepare tablets for nasogastric tube administration. J Pharm Technol. 1990;6:60-62

Shift Study Results in Heart Failure Patients

6) White R, Bradnam V. (eds.) Handbook of Drug Administration via Enteral Feeding Tubes. The Pharmaceutical Press 2010. 2nd Edition.

New results from SHIFT (Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial), the largest-ever morbi-mortality study of treatments for chronic heart failure, reveal for the first time a direct link between heart rate reduction and quality of life in patients with heart failure.

clearly told us that the If Inhibitor Procoralan (ivabradine) prevents the progression of heart failure and improves survival”, explained Prof Ken McDonald, HSE National Clinical Programme Director of Heart Failure and Consultant Cardiologist, St Vincent’s University Hospital in Dublin.

The new data from the SHIFT study with ivabradine (Procoralan®), presented during recent European Society of Cardiology congress, are clinically important as quality of life is greatly impaired in patients with chronic heart failure and poor quality of life in these patients is associated with worse disease outcomes.

“New analyses show that Procoralan (ivabradine) also improves the quality of life as reported by patients with heart failure and that this improvement is directly proportional to heart rate reduction. Put simply, the lower the heart rate, the better the quality of life and the better the patient outcome,” he added.

7) Smyth JA. The NEWT Guidelines for Administration of Medication to Patients with Enteral Feeding Tubes or Swallowing Difficulties North East Wales NHS Trust 2010. 8) Dickerson RN, Melnik G Osmolality of oral drug solutions and suspensions. Am J Hosp Pharm 1988;45(5):832-4 9) Edes TE, Wlak BE, Austin JL Diarrhea in tube-fed patients: feeding formula not necessarily the cause. Am J Med 1990 88(2);91-3 10) Stockley IH. Drug Interactions, 6th Edn. London: Pharmaceutical press; 2002.

“The main SHIFT results presented at last year’s ESC congress

The new SHIFT analysis set out to assess if quality of life in heart failure patients was related to

prognosis and changes in heart rate. It involved 1944 patients with chronic heart failure from 24 countries who were randomised to receive either ivabradine or placebo on top of standard heart failure therapy. Health related quality of life was assessed using the Kansas City Cardiomyopathy Questionnaire (KCCQ), a validated, disease-specific measure of functional status and quality of life. The 23 items of the questionnaire are divided into 2 sets of scores, the clinical summary score assessing physical limitation and symptoms and the overall summary score assessing social limitation in chronic heart failure patients. The higher the score, the better the quality of life. By year one, the study showed that the risk of a cardiovascular

event increased in patients with lower KCCQ scores (equating to a lower health related QoL). While reducing heart rate with ivabradine was associated with a 60% improvement in quality of life compared to the control group.i This improvement was observed in both the disease related component and the social component of the scores. Practically speaking, this means that patients who received ivabradine were able to participate in a greater number of everyday activities, considerably changing their day to day life. Thus, with these new results it is important to note that heart rate reduction with ivabradine, unlike beta-blockers, improves both survival and QOL in heart failure patients.i

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MSD invest €28.6m in Ireland “Continuous innovation plays a central role in Ireland’s future as a knowledge-based economy. The harnessing of the skills and creativity of the people here at Brinny has been instrumental in the decision by MSD to base these two facilities here, representing a financial investment of €28.6 million and the provision of 70 jobs,” according to the Minister for Research and Innovation, Séan Sherlock TD at the official opening of two new state of the art facilities at the existing MSD Brinny site in Co. Cork. The new facilities include the Brinny Bioassay Centre of Expertise and the Brinny Pneumococcal Vaccine Conjugation Facility. This event is the first the Brinny facility (previously known as Schering-Plough) has celebrated as part of global healthcare leader MSD. The company is known as MSD worldwide, except in the United States and Canada where it is Merck. The Minister joined with Dr. Mike Kamarck, President Merck BioVentures and Senior Vice President, Vaccines and Biologics Manufacturing at Merck & Co. Inc., other senior MSD representatives and CEO IDA Ireland, Barry O’Leary at the event. The pharmaceutical and chemical sector exported products to the value of over €50 billion in 2010 (over 50% of the national total) and accounted for over 50000 jobs directly and indirectly.

Welcoming the announcement, Barry O’Leary said: “This IDA supported investment demonstrates MSD’s continued commitment to Ireland and adds to the strategic importance of the Irish operations within the parent company. The company’s decision is a significant vote of confidence in Ireland’s international reputation and standing as an excellent investment location. “MSD in Ireland employs 2,300 people through our operations in Carlow, Cork, Dublin, Tipperary and Wicklow,” according to Dr. Mike Kamarck. “We have an excellent relationship with the IDA and we are grateful to the Minister and the IDA for their ongoing support of MSD in Ireland.

“The opening of the two new facilities here at Brinny is a tangible manifestation of the site business transformation plan we announced last year,” said Mr John Howell, General Manager, MSD Brinny. “As a site we are continually focussed on our costs and our operational excellence. The locating of these two facilities at Brinny underlines the strategic importance of this site within the MSD global network.” MSD is committed to leading the industry in the development and commercialisation of biologic medicines that improve human health. A bioassay measures the biological effect of a test substance on a living cell and is an essential tool for research and development in biologics manufacture. The new Brinny Bioassay Centre of Expertise will focus on bioassays for therapeutic protein products and will support other MSD sites including Carlow.

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Brinny has 20 years expertise in bioassay which was a major contributing factor in MSD’s decision to base the Bioassay Centre of Expertise at Brinny. Ten highly qualified individuals will work at the Bioassay Centre. MSD is the leading supplier of adult pneumococcal vaccine globally, having distributed more than 140 million doses worldwide. Pneumococcal Conjugate Vaccine (PCV) will protect infants from this life- threatening disease which is the leading cause of vaccine-

preventable death in children less than 5 years old worldwide. The Brinny Pneumococcal Vaccine Conjugation Facility will produce vaccine for clinical trials in immunisation against pneumococcal disease for pediatric use. The Brinny facility will employ 60 people initially through construction, commissioning, qualification and clinical supply phases and 30 highly qualified technicians long term, subject to clinical trial success. The facility will have

the capacity to produce 100 million doses of pneumococcal conjugate vaccine a year. MSD’s site in Brinny, Co. Cork is an Active Pharmaceutical Ingredient (API) and sterile manufacturing centre of expertise. Established in 1980, 511 people are currently employed at the site. The products made at Brinny have approvals in over ninety markets worldwide. PharmaChemical Ireland, the body within IBEC representing the pharmaceutical and chemical manufacturing sector, welcomed

the announcement by MSD-Brinny. PCI Director, Matt Moran, said: "The decision by MSD to invest €29 million at the former Schering Plough biotech plant in Brinny is a massive boost for the company and a further vote of confidence in the sector in Ireland. Given that the industry is going through a period of global consolidation each and every new investment by the sector in Ireland bodes very well for the long term future of the sector. Enormous credit is due to the management team at Brinny."

The opening of the two new facilities here at Brinny is a tangible manifestation of the site business transformation plan we announced last year

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34 Report


Nilvad research consortium granted €6m funding An international research consortium led by Trinity College Dublin that aims to develop a new Alzheimer’s disease treatment has just been selected for grant funding of €6 million by the European Commission Seventh Framework Programme (FP7). The consortium NILVAD*, comprising 18 European universities, hospitals and pharmaceutical companies, will conduct European clinical trials of NILVADIPINE in the treatment of Alzheimer’s disease (AD). Trinity College Dublin researchers at the School of Medicine and St James’s Hospital, Dublin, are coordinating this major clinical trial that will determine whether NILVADIPINE can improve memory and also slow the rate of progression of Alzheimer’s disease. NILVADIPINE is an approved medication used for the treatment of high blood pressure and has been already shown to decrease the risk of developing dementia. There have been no new drug treatments developed for Alzheimer’s disease since 2003. Commenting on the significance of the clinical trials and research, Professor Brian Lawlor, Conolly Norman Professor of Old Age Psychiatry at Trinity College Dublin and Consultant Psychiatrist at St James's Hospital who is leading the research said: “Considering the devastating health and social cure impact that Alzheimer's disease has on Europeans, there is relatively little research funding made available to tackle this major killer. This research consortium, NILVAD represents a change in this trend in Europe and a step in the right direction. It not only offers hope for a new treatment but also strengthens research networks and collaborations in Europe and means that research developments in Alzheimer's disease can be accelerated for the benefit of all Europeans.”

Prof Brian Lawlor

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Alzheimer’s disease is an everincreasing public health concern among the ageing population and is the most common form of dementia affecting more than 15 million individuals worldwide and around 5 million Europeans. The direct and indirect costs of AD and other dementias amount to more than €440,000 million each year (, 2010). It is estimated that by 2050, 1 in 85 of the population worldwide will

have AD. There are few effective symptomatic treatments and as of the moment, no treatment that can delay or prevent Alzheimer’s disease. Treating high blood pressure with medications like NILVADIPINE has been shown to decrease the risk of developing dementia and Alzheimer’s disease. In partnership with The Roskamp Institute in Florida, which developed the basic science evidence for the potential effectiveness of NILVADIPINE, Mercer’s Institute for Successful Ageing at St James’s Hospital, Dublin, conducted an earlier safety study also led by Professor Lawlor, on Alzheimer’s disease patients that formed the basis for this new clinical trial. Now, in collaboration with key partners* and Alzheimer’s disease experts, NILVAD will conduct these multi-centre European trials. The trials will determine if NILVADIPINE can improve memory and functioning but also slow the rate of progression of Alzheimer’s disease. In preclinical studies NILVADIPINE lowers brain levels of amyloid which is thought to contribute to the development of Alzheimer’s Disease. The study will be conducted over a period of 18 months involving 500 people. Because NILVADIPINE is already available and licensed, this type of study can be carried out more quickly, to the potential benefit of future generations of people with Alzheimer’s disease, their caregivers and society.

Hospital based pharmacy services in cancer treatment A decade or so ago, patients could leave the hospital without seeing, speaking with or even thinking about a vital member of their healthcare team: The pharmacist. Tucked away from patients, pharmacists typically dispensed medications that physicians prescribed and nurses administered. Today, pharmacists have more clinical training and are eager to use it as they step onto patient floors and assume an integral spot on patient-care teams. Pharmacists are the experts in medication therapy, it is their area of expertise and in the field of oncology this remit falls largely to chemotherapy treatment. Much work is currently being done within Irish Hospital Pharmacy departments in this area and below we feature a case study on this very issue. There is an urgent need for improved drug treatments for cancer, which is emerging as the leading cause of mortality in Ireland and other western countries. In 2005-2007, the National Cancer Registry registered an annual average of 27023 new cases of cancer. The commonest invasive cancers overall (apart from nonmelanoma skin cancer, NMSC) were prostate (2462 cases), breast (2335 cases; 2315 in females), colorectal (2156 cases) and lung cancer (1810 cases). The risk of developing invasive cancer over the period 2005-2007 was roughly 570 cases per 100,000 persons per year (420 per 100,000 excluding NMSC). Breast cancer was, apart from NMSC, the commonest diagnosis in women, making up 30% of all invasive cancers (excluding NMSC), while colorectal cancer accounted for 12% and lung cancer for 10%. In men, prostate cancer was the commonest diagnosis, accounting for 29% of cases, followed by colorectal cancer at 15% and lung cancer at 13%. No other cancer, in either men or women, accounted for more than 5% of cases. The next most common cancer in women was melanoma of skin (4.8%) and in men was lymphoma (4.3%). Case Study: A guide to Pharmacy Services at the Oncology/haematology unit, University Hospital, Galway,

written by Caroline Whiriskey, Pharmacist, UCG. Three pharmacists and five pharmacy technicians staff the UHG Pharmacy Aseptic Services Unit (PASU). The unit prepares chemotherapy for an average of 450 patients each month, some of whom are outpatients and some inpatients. An average of 1050 items is prepared per month. Preparation of Chemotherapy Chemotherapy is commonly administered as specific combinations of drugs, given in specific doses at specific intervals. These combinations are known as regimens. New regimens must be validated by a pharmacist, checking the details against the journal article where the regimen was first published. Individual patient doses are calculated using the patient’s weight or body surface area. Body surface area is calculated using height and weight. The prescribing doctor selects the regimen, and calculates the doses to be given. These calculations are checked by a pharmacist. Once checked, the prescription is input into a computer system, which generates worksheets and labels. A team of pharmacy technicians prepares the individual components of the regimen. This involves reconstituting vials of cytotoxic chemotherapy, drawing up the required dose and adding to a suitable infusion fluid, if necessary. This preparation is carried out in a closed cabinet or isolator to prevent exposure to the cytotoxic drugs. To protect this vulnerable group of patients from infection, the areas where chemotherapy is prepared is maintained to cleanroom standards. This involves rigorous cleaning, and a regular microbiological testing for contaminants.

Clinical pharmacy service The PASU provides a clinical service to the two oncology/ haematology/ radiotherapy wards in the hospital. The clinical pharmacists help ensure that patients receiving chemotherapy are fit to do so, by checking blood counts, renal and hepatic function. They ensure that patients are prescribed supportive therapy, if needed. Some patients are admitted because

of problems associated with chemo or radiotherapy. These include infection (sepsis), nausea and vomiting or sore mouth and throat (mucositis). The clinical pharmacists check that treatment given is appropriate, and given at the correct dose. Some antibiotic doses need to be adjusted if a patient has poor renal or hepatic function and some need to be adjusted according to blood levels. Pharmacists monitor this treatment to ensure efficacy. Other patients are admitted for palliative treatment. Here again the clinical pharmacists monitor treatment efficacy and can offer advice on alternate routes of administration of medicines. An important part of the clinical pharmacists’ work is ensuring that any regular medicines that a patient is taking are continued while in hospital, and any new ones are continued on discharge. Liaison with community pharmacies is crucial. Supportive treatment for patients receiving chemotherapy Many chemotherapy regimens, because of the way in which they kill rapidly dividing cells will cause depletion of white cells, red cells and platelets. Depletion of a sub-group of white cells, called neutrophils, leaves patients prone to a variety of opportunistic infections. A small infection can be very serious in a neutropenic patient. Granulocyte colony stimulating factor (GCSF or pegylated GCSF) is given to shorten the duration of neutropenia. It is given as an integral part of some regimens, to ensure that patients’ counts recover in time for the next cycle of treatment. In other cases, it is given in response to an infection. To aid in preventing these infections, patients are asked to take a number of prophylactic anti-microbials. Valaciclovir protects against viral (mainly herpes) infections and is taken continuously. Fluconazole protects against fungal infections and is taken during periods of neutropenia. Patients receiving treatment for acute leukaemias experience a more profound neutropenia. Posaconazole is used instead in these patients as it has a broader spectrum of activity. Cotrimoxazole is given to protect against pneumocystis jirovecii pneumonia (PJP, formerly PCP)–

Caroline Whiriskey a protozoal infection, which can be problematic in-patients on long courses of high-dose steroids or some other cytotoxic agents. To guard against oral infections, and help prevent oral mucositis, all patients receiving chemotherapy are asked to use Chlorhexidine and Nystatin mouthwashes regularly until treatment has finished. The initial courses of chemotherapy can result in massive breakdown of tumour cells. The breakdown products can overwhelm the body ability to excrete them. Allopurinol is given to reduce the formation of uric acid, which can crystallise out in the kidneys causing damage. This is commenced before the first cycle of chemotherapy, and normally stops after the first few courses. Many chemotherapy regimens have the potential to cause severe nausea and vomiting. Prophylactic antiemetics are given to prevent this. The type and duration of antiemetics used depends on the emetic potential of the particular regimen. Aprepitant is used orally for three days for highly emetogenic regimens. Intravenous ondansetron and dexamethasone is given to patients prior to highly or moderately emetogenic regimens. These are continued orally for 2-3 days after treatment. If nausea and vomiting becomes a problem despite these measures, patients are treated with metoclopramide or cyclizine.

HPN • Issue 2

36 Biosimilars



Biosimilars: Growth, Complexity and Demand Written by Kelly Jo Eastwood

The issues around Biosimilars are heating up. Between them, pharmaceutical companies and government regulatory agencies have been trying to deal with the associated benefits and arguments for quite some time but, the time has come for cohesive action as the biosimilars market continues to grow, albeit at different paces across the world. Those in the pharmaceutical industry more often than not fall on one side of the fence with regards to the positives and negatives in the development of this market. Hospital Pharmacy News takes a brief look at the background to these ‘new brand’ medicines, the complexity of their birth into the medicines market and the momentum around the globe. Due to their complexity, cost, and development risks, biosimilar production and commercialisation in developed markets is concentrated among only a handful of pharmaceutical companies. In Ireland this includes Teva, ICON and Genemedix. Key factors driving market growth include patent expiries of key biological drugs, cost containment measures from governments, aging population, and supporting legislations. The recent establishment of regulatory guidelines for biosimilars in the US is expected to add further momentum to the growth of the global biosimilars market. There are relatively few factors which limit the growth of the biosimilar industry in the developing markets, although the introduction of biosimilar pathways will restrict market access to many domestic biosimilar players, while low purchasing power and a high proportion of out-of-pocket expenditure, coupled with brand loyalty, limits access.

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The already expired patents of biologics, such as Epogen, Neupogen and Enbrel, and the near term patent expiry of the currently leading biologics, such as Herceptin and Avastin, will help the global biosimilars market gain traction and expand wings across the globe. The absence of widespread legislations for biosimilars is primarily due to the complexity of biological drugs, as compared to the small molecule drugs. Production of biosimilars is also marred with huge technological investments and other clinical entry barriers, which is not the case with generic copies of small molecule drugs. The high-cost and complex technology involved in the production of biosimilars also restricts biosimilar companies from offering huge price discounts. As a result, a well-established regulatory framework, as seen in most countries for the approval of small molecule generics, is conspicuously absent in case of biosimilars, except in Europe and Japan, and recently in the US. The regulatory agencies, across the rest of world, have been adopting a rather slow approach to frame a clear set of guidelines for the approval of biosimilar products, precisely in view of the enormous safety and efficacy risks involved with biosimilars. The European Union, with biosimilar approval framework in place, and biologic drug categories, such as epoetin alpha, Granulocyte colony-stimulating factor, and recombinant growth hormone already approved, is far ahead of the United States, where regulatory guidelines for biosimilars have been established only recently, in 2010. Europe represents the largest affiliate regional market for biosimilars worldwide. Markets outside the US, Japan and Europe for biosimilars, however, collectively account for a larger share of the global biosimilars

market. Now that a regulatory framework for a pathway in approval of biosimilars is in place, the US biotech drug market is expected to experience cost competition in the following years. But there is a place for biosimilars in the pharmaceutical market. Some major biotechnology-derived medicines are, or will soon, no longer be protected by patents. As for all other medicines when their 20-year patent expires, they will become open to development and manufacture by other companies. This introduces competition on the market which ensures patient access to safe and effective, and more affordable, biotechnologyderived medicines. Without competition the prices of the originator biotechnology-derived medicines would remain artificially high. Similarly, this competition will serve to stimulate research into new originator medicines. In addition, Europe has a critical need to control healthcare costs. Europe cannot afford not to have competition from biosimilar products. By 2015 there are expected to be over 90 million people aged 60 and over in the EU alone. Since this age group spends on average three to four times more on medicines than when they were 30, the cost of providing adequate access to medicines for these people is exploding. Many biopharmaceuticals are also often used to treat long-term conditions such as diabetes, cancer, chronic kidney failure and multiple sclerosis. On average, biopharmaceuticals cost much more per patient than conventional pharmaceuticals, and their use is growing at more than 20% per year. As already noted, the biologicals pipeline is expanding. Study after study shows that not all patients who could benefit from these medicines have access to them — and with pharmaceutical spending growing more than twice as fast as the gross domestic product (GDP), that situation can

of the production process and conditions during fermentation can alter the outcome, posing a major challenge to manufacturers of biosimilars that are required to reproduce the glycosylation of the original product.

only worsen. It is therefore critical that everything possible be done to maximise patient access to cost-effective biopharmaceuticals.

The Sophisticated but Complicated Process As already highlighted, the production of biosimilars is a hugely complex process. Reference to the innovator product is an integral component of the approval. Unlike the more common smaller molecule drugs, biologics generally exhibit high molecular complexity, and may be quite sensitive to manufacturing process changes. The followon manufacturer does not have access to the originator's molecular clone and original cell bank, nor to the exact fermentation and purification process, nor to the active drug substance. The first step in developing a biosimilar is creating a thorough understanding of the molecular properties of the reference product. For this purpose, multiple lots of reference material are purchased over a number of years and subjected to thorough analytical and biological characterization. With the help of multiple powerful and orthogonal analytical methods and bioassays, even complex glycoproteins can be described in great detail. In the course of this process, the biosimilar developer learns much about the variability of the molecular properties of the reference product – both from batch to batch and over time. Manufacturing changes in the reference product are easily picked up by modern analytics and manifest themselves as pronounced quality shifts. This variability of the reference products defines the target ranges, or the “goalposts” for the molecular properties of the biosimilar. Once the target ranges are defined, the company systematically engineers a

“Glycosylation analysis remains a major challenge, especially in the production of biologicals,” she says. “We approach the complexity of glycosylation analysis using orthogonal technologies, including state of the art quantitative, UHPLC separations coupled with specific exoglycosidase digestions, CE and mass spectrometry.

Professor Pauline Rudd

cell line and a manufacturing process to create a biosimilar whose molecular properties optimally match those of the reference products, aiming to lie between the goalposts for all relevant properties. With modern technologies and the significant efforts of EGA members, this can be achieved with great success today. It must be noted that the biosimilar company is at a distinct disadvantage. ‘The innovator is not going to give you the details of their analysis or production,’ says Pauline Rudd, head of the Oxford Glycobiology Laboratory at the National Institute for Bioprocessing Research and Training in Dublin, Ireland. Professor Rudd is leading important research in the area of glycosylation changes which play a crucial role in the production of advanced biopharmaceuticals and which is also important in disease, particularly cancer and autoimmunity. NIBRT is one of Europe, if not the world’s foremost centres of excellence for the study of protein glycosylation under the leadership of Professor Rudd, a

principle international authority in this area. Understanding protein glycosylation, glycan linkage and composition is important throughout the development of a biopharmaceutical as it can potentially affect bioactivity, safety and efficacy of the final product. Professor Rudd told HPN: “There are approximately 34 approved biosimilars and 300 in the pipeline. It is vitally important that biosimillars are produced authentically. To get the wrong glycosylation would mean the sugars leaving a patient after only three minutes, rendering the efficacy of the medicine as void. This is a big challenge for those developing a biosimilar medicine. Glycosylation is a highly complex process, involving a network of several hundred enzymes and transporters, and – in contrast to the protein’s genetically encoded amino acid sequence – varies with the capabilities of the cell line and even the cell clone used for production. Furthermore, design

“We have the best glycosylation facility in the world and so we can interrogate the processing, working alongside both innovator companies and producers of biosimilars.” While Ireland, she points out, doesn’t innovate new drugs, we are the largest manufacturer of pharmaceuticals in the world. Professor Rudd believes there is a great need for the continued development of these drugs: “We observe first hand the sophisticated process involved with biosimilars, ensuring their safety and efficacy. These drugs are and can be extremely useful to patients.” The EGA Viewpoint The European Generics Medicines Association believes that the regulatory environment for biosimilars needs to be optimised in order to fully exploit the advantages offered by generic and biosimilar medicines for the sake of healthcare sustainability. The EGA Vision 2015, published towards the end of last year, puts forward a series of proposals to improve the existing legal and regulatory framework aimed at guaranteeing timely patient access to affordable treatments by: • enhancing the competitiveness of the generic and biosimilar medicines industry by creating

a level playing field for global competition, harmonising GxP practices and introducing a broader interpretation of the EU reference product; • maintaining competition and sustainable healthcare by preventing anti-competitive strategies aimed at delaying generic entry, rejecting patent linkage in regulatory processes and extending the Bolar provision to cover pricing and reimbursement; • improving patient access to affordable medicines through better regulation by increasing the role of the CMD(h) and streamlining the decentralised procedure, adapting the marketing authorisation procedure to the realities of the off-patent market, reducing bureaucracy through employing electronic interfaces and adopting a homogenous and consistent implementation of the revised EU bioequivalence guideline; • reinforcing regulatory harmonisation by removing country-specific requirements, building efficient marketing authorisation procedures through efficient use of resources, improving the mutual recognition of the assessment performed by one authority by other authorities to avoid a duplication of work , optimising work-sharing across Member States; and • providing patients with necessary and appropriate information by encouraging agencies to devote website space for information on generic and biosimilar medicines and preventing negative campaigns against generic and biosimilar medicines. Today, generic medicines in Europe represent almost half of the pharmaceutical market by volume but account for only 18% of the total cost. Generic medicines already create savings of over 30Bn Euros and newly established

HPN • Issue 2

38 Biosimilars


Value of web recognised Dr Rebecca Cramp

biosimilar medicines contribute 1.4Bn Euros per year to European healthcare systems. Increased focus on a more effective regulatory environment will only serve to increase these savings says the EGA. The Irish Pharmaceutical Healthcare Association (IPHA) has launched the 2011/2012 version of its highly successful CD-ROM.

Importantly, the FDA are currently in the process of implementing a new, abbreviated biosimilar pathway in the US. The EGA has presented a submission regarding the experiences in Europe with regards to biosimilars. Their report highlights with the use of biosimilars in the EU for over four years, there have been ‘no unexpected or unusual adverse events with any of them.’ A total of 13 biosimilars are now approved, including somatropin, epoetin and filgrastim products. Their submission states: “Global development for biosimilars is an essential prerequisite for ensuring affordability and patient access, which were the key motivation of US legislators in creating the BPCIA. If there is sufficient evidence that a reference product from another ICH region (esp. the EU) is equivalent to the US reference product, the repetition of nonclinical and clinical studies should not be required. “EGA believes the best way of developing guidance documents is by basing them on the experience gained in the course of the review and approval of biosimilar products. Approvals should not be held up by the lack of written guidance.”

Seizing New Opportunities The key message to come out of the 17th Annual Conference of the European Generics Medicines Association in Lisbon, held in June of this year, was that Europe must seize on new opportunities to increase employment and create growth in the generic and biosimilar medicines markets. With the global biosimilar and generic medicines markets set to expand significantly over the next 10 years, it is imperative that Europe acts swiftly on the global

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The initiative, which is an extract of the website and has been running since 2000, provides comprehensive and independently approved information on over 2,000 medicines currently available in Ireland. As with previous editions, the CD-ROM is being sent free of charge, to over 7,000 consultants, GPs, nurse prescribers, nursing homes and community and hospital pharmacists in Ireland.

Greg Perry, EGA

stage. The EGA has therefore called for the establishment of an EU export Bolar provision to take advantage of this new situation. This would allow the European generic and biosimilar medicines manufacturers to develop and manufacture within the patent/SPC life, provided these products are intended for export. Over the next decade, patent expiries in biopharmaceuticals will be the equivalent of 90 billion Euros in sales. At the same time, the global generics market is set to experience a predicted 10% in annual net growth, reaching 92 billion Euros in 2012. “The global expansion of these more affordable treatments is clearly of major importance to patients and healthcare systems, but the EU must take the opportunity to lead the world in the development and manufacturing of these products,” EGA Director General Greg Perry tell us. Europe has a history of high quality production and significant manufacturing capacities in the

medicines sector. However, other countries, such as India and South Korea, have already established task forces in order to promote strategies that would see them evolve into important hubs for medicines discovery. If the EU legislators do not act now, Europe will fall behind in its drive to deliver sustainable and high quality medicines to patients. Moreover, by acting quickly the EU will have the chance to create jobs and enhance its competitiveness. Director General Greg Perry comments: “There is a need to reach a global agreement on The criteria and guidelines in the interest of patients and better availability of high-quality medicines. The EU, Japan, Canada, Australia, Turkey and Malaysia to name but a few now have a regulatory framework in place. The WHO guideline is to be rolled out worldwide and now is the time for a benchmarking exercise. It is also time for a consistent scientific global approach, key for true

global development.” He points out an important milestone in the first NICE guidance. NICE has assessed seven different biosimilar products including biosimilar Omnitrope® and the organisation has declared ‘no differences in clinical effectiveness.’ “Biosimilars gaining significant market shares, with no reports on safety issues. Support for wider use should be strengthened as this helps to secure access to essential biopharmaceuticals and helps to contain sky-rocketing health care expenditure.” Despite the introduction of approval pathways in the EU, US and Japan, the growing use of biologics, and the need for more cost-effective treatments, all of which help drive biosimilar uptake, there remain a large number of barriers to uptake. This remains obvious.

Speaking about , Dr Rebecca Cramp, Scientific and Regulatory Affairs Manager, IPHA, commented that with over 100,000 visitors a month to the site, its value to the public and healthcare

professionals alike is increasingly apparent: “The use of the web by those seeking health information continues to grow and it is critical to patient safety that websites containing accurate information are readily accessible. Conscious of this, IPHA has ensured that the content of is search engine optimised so that when patients search online, they are able to find high quality, up to date, regulatory authority approved information quickly. "Furthermore, has a powerful search facility that allows users to readily drill down to the detail of their medicine or easily search for medicines on the market in Ireland that meet their pre stated criteria”.

Treatment Doubles Progression-Free Survival Results presented at the 2011 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago recently, confirmed that treatment with sunitinib (Sutent) more than doubled the time period that patients with pancreatic neuroendocrine tumours (PNET) were free from disease progression or death compared to placebo. Sunitinib is an oral multi-kinase inhibitor approved for the treatment of advanced/metastatic renal cell carcinoma (RCC) and gastrointestinal stromal tumor (GIST) after failure of imatinib mesylate treatment due to resistance or intolerance.

In November 2010, sunitinib was approved in Europe for the treatment of unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumors (NET) with disease progression in adults. It is the first treatment to be approved for patients with pancreatic NET in twenty-five years representing a significant milestone in the management of patients with progressive pancreatic NET. Dr David Fennelly, Consultant Medical Oncologist, St. Vincent’s Hospital, said: “For patients with

pancreatic NET that is metastatic, prognosis is poor, similar to that seen with metastatic breast cancer or colon cancer. We welcome these findings which reinforce the clinical benefit of sunitinib in the treatment of advanced pancreatic NET, a difficult to treat disease which has a high unmet medical need.” The study was discontinued early on the recommendation of the data and safety monitoring committee because of the greater number of serious adverse events and deaths in the placebo group as well as a difference in progression-free survival favouring sunitinib. Almost

70% of patients in the placebo arm crossed over to receive sunitinib treatment either after disease progression or at study closure. Although rare, the reported incidence of pancreatic NET is rising. It is reported in two to four people per million annually worldwide and accounts for approximately 9% of neuroendocrine tumors.

HPN • Issue 2

40 News

Liver Cancer

Drug Interventions: What Works?

Current Strategy for Staging and Treatment: The BCLC Update and Future Prospects

As HPN was going to press, the second National Drugs Conference of Ireland was hosting a conference in Dublin entitled Drug Interventions: What Works? The conference was opened by Ms. Roisin Shorthall, TD, Minister of State, Department of Health with responsibility for Primary Care. The Steering Group hosting the conference was comprised of a partnership of organisations including the HSE, the Irish Needle Exchange Forum, the Ana Liffey Drug Project, Coolmine Therapeutic Community and the Irish Association of Alcohol and Addiction Counsellors (IAAAC). This year, the delegates - made up of experts in the delivery of addiction services and therapies as well as service user representative groups focused on learning from each other by exchanging ideas, sharing knowledge and best

practice as well as showcasing evidence based projects that have worked both here in Ireland and internationally. The conference has attracted a high calibre of speakers including Dr. Joao Goulao, National Drugs Coordinator in Portugal whose presentation was entitled Drug Policies in Portugal: Was Decriminalisation Helpful? Dr Jenny Scott, Senior Lecturer in Pharmacy Practice at the University of Bath, who spoke on The Role of the Pharmacist within a Pharmacy Needle Exchange. Her research interests include safer

Regulatory Affairs Training Course The PharmaChemical Ireland CMC Regulatory Affairs Training Course will be held on the 11th & 12th October 2011 at the Conrad Hotel, Earlsfort Terrace, Dublin 2. This training course is the 7th CMC Regulatory Affairs training course that PCI have run. PCI are indebted to the Irish Medicinces Board for the significant time and

input they have provided in the design of this course, in particular with respect to the updated legislation and guidance for the European variations procedure The key US and EU legislation and regulatory systems for drug and biologic approval and submission of changes is covered. Some more

advanced topics are also covered. The concept of QbD/Design space is explored in a workshop setting where trainees take a QbD example and write it up as a regulatory submission. Registration Cost: €500 Please visit for further details.

Beline Capsules The Irish Medicines Board (IMB) wishes to advise the general public, retailers of herbal medicines and healthcare professionals that samples of the herbal product Beline capsules have been found to be adulterated with medicines, including prescription-only substances. The capsules, when tested, were found

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to contain the following medicines: • Chlorphenamine, an antihistamine • Piroxicam, a non-steroidal antiinflammatory drug (NSAID) • Oxetacaine (also known as oxethazine), a local anaesthetic Products containing these

medicines require a medicinal product authorisation in order to be legally sold on the Irish market. These medicines are not indicated on the product labelling as being present and they render this product to be an illegal medicine. Beline capsules are not authorised for marketing in Ireland and cannot be considered safe.

injecting and the performance of injecting paraphernalia, needle exchange and the pharmaceutical care of drug users. She runs a specialist course for pharmacy students on caring for drug users. She also provides training for local needle exchange pharmacists. HPN will have full coverage in our next issue.


Alejandro Forner, M.D.,1,2 Marı´a E. Reig, M.D.,1,2 Carlos Rodriguez de Lope, M.D.,1 and Jordi Bruix, M.D.1,2 ABSTRACT Staging and treatment indication are relevant topics in the management of patients with hepatocellular carcinoma (HCC) and for optimal results, they have to take into account liver function, tumor stage, and physical status. For any staging system to be meaningful it has to link staging with treatment indication; this should be based on robust scientific data. Currently, the sole proposal that serves both aims is the Barcelona Clinic Liver Cancer (BCLC) approach. It takes into account the relevant parameters of all important dimensions and divides patients into very early/early, intermediate, advanced, and end-stage. Early-stage HCC patients should be considered for potentially curative options such as resection, ablation, and transplantation. Patients at intermediate stage benefit from chemoembolization, whereas patients at an advanced stage, or who cannot benefit from options of higher priority, have sorafenib as the standard treatment. Finally, patients at end-stage should merely receive palliative care. KEYWORDS: Hepatocellular carcinoma, staging, prognosis, treatment, survival

Patient Hospital Experience The Irish Society for Quality and Safety in Healthcare’s National In-patient Survey, ‘Measuring the Patient’s Experience of Hospital Services,’ has shown exceedingly good levels of satisfaction in care received by members of the public as an in-patient. Quality and safety are at the heart of health policy and the achievement of enhanced standards of patient care will inevitably lead to a reduction in overall costs resulting in a more effective and efficient health service. Service User involvement by patients, their families and carers, is central to the development of a robust health service. The information gained from surveys such as this and the standardised tool designed by ISQSH and the University of Ulster to facilitate other such studies, will enhance health services provided into the future.

Clinical management of patients with HCC is a decisionmaking process that should be approached following evidence-based data. In that way, the care offered to patients will be supported by a reliable background and result in the best available outcomes. Upon diagnosis of HCC, patients need to be adequately staged so that a treatment option may be proposed that would best

serve that individual patient.1 Obviously, recommendations and guidelines serve to frame the situation, but ultimately, the decision to be made will never be automatic, but rather the result of a personalized evaluation that takes into account the scientific evidence and the specific profile of the patient. Any available information such as guidelines or consensus documents should not be disregarded: the best

Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, ICMDM, Hospital Clı´nic, IDIBAPS, University of Barcelona, Barcelona, Spain; 2 Centro de Investigacio´n Biome´dica en Red de Enfermedades Hepa´ticas y Digestivas (CIBERehd), Barcelona, Spain. 1

Address for correspondence and reprint requests: Jordi Bruix, M.D., BCLC Group, Liver Unit, Hospital Clı´nic, c/Villarroel, 170, Escala 11, 4 planta, 08036 Barcelona, Spain (e-mail:

PROGNOSTIC PREDICTION Outcome estimation is one of the main questions that physicians have to face when a patient is diagnosed with HCC. Years ago, there was not much difficulty as the majority of the patients were diagnosed at an advanced symptomatic stage that usually coincided with liver decompensation.4–9 There was no difficulty in envisioning a dismal outcome with no hope for effective therapy. All type of data can be retrieved from those years to show that

any indication of advanced cancer stage, heavily impaired liver function, and presence of intense cancerrelated symptoms, easily predicts poor short-term survival. Hence, HCC patients with impaired performance status10 or who fit into the Child–Pugh C category are to be classified as end-stage.4–9 Obviously, patients with Child–Pugh C without HCC should be considered for liver transplantation11 and if HCC is diagnosed, it may become a transplant contraindication if not at an early stage. This is relevant because the evaluation of the

health care will be achieved when the evidence-based data are combined with the expert medical evaluation that is mandatory when managing patients with HCC. It has to be stressed that HCC usually affects patients with underlying liver disease2 and this results in the need to carefully evaluate both tumor burden and liver function at the time of prognostic prediction and treatment recommendation.1

In this article, we explore both aims in the Barcelona Clinic Liver Cancer (BCLC) current strategy. The BCLC was first presented in 1999 in Seminars in Liver Disease3 and constitutes an evolving approach as it has regularly incorporated changes that have emerged since its original publication.

Hepatocellular Carcinoma; Guest Editors, Jordi Bruix, M.D., and Josep M. Llovet, M.D. Semin Liver Dis 2010;30:61–74. Copyright © 2010 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. DOI: ISSN 0272-8087.

patient should be done because of end-stage liver disease and not because of HCC. This distinction is critical when staging is linked to treatment and should be taken into account when classifying an HCC patient as endstage and not a candidate for any therapeutic option. If end-stage patients are easily identified, it is controversial as to how to establish a stage for those patients that are diagnosed prior to such a dismal scenario. The old division between ‘‘surgical’’ and ‘‘nonsurgical’’ makes no sense

today, as surgery is no longer the sole established therapy that can aim for cure. In addition, ‘‘nonsurgical’’ would include those already classified as end-stage and also patients with early HCC who would be candidates for ablation. Several groups have developed different systems or scores to permit a stratification of HCC patients escaping from the dichotomous surgical approach3,12–22 Most of them result from an analysis of the association of any clinical or pathology parameter with survival, ultimately resulting in a division according

HPN • Issue 2

42 Liver Cancer

Liver Cancer


64 to an equation derived from the multivariate Cox regression analysis or to a score obtained by the sum of the values allocated to the significant parameters. The value of each variable would vary according to the statistical predictive power and in that way balance their relevance. In almost all instances, the systems are the result of assessing liver function and tumor burden; however, it is unfortunate that in some patients, there is no assessment at all of the presence of cancer-related symptoms.14,15,17,19–21 All physicians dealing with patients are aware that asking for symptoms using the usual ‘‘how do you feel’’ is standard clinical practice, and the answer given by patients is always taken into account. Not surprisingly, assessment of ECOG performance status10 or Karnofsky index23 is a wellestablished procedure in an oncology practice. Patients with a performance status >2 carry a grim prognosis with highly doubtful survival impact of any therapy. Most research trials exclude

patients just because of this easy and validated assessment. Table 1 describes the proposals that have gained more visibility and may have been considered for stratifications of patients when including in the analysis all evolutionary stages. All of them may successfully divide the cohorts according to outcome, but unfortunately their application in clinical practice and research is not optimal. As previously commented, identification of end-stage patients is no longer a challenge and some classifications may just gain power because of this capacity that would equally be achieved by asking for cancer-related symptoms. Furthermore, because a staging system should optimally attempt to link prognostic prediction and treatment indication, any system aiming to be clinically successful has to serve both aims. Unfortunately, this is not the case with any of the scoring or category allocation systems, which, to some extent, may include in the same category patients who would be

candidates for curative therapy and patients who would merely receive palliation. Years ago, we approached this problem in a different way. It is clear that patients with early-stage HCC (whatever definition is used) would be treated by resection, liver transplantation, or ablation. Those patients with advancedstage HCC would be considered for chemoembolization (its efficacy was still controversial at that time) or for inclusion in any research trial with novel agents because there was no therapy with proven positive impact on survival for patients who would not benefit from the three well-established potentially curative options. According to this concept, we had two well-defined populations: early and end-stage; in the middle group we had a mix of patients with very heterogeneous profiles according to liver function (Child– Pugh A and B), tumor burden (confined to the liver or with vascular invasion or extrahepatic dissemination), and presence/ absence of symptoms. The fact


that we had run two prospective trials with an untreated control group24,25 allowed us to reevaluate the natural history of this segment of patients and define their independent predictive factors for prognosis. Findings were straightforward and established the presence of constitutional syndrome and cancer-related symptoms as per ECOG performance status, presence of vascular invasion, and/or extrahepatic spread as the sole independent predictors.26 Hence, we could define the socalled intermediate stage defined by the absence of any adverse predictor, and the real advanced stage that included those with symptoms and/or vascular invasion and/ or extrahepatic spread (Fig. 1). Liver function did not emerge as significant as in those trials: the number of patients with impaired liver function reflected by advanced Child–Pugh B stage were a minority. Indeed heavily impaired liver function is usually associated with impaired physical condition and obvious poor prognosis. 63

Table 1 Prognostic Systems to Predict Outcome in Hepatocellular Carcinoma (HCC) Patients Author (year)


Tumor Stage

Liver Function

Health Status

Primack et al (1975)4



Ascites, bilirubin, portal

Weight loss

Chlebowski et al (1984)6




Okuda et al (1985)12


Tumor involvement >50%

Bilirubin, albumin, ascites

Attali et al (1987)7



Encephalopathy, alcohol

Falkson et al (1988)8




Male sex, PS, appetite, age

Calvet et al (1990)13


Tumor size, metastases

Bilirubin, serum sodium, BUN, GGT, ascites

Constitutional syndrome, age

Stuart et al (1996)14


Portal vein invasion, AFP


CLIP (1998)15


Tumor morphology, AFP,


Chevret et al (1999)16


Portal vein invasion, AFP

Bilirubin, alkaline phosphatase


Llovet et al (1999)26


Portal vein invasion,



Villa et al (2000)17 CUPI (2002)18

96 926

Estrogen receptor status TNM, AFP

Bilirubin Bilirubin, ascites, alkaline

— Symptoms

JIS (2003)19




SliDE (2004)20



Liver damage by LCSGJ, PIVKA

Tokyo score (2005)21


Size, number

Albumin, bilirubin

Bonnetain et al (2008)22


Portal thrombosis, AFP,

Bilirubin, albumin, ascites

Hepatomegaly, hepatalgia,

hypertension Age

bilirubin, AST, BUN

portal vein invasion



small HCC

Spitzer QoL Index

HCC, hepatocellular carcinoma; AFP, a-fetoprotein; TNM, tumor node metastases; GGT, gamma-glutamyl transferase; BUN, blood urea nitrogen; PS, performance status; LCSGJ, Liver Cancer Study Group of Japan; QoL, quality of life; small HCC, inside Milano Criteria (1 nodule <5 cm or 2–3 nodules <3 cm).

This 2set• HPN of data permitted the birth of the first BCLC Issue 3 proposal that ultimately became the basis for the strat-

appears when a wide range of impairment is present. At this point it is worth stating that the Child–Pugh

Table 1 Prognostic Systems to Predict Outcome in Hepatocellular Carcinoma (HCC) Patients

This set of data permitted the birth of the first BCLC proposal3 that ultimately became the basis for the stratification of a double-blind placebo controlled trial testing the efficacy of seocalcitol.27 The trial was negative, but as a collateral outcome helped to validate the stratification using the BCLC model. Later on, the SHARP trial testing sorafenib also followed the same methodology and again, the stratification capacity was externally validated.28 Finally, the Asian–Pacific trial also testing sorafenib with positive results confirmed the stratification capacity of the BCLC system in Eastern countries.29 In addition to these prospective validations, several studies have shown the capacity of the model30,31 and this has prompted its wide recognition and endorsement.1,32–34 Obviously, no model is a dogma to stay unchanged and the prospective trials conducted so far will give the rationale to incorporate more parameters for a refined stratification. Among them, a-fetoprotein (AFP) is likely to gain some relevance as it emerges as an independent predictor in some of these trials35–41 and also in other studies and prognostic systems.15,16,18,42,43 In a recent meta-analysis of all cohorts of untreated HCC patients, the parameters of the BCLC system are again identified,44 whereas other data suggest a potential prognostic power for AFP.45 Clearly, liver function is relevant and its value sure appears when a wide range of impairment is present. At this point it is worth stating that the Child–Pugh classification was developed to predict the risk of portosystemic surgery for the treatment of variceal bleeding.46 Hence, its value outside this initial aim is relevant, but lacks enough capacity to accurately stratify patients according to prognosis. This is why the Mayo Model for End Stage Liver Disease (MELD) was developed.47 It is highly useful to predict mortality at 3 months in patients with cirrhosis and some have tested if it would serve to predict survival in HCC patients.48 Despite some positive



suggestions in that regard, it is acknowledged that it will be merely useful to detect end-stage patients. However, it will not have any efficacy for the evaluation of patients where proper stratification is needed. This limitation is valid for all proposals that take into account only one of the dimensions to be considered: liver function, tumor burden, and symptoms.Accordingly, neither the Child–Pugh,46 the MELD,47 the TNM classification,49 the estimation of tumor volume, 50 the assessment of ECOG/ Karnofsky,10,23 nor any other unidimensional system will be clinically valuable. Figure 1 Barcelona Clinic Liver Cancer (BCLC) staging and treatment strategy. As explained in the text, patients d

with hepatocellular carcinoma (HCC) are stratified into five stages: very early, early, intermediate, advanced, and e

1 Barcelona Clinic Liver CancerStaging (BCLC) staging and treatment Having exposed the tools to use according to tumor Figure burden, liver function and physical condition. is linked to treatment indication according to e strategy. As explained in the text, patients diagnosed LDLT, with hepatocellular cadaveric liver transplantation; living donor liver transplantatio based (Modified from Llovet et al.32) CLT, for the ‘‘middle class’’ patients, carcinoma (HCC) are stratified into five stages: very early, early, intermediate, became obvious that patients at and end-stage according to tumor burden, liver function and an earlier stage would prognostic be better modelsadvanced, both at baseline andStaging according to theto treatment predictionindication requires different physical condition. is linked accordingtools. to Baseline tum served by different prognostic treatment proposed and potentially received. Patients multinodularity, AFP concentration, evidencebased data. (Modified from Llovet et al.32) CLT, cadaveric liver treatment f models both at baseline and with earlier stage transplantation; HCC should be free of cancer-related tumor necrosis and growth while wai LDLT, living donor liver achieve transplantation. according to the treatment symptoms as per ECOG performance status (several markers of risk of uncontrolled HCC progres proposed and potentially studies link symptomatic disease to advanced stage and exclusion from the waiting list.62–64 As such, ha received. Patients with earlier of recurrence: microvascular parameters is included in theprognosis, likeli considered when informing poor outcome and several others show that early tumors stage HCC should be free of invasion and presence of satellites MELD system; this explains the transplantation, and ultimately, development of are unlikely associated to symptoms). Indeed, this is the cancer-related symptoms as or additional nodules53 (Fig. difficulty in getting an effective policy. Interestingly, none of these paramete rationale for early detection plans based on surveillance: per ECOG performance status 2). Poor differentiation degree and qualitative priority policy for cluded in the MELD system; this explains the d to detect early-stage disease at an asymptomatic stage (several studies link symptomatic is less robust for prediction54 HCC patients by granting MELD in getting an effective and qualitative priority p amenable to potentially curative therapy.1 Obviously, disease to advanced stage and tumor size may also have points. After transplantation, the vascular invasion and extrahepatic disease also exclude HCC patients by granting MELD points. Aft and poor outcome and several reduced power in the absence of outcome prediction is far more early-stage HCC. In a study in surgical patients, we plantation, the outcome prediction is far more others show that early tumors are satellites or vascular invasion.55–57 complex and involves tumor established that the presence of portal hypertension and and involves tumor profile,62 but also graft unlikely associated to symptoms). These considerations show that profile,62 but also graft quality, etiology of underlying liver disease, and severa increased bilirubin predicted a worse outcome as comIndeed, this is the rationale for surgical patients require a set of etiology of underlying liver disease, Vascular invasion is associated with higher pared with patients without such findings even if limitearly detection plans based on data to predict prognosis that and several others. Vascular recurrence, but even if present just microsc ing resection to Child–Pugh A patients.51 Accordingly, surveillance: to detect early-stage differs from that used for patients invasion is associated with higher these parameters serve to predict survival in these strata recurrence will affect less than 50% of the s disease at an asymptomatic stage undergoing liver transplantation risk of recurrence, but even if of patients and their value has recently been validated in patients.62 Finally, patients considered for abla amenable to potentially curative or ablation. Outcome prediction present just microscopically, 52 not have the data from pathology and differe Japan. Resected patients can have further refinement of therapy.1 Obviously, vascular in patients considered for recurrence will affect less than their prognostic prediction by the presence of established degree will never be robust enough. Vascular invasion and extrahepatic disease transplantation should take 50% of the surviving patients.62 pathology markers of high risk of recurrence: microwill not be captured and the potential correla also exclude early-stage HCC. In into account expected waiting Finally, patients considered for vascular invasion and presence of satellites or additional tween poor differentiation and vascular invasion a study in surgical patients, we time (it may differ according to ablation will not have the data nodules53 (Fig. 2). Poor differentiation degree is less be useful as HCC 3cm (the optimal candid established that the presence blood from pathology and differentiation 54 group and geographic tumor size may also have robust for prediction and58–61 ablation) do not frequently show poor differe of portal hypertension and location) and liver function has degree will never be robust reduced power in the absence of satellites or vascular Several studies have shown that prognosis pr increased bilirubin predicted a 55–57 no impact in outcome. Hence, enough. Vascular invasion These considerations show that surgical invasion. can be refined after therapy as achievemen worse outcome as compared prognostic prediction requires will not be captured and the patients require a set of data to predict prognosis that initial complete response is associated to im with patients without such different tools. Baseline tumor size, potential41,65,66 correlation between differs from that used for patients undergoing liver survival. findings even if limiting resection multinodularity, AFP concentration, poor differentiation and vascular transplantation or ablation. Outcome prediction in pato Child–Pugh A patients.51 treatment failure to achieve tumor invasion will not be useful as HCC tients considered for transplantation should take into Accordingly, these parameters necrosis and growth while waiting, ≤3cm (the optimal candidates GENOMIC PROFILING AND PROGNO account expected waiting time (it may differ according to serve to predict survival in these are markers of risk of uncontrolled for ablation) do not frequently Molecular biology has experienced a major ex blood group and geographic location)58–61 and liver strata of patients and their value HCC progression and exclusion show poor differentiation. Several function has no impact in outcome. Hence, and our knowledge about the events that promo 62–64 prognostic has recently been validated from the waiting list. As such, studies have shown that prognosis in Japan.52 Resected patients have to be considered when prediction can be refined after can have further refinement of informing prognosis, likelihood of therapy as achievement of an initial their prognostic prediction by transplantation, and ultimately, complete response is associated the presence of established development of priority policy. to improved survival.41,65,66 pathology markers of high risk Interestingly, none of these

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44 Liver Cancer

GENOMIC PROFILING AND PROGNOSIS Molecular biology has experienced a major expansion and our knowledge about the events that promote cancer development and progression has grown in recent years.67 The goal here is to identify the abnormalities that reflect a higher risk of cancer and the biologic profile as well. Genomic studies have attempted to provide the basis for such refinement and link a specific profile with etiology and prognosis.68–70 However, despite the appealing nature of such an approach, the findings have not allowed for the incorporation of any criteria in clinical practice. The approach should be considered a work in progress as reflected by a recent meta-analysis where all the proposed molecular classifications have been merged and resulted in a system with just three strata.71 Clearly, the future is in this direction, but we are not there yet The same applies to the prediction of recurrence after resection and the identification of the profile that may predict a higher risk of de novo tumors or response to interventions aimed to prevent this unfortunate event.72

THE BCLC STAGING IN 2010 All these comments should serve to expose the validity of the BCLC staging system and treatment allocation that is reflected in Fig. 2 and summarized as follows. The connection to treatment indication is briefly outlined for each stage, but the rationale for each recommendation is further specified when commenting on the different treatment options.

Liver Cancer

exposed the fact that we consider in this scheme those patients diagnosed with HCC and being evaluated for it; those with impaired liver function and candidates for transplantation constitute another scenario. Tumor size is an established criteria for transplant selection77 as the proposals for expansion according to imaging information at the time of decision making are not yet validated. Size is also key for ablation success and nodules beyond 5 cm are seldom fully necrosed, and the same applies in multifocal nodules <3 cm.39,65,78,79 By contrast (and as mentioned above), in some instances HCCs may grow beyond 5 cm and still be compact and show no vascular invasion or satellites. This is especially frequent in hepatitis B virus (HBV) carriers and justifies no clear cutoff for surgical resection. However, the risk of vascular invasion goes in parallel with tumor size;62 hence, such large HCCs should never be classified as optimal candidates.

 The first stratum consists of patients with very earlyor earlystage HCC. Very early stage (stage 0) is formed by those patients with single HCC ≤2cm in a wellcompensated cirrhotic liver without portal hypertension. These patients present what may be named carcinoma in situ and if treated by resection have an optimal outcome exceeding 90% at 5 years.73 The presence of vascular invasion and or satellites is anecdotal if they correspond to the indistinctly nodular type defined by Kojiro et al.74 A proportion of such small nodules will show the distinctly nodular type and in them the risk  Intermediate stage (BCLC B) of vascular invasion and satellites is formed by those patients with is slightly higher (27% and 10%, single large HCCs and those respectively). Establishing an with multifocal disease who are unequivocal diagnosis prior to asymptomatic and do not present BCLC UPDATE AND FUTURE PROSPECTS/FORNER ET AL 65 resection isTHE a current challenge vascular invasion or extrahepatic as this stage should be the target spread. Liver function is again further specified when commenting on the different of early detection plans. Both preserved fitting into Child– treatment options. imaging75 and molecular biology Pugh A and B classification. If tools76 should help to properly compensated, these patients The first stratum consists of patients with very earlydefine theortype of tumor and Very early are early-stage HCC. stageoptimal (stage candidates 0) is for the risk offormed recurrence. With this 1,80 by those patients with single HCC 2cm in chemoembolization. Expected information, prognosis and optimal a well-compensated cirrhotic liver without portal is around 16 median survival therapy should be established. hypertension. These patients present whatwith maywide be variation months

named carcinoma in situ and if treated by resection according to confounding  Early-stage HCC (BCLC A) 73 have an optimal outcome exceedingfactors 90% at such 5 years. as prior therapies classification consists of patients The presence of vascular invasion and and/or satellites is degree of renal function with single HCC orif with up to threeto the indistinctly anecdotal they correspond nodimpairment with requirement for 74 nodules <3 cm. Liver function ular type defined by Kojiro et al. A proportion of sodium diet and diuretics.27 is definedsuch by Child–Pugh andshow the low small nodulesAwill distinctly nodular Treatment with chemoembolization Child–Pugh B status not reaching type and in them the risk of vascular invasion and to a median the criteria for transplantation satellites is slightly higher (27% improves and 10%, outcome respec80–82 of 20 months, because tively). of impaired liver function Establishing an unequivocal diagnosis prior and is further expanded reflectingtopoor short-term survival resection is a current challenge as this stage should according to the of an be the transplantation target of early detection plans. Bothachievement imaging75 and deserving in objective response, which in and molecular biology tools76 should help to properly the absence of contraindications. is recurrence. mediated by the tumor the typewe of already tumor and the part risk of As noteddefine here earlier, With this information, prognosis and optimal therapy Figure 2 Small hepatocellular carcinoma (HCC) treated by should be established. liver transplantation. Pathology examination carcinoma shows the alFigure 2 Small hepatocellular (HCC) treated by liver transplantation. Pathology examination shows the  Early-stage HCC (BCLC A) classification consists of ready known tumor as welltumor as satellite nodules located in nodules the already known as well as satellite located in the vicinity. It is conventional to define as satellites those patients with single HCC or with up to three nodules vicinity. additional It is conventional define as satellites addisites to located within 1 cmthose of the main nodule, but in this case obvious satellites were encountered beyond <3 cm. Liver function is defined by Child–Pugh A tional sites located within 1 cm of the main nodule, but in this this limit, but still in the same segment. and Child–Pugh B status not reaching the criteria for case obvious satellites were encountered beyond this limit, but still in the same segment. transplantation because of impaired liver function reflecting poor short-term survival and deserving transplantation in the absence of contraindications. development progression has grown in recent As noted here earlier, we already exposed the fact that Issue 2and • HPN 67 years. The goal here is to identify the abnormalities we consider in this scheme those patients diagnosed

characteristics. However, there are no robust criteria to stratify candidates according to HCC characteristics.  Advanced stage (BCLC C). This stage applies to patients who have evolved beyond the profile depicted in BCLC B. They may have symptoms and/or present vascular invasion or extrahepatic spread. Any degree of vascular invasion (segmental or lobar or trunk) has the same implications in terms of tumor invasiveness and prognosis. Liver function is not well established as a prognostic predictor, but the presence of ascites and diuretic requirement as well as increased bilirubin level that qualify for Child–Pugh B status may imply a worse prognosis. Advanced Child–Pugh B stage should raise the consideration of transplant; it is unlikely that they present as just mildly symptomatic as per performance status.  End stage (BCLC D) includes those patients with severe impairment of liver function (Child–Pugh C) who are not candidates for liver transplantation and those patients with heavily impaired physical condition as established by an ECOG performance status >2. TREATMENT STRATEGY It is important to stress that the aim of treatment is to improve survival of patients while maintaining the most preserved quality of life. This apparently simple statement is of paramount importance as quite frequently the debate of treatment indication is established around what can be done, rather than around what is worth being done. In all life-threatening conditions, physiciansand patients would like to have an option that would provide a cure or at least, a significant life improvement. However, evidence for such a benefit may not be available and this should not serve as a basis for any desperate attempt to engage in a treatment approach, but rather as a trigger for designing a research trial to evaluate prospectively the benefits of any

therapy that could be considered potentially effective. Through this approach, relevant information will be made available and if strong and positive, it may become ultimately part of the standard of care. This raises the need to recall that the strength of scientific evidence is ranked as shown in Table 2. Major data will come from large randomized double-blind placebo controlled trials or even unblinded. The least robust information comes from personal opinions and isolated clinical observations, but in several debates such personal experiences and unusual case reports are proposed as the proof of the value of any type of atypical or uncommon therapeutic approach. The same value could be given to the well-known cases of spontaneous regression,83 but no one should use these fortunate observations as the basis to recommend no therapy when an effective one would be feasible It is also worth stressing that the management and treatment of patients with HCC should be done in expert settings where all the knowledge and skills related to the specialities involved is readily available.33 Only if this partnership is in place will optimal care be delivered with state of the art outcomes. All effective options should be available (it is acknowledged that liver transplantation is not an option in some areas and access to it is unfeasible), but resection, ablation, chemoembolization, and sorafenib should be currently considered standard of care and be integrated into the treatment algorithm. Cost is a frequent concern, but this is beyond the focus of this review and will not be discussed. Treatment of BCLC 0 (Very Early HCC) If this entity could be properly diagnosed and the absence of vascular invasion/satellites guaranteed, it is clear that the optimal choice would be percutaneous ablation. An almost 100% success rate is feasible because of tumor location and if


Table 2 Levels of Evidence According to Study Design Grade



Randomized controlled trials


Controlled trials without randomization


Cohort or case-controlled analytic studies


Multiple time series, uncontrolled experiments

III Opinion of respected authorities; descriptive epidemiologic studies Adapted from Bruix and Sherman.1

the risk of dissemination is almost zero, the treatment would have a high curative rate—just leave behind the cirrhotic liver with its risk of metachronic tumors. Cohort studies indicate that the survival of patients treated by ablation is very similar to that of resected patients in such a very early stage;84 hence, both options could be considered equally effective However, unequivocal diagnosis of very early HCC is still not consolidated in real practice and ablation may not be feasible in all cases. Expert surgery may also provide optimal results in expert settings. Because of the preserved liver function and the low risk of recurrence, these patients would not need to be considered for transplantation. However, as said above, because diagnosis of this very early HCC is now unreliable, the Table 2 Levels of Evidence According to Study Design decision process will in most instances still be the same as that of early stage. Treatment of BCLC A (Early HCC) There are no large randomized controlled trials comparing any of the available options in patients that would be optimal candidates for all options. Small trials comparing surgical resection and ablation report a very similar survival rate.85–87 According to available data from cohort studies, the survival and recurrence rate in patients treated for solitary HCC 2 cm is very similar between resection and ablation.84 Ablation has a marked decrease in efficacy

when tumor size exceeds 3 cm and when more than 2 nodules are targeted.39,65,78,79,88,89 Current data with both options indicate a 5 year survival of 70% at 5 years in patients with well preserved liver function, but as previously commented, if portal hypertension is present and/or HCC is multifocal the survival rate at 5 years decreases to around 50% for surgical candidates52,58 and in ablated patients that have not been considered for surgical resection. Contrarily, liver transplantation would offer a 70% survival rate irrespective of liver function,58,77,90,91 but in cases where pathology shows microscopic vascular invasion and/ or satellites, the risk of recurrence is significantly less compared with surgical resection and ablation. A major limitation for the successful application of transplantation is the shortage of donors, which implies a waiting time of varying magnitude. During this period, the tumor may progress and impede the procedure. Despite the lack of any trial showing the benefits of any adjuvant therapy, it is common practice to perform adjuvant therapy by ablation or chemoembolization, whereas chemotherapy has no efficacy.63 These locoregional interventions may be effective at the individual level, but will not address the lack of enough donations.92 Thus, a major emphasis has to be placed on anyaction aiming to induce donation, either from a brain death donor or from live donations. The shortage of donors justifies a strict

selection of candidates toensure adequate posttransplant survival. The successful Mazzaferro criteria77 are still the accepted standards for selection, as all the proposals for expansion have not been properly validated using homogeneous radiology definitions for staging.93–97 The same applies to the so-called downstaging that would allow patients with excessive tumor burden to be transplanted if they meet the Mazzaferro criteria after any sort of therapy.98–100 Until these data are available with enough strength, it is not feasible to recommend the acceptance of these approaches. Recurrence during follow-up is frequent after resection and ablation as it affects more than 70% at 5 years.36 Early recurrence before 2 years is conventionally attributed to dissemination; recurrence beyond this time point may be more likely due to metachronic HCC in the oncogenic cirrhotic liver. Whatever the mechanism, there is no option of proven efficacy to prevent recurrence in patients with HCV or HBV cirrhosis.63 Controlling viral replication may prevent deterioration of liver function in HBV patients101 and to a lesser extent in patients with HCV, but this should not be expected to prevent tumor dissemination (the most frequent path to recurrence), but rather potentially impact metachronic oncogenesis at long term.102 Large size per se should not be taken as a contraindication to surgery if staging suggests it is still a solitary HCC that has grown in a compact way. Risk of liver failure becomes an issue, but if such a big mass occupies the whole lobe, it is already not providing normal liver function and tolerance is better than that of resection of a small HCC that requires large nontumor removal because of location in the central part of the liver. As said, the risk of microscopic vascular invasion increases in parallel with tumor size, but the same risk is present in smaller tumors with the same degree of vascular invasion. In

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46 Liver Cancer

Liver Cancer

Figure 3 Survival of patients with hepatocellular carcinoma (HCC) in the SHARP trial comparing sorafenib versus placebo in a double-blind randomized controlled trial. The median overall survival of sorafenib-treated patients was 10.7 months versus the 7.9 months in those treated with placebo, that represents a 0.69 hazard rate of dying during follow-up (95% CI 0.55–0.87; p < 0.001).

blockade of aurora kinase, epidermal growth factor, insulin-like growth factor, c-MET, or fibroblast growth factor among several others, while at the same time still acting through the sorafenib mechanisms of action. The critical point will be how to balance the willingness to enhance the antitumoral effect while assuring safety, and how to evaluate the potential efficacy. In most instances, there is no reduction in tumor burden and hence, that sense, recent retrospective assessment of a large surgical series at Mount Sinai suggests a correlation with magnitude of vascular invasion and risk of recurrence.103 Prospective validation is needed prior to using this criterion to estimate outcome As previously mentioned, ablation is highly effective and even curative in patients with small HCC. However, when the nodule size exceeds 3 cm the likelihood for complete response and the absence of recurrence within or surrounding the treated nodule is significantly reduced.39,65,78 The decrease of efficacy with nodule size is well known with ethanol injection because tumor septa may prevent adequate tissue diffusion, but all data indicate that the reduction in effectiveness is also registered with radiofrequency (RF), despite its capacity to induce complete necrosis and ablation of the peritumoral area, where microscopic satellites may already be present. The higher initial control rate may translate a better outcome in patients treated with RF.88,104,105 Hence, RF is currently the first ablation technique to be considered and is established as the standard ablation technique to be beaten by any other technology. High-intensity focused ultrasound is still in the evaluation phase. Unfortunately, it requires more time for therapy to be effective; in some instances, it may require higher invasiveness. Breath movements may impede its successful application: this is a relevant limiting factor for its application in liver tumors.106 Some authors have suggested that tumors beyond 3 cm could benefit from sequential treatment by transarterial chemoembolization (TACE) and RF, as also proposed years ago with ethanol injection.107 Despite several suggestive phase 2 studies,108,109 no valid prospective controlled trial has proven yet the benefit of this combined approach. Treatment of BCLC B (Intermediate HCC) This stratum of patients is formed by patients in whom

Issue 2 • HPN


conventional RECIST125 will fail to capture any existing positive signal. New criteria based on functional imaging measuring perfusion and diffusion will be developed in the near future and become instrumental for efficacy evaluation. Meanwhile, the most reliable parameter should be time to progression. Optimally, studies should be run in a randomized fashion so that a comparator is available to ensure unbiased assessment.32

as VEGF concentration have ACKNOWLEDMENTS been correlated with survival.120 BCLC is funded through the Several agents were in the race This has been an area of extensive Spanish Biomedical Research for success and the one that research as until very recently, Network (CIBER) for the area of was unequivocally effective in there was no effective therapy hepatic and digestive disorders. improving survival has been It is important to note that to be offered to those patients This work was in part supported sorafenib. This agent is an oral arterial embolization without that were diagnosed at advanced by a grant of the Instituto de tyrosine kinase inhibitor that associated chemotherapy can stage or transitioned into it after Salud Carlos III (grant PI 08/ blocks the Raf/MEK/ ERK pathway induce a relevant rate of objective initial therapy. Chemotherapy has 0146). Alejandro Forner is partially and the receptor for VEGFR 2 tumor response.80 However, no activity either intravenously supported by a grant of the 121,122 and PDGFR-β. After showing there is no proof of a positive or intraarterially, both if tested Instituto de Salud Carlos III (PI activity in experimental models impact in survival as proven for as a single agent regimen or in 05/645). Maria Reig is funded by and potential delayed tumor chemoembolization. Selective combination.117 In addition, in all a grant of the BBVA foundation. progression rate in a large phase arterial injection of chemotherapy instances the lack of impact on Carlos Rodriguez de Lope is 2 study,123 it was tested in a phase without arterial obstruction does survival is associated with toxicity partially supported by a grant of III, multicenter, randomized, not result in relevant antitumor that results in impaired quality of the Instituto de Salud Carlos III double-blind, trial including 602 effect and has never been shown life or even impaired survival.118 (PI09/510) and funded by a grant patients. The median overall to improve survival. Because of this unmet need, a of the BBVA Foundation. survival of sorafenib treated major expectation was placed in patients treated was 10.7 months Recently, a major emphasis has ABBREVIATIONS Figure 4 Time to tumor progression of patients in the SHARP trial. Median time to progression (TTP) was 5.5 months in the potential of targeted therapies versus the 7.9 months in those been placed on the potential sorafenib-treated patients, whereas it was just 2.8 months in the placebo arm (HR 0.58; 95% CI 0.45–0.74; p < 0.001). Because that would aim to abrogate the BCLC Barcelona Clinic Liver treated with placebo (HR 0.69; efficacy of radioembolization sorafenib administration was not associated with any tumor burden reduction as per Response Evaluation Criteria in Cancer Solid abnormal molecular events that 95% CI 0.55–0.87;Tumors p<0.001) with Yttrium-90 labeled spheres. Figure 4 Time of to the tumor patients the SHARP trial.this Median (RECIST) criteria, the efficacy drugprogression in improvingofsurvival is in mediated through impact in tumor growth and govern tumor progression and (Fig. 3). The impactdissemination. on survival Phase 2 studies confirm that this HCC Hepatocellular time to progression (TTP) was 5.5 months in sorafenib-treated patients, dissemination. Several studies was preceded by a slower tumor option has antitumor activity,114–116 Carcinoma whereas it was just 2.8 months in the placebo arm (HR 0.58; 95% CI identified angiogenesis as one progression that confirmed the but unfortunately, there is no 0.45–0.74; p<0.001). Because sorafenib administration was not associated of the most promising targets for ECOG PS Eastern Cooperative data raised in the phase 2 trial. information available comparing with any tumor burden reduction as per Response Evaluation Criteria in intervention in HCC.119 It is a highly Oncology Group Median time to progression (TTP) this option versus any other Solid Tumors (RECIST) criteria, the efficacy of the drug in improving survival vascularized cancer and markers Performance Status was 5.5 months in sorafenibtreated is mediated through this impact in tumor growth and dissemination. established treatment. Hence, its of enhanced vascularization such patients, whereas it was just 2.8 real value is not yet established. AFP Alpha-fetoprotein THE BCLC UPDATE AND FUTURE PROSPECTS/FORNERmonths ET AL in the 69placebo arm (HR MELD Mayo Model for End 0.58; 95% CI 0.45–0.74; p<0.001) Stage Liver Disease (Fig. 4). The most frequent severe drug-related adverse events were TNM Tumor node metastasis hand–foot skin reaction, diarrhea, to enhance the antitumoral effect all aspects related to this cancer. 28 and fatigue. The same positive RF Radiofrequency Unfortunately, after an initial while assuring safety, and how Until very recently, the activity in findings have been registered in treatment response, the treated to evaluate the potential efficacy. the research clinical arena was TACE Transarterial a randomized placebo controlled tumors gain vascularization In most instances, there is no moving at a slow pace, but now chemoembolization 29 trial in Eastern countries. Thus, again, the disease progresses, reduction in tumor burden and several competitive initiatives are sorafenib is confirmed across 125 RECIST Response Evaluation and despite repeated treatment hence, conventional RECIST taking place. These affect not only geographic regions and in different Criteria in Solid Tumors sessions, the capacity to keep the will fail to capture any existing the treatment of advanced stage, etiology populations and is now cancer under control is lost. This positive signal. New criteria based but have also involved earlier standard of care for advanced emphasizes the need to develop on functional imaging measuring evolutionary stages. Recurrence HCC.32,124 better techniques to perform perfusion and diffusion will be after resection or ablation is a the procedure and enhance the developed in the near future and These results represent a major major problem and there is a need References on request efficacy of chemoembolization become instrumental for efficacy breakthrough and have initiated to develop effective preventive by increasing the exposure of the evaluation. Meanwhile, the most the quest to develop combination agents for this setting. Progression tumor to chemotherapy, while reliable parameter should be time or sequential strategies to further after effective chemoembolization reducing its systemic toxicity. to progression. Optimally, studies enhance the impact achieved is also an area where investigation This has been partially achieved should be run in a randomized with sorafenib as a single agent. with adjuvant strategies is being by the use of drug-eluting fashion so that a comparator Several trials are now ongoing (see conducted. beads that can produce a highly is available to ensure unbiased and affect calibrated obstruction while The treatment of HCC has assessment.32 Figure 3 Survival of patients with hepatocellular carcinoma (HCC) in the SHARP trial comparing sorafenib versus placebo in a pathways and agents such several simultaneously slowly releasing changed dramatically: years ago, double-blind randomized controlled trial. The median overall survival of sorafenib-treated patients was 10.7 months versus as the mTOR inhibitors, blockade of FUTURE PERSPECTIVES the drug into the blood flow. in those treated with placebo, that represents a 0.69 hazard rate of dying during follow-up (95% CI 0.55–0.87; patients diagnosed with this 7.9 months aurora kinase, epidermal growth Treatment methodology is highly Figure 3 Survival of patients with hepatocellular carcinoma (HCC) in cancer had no safe and reliable p < 0.001). factor, insulin-like growth factor, The impact of sorafenib on standardized and the efficacy is the SHARP trial comparing sorafenib versus placebo in a double-blind therapies to benefit from and their c-MET, or fibroblast growth factor advanced-stage HCC is a maintained, if not increased, while randomized controlled trial. The median overall survival of sorafenib-treated prognosis was uniformly grim. among several others, while at landmark finding in the treatment 125 blockade of aurora patients kinase, was epidermal growth factor, conventional RECIST will fail to capture any existing avoiding the systemic toxicity 10.7 months versus the 7.9 months in those treated with Now, all stages of the disease the same time still acting through of liver cancer. It has triggered a 111–113 insulin-like growth factor, c-MET, or fibroblast growth positive signal. New criteria(95% based on functional imaging due to chemotherapy. The placebo, that represents a 0.69 hazard rate of dying during follow-up may receive effective therapy and the sorafenib mechanisms of major interest in the development factor among aseveral CI others, while p<0.001). at the same time still measuring perfusion and diffusion will be developed in The critical point will be current challenge is to evaluate 0.55–0.87; current research will expand the action. and testing of several new agents combination of TACE using this the sorafenib mechanisms of action. The acting through the near future and become instrumental for efficacy how to balance the willingness and primed the investigation of existing benefits. resection, transplantation, and ablation have been dismissed because of too large tumor size and/or multifocality; however, they still are asymptomatic and maintain a preserved liver function. The standard of care in them is chemoembolization according to the results of randomized controlled trials and cumulative meta-analysis.80–82 Chemoembolization induces a >50% response rate and this translates in slower tumor progression and improved survival. Some groups propose to perform TACE even in symptomatic patients or even if they have segmental vascular invasion and/ or extrahepatic spread. Impact of therapy is significant in patients without symptoms and the existence of vascular invasion as detected by imaging increases the risk of severe adverse events and liver failure. The same applies to patients with decompensated cirrhosis or fitting into Child– Pugh B classification.110 Hence, the patients that will benefit the most from this therapy are those without any of these adverse characteristics; those with them may not benefit at all from this locoregional intervention.

refined technology with moleculartargeted agents (sorafenib) that have been shown to reduce tumor proliferation and angiogenesis (see Treatment of BCLC C section)

critical point will be how to balance the willingness to enhance the antitumoral effect while assuring safety, and how to evaluate the potential efficacy. In most instances, there is no reduction in tumor burden and hence,

Treatment of BCLC C (Advanced HCC)

evaluation. Meanwhile, the most reliable parameter should be time to progression. Optimally, studies should be run in a randomized fashion so that a comparator is available to ensure unbiased assessment.32

HPN • Issue 2

48 Clinical Profiles

Dovonex® Scalp Solution 60ml Discontinued

Positive results for Hedgehog Pathway Inhibitor


LEO Pharma wishes to announce that Dovonex® Scalp Solution 60ml will be discontinued from July 2011. This discontinuation is not due to any safety or quality issues with Dovonex®, therefore pharmacists and patients may

continue to dispense or use any pack presentations of Dovonex® that they currently have. Please note that Dovonex® Cream 120g will continue to be available.

Roche recently announced that a pivotal Phase II clinical study of its investigational Hedgehog Pathway Inhibitor, vismodegib (RG3616/GDC-0449), showed positive results in people with advanced basal cell carcinoma (aBCC), a particularly severe and debilitating form of skin cancer. The study met its primary endpoint (overall response rate), showing vismodegib shrank tumours in a pre-defined percentage of people in the study. A preliminary

safety assessment showed the most common adverse events were consistent with previous experience with vismodegib. A detailed safety assessment is ongoing.

information, please contact LEO Pharma Marketing Department at 01 4908924 or email paul.kirwan@

Four year Stelara data show consistent safety profile

If you require any further

Data from the study will be submitted for presentation at a future medical meeting. The Hedgehog signalling pathway plays an important role in regulating proper growth and development in the early stages of

STELARA is currently approved in all 27 member states in the European Union for the treatment of moderate to severe plaque psoriasis. The four year safety

life and then becomes less active in adults. However, mutations in the pathway that reactivate Hedgehog signalling are seen in several different types of cancer. Abnormal signalling in the Hedgehog pathway is implicated in the majority of BCC cases. Roche is also evaluating vismodegib in a Phase II trial in people with operable forms of BCC, which opened in October 2010.

New findings from pooled analyses of the STELARA (ustekinumab) psoriasis clinical development program showed that the safety profile of STELARA and rates of adverse events remained consistent and stable over time in adults with moderate to severe plaque psoriasis receiving up to four years of treatment.

Eli Lilly and Company advises of withdrawal of Celance (pergolide)

Eli Lilly and Company (Ireland) Ltd. wishes to advise of the withdrawal of Celance (pergolide), indicated in the treatment of Parkinson's disease, with effect from 31st October 2011. Patients currently taking Celance

Saflutan available in Ireland for IOP

Breast Cancer trial results

Noctamid 1mg x 30 Out of Stock

Issue 2 • HPN

MSD has announced that ‘Saflutan’TM (tafluprost), the first preservative-free ophthalmic prostaglandin is now available in Ireland. It is available for the reduction of elevated intraocular pressure (IOP) in the most common type of glaucoma (open angle glaucoma) and in ocular hypertension. Treatment with tafluprost has been shown to provide sustained IOP control with a clinical study showing a 33%

Roche recently announced topline results of its first randomized trial of trastuzumab emtansine (T-DM1) in HER2-positive metastatic breast cancer. The Phase II trial, known as TDM4450g, compared trastuzumab emtansine (T-DM1) single agent to the combination of Herceptin (trastuzumab) and chemotherapy (docetaxel) in previously untreated patients. The results showed that patients treated with trastuzumab

Bayer Ltd. regrets to inform you that due to technical issues with the packaging process for Noctamid 1mg we will be out of stock until the end of August

mean reduction in IOP. Unlike tafluprost, all other prostaglandins currently available for glaucoma contain a preservative that can cause adverse reactions in some patients including burning, itching, tearing or dry-eye sensation. According to a multinational Phase III study involving 533 patients, tafluprost provided significant reductions in IOP (7.0mmHg at 24 months).

emtansine in this study had increased progression-free survival and experienced fewer side effects typical of chemotherapy. Data from the TDM4450g study will be submitted for presentation at a future medical congress. An earlier analysis of this study presented at the 35th Congress of the European Society of Medical Oncology (ESMO) in 20101

2011. We apologise for any inconvenience caused by this unforeseen situation. For further information please contact Robert Stanton, Customer

Tafluprost is a novel prostaglandin with high affinity and high selectivity for the Prostaglandin F receptor (FP). Activation of this receptor results in increased outflow of aqueous humour, thereby reducing intraocular pressure in the eye. For full prescribing information, please

showed encouraging results in tumour shrinkage (overall response rate, ORR) in patients with a minimum of four months of followup. In addition, the study showed that trastuzumab emtansine (T-DM1) significantly reduced the burden of typical side effects associated with conventional chemotherapy.

Service, Bayer Ltd. Phone: 01 2999313. Email: robert.stanton

United Drug Elements meet medical need

At United Drug Elements our extensive experience and impeccable customer service etiquette offers a swift and efficient service for sourcing Unlicensed/ Exempt medicinal products and pharmaceutical supplies not normally available through regular pharmaceutical distribution channels. When Drugs are discontinued for commercial reasons it is important to have a dependable, quick

BRINAVESS approved in Ireland

MSD has announced that BRINAVESS®™ (vernakalant), intravenous (IV) formulation for the conversion of recent onset atrial fibrillation (AF) to sinus rhythm in adults has been approved in Ireland. The full indication for BRINAVESS is for the rapid conversion of recent onset atrial fibrillation to sinus rhythm in adults: for non-surgery patients with atrial fibrillation of seven days or less and for post-cardiac surgery patients with atrial fibrillation of

analysis of the STELARA Phase 2, PHOENIX 1, PHOENIX 2 and ACCEPT trials evaluated the largest psoriasis-focused clinical trial safety database for a biologic reported to date, with more than 1100 patients who have had at least three years of treatment with STELARA and more than 600 patients treated for four or more years for a total of nearly 6800 patient years (PY). The pooled safety data, from a total of 3117 patients, showed rates of adverse event (AEs) to be

generally stable over time through up to four years of treatment with STELARA. Observed occurrences of AEs of interest, including serious infections (0.8 and 1.32 for 45 mg and 90 mg STELARA patient groups, respectively, per 100 PY), non-melanoma skin cancer (0.70; 0.53 per 100 PY, respectively), other malignancies (0.63; 0.61 per 100 PY, respectively) and major adverse cardiovascular events (MACE) (0.42; 0.36 per 100 PY, respectively) remained generally stable during the time periods evaluated.

should be advised to contact their doctors to arrange a review regarding the possible need for alternative treatments. Healthcare professionals should re-assess their patients' condition, giving consideration to the prescribing of

a therapeutic alternative.

supply source for your exempt medicinal needs. We aim to hold stock of products for which there is a demand.

available and no request is too big or too small.

As well as the procurement of unlicensed medicines we specialise in the supply of compression hosiery with brands such as Mediven, Duomed, Kendall and Activa all readily available in all shapes and size. All forms of Medical supplies from a simple pill box to a nebuliser are

three days or less.

For further information, please contact: Lilly Ireland on 01 661 4377 or the Lilly Medical Information service via 01 664 0446.

You can order by fax, phone or email – UDW Dublin - P: 01 4632300 F: 01 4637767 E: UDW Limerick - P: 061 315 411 F: 061 315012 UDW Ballina - P: 096 72 555 F: 096 72400

BRINAVESS has a unique mechanism of action from other antiarrhythmic medicines and is the first product in a new class of pharmacologic agents for cardioversion of atrial fibrillation to launch in Ireland.

In ACT I and III, the efficacy of vernakalant at converting patients from AF to sinus rhythm for a minimum duration of one minute within 90 minutes of initiating therapy was evaluated in 390 haemodynamically stable adult patients with short duration AF (3 hours to 7 days) versus placebo.

The approval of vernakalant is based on the results of three randomized, double-blind, placebo-controlled studies (ACT I, ACT II, and ACT III) and an active comparator trial (AVRO).

In the AVRO study, vernakalant was significantly more effective than amiodarone IV in providing rapid conversion to sinus rhythm within 90 minutes of initiating therapy.

HPN • Issue 2

50 Appointments

Dr David Hall The Irish Pharmaceutical Healthcare Association (IPHA) is pleased to announce the election of Dr. David Hall PhD MEng MBA to the Board of Directors of the Association.

Pharmaceutical Refrigerators Between 1998 and 2001 he worked as an IT and telecoms consultant. From 2004 to 2009 he worked for Johnson and Johnson (UK) Ltd, where he held various roles in marketing,

category management, pharmacy and professional sales, as well as working across consumer products at McNeil OTC Medicine.

– Quality, Reliability, Safety

Dr Frank Dolphin and Dr Barry White Irish health services have entered a new phase with a significant change in the relationship between the HSE and the Minister for Health/Department of Health. Health Minister Dr James Reilly has announced the members of the new Interim Executive Board of the HSE, which will run the health services in a more effective

manner “with greater emphasis on service delivery, more integration and less duplication.” The new board will see senior figures from the Department of Health and from the HSE, including clinicians, establish a new, more direct line of accountability between the management of our

health services and the Minister for Health. The board will be chaired by Dr Frank Dolphin who has accepted Minister Reilly’s request to remain as chair until its later dissolution. Dr Barry White has also been appoingted HSE National Director, Clinical Strategy Programmes.

Exterior Powder coated galvanised steel prevents rusting Door Lockable door with optional triple glazed glass

PC Interface Real time monitoring, data recording and reporting through network or USB connection to PC

Isabelle Adenot The Pharmaceutical Group of the European Union has unanimously elected Ms Isabelle Adenot as PGEU President for the year 2012. Ms Adenot has been active in French and

European pharmacy related issues for 30 years and was closely involved in the development of the Pharmaceutical Dossier, an innovative medication record system established by French

pharmacists. Ms Adenot is the first female President of PGEU since its creation 52 years ago. This election clearly represents the fact that nowadays 75% of pharmacists in Europe are women.

Joan Peppard

Yvonne Sheehan

Joan Peppard has been appointed President of the Hospital Pharmacists Association of Ireland. Joan takes over the post from Elaine Conyard. Joan is Head of Pharmacy at Tullamore Hospital.

Yvonne Sheehan has been appointed President of the National Association of Hospital Pharmacy Technicians of Ireland. Yvonne takes over this role from outgoing President Fran Glynn.

Versatility Roller drawers, height adjustable with removable dividers

Model shown: MED-340

Olivier Feray & Stefano Dessena The Pharmaceutical Wholesale Division of Alliance Boots has announced two key appointments for its businesses in France and Spain. Joaquim Fausto Ferreira (Managing Director of Alliance Healthcare España) is appointed as Managing Director of Alliance

Issue 2 • HPN

Healthcare France, reporting to Ornella Barra (Chief Executive, Pharmaceutical Wholesale Division, Alliance Boots). Consequently, Olivier Feray (former interim Managing Director of Alliance Healthcare France) takes up the role of Company Secretary (Secrétaire Général) for Alliance Healthcare France,

reporting to Joaquim. Stefano Dessena (Upstream Commercial Director for Alliance Healthcare España) is appointed as Managing Director of Alliance Healthcare España, replacing Joaquim Fausto Ferreira. He reports to Terry Scicluna (Managing Director, International).

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Company information Alchemy is the exempt medicines division of Cahill May Roberts. Our service is integrated into the CMR wholesale model.This offers our customers additional benefits as we have full support of customer service, telesales, accounts and finance management, logistics and operational staff. Alchemy is an Irish company and employs pharmacists, technicians and tele-sales personnel to guide you through the complete process of ordering/sourcing exempt medicinal products for your customers & patients needs.

Our service Is a comprehensive service for sourcing exempt medicinal products. We source and supply manufactured specialsextemporaneous products within 72 hours. We have a specialist team in place (pharmacists, technicians and telesales personnel) to guide you through the process in an ethical and professional manner from order to delivery. Full supplier verification ensures complete traceability of all our products. Source and supply short, discontinued, irregular and once off products. No extra delivery charges using customers current delivery arrangements*. * Express emergency deliveries may incur a fee

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NEW WEB PORTAL allows you to easily place your order for exempt medicinal products electronically removing the need to fax your order through. This new site allows you to manage all aspects of the exempt medicines part of your business including: Checking the availability of stock, pricing and re-printing of invoices. To access our site visit: We have a large number of exempt medicines in stock and immediate access to a database of more than 650,000 medicines worldwide. Market leading price structures.

Contact details Cahill May Roberts, Pharmapark, Chapelizod, Dublin 20. Telesales: (071) 9161801 Technical queries: (01) 630 5432 Fax number: (071) 9161977

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IN THIS ISSUE: Conference: EAHP Annual Meeting in Dublin - Report: Antibodies detected to block onset of Alzheimers - Feature:Pharmaceutical...