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Issue 9

HOSPITAL PHARMACY NEWS IRELAND THE INDEPENDENT VOICE OF HOSPITAL PHARMACY IN THIS ISSUE: News: Recognition for Kerry hospital pharmacists Page 4 Report: Revised biosimilar guideline released Page 14 Profile: Tony Hynds on Actavis re-branding whilst keeping value Page 18 Awards: Further coverage of the Hospital Pharmacy Awards 2013 and all the categories Page 20

Now using a validated diagnostic tool1,2, you can accurately identify specific patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who may benefit from targeted therapy3. In patients harbouring BRAFV600 mutations, Zelboraf significantly improves response rate, progression-free survival and overall survival as compared with DTIC4.

ABRIDGED PRESCRIBING INFORMATION For full prescribing information refer to the Summary of Product Characteristics (SmPC) ZELBORAF® (vemurafenib) 240mg film-coated tablets. Indication: As monotherapy for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. Dosage and Administration: Confirm BRAF V600 mutation-positive tumour status by a validated test prior to treatment. Treat until disease progression or the development of unacceptable toxicity. Recommended dose is 960mg (4 tablets of 240mg) twice daily. Vemurafenib may be taken with/without food, but avoid consistent intake of both daily doses on an empty stomach. Swallow tablets whole with water. If a dose is missed, it can be taken up to 4 hours prior to the next dose to maintain the twice daily regimen. Both doses should not be taken at the same time. Vomiting – continue treatment as usual. Management of symptomatic adverse drug reactions or QTc prolongation may require dose reduction, temporary interruption and/or treatment discontinuation – refer to SmPC. Dose reduction for cutaneous squamous cell carcinoma (cuSCC) is not recommended. Adjustments to <480mg twice daily are not recommended. Paediatric population: The safety and efficacy of vemurafenib has not yet been established in children and adolescents (<18 years). Contraindications: Hypersensitivity to the active substance or to any of the excipients. Warnings and Precautions: CuSCC and new primary malignant melanoma: cuSCC (including keratoacanthoma or mixed keratoacanthoma subtype) and new primary malignant melanoma have been reported. Evaluate prior to and monitor routinely while on therapy. Excise any suspicious skin lesions, and obtain dermatopathologic evaluation; treat as per local standard of care. Examine patient monthly during and for 6 months after treatment. In patients who develop cuSCC or new primary malignant melanoma, continue treatment without dose adjustment. Monitoring should continue for 6 months following discontinuation of vemurafenib or until initiation of another anti-neoplastic therapy. Patients should inform their physician upon the occurrence of any skin changes. Non-cuSCC: Cases of noncuSCC have been reported in clinical trials. Patients should undergo a head and neck examination, with a visual inspection of oral mucosa and lymph node palpation prior to initiation and every 3 months during treatment. Patients should undergo a CT scan prior to and every 6 months during treatment. Perform anal and pelvic examinations (women) before and at the end of treatment or when clinically indicated. Monitoring should continue for 6 months following vemurafenib discontinuation or until initiation of another anti-neoplastic therapy. Abnormal findings should be managed according to clinical practices. Hypersensitivity reactions: Serious hypersensitivity reactions, including anaphylaxis have been reported. Vemurafenib treatment should be permanently discontinued if severe hypersensitivity reactions occur; these may include Stevens- Johnson syndrome, generalised rash, erythema or hypotension. Ophthalmologic reactions: Serious reactions have been reported; monitor patients routinely. QT prolongation: Exposure-dependent QT prolongation has been observed and may lead to an increased risk of ventricular arrhythmias including Torsade de Pointes. Treatment not recommended in patients with uncorrectable electrolyte abnormalities (including magnesium), long QT syndrome or who are taking medicines known to prolong the QT interval. ECG and electrolytes (including magnesium) should be monitored before treatment with vemurafenib, after one month of treatment and after dose modification. Further monitoring recommended (particularly in patients with moderate-severe hepatic impairment) monthly for first 3 months and then 3 monthly thereafter, more frequently if clinically indicated. Initiation of vemurafenib is not recommended in patients with QTc >500ms. If during treatment the QTc >500ms, temporarily interrupt vemurafenib and correct electrolyte abnormalities (including magnesium); control cardiac risk factors for QT prolongation (e.g. congestive heart failure, bradyarrythmias). Re-initiate treatment once the QTc <500ms, and at a lower dose as per SmPC. Permanently discontinue vemurafenib if the QTc increase is both >500ms and >60ms change from pre-treatment values. Liver injury: Monitor transaminases, alkaline phosphatase and bilirubin before initiation and monthly during treatment, or as clinically indicated. Hepatic impairment: No adjustment to starting dose needed. Patients with moderate to severe hepatic impairment may have increased exposure; monitor closely and be aware of accumulation. Renal impairment: Mild or moderate – no adjustment of starting dose needed. Severe impairment – use with caution and monitor closely. Photosensitivity: Has been reported; avoid sun exposure and protect against sunburn. Drug Interactions: Vemurafenib may increase plasma exposure of drugs metabolised by CYP1A2 and decrease that of those metabolised by CYP3A4. The efficacy of contraceptive pills metabolised by CYP3A4 used with vemurafenib might be decreased. Exercise caution when co-administered with warfarin (CYP2C9), or CYP2B6 substrates (e.g. bupropion). May affect pharmacokinetics of medicines transported by P-gp. Vemurafenib inhibited CP2C8 in vitro. A risk for a clinically relevant effect in vivo on concomitantly administered CYP2C8 substrates cannot be excluded. A wash out period of ≥8 days is recommended between vemurafenib and initiation of a new therapy. Fertility/pregnancy/lactation: Women of childbearing potential should use effective contraception during treatment and for at least 6 months afterwards. Vemurafenib might decrease efficacy of hormonal contraceptives. No data in pregnant or lactating women. Side Effects and Adverse Reactions: See SmPC for full details. Very common(>1/10): arthralgia, myalgia, pain in extremity, musculoskeletal pain, back pain, fatigue, pyrexia, oedema peripheral, asthenia, pruritus, cuSCC, seborrheic keratosis, skin papilloma, decreased appetite, headache, dysgeusia, cough, nausea, diarrhoea, vomiting, constipation, rash, photosensitivity reaction, alopecia, actinic keratosis, rash maculo-papular, rash popular, hyperkeratosis, erythema, dry skin, sunburn, and GGT increase. Common(>1/100-<1/10): folliculitis, basal cell carcinoma, new primary melanoma, 7th nerve paralysis, dizziness, uveitis, palmar-plantar erythrodysaesthesia syndrome, erythema nodosum, keratosis pilaris, arthritis, ALT increase, phosphatase increase, bilirubin increase, weight decreased and QT prolongation. Serious or potentially serious: Hypersensitivity reactions, including anaphylaxis and Stevens-Johnson syndrome. Legal category: Product subject to prescription which may not be renewed Presentations and MA Numbers: 56 film-coated tablets (Aluminium/Aluminium blisters). EU/1/12/751/001 MA holder: Roche Registration Ltd., 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, UK. Further information is available from Roche Products (Ireland) Limited, 3004 Lake Drive, Citywest, Naas Road, Dublin 24. Telephone: (01) 4690700. Fax: (01) 4690791. Date of preparation: February 2013. References: 1. Bloom J, et al. Molecular testing for BRAFV600 mutations in the BRIM-2 trial of the BRAF inhibitor vemurafenib (RG7204/PLX4032) in metastatic melanoma. Abstract #10523. ASCO Annual Meeting. 2011. 2. Anderson S, et al. Molecular testing for BRAFV600 mutations in clinical trials of the BRAF inhibitor vemurafenib (RG7204/PLX4032) in metastatic melanoma: clinical validation studies of the analytic performance of a companion diagnostic assay. Abstract #1403. ESMO Annual Meeting. 2011. 3. Bollag G, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAFmutant melanoma. Nature 2010; 467: 596-599. 4. Zelboraf Summary of Product Characteristics, 17th January 2013.

The power of personalisation

p23/02/13

CPD: Advanced Renal Cell Carcinoma Page 27 Feature: HIV and the role of the pharmacist Page 32


Sustain response. Reduce recurrence1,2

Treat C. difficile infection...

...and help release your patients from the threat of recurrence1,2 Abbreviated Prescribing Information - DificlirTM Presentation: DIFICLIR film-coated tablets containing 200 mg fidaxomicin. Indications: DIFICLIR is indicated in adults for the treatment of Clostridium difficile infections (CDI) also known as C. difficile-associated diarrhoea. Posology: Adults including elderly: 200 mg administered twice daily for 10 days with or without food. Children: no data available. Renal and hepatic insufficiency: No dose adjustment is considered necessary (see special warnings and precautions) Contraindications: Hypersensitivity to active substance or any of the excipients. Special Warnings and Precautions: Due to limited clinical data, fidaxomicin should be used with caution in patients with severe renal impairment or moderate to severe hepatic impairment, pseudomembranous colitis,

fulminant or life threatening CDI or concomitant inflammatory bowel disease. Co-administration of potent P-glycoprotein inhibitors, such as cyclosporine, ketoconazole, erythromycin, clarithromycin, verapamil, dronedarone and amiodarone are not recommended. Drug interactions: DIFICLIR is both a substrate and may be an inhibitor of intestinal P-glycoprotein. DIFICLIR had a small but not clinically relevant effect on digoxin exposure. However, a larger effect on P-glycoprotein substrates with lower bioavailability or which are more sensitive to intestinal P-glycoprotein inhibition such as dabigatran etexilat cannot be excluded. Pregnancy and Lactation: Pregnancy: There are no data available. Animal studies did not indicate direct or indirect harmful effects. It is preferable to avoid the use of DIFICLIR during

pregnancy. Breast-feeding: It is unknown whether fidaxomicin and its metabolites are excreted in human milk. Although no effects on the breastfed newborns / infants are anticipated, a risk cannot be excluded. Undesirable Effects: The most common treatment related adverse reactions were vomiting (1.2%), nausea (2.7%) and constipation (1.2%). Uncommon adverse events reported in clinical trials included decreased appetite, dizziness, headache, dysgeusia, abdominal distension, flatulence, dry mouth, alanine aminotransferase increased. Consult DIFICLIR Summary of Product Characteristics for a full list of side effects. Legal Classification: Prescription Only Medicine (POM). Packs: Blister cards: 20 x 1 film coated tablets (10 x 2 cards) EU Number (PA Number): EU/1/111/733/001004. MA holder: Astellas Pharma Europe B.V.

References: 1. Cornely O.A. et al. Lancet Infect Dis 2012;12:281-89. 2.Louie T.J. et al. New Engl J Med 2011 ;364 :422-31

Sylviusweg 62, 2333 BE Leiden, The Netherlands. Date of Preparation of API: January 2013 Summary of product characteristics and further information from: Astellas Pharma Co Ltd, 5 Waterside, Citywest Business Campus, Naas Road, Dublin 24. Tel: 01 4671555 Adverse Events should be reported to Astellas Pharma Co. Ltd.

Dificlir/02 2013/384


3

Issue 9

Contents

Foreword

Irish hospital teams target HIV epidemic P9

Editor

UCC School of Pharmacy celebrate ten years in existence P12

The deadline for applications to the inaugural Hospital Pharmacy Awards 2013 has now passed and we have been astounded, and equally excited, by the level in numbers and quality of submissions. This goes a long way towards promoting the key message of these awards, which is to recognise and reward the ongoing excellence and innovation within this pharmacy sector in Ireland.

Kelly Jo Eastwood

Industry Profile as we speak to Tony Hynds, Actavis P18

6

Learning from excellence - hospital pharmacy survey P42

The standard of entries has been overwhelming and therefore being shortlisted as a finalist is to be viewed as a real achievement. The future decisions now lie with our esteemed panel of judges, who face a difficult task ahead as they whittle down the applicants to a shortlisted category of three finalists, who will be put forward for a second round of judging in September at Carton House, Maynooth. Our panel, comprised of leading professionals from the pharmaceutical industry will then decide on the ultimate winners of these coveted awards.

Out and about at the Irish Pharmacy Awards 2013 P47 12

Regulars Mapping a new future for professional development – EAHP’s Richard Price P16

If you want to be there on the night to partake in this tremendous celebration, tickets are now available but are limited in numbers so please contact our offices as soon as possible to secure your place.

CPD – Advanced Renal Cell Carcinoma by Dr Ray McDermott and Dr Min Yuen Teo P27

46

Clinical feature – HIV and the role of the clinical pharmacist P32

Recently, the EAHP has been advocating the need for a more European approach to the hospital pharmacy qualification. However, a difficulty exists in that each country has developed these qualifications independently with the consequence that the qualifications have different durations and different requirements.

Clinical Profiles P51 Appointments P54

47

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 Clifton House, Lower Fitzwilliam Street, Dublin 2 (01) 669 0562 MANAGING DIRECTOR Natalie Maginnis n-maginnis@btconnect.com EDITOR Kelly Jo Eastwood kelly@hospitalpharmacy.ie ACCOUNTS Julie Daly cs.ipn@btconnect.com

Elsewhere, we have a busy issue; reflective of the work being undertaken by hospital pharmacists across Ireland the rest of Europe in standardising protocols and improving working conditions.

SALES MANAGER Debbie Graham debbie.hpn@btconnect.com Mobile: 0044 7450274112 CONTRIBUTORS Dr Ray McDermott Dr Min Yuen Teo Richard Price Kay McNamee Paul Knox Fiona McCann

This means an Irish hospital pharmacist obtaining, for example, the two year Masters in Hospital Pharmacy from Trinity College Dublin may not be successful in having the qualification recognised in another country, such as France or Belgium, should they wish to practice in those countries. Richard Price highlights this further as he continues his correspondence to HPN this issue on page 16. Interestingly this month, the European Federation of Pharmaceutical Industries and Associations (EFPIA) has announced the release of its disclosure code of transfers of value to healthcare professionals and organisations. The code requires all members of EFPIA to disclose transfers of value to HCP’s and HCO’s as of 2016 regarding all transfers in 2015. This is a unique development and we at Hospital Pharmacy News will be following its progress and keeping you abreast of the news as it happens.

ART DIRECTED BY Smart Page Design www.pharmacynewsireland.com www.facebook.com/ HospitalPharmacyNews HPN • Issue 9


4 News

Clinical trial transparency calls Dr Roberto Frontini, EAHP President

Hospital pharmacists throughout Ireland are joining forces with European colleagues in calling for improved transparency and disclosure of clinical trial results. The European Association of Hospital Pharmacists has joined over 200 health sector associations and organisations from across Europe. Adding its signature to the AllTrials campaign EAHP President Dr

Roberto Frontini said, “Hospital pharmacists are intimately involved in the conduct of clinical trials all over Europe and therefore have a strong interest in seeing transparent reporting of trial results become a standard reality. We are therefore pleased to join with so many other likeminded organisations in the All Trials campaign and look forward to progress being made in this area in the context of the current European regulation which is currently the subject of scrutiny in the European Parliament.” The AllTrials campaign calls for all clinical trials, past and present, to be registered,

and the full methods and the results reported. It calls upon governments, regulators and research bodies to implement measures to achieve this. The campaign cites an estimate from a 2010 systematic review that half of all the clinical trials that have been conducted and completed have never been published in academic journals, and trials with positive results are twice as likely to be published as others. The problem is considered to be common for industry and nonindustry trials, internationally, at all stages of drug development, and for trials of all sizes.

Recognition for Kerry pharmacists The Hospital Pharmacists Association of Ireland made two recognitions are the recent conference. Dr Sile O’Connor, who specialises in antibiotics management at the Bon Secours Hospital, Tralee, was recognised for her research into quality measures surrounding the appropriate use of antibiotics.

Along with Dr O’Connor, Kerry pharmacist Eileen Butler, was also recognised at the HPAI’s Annual Educational Conference. Dr Butler who works at Our Lady’s Children’s Hospital, Crumlin and was recognised for her research into medicines used in paediatric intensive care.

Eileen Butler and Caroline Reidy, Pfizer Healthcare Ireland

Specialist qualifications ‘necessary’ Organisations representing professionals with specialised qualifications in the fields of pharmacy, veterinary and nursing from Ireland and the rest of Europe have made a joint appeal to the European Commission and national governments to support proposals from the European Parliament that would improve the possibility of specialist qualification mobility across Europe. The Directive governing Issue 9 • HPN

qualification recognition across EU states (Directive 2005/36) allows for mutual recognition of medicine and dentistry specialisms, but not for any of the other five ‘automatically recognised’ professions such as veterinary surgery, pharmacy and nursing. The European Parliament has therefore proposed that specialisms of these professions be allowed to form ‘common training frameworks’ to achieve

recognition of a qualification across countries. This would involve nine countries or more coming together to make a voluntary arrangement for recognising a qualification. This could be based on agreed competencies and obtained skills, rather than requiring a strict agreement on the duration of a qualification, as previous models of qualification recognition have been based upon.

No EU countries would be forced to take part in such a framework. Instead countries could “opt in” at the start of the process, or at a later point. However, the European Commission’s proposals for reform of Directive 2005/36 (December 2011) prohibited any of the seven automatically recognised professions from making use of such a framework. It is this prohibition that the European Parliament is seeking to remove.


5

Clinical pharmacy should be ‘parallel’ with other services Access to hospital pharmacy services is restricted in most hospitals at present to weekday “office hours”. This was a key message from the recent PSI Baseline Report into Hospital Services in Ireland. A key issue, says the report, is that clinical pharmacy services should be available in parallel with other medical services when this is required. Hospitals and hospital pharmacists need to address this issue and find solutions that allow for patients to access professional pharmacy input when they require it. In addition, it showed, the recruitment embargo and budget cuts in the health services are creating significant challenges in relation to the financial and

human resources for hospital pharmacies. An average of just under 2,500 items are dispensed by hospital pharmacies each week, ranging up to 14,600 for one respondent. The vast majority of the items (average 2,040) are for inpatients, with very few outpatient items routinely dispensed. Many pharmacies do supply medicines for long-term residential care patients and to other sites, but they account for low levels of activity in most hospitals. Most hospital pharmacies (87%) have a centralised distribution service. Whilst 39.8% of respondents indicated that they dispensed medication to individual patients, the site visit interviews indicate that where there is named-

Pharmacy involvement in outpatient clinics is very limited. Nearly 85% reported that there were no pharmacist-led outpatient clinics in their hospitals.

Pharmacy involvement in outpatient clinics is very limited. Nearly 85% reported that there were no pharmacist-led outpatient clinics in their hospitals.

patient or individual dispensing, this is often to only a small number of patients for specified medicines, for example, rather

than the main mechanism for the distribution of medicines to wards and patients in the hospital.

Work on oncology drug protocols The National Cancer Control Programme has announced that work is commencing on the development of national drug protocols, for the treatment of patients with cancer, for those drugs already in use. Drug protocols have already been developed for all new drugs for the treatment of cancer since late 2012.

The aim of these protocols is to support the safe, evidencebased, and cost-effective cancer treatment of all cancer patients in Ireland. Once the protocols have been developed and approved, they will be disseminated to the hospitals involved in the care of cancer patients, in addition to being published on the NCCP website.

The NCCP drug protocols are being developed based on the latest evidence, related to the management of specific cancers, under the guidance of a Medical Consultant. The intention is to develop these protocols on a collaborative basis with the health care professionals involved in the drug treatment of cancer patients.

To this end, the NCCP would like to invite all pharmacists, involved in the treatment of patients with cancer, to register their interest in collaborating in these landmark developments. Expressions of interest should be emailed to: oncologydrugs@ cancercontrol.ie.

FIP programme for hospital pharmacists The date is drawing nearer – the International Pharmaceutical Federation (FIP) will host its Annual Congress in collaboration with the Pharmaceutical Society of Ireland (PSI) and its Irish partners, from August 31stSeptember 5th this year in Dublin. In a constantly evolving

environment, where advances in science, technology and communications require us all to adapt, it is vital that the pharmacy profession is at the forefront of change; responding to medical innovations alongside changing patient needs. The theme of the 2013 conference- Towards a future

vision for complex patients: Integrated care in a dynamic continuum - will address these developments, and the central role of the pharmacist in delivering patient care in an ever more challenging setting.

impairment,organised by the FIP Community Pharmacy Section, the FIP Hospital Pharmacy Section and the FIP Clinical Biology Section For further details please visit www.fip.org

Talks for hospital pharmacists will include a look at their role in managing patients with renal

HPN • Issue 9


6 News

¤9 million towards drug discovery [From left to right] Professor Helen Sheridan, Trino Therapeutics, Professor Neil Frankish, Trino Therapeutics and Dr Ena Prosser, Fountain Healthcare Partners. Photograph: Nick Bradshaw

The Trinity College spinout company, Trinity Therapeutics which is developing a new class of drugs to tackle inflammatory diseases has raised over ¤9 million to fund clinical trials. The drug discovery and early drug development company focused on anti-inflammatory therapeutics, recently announced the funding from new investors, Fountain Healthcare Partners and founding investor, the Wellcome Trust. Other investors in Trino include Enterprise Ireland and Growcorp.

The company is developing PH46A, the lead candidate from a novel, proprietary, class of drugs which was inspired by the indane scaffold molecule derived from a Taiwanese fern. PH46A is a potential first-in-class oral small molecule drug for the treatment of inflammatory bowel disease (IBD), which could be used in both ulcerative colitis (UC) and Crohn’s disease (CD). Other molecules in Trino’s drug class show promise with broad anti-inflammatory activity that

could be suitable for applications in dermatology, pulmonary and auto-immune disease and the company will work to develop these compounds internally and in partnership with major international research centres. The additional funding from the Wellcome Trust is in the form of a prestigious, international and highly competitive Strategic Translation Award. Head of Business Development at the Wellcome Trust, Dr Richard

Seabrook commented, “Current treatments for inflammatory bowel diseases often have significant side effects and patients are faced with tough decisions in how to manage their condition. We are pleased to extend our successful partnership with Trino to support the development of PH46A as a potential new therapy for these debilitating disorders.” The company founded by Trinity pharmacologist Professor Neil Frankish and medicinal chemist Professor Helen Sheridan centres on their highly innovative work on pharmaceutical grade drugs based on the indane skeleton as derived from a Taiwanese fern, used historically in plant-based medicine. Commenting on this investment on behalf of the company Professor Frankish said, “This significant investment validates our research, enabling us to expand the Trino team and develop our clinical partnerships so that we can investigate the effectiveness of our research where it is needed – in patients with inflammatory diseases and ineffective drugs”.

No to clinical trial of MS drug There are currently no clinical trials authorised for low dose Naltrexone in the treatment of multiple sclerosis or autoimmune disorders, despite the issue making a recent Oricheateas debate.

Deputy Bill Kelleher

The issue was high on the agenda during a recent debate in which Deputy Bill Kelleher asked the Minister for Health if he had any plans to carry out the clinical trials. Minister of State at the Department of Health, Deputy Alex White, commented that, “The Irish Medicines Board (IMB) is the competent authority for the authorisation of clinical trials with medicines in Ireland. However, the IMB does not carry out trials and neither does the Department of Health. Clinical trials are conducted by sponsors

Issue 9 • HPN

from industry or academia and carried out by healthcare professionals according to protocols authorised by the IMB and approved by an ethics committee. “Naltrexone is authorised in

Ireland for the treatment of alcohol and drug dependence; it is not authorised for the treatment of multiple sclerosis or autoimmune disorders and there are currently no clinical trials authorised for these conditions in Ireland.”

Mr Kelleher also asked if the Minister would consider adding low dose Naltrexone to the long term illness and GMS card schemes.


Choose BRILIQUE™ instead of clopidogrel for your ACS patients...

...89 more lives could be saved in Ireland each year * 1

As measured by CV deaths (PLATO study)2

Recommended in the latest ESC Guidelines3-5

*Based on Republic of Ireland HIPE (Hospital In Patient Enquiry) figures. Based on all eligible patients receiving BRILIQUE instead of clopidogrel and CV mortality results from the PLATO study. BRILIQUETM 90MG FILM-COATED TABLETS (ticagrelor) Abridged Prescribing Information (For full details see Summary of Product Characteristics (SmPC)) Use: Adults aged 18 years and older, co-administered with acetylsalicylic acid (ASA) daily: for the prevention of atherothrombotic events in patients with acute coronary syndromes (unstable angina, non-ST-segment elevation myocardial infarction [NSTEMI] or ST-segment elevation myocardial infarction [STEMI]); including patients managed medically, and those who are managed with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). Presentation: 90mg ticagrelor film-coated tablets. Dosage and administration: Treatment should be initiated with a single 180mg loading dose (two tablets of 90mg) and then continued at 90mg twice daily. Following an initial dose of ASA, patients should also take a daily maintenance dose of 75-150mg of ASA with Brilique, unless ASA is specifically contraindicated. Treatment is recommended for up to 12 months unless discontinuation is clinically indicated. Premature discontinuation of treatment or lapses in therapy should be avoided. Patients treated with clopidogrel can be directly switched to Brilique. For oral use. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Active pathological bleeding. History of intracranial haemorrhage. Moderate-to-severe hepatic impairment. Co-administration with strong CYP3A4 inhibitors (e.g. ketoconazole). Precautions: Due to the increased risk of non-fatal or non-life threatening bleeding, use with caution in patients at an increased risk for bleeding (e.g. recent trauma or surgery, bleeding disorders or recent gastrointestinal bleeding) or those on concomitant medication that may increase bleeding risk (e.g. NSAIDs, anticoagulants) within 24 hours of taking Brilique. Brilique should be stopped 7 days prior to elective surgery if the antiplatelet effect is not desired. Use with caution in patients with an increased risk of bradycardic events (e.g. patients on digoxin), as asymptomatic ventricular pauses have been observed with Brilique, a history of asthma and/or COPD, a history of hyperuricaemia or gouty arthritis. Creatinine levels may increase during treatment with Brilique. Renal function should be checked after one month and thereafter according to routine medical practice, paying special attention to patients ≥ 75 years, patients with moderateto-severe renal impairment and those receiving concomitant treatment with an ARB. Co administration of Brilique is not recommended with a high maintenance dose of ASA (> 300mg) or with doses of simvastatin > 40mg. Co administration of ticagrelor with strong CYP3A4 inducers is discouraged, as this may lead to a decrease in exposure and efficacy of ticagrelor. Co-administration with CYP3A4 substrates with narrow therapeutic indices is not recommended. Concomitant use of ticagrelor with doses of simvastatin or lovastatin > 40mg not recommended. Caution with concomitant use of P-gp inhibitors or P-gp substrates with narrow therapeutic indices e.g. verapamil, quinidine and cyclosporin. Caution with concomitant administration of SSRIs. Brilique is not recommended during pregnancy and breastfeeding. Undesirable effects: Common: Dyspnoea, epistaxis, gastrointestinal haemorrhage, subcutaneous or dermal bleeding, bruising and procedural site haemorrhage. Other undesirable effects include intracranial bleeding, elevations of serum creatinine and uric acid levels. Consult SmPC for a full list of undesirable effects. Legal category: POM. Marketing Authorisation Number: EU/1/10/655/004. Market Authorisation Holder: AstraZeneca AB, S 151 85, Södertälje, Sweden. Further information on request from: Freephone 1800 800 899 or contact AstraZeneca UK Limited, Horizon Place, 600 Capability Green, Luton, Bedfordshire, LU1 3LU, United Kingdom. Abridged prescribing information prepared: 04/12. BRILIQUE is a trade mark of the AstraZeneca group of companies. Reference 1: HIPE (Hospital In Patient Enquiry) Casemix data- Ready Reckoner 2013 (2011 costs and activity). 2: Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Eng J Med 2009;361:1045-57. 3: Steg G and James SK et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012 Aug 24. OI:10.1093/eurheartj/ehs215. 4: Hamm CW et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J. 2011 32(23):2999-3054. 5: Wijns W et al. ESC Guidelines on Myocardial Revascularisation. European Heart Journal (2010) 31, 2501–2555 doi:10.1093/eurheartj/ehq277. URN: 13/0421. Date of preparation: June 2013

Cardiovascular


The 1st Leuprorelin Depot Implant Now less is more

Leuprex 3 5 mg I mplant Leuprorelin

Ready to use formulation Most cost-effective Leuprorelin 1 No need to refrigerate

Product Name: Leuprex 3, 5mg Implant. Composition: Each implant contains 5mg leuprorelin (as acetate). Description: Implant. Biodegradable white to slightly yellowish cylinder shaped stick (length 10mm) in a pre-filled syringe. Indication(s): Palliative treatment of patients with advanced hormone-dependent prostate carcinoma Dosage: The 5mg leuprorelin implant is inserted subcutaneously into abdominal skin, using an aseptic technique once every 3 months. (Refer to SPC and PIL for directions). Monitor PSA levels and serum testosterone at regular intervals. Contraindications: Hypersensitivity to leuprorelin, other GnRH analogues or to polylactic acid. In cases where carcinomas are shown to be hormonally independent. After surgical castration, the implant does not cause further reduction in testosterone levels. In women and paediatric patients. Warnings and Precautions for Use: Leuprorelin causes a transient increase in the serum concentration of testosterone during the first week of treatment; this may be associated with a ‘flare’ or exacerbation of the tumour growth and can include worsening of symptoms or onset of new symptoms. These symptoms usually subside on continuation of therapy. To reduce risk of ‘flare’ an anti-androgen may be administered beginning 3 days prior to leuprorelin therapy and continue for the first 2-3 weeks of treatment. Close monitoring is required of patients with vertebral or cerebral metastases and/or those with a urinary tract obstruction as spinal cord compression and impaired renal function have been observed in isolated cases. Patients may experience metabolic changes and cardiovascular disorders. Patients at high risk for metabolic or cardiovascular diseases should be carefully assessed before treatment and adequately monitored during androgen deprivation therapy. Increased risk of incident depression (which may be severe). Inform patients accordingly and treat as appropriate if symptoms occur. Interactions: There are no known interactions with other agents. Pregnancy and Lactation: Not applicable. Ability to Drive and Use Machinery: This medicinal product may alter reactivity to such an extent that the ability to drive or to operate machinery is impaired. This applies to a greater extent in combination with alcohol. Undesirable Effects: Very common: hot flushes, ostalgia, reduction in or loss of libido and sexual potency, testicular size reduction, increased diaphoresis, reactions at the injection site e.g. reddening, pain, oedema, itching which usually subsided even when treatment was continued, weight gain. Common: gynaecomastia, decreased appetite, sleep disorders, headache, paraesthesia, nausea, arthralgia or dorsalgia, myasthenia, perineal pain, upper abdominal pain, nocturia, dysuria, fatigue, peripheral oedema, generalised weakness, weight loss, increases in LDH, transaminases (ALT, AST), gamma-GT and alkaline phosphatase, which may also be a manifestation of the underlying disease. Common in long term use, but uncommon in short term use: mood disorders and depression. Marketing Authorisation Holder: Rowex Ltd, Bantry, Co. Cork. Marketing Authorisation Number: PA 711/188/1. Further information and SPC are available from: Rowex Ltd, Bantry, Co. Cork. Freephone: 1800 304 400 Fax: 027 50417 E-mail rowex@rowa-pharma.ie Legal Category: Medicinal product subject to prescription which may not be renewed. Date of Preparation: June 2013 References 1: MIMS

07-13

ABBREVIATED PRESCRIBING INFORMATION


9

News

Diabetes Smartphone app goes down a treat Children with Type 1 diabetes can now use a smartphone application to learn about insulin pumps and to troubleshoot problems, thanks to a team based in UCC and Cork University Hospital (CUH). The team have won a Healthcare Innovation Award for their efforts in developing the first smartphone based educational application for children with Type 1 diabetes learning to use insulin pumps. Pumps4Kids was developed on the iPhone and Android platforms by a team lead by Drs Colin Hawkes and Stephen O’Riordan, (Department of Paediatrics and Child Health, CUH and UCC. The software development and design that was key to winning the ‘Innovation in Patient Support’ category was carried out by Debbie Hawkes and Elaine Kinsella. Transitioning from insulin injections to the insulin pump can be a huge challenge for

children and their families. Extensive education and support is required to achieve this and the 24-hour availability of emergency advice can be required. A 2-day “Pump School” is a key part of this education in Cork University Hospital, and this application will complement this essential teaching.

Joint Winner: Colin Patrick Hawkes, Debbie Hawkes, Elaine Kinsella, Peter Hindmarsh, Nuala Murphy, Marian McCarthy & Stephen O' Riordan of Dept. of Paediatrics & Child Health, CUH in recognition of Pump 4 Kids.

Pumps4Kids was developed using extensive patient feedback to ensure that it meets the educational needs of children at various levels of knowledge regarding this treatment. Following release, ongoing feedback will ensure that content evolves to meet the users’ learning needs. This application was released in February 2013 and has been downloaded over 700 times and used over 2000 times in over 40 countries. Smartphones are increasingly being used by children and teenagers and may provide an opportunity to enhance medical care in this population. Initial feedback has been extremely

positive and uptake to date suggests that there is significant demand for this educational tool. Adaptation of this application

with enhanced video is planned, and the development of further educational tools for children with Type 1 diabetes may follow.

Irish hospitals team up to tackle HIV An innovative new programme was launched this month, designed to tackle HIV and improve healthcare for women and babies by twinning Irish hospitals with counterparts in the developing world; to share skills and experience. The programme, launched byMinister for Trade and Development, Joe Costello TD, ESTHER Ireland is led by a partnership between the Health Service Executive (HSE) and Irish Aid and forms part of a wider European alliance of hospitals and healthcare institutions working with the developing world.

Ireland has approved its first two ESTHER Ireland partnerships: Cork University Maternity’s Hospital’s partnership with the Omdurman Maternity Hospital in Sudan and the collaboration programme between the Royal College of Surgeons in Ireland and the College of Surgeons of East, Central and Southern Africa. Speaking at the launch in the Royal College of Surgeons in Ireland, Minister Costello said: “I am delighted today to launch the ESTHER Ireland programme. This initiative will promote skillsharing partnerships in countries with the greatest health needs.

“We are already seeing very encouraging results: the partnership between Cork University Hospital and the Omdurman Maternity Hospital in Sudan is associated with an 86 per cent reduction in maternal mortality and a 50 per cent drop in stillbirths and early neonatal deaths.” The ESTHER Alliance is a French acronym for ‘Together for a Networked Hospital Therapeutic Solidarity’. Members include France, Italy, Spain, Germany, Norway and Switzerland. It is active in over 40 partner countries Africa, southeast Asia, Central and South America,

the Middle East and southeast Europe with more than 120 projects being supported. The Alliance is committed to developing high quality partnerships and ESTHER projects are based on best development practice.

HPN • Issue 9


10

Knitting pharmacy into enhancing molecules

Professor Fergal O'Brien

The Royal College of Surgeons Ireland (RCSI) Pharmacy School is working closely with the Tissue Engineering Research Group to develop a new technology for controlled drug delivery. TheraColl is a new, porous collagen-based scaffold that has the texture of polystyrene and foam, which can be implanted into the body to promote bone tissue regeneration and faster bone healing. Working closely with pharmacy final year students and Pharmacy school professors, including Dr Sally Ann Cryan, who is Associate Professor in Pharmaceutics, Professor Fergal O'Brien and the RCSI spin-off company, SurgaColl are evolving the TheraColl controlled drug delivery system. O’Brien told Hospital Pharmacy News, “I think pharmacy is very important in regenerative medicine. We are incorporating traditional pharmacy methods into the scaffolding in order to enhance the molecules.” He continued, “At present two bone morphogenetic proteins (BMP) products,

Issue 9 • HPN

which use collagen as a carrier are approved for use in bone repair clinically. Both of them have been the subject of much controversy because of safety concerns, due to the associated severe side effects of their noncontrolled delivery, which include a risk of cancer. TheraColl would overcome these drawbacks by releasing protein in a controlled way.” O’Brien and the RCSI Pharmacy School are currently working on furthering the technology for tissue regeneration in areas including respiratory, cardiac and cornea repair. O’Brien said, “The death of tissue because of the lack of a blood supply is one of the most common causes of failure of biomaterials for tissue regeneration. Along with the expertise from pharmacists, TheraColl proposes to overcome this problem by slowly releasing vascular endothelial growth factor (VEGF), a protein which is widely known to increase blood vessel formation.” The cost of developing TheraColl has been ¤400,000 to date and the project has been supported by Enterprise Ireland.

Prescribing the PPI Lansoprazole (for reflux/peptic ulcer disease) and the statin Simvastatin (for lowering cholesterol) saves the HSE and patients money.

MEDICINES MANAGEMENT PROGRAMME


11

Pharmaceutical Companies to disclose financial relations The European Federation of Pharmaceutical Industries and Associations (EFPIA) has announced the release of its disclosure code of transfers of value to healthcare professionals and organisations. The code requires all members of EFPIA to disclose transfers of value to HCP’s and HCO’s as of 2016 regarding all transfers in 2015. EFPIA is committed to introducing greater transparency around industry’s interactions with HCP’s and HCO’s. “As an industry, we understand the need to provide a well-managed framework for collaboration for these relations to be as transparent as possible,” they state. The industry’s collaboration with healthcare professionals requires a

well-regulated, ongoing scientific dialogue in both directions. This is fundamental to ensuring a positive working relationship that best serves the interests of patients. Collaborations and partnerships between HCP's and industry are subject to stringent legislation and require that all parties respect high ethical standards. EFPIA’s code will enhance transparency around these relationships, and ensure that the industry’s work with HCP's and HCO's is well understood by the public and healthcare stakeholders. Locally, as a member of EFPIA, IPHA is obliged to adopt the Code which must be transposed into its own Code by 31st December 2013.

Stop Press As Hospital Pharmacy News was going to press, the Council of the PSI declared they had elected a new President, Eoghan Hanly, who was previous Vice-President. Noel Stenson has been elected the new Vice-President. So remember:

Thinking PPI? Think LANSOPRAZOLE. Thinking Statin? Think SIMVASTATIN. Visit www.hse.ie/yourmedicines for more information.

The PSI has also announced changes to its Council. The following pharmacists have been appointed (or reappointed) following the election process earlier this year: Nicola Cantwell, Richard Collis, Georgina Ann Frankish, Eoghan Hanly and Conor Phelan. Rita Purcell has been reappointed to the Council as the nominee of the Irish Medicines Board. Dr Chantelle McNamara, GP, is a new appointment. In addition, Pat O’Dowd has been appointed to the Council as the nominee of

the HSE. A further four Council members are expected to be appointed by the Minister for Health shortly. Hanly succeeds Paul Fahey who served as President for two years. Eoghan Hanly graduated from Robert Gordon University Aberdeen in 1995 with a degree in Pharmacy. Since 1996 he has practised as a pharmacist in his family’s pharmacy in Loughrea, Co Galway, which was established by his grandfather, P.J. Killian in 1940.

HPN • Issue 9


12 News

UCD student and Olympic sailor says to ‘dream big’ UCD Science student and Olympic sailor Annalise Murphy was on hand to launch a new campaign designed to encourage Irish people to live their dream. 62% of Irish people say they are not living their life to the full, with people aged 25-44 most likely to feel that they are missing out (71%). Over four in five Irish people (83%) think they are unlikely to live out their Big Life dream, with the majority (65%) attributing this to lack of money.

Pictured at the launch of is Nurofen Big Lives Ambassador Annalise Murphy, alongside Hazel Roche, Reckitt Benckiser and Annemarie Reen, Pharmacist, Reen’s Pharmacy.

The research was released by Nurofen, as the deadline for the Nurofen Big Lives Trust draws close. The Nurofen Big Lives Trust is offering ten Irish people who are passionate about life and have a Big Life dream ¤1,500 each to help make their plans a reality. The closing date for entry is 26 July.

To apply, visitwww.facebook.com/ nurofenireland and tell Nurofen about your Big Life passion and how you would go Big with ¤1,500. Nurofen Big Lives Trust Ambassador and Olympic sailor, Annalise Murphy, said, “I have always tried to follow my Big Life dream and am already training for Rio 2016. It’s about having resilience and passion, and not letting anything get in the way of what you want to do. A Big Life can be about anything, as long as you are passionate about it and pursue it to the full. The Nurofen Big Lives Trust is an amazing opportunity for ten people to do the one thing they have always wanted to do.”

The future is CPD The School of Pharmacy at University College Cork is celebrating ten years in existence this year. These celebrations commenced with an evening event for both hospital and community pharmacists – entitled "The future is bright: The future is CPD". During the evening the School showcased a number of research projects currently being undertaken by the Clinical Pharmacy Practice staff, as well as a CPD overview based on the Northern Ireland model. Dr Laura Sahm and Dr Suzanne McCarthy gave a presentation on the issue of health literacy and the impact it can have on patients’ health. Suzanne outlined the research that she and Laura have been conducting in this area, in collaboration with researchers from Northwestern University, Chicago. Their study

Issue 9 • HPN

57% experience limited health literacy examining the prevalence of limited health literacy, which was published in the Journal of Health Communication, revealed that up to 57% of patients can experience limited health literacy, and it is associated with increased age and lower educational attainment. The results of another study, published in the European Journal of Clinical Pharmacology, looked at the

impact of patient-centred labelling on prescription medication. Dr Paul McCague outlined the PSI vision for CPD in Ireland and spoke of his experience of undertaking CPD in Northern Ireland. Paul discussed how the School of Pharmacy have engaged with community and hospital pharmacists in research projects which have led to developments in their

professional practice. He highlighted the success of the MSc in Clinical Pharmacy and other standalone modules available in facilitating CPD for community and hospital pharmacists, and how all pharmacists will be able to work with the School as we move forward with a 5-year integrated MPharm programme.


In bipolar disorder find the right balance

NEW

*

Rapid efficacy with a fast-dissolving sublingual tablet1,2

Abbreviated Prescribing Information: For full prescribing information refer to the Summary of Product Characteristics. Name: Sycrest 5 mg & 10 mg sublingual tablets. Active Substance: Asenapine (as maleate). Indication: Treatment of moderate to severe manic episodes associated with bipolar I disorder in adults. Dosage: Treatment is twice daily (one dose to be taken in the morning and one dose in the evening). Monotherapy: starting dose is 10 mg twice daily, may be reduced to 5 mg twice daily according to clinical assessment. Combination therapy: starting dose is 5 mg twice daily, may be increased to 10 mg twice daily depending on the clinical response and tolerability in the individual patient. Paediatric population: No recommendation on posology can be made. Elderly patients: Use with care. Renal impairment: No dose adjustment required (no data in severe renal impairment CrCL < 15 ml/min). Hepatic impairment: Mild: no dose adjustment required; Moderate: caution; Severe: not recommended. Administration: Sublingual, only to be used by patients who can comply with instructions (due to poor bioavailability when taken orally). Use dry hands and do not remove the tablet until just before it is to be taken. Peel back the coloured tab and remove gently. Place the tablet under the tongue and allow it to dissolve completely. Do not chew or swallow. Avoid eating and drinking for 10 minutes after administration. When using Sycrest in combination with other medication, take it last. Contraindications: Hypersensitivity to the active substance or any of the excipients. Pregnancy and Lactation: Pregnancy: Sycrest should not be used in pregnant women unless clearly necessary and only if the potential benefit outweighs the potential risk to the foetus. Neonates exposed to antipsychotics (including Sycrest) during the third trimester should be monitored carefully for extrapyramidal/withdrawal symptoms. Lactation: Women taking Sycrest should not breast-feed. Special Warnings and Precautions for use: Elderly patients with dementia-related psychosis: Not recommended. Neuroleptic Malignant Syndrome: Sycrest must be discontinued if signs or symptoms develop. Seizures: Caution in patients with a history of seizures or a condition associated with seizures. Suicide: Closely supervise patients at high risk. Orthostatic hypotension: Caution in early treatment, in the elderly, in patients with cardiovascular/ cerebrovascular disease or with conditions predisposing to hypotension. Tardive dyskinesia: Discontinue Sycrest if signs or symptoms develop. Hyperprolactinaemia: Some reports have been received. QT interval: Caution in patients with known cardiovascular disease, family history of QT

prolongation or concomitant use of other QT-prolonging medicinal products. Hyperglycaemia and diabetes mellitus: Clinical monitoring is advised for at risk patients. Dysphagia: Some reports have been received. Body temperature regulation: Appropriate care is advised in patients at risk of an elevation of core body temperature. Severe hepatic impairment: Not recommended. Parkinson’s disease and dementia with Lewy bodies: These patients are at increased risk of adverse events (including NMS), benefits and risks should be carefully considered. Interactions: Caution: in combination with other centrally acting medicinal products; with CYP1A2 inhibitors (e.g. fluvoxamine), CYP2D6 inhibitors or substrates (e.g. paroxetine), antihypertensive agents, levodopa, dopamine antagonists. Avoid: Alcohol & eating / drinking for 10 minutes after administration. Adverse reactions: Very common (≥1/10): anxiety, somnolence. Common (≥1/100 to <1/10): weight increased, increased appetite, dystonia, akathisia, dyskinesia, parkinsonism, sedation, dizziness, dysgeusia, hypoaesthesia oral, ALT increased, muscle rigidity, fatigue. Uncommon (≥1/1,000 to <1/100): hyperglycaemia, syncope, seizure, extrapyramidal disorder, dysarthria, sinus bradycardia, bundle branch block, electrocardiogram QT prolonged, sinus tachycardia, orthostatic hypotension, hypotension, swollen tongue, dysphagia, glossodynia, paraesthesia oral, sexual dysfunction, amenorrhoea. Rare (≥1/10,000 to <1/1,000): neutropenia, neuroleptic malignant syndrome, accommodation disorder, pulmonary embolism, rhabdomyolysis, gynaecomastia, galactorrhoea. Not known (cannot be estimated from available data): allergic reactions, restless legs syndrome, nausea, oral mucosal lesions, salivary hypersecretion, drug withdrawal syndrome (neonatal). Other findings: Cerebrovascular events have been reported. Asenapine has anaesthetic properties – oral hypoaesthesia/ paraesthesia may occur directly after administration and usually resolve within 1 hour. Post marketing reports of serious hypersensitivity reactions (including anaphylactic reactions e.g. swollen tongue & throat) have been received. Overdose: Cardiovascular monitoring & supportive therapy. Close monitoring advised until patient recovers. Legal Category: POM. Marketing Authorisation Holder: N.V. Organon, Kloosterstraat 6, NL-5349 AB Oss, The Netherlands. Marketing Authorisation Numbers: EU/1/10/640/002 Sycrest 5 mg sublingual tablets, 60 pack. EU/1/10/640/005 Sycrest 10 mg sublingual tablets, 60 pack. Further information may be obtained from: Lundbeck (Ireland) Ltd., 7 Riverwalk, Citywest Business Campus, Dublin 24. Date of Preparation: January 2013. The person depicted is a model and is used for illustrative purposes only.

* Sycrest is licensed for the the treatment of moderate to severe manic episodes in bipolar I disorder. References: 1. McIntyre R, et al. A 3-week, randomized, placebo-controlled trial of asenapine in the treatment of acute mania in bipolar mania and mixed states. Bipolar Disord 2009: 11: 673-686. 2. Sycrest Summary of Product Characteristics.

SY2/1/13


14 Report

News Extra

Revised Biosimilar guideline for public consultation

Virotherapies to be licenced within eighteen months?

Professor Rudd

Pharmaceutical research and development is changing quite radically with the result that future solutions to health problems will be quite different in certain areas, and one of the latest research pathways is that of virotherapy. It has been known since 1949 that viral infections can help to eliminate cancer cells. However, it is only now, with the advance of genetic engineering, which has been key in this breakthrough that scientists have been able to target and attack these cancer cells.

The European Medicines Agency has released a revision of the guideline addressing the clinical and non-clinical issues related to similar biological products (biosimilars) containing biotechnology-derived proteins as the active substance for a sixmonth public consultation. The document lays down the nonclinical and clinical requirements for marketing authorisation of a biosimilar claiming to be similar to a biological product already marketed. This guideline updates the previous guidance, which came into effect in 2006. Since then, 14 biosimilar medicines have received marketing authorisation in the European Union and the number of scientificadvice requests received by the Committee for Medicinal Products for Human Use (CHMP) on the development of biosimilar medicines has increased significantly. On the basis of the experience gained since the release of the initial guideline, the revision provides additional guidance on Issue 9 • HPN

the following topics: • the risk-based approach for the design of non-clinical studies; • the use of pharmacodynamic markers for the demonstration of clinical comparability; •

study design (non-inferiority versus equivalence), choice of an appropriate patient population and choice of surrogate endpoints in efficacy trials;

• the design of immunogenicity studies; • extrapolation of efficacy and safety from one therapeutic indication to another. This guideline is one of three overarching biosimilar guidelines, which are complemented by productspecific biosimilar guidelines. The other two overarching guidelines are: • the guideline on similar biological medicinal products, which describes the concept

of biosimilars and the general principles to be applied in demonstrating biosimilarity. A revision of this guideline was released for public consultation in May 2013;

• a guideline addressing the quality issues related to biosimilar development. A revision of this guideline was released for a six-month public consultation in May 2012. The next issue of Hospital Pharmacy News will feature an in-depth look at a recent conference held by NIBRT which focused on the emerging use of biosimilars throughout Europe and indeed Ireland. This education symposium on biologic medicines, provided a unique educational opportunity for hospital pharmacists, healthcare professionals, regulators, insurers and patient associations to learn about the very latest thinking on the complexity of biologic medicines and the emergence of ‘biosimilar’ medicines.

Some common viruses can be modified to infect cancerous cells by almost exclusively bypassing the healthy cells. These ‘weakened’ vaccine strains of common viruses are engineered genetically to grow in cancer cells and this triggers immune reactions that switch on the immune response in the tumours. In simple terms, the cancerous cells replicate themselves until such time as the cell membranes rupture and then die. The virus subsequently releases a protein, which sends a signal to the immune system, thus triggering an immune reaction against the cancerous tissue. In a recent trial, involving 400 patients with aggressive melanoma, it was found that when the patients’ tumours were injected with a modified form of the herpes virus, T-Vec, almost a fifth of them went into complete or partial remission some six months later, compared with only 2% of the patients in the control group. The development of these drugs is difficult because of the risk that a modified virus can spread to other people and, because of the amount of work that has to be carried out on the viruses, the treatment is also likely to be expensive. However, it is predicted by the medical profession that virotherapies for cancer could be licensed within the next 18 months. Once these drugs are licensed, they will, initially be used alongside conventional treatments.


THE FUSION OF ACTION, VISION AND STRENGTH Actavis, Inc. represents the powerful combination of Watson Pharmaceuticals and the Actavis Group. Together we share a broader commercial footprint, an expanded product portfolio and enhanced capabilities in Ireland and around the world. With 2 EU cytotoxic manufacturing sites, we are the partner you can trust.

Actavis Ireland Ltd. Euro House, Euro Business Park Little Island, Co. Cork T: 1890 33 32 31 F: 021 461 90 49 E: contact@actavis.ie NA -009h-01

www.actavis.ie


16 Report

Mapping a new future of professional development in European hospital pharmacy Richard Price, Policy and Advocacy Officer at the European Association of Hospital Pharmacists, discusses the potential opportunities for the future of the pharmacy profession in Europe if recent votes by the European Parliament receive approval by the Council of Ministers.

Richard Price

For many years the European Association of Hospital Pharmacists has advocated the need for a more European approach to the hospital pharmacy qualification. As hospital medicines have grown more complex and the hospital pharmacist has become involved in many new areas of practice most countries in Europe have now recognised a need to verify the skills and competencies of individuals to work at these new levels and have consequently created frameworks for hospital pharmacy related post-graduate qualifications. However, a difficulty exists in that each country has developed these qualifications independently with the consequence that the qualifications have different durations and different requirements. This means an Irish hospital pharmacist obtaining, for example, the two year Masters in Hospital Pharmacy from Trinity College Dublin may not be successful in having the qualification recognised in another country,

Issue 9 • HPN

such as France or Belgium, should they wish to practice in those countries. Furthermore, there is nothing within the current European Directive on the Mutual Recognition of Professional Qualifications to even commence a process to work towards mutual recognition. EAHP has been working hard with partners in 2012 to try and address this situation. In December 2011 the European Commission published proposals for reforming the current Directive on Mutual Recognition of Professional Qualifications with the express intention of increasing labour mobility in Europe, thereby strengthening the Single Market, and, it is hoped, economic activity and growth. As the Directive is currently written only 7 professions benefit from “automatic recognition” across the European Union: Medicine, Dentistry, Nursing, Midwifery, Pharmacy, Veterinary

Medicine and Architecture. All other professions seek mobility through, what is called, “the General System”. This can often be ad hoc and require many conditions to be imposed before an individual is given recognition for their professional qualification (e.g. periods of supervised practice, assessments etc) and can also be a lengthy and time-consuming process. The Commission wanted to address this through the creation of a new recognition tool called “the Common Training Framework”. This would enable 9 countries or more (not all EU countries would need to participate) to form a voluntary agreement on recognising a qualification that could be based on a competence framework, rather than a strict need to agree the duration period of a qualification. The Commission’s Common Training Framework idea has been subsequently broadly welcomed by stakeholders as a sensible and useful suggestion. However as EAHP and others began to read the fine print on the legal text of the Commission’s proposal it became clear there was an important deficiency in the idea. The Commission were explicitly precluding its use by any of the seven automatically recognised professions for the purpose of specialty recognition. EAHP, and colleagues at the European Union of Medical Specialists (UEMS) and the European Board of Veterinary Specialisation (EBVS) have been of one view, that this is a real missed opportunity for improving specialist mobility in Europe, and together we have campaigned in the European Parliament to amend the Commission’s proposals.

It was therefore very pleasing that, through the support of Members of the European Parliament such as Phil Prendergast (Labour Party, Ireland), Robert Rochefort (Mouvement démocrate, France) and Bernadette Vergnaud (Parti Socialiste, France), in January 2013 the European Parliament agreed a set of amendments to correct this problem, and allow specialisations of pharmacy to be recognised at the European level through a Common Training Framework. As I write, the European Parliament and the Council of Ministers (representing the national governments of the 27 Member States) are in dialogue in order to try and reach agreement on the final shape of a reformed Directive on the Mutual Recognition of Professional Qualifications. EAHP must therefore continue to make representations to ensure the value of improving pharmacy specialty recognition can be appreciated and supported. For over 30 years, medical and dental specialists have enjoyed the ability to move through Europe, taking their muchneeded skills and experience to where the demands of patient care most require it. As we seek to raise the level of hospital pharmacy practice across Europe, for the benefit of patient safety and welfare, it is surely time that pharmacy specialists also be given similar opportunities for mobility.


18 Industry Profile

Re-branding whilst keeping value At the start of the year, Watson Pharmaceuticals announced that the company had adopted Actavis, as its new global name. The company first announced its intention to change its name in 2011, following its acquisition of the Actavis Group. The combination created the world's third largest generic pharmaceutical company. Tony Hynds

will work more efficiently,” he adds. “The last thing we want is for the bill to be rushed and incorrectly implemented. Actavis is currently developing biosimilar drugs.

‘A’ - in lists, starting with ‘A’ has its advantages, but mainly due to the strength and values associated with the Actavis name. “Watson wanted a new look Actavis brand which reflected the new combined company and represented something new, vibrant and different in the pharma industry. Green was chosen as the predominant colour – to really stand out and make a statement. “The new logo bears the company name, topped off with a distinctive helix shape, which reveals a ‘W’ emerging from a shaded ‘A’, a subtle but historical reference to the Watson and Actavis heritage. “Actavis is a global base now, which is good for us in Ireland,” he continues. “The old legacy of Watson has a manufacturing factory in Coleraine, Northern Ireland, so Actavis maintains manufacturing on the island of Ireland.” The generic health bill which seeks to introduce generics substitution and reference pricing for medicines in Ireland was published as law recently. Tony explains what effect this will have on Actavis:

Actavis set about initiating a multi-year rebranding campaign to guide the transition of its facilities, operations and commercial presence around the world to the new company name and logo. "Today marks an historic day for Actavis and a milestone in our evolution into a global pharmaceutical leader," said Paul Bisaro, President and CEO of Actavis, at the time. Hospital Pharmacy News spoke to Actavis Ireland Managing Director

Issue 9 • HPN

Tony Hynds about rebranding, what the acquisition will mean to pharmacy in Ireland and of course, their excitement at being a lead sponsor at the inaugural Hospital Pharmacy Awards. Tony begins by outlining the history of maintaining the Actavis name during a time of acquisition. “Watson US played around with a number of new titles,” he says. “However they settled on keeping the Actavis name; in part due to the fact it begins with the letter

“This is going to be a big opportunity for us. I have always been an advocate for generic prescribing and substitution; some markets have mandatory generic subscribing. I always thought that generic prescribing would be difficult to sell in Ireland as doctors are so used to writing prescriptions with brands throughout the years. It would be a big culture change to alter that. I think the first step is generic substitution, it is fundamentally much easier to implement.” The health bill will see generic substitution products being introduced in phases. “I think this

“We have a Biosimilar plant called ‘Eden bio-science’ in Liverpool, UK and we have some good innovations in the pipeline for this market, which we anticipate seeing come to fruition in 2015. This is a challenge for us and a change in mind-set from the generic sell; we are influencing what is prescribed rather than what is dispensed.” The last issue of HPN featured the exclusive launch of the Hospital Pharmacy Awards 2013, a first for Ireland and an initiative Actavis is proud to be associated with. “Actavis is truly delighted to be sponsoring the ‘Aseptic Hospital Unit of the Year’ category for the Hospital Pharmacy Awards,” he told us. “It is an excellent synergy for us as Actavis specialises in oncology; having two plants in Italy and Romania making generic oncology products that are sold in Ireland. So sponsoring this award feels like a natural fit for us. “Having two European sites has meant that we have a robust supply chain. Often, companies make these products in Asia and thus render the supply chain unreliable.” And of their support of hospital pharmacists? Tony adds: “We have a full time hospital sales force and spend a great deal of time and resources on oncology and injectable products. In our attendance at both the HPAI and NAHPT conferences we strive to maintain and develop our already established close links with the profession. “I firmly believe that hospital pharmacists deserve recognition in their own right and consequently the very notion of a separate awards ceremony highlighting this fact is not only timely, but is to be applauded.”


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Hospital Pharmacy Awards 2013

Hospital Pharmacy Team of the Year Award Investing in education and the health of the nation

Excellence in Pharmacy

Pfizer Healthcare Ireland

There are many key elements to building a productive team, including communication and co-operation. Good communication means everyone is aware of their own responsibilities and what the team's goals are whilst co-operation leads to increased productivity. The judging panel will be looking for the pharmacy that can demonstrate a close working relationship internally and with the doctors, nurses and other members of the multi-disciplinary team to ensure that patients receive optimal pharmaceutical care while attending the hospital. Teams that have adopted a key role in monitoring and reviewing patients and their medications, providing medication counselling where appropriate and liaising with community pharmacy colleagues and GPs to promote seamless pharmaceutical care. This can also include pharmacists and technicians, who are involved in ongoing research projects, in teaching and tutoring undergraduate and postgraduate healthcare personnel and in clinical training that enhances the overall performance of their department. A team that excels is the one who, together, endlessly work to improve their efforts. They comprehend the importance of on-going improvements and how this helps support the overall objectives of the department. The Award is open to any hospital pharmacy team with a minimum of three team members Examples:  Display of how team members are motivated and keep each other in team spirit positively  What is the methodology for this particular team in tackling a particular project?  Describe a project the team worked on recently and how individual team members worked towards a shared goal  How do you identify each other’s strong skills and structure them to the betterment of the team as a whole?  Please give examples of your success from working together as a team Criteria:  You may enter more than one category but each individual entry can only be submitted for a maximum of two categories  You will need to submit a short summary of no more than 500 words with supporting information  Entries should generally cover the twelve month period from January 2012 – December 2012 Judging:  There will be three finalists selected from all applications submitted  Each finalist submission will be judged by our independent judging panel  Each finalist will be invited to attend the gala awards ceremony on September 21, 2013 at the Crowne Plaza Hotel, Santry where the winner will be announced  For further information please visit our website at www.pharmacynewsireland.com Company Mission Statement At Pfizer, we apply science and our global resources to improve health and well-being at every stage of life. We strive to set the standard for quality, safety and value in the discovery, development and manufacturing of human medicinal products. Our diversified global health care portfolio includes human biologic and small molecule medicines and vaccines, as well as many of the world’s best-known consumer products. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as the world’s leading biopharmaceutical company, we also collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For more than 150 years, Pfizer has worked to make a difference for all who rely on us. Pfizer’s business interests in Ireland are diverse. There is a manufacturing presence in Active Pharmaceutical Ingredients, Solid Dose Pharmaceuticals, Sterile Injectables, Vaccines and Biopharmaceuticals; Commercial Human Prescription and Consumer Health Businesses; Global Financial Services Centre and a Global Treasury Operation. Ireland is a leading manufacturing base for Pfizer globally, exporting to global markets. Total capital investment by the company in Ireland exceeds $7billion. For more information please visit www.pfizer.ie Issue 8 9 • HPN


Awards

Hospital Pharmacist of the Year Award Investing in education and the health of the nation

Roche Products Ireland

We Innovate Healthcare

Hospital Pharmacy Technician of the Year Award Investing in education and the health of the nation

Medisource

This aim of this award category is to recognise those who, through their service to patient care, education or research, to the profession and to the society, are worthy of being rewarded.

This Award category serves to recognise and salute those pharmacy technicians whose hard work quite often flies under the radar. If you know someone that has enriched the depth and broadened the scope of pharmacy technicians then this award category is for you.

The judges will be looking for those individuals whom exhibit promising leadership, dedication and commitment to practice excellence and professional growth. This may be through hospital pharmacy activities or their experiential training in direct patient care, research or education.

Hospital pharmacy technicians have a vital role to play in supporting the team within hospital pharmacy departments. In recognition of this, this award will be given to someone who have provided an outstanding support for the pharmacy profession within their department.

The winner will exhibit eagerness, dedication and a positive attitude toward the academic learning, the practice, and the profession of hospital pharmacy.

We will be looking for those that have been able to demonstrate exemplary accomplishments which foster the advancement of patient care and/or the profession of pharmacy technicians. Judges will want to see professionalism / leadership, support for and participation in continuous professional development, with a commitment to safe, rational, economic pharmaceutical care within the pharmacy technician role.

This Award is open to any pharmacist working within a Hospital Pharmacy unit in Ireland Examples:  What campaigns have you/they been involved in within the last twelve months worthy of recognition?

Examples:

 What has been the measurable outcomes/success of these?

 Evidence of new innovation or new thinking which has enhanced the hospital pharmacy department within which they work

 What benefits have others derived as a result of your/their innovation and hard work?  Give examples of their outstanding work and commitment to the betterment of the hospital pharmacy profession  Evidence of an ability to identify opportunities and develop them through initiative and excellent interpersonal skills  What additional groups and bodies do you/they subscribe to in assisting towards the future growth of the profession?

 Excellent communication with staff and additional pharmacy team members  Examples of your/their expertise exceptional effort resulting in a milestone being achieved or target exceeded  Examples of collaboration whereby outstanding teamwork and/or leadership skills have ensured a task was completed regardless of challenges faced

HPN • Issue 9


Awards

Hospital Pharmacy Manager of the Year Award Investing in education and the health of the nation

Hospital Innovation and Service Award Investing in education and the health of the nation

Novartis

Hospira A successful manager creates a productive environment to work in as well as the drive and impetus to make things happen. They must balance technical and management skills.

This award will be presented to a practising hospital pharmacist and/or team in recognition of a project which could easily be accomplished regardless of hospital size or staff, which need not be sophisticated, and which serves a useful purpose or has recently been published.

This Award is aimed at any individual who has made a significant contribution in the past year to their pharmacy department, to those pharmacy managers who have been instrumental in driving the department forward. This could be through improving financial and clinical performance through effective medication management, inter department relations, reviews or clinical trials, developing a new service or development of staff

The judges will be looking for significant innovation in practice, method or service directly or indirectly resulting in improved patient care and/or advancement of the profession of hospital pharmacy. We know that many pharmacists have initiated exciting programmes in their hospitals and we would like to recognise them.

The judges will be looking for that candidate who has exceeded expectations by an innovative approach, who plans, directs, revises, and modifies pharmacy procedures.

This award is ultimately for the forward thinking hospital pharmacists who are sourcing new ways of overcoming challenges faced. Key to this is optimising the health status of the patients under the care of hospital team, targeting areas of need and effective health enhancement and promotion.

Pharmacy Manager of the Year award recognises those who provide the most effective demonstration of their pharmacy management competence, no matter the scale of the hospital or department. Examples:  How have you/they made a personal contribution to the hospital pharmacy team as a whole?  How have you/they managed and handled the team over the last twelve months to improve the working of the pharmacy department?  Please give examples of challenges faced over the last twelve months and how they have been overcome  How does your/their management approach make them special and stand out from any other hospital pharmacy manager?  Demonstrate techniques for motivating staff and detail any major achievements worthy of the Hospital Pharmacy Manager of the Year Award

Issue 9 • HPN

Examples:  How and why was the project started and what were the key objectives?  Examples of how this particular innovation is unique and the development process in getting it to fruition  Examples of the fundamental changes made by this innovation and the practicality of its application  Examples of published work directly relevant to the innovation  Impact of the innovation on patient care and for the wider hospital pharmacy industry


Awards

Antimicrobial Project of the Year Award Investing in education and the health of the nation

Mylan

Oncology Pharmacist of the Year Award Investing in education and the health of the nation

BD Due largely to the overuse and misuse of antibiotics, bacteria have become increasingly resistant to many of the compounds we rely on to treat serious infections in our hospitals. Antibiotic pharmacists have been shown to be effective in many ™ situations and as they become more accomplished their role is greatly expanding to include direct intervention in patient treatment.

BD PhaSeal

Recognising those who provide quality patient care in relation to a patient’s oncologic diagnosis, prescribed treatment, age group and other identified needs and provides comprehensive pharmaceutical care to oncology patients to assure safe and effective drug therapy.

Proven safe handling of hazardous drugs

The judges within this category will be looking for an innovative project promoting health development, it could ideally include reviewing antibiotic orders (including drug selection and duration of therapy), design and promotion of clinical practice guidelines, implementation and operation of antibiotic “switch “programmes and documenting the effectiveness of interventions.

The judging panel will be looking for a high calibre individual who can demonstrate organisation, management and quality of care and services that optimise outcomes in patients with malignant diseases. This person will be able to show how they coordinate the drug therapy process through drug selection, drug information, dosing, monitoring, outcomes management, and patient education/counselling. Examples:

The winning project will show a clear indication of how the pharmacy profession can play a key role long side other professions in tackling the problem of antibiotic resistance. As with medicine, pharmacy is becoming increasingly specialised, with lead pharmacists playing key roles in clinical areas such as critical care, haematology, oncology and neonatology. The development of the antibiotic pharmacist role over the past decade is a reflection of this, coupled with the recognised need for prudent antimicrobial prescribing. Examples:  Examples of a dedication and commitment to expanding and enhancing the role of antimicrobial hospital pharmacists for the whole profession  Examples of particular project(s) carried out within the field of antimicrobial pharmacy and/or recent work published

1

 Judges will want to see examples of where knowledge and expertise have been used to both inspire colleagues within the industry and/or enhanced the patient experience within the field of oncology  How have you/they shown inventive thinking and novel application of techniques to solve a problem, improve efficiency or develop a new concept?  How have you/they undertaken significant personal development and/or increased your/their knowledge and ability to the benefit of the wider hospital pharmacy team and the profession?  Examples of the overall contribution to pharmacy oncology which has directly or indirectly had an impact on service delivery and standards

 Education and expansion of knowledge in order to provide greater volume of service  Training and teamwork with the great antimicrobial team and hospital staff

HPN • Issue 9


Awards

Aseptic Hospital Unit Hospital Pharmacy of the Year Award Representative of the Year Award Investing in education and the health of the nation

Actavis This award category is open to qualified, trained pharmacists and technicians engaged in the preparation of injectable and other sterile products for individual patient use. The judges will be looking for the unit that can best demonstrate safety and quality within their department while incorporating initiatives. This could be through SOPs, cost saving projects, clinical trials medication, interaction with other departments, identification and fulfilment to training needs or other. An aseptic hospital unit can be made up of pharmacists, technicians, assistants and support staff and this award is open to any number of team members working within this capacity to ensure that the products prepared are sterile and free from contamination. In addition, the judges will be looking at the team that offers an exceptional level of Good Clinical Practice and puts patient safety and efficacy at the heart of its objectives. Examples:  Have you/they displayed observation in following strict procedures to ensure accuracy and/or to improve accuracy within the aseptic unit?  Have you/they engaged in training, development and/or further education to ensure continuation in meeting patient needs? Judges will expect to see evidence and results  Can you show examples of reducing wastage by improving efficiency and effective team working?  Have you recently carried out any internal audits, with documented results completing an accurate assessment checklist to ensure smooth and effective running of the unit?

Issue 9 • HPN

Investing in education and the health of the nation

Hospital Pharmacy News This aim of this award category is to recognise the sales representatives who excel in customer service, knowledge of their product base and a commitment to their profession in terms of future growth and development. The winner of this category must stand out in business ethics and integrity. Judges will be looking for exceptional applicants that show creativity and an inspiring work ethic. Whether it’s interacting with customers, going that extra mile, running new initiatives or training and promotional campaigns, this person will be an integral part of their company’s business. Nominated individuals may stand out due to their excellent team morale and motivation boosting techniques; their involvement in staff education and training or may be known to hospital pharmacists and the wider pharmacy team as being a beacon of knowledge for the products which form their sales list. Examples:  How have you/they improved the company’s operation, resulting in positive sales growth and tangible results?  Can you/they demonstrate a commitment to outstanding customer/client service?  How have you/they shown a commitment to provide innovative and driven services?  How have you/they demonstrated a sales service above and beyond that from which is expected to motivate team members, clients and colleagues?


Hospital Pharmacy Awards 2013

Awards

Lifetime Achievement Award

Table Sales are now available and selling fast - There is only limited availability so to guarantee your place at the hospital pharmacy event of the year or for details of our sponsorship opportunities.

Investing in education and the health of the nation

Accord The Evolution of Generics

An evolving company

Part of the Intas Group, Accord Healthcare is a young and dynamic pharmaceutical company, involved in the development, manufacturing and distribution of pharmaceutical products to over 50 markets around the world.

By being vertically integrated and owning all steps of the process, Accord can bring high quality medicines to patients faster, more economically and with greater efficiency than our rivals.

IE/ACC/003/01/13

This award will be given to a hospital pharmacist that has made a major impact on the arena of pharmacy in Ireland and will honour those individuals who have made a difference. The award provides special recognition to those who have provided outstanding service over a sustained period of years to the pharmacy/pharmacy academic community.

Please contact Debbie Graham on 0044 7450 274112 Kelly Jo Eastwood on 0044 787 6548989

The Lifetime Achievement Award recognises the career and achievements of a hospital pharmacist who has made an indelible impact on the pharmacy industry within Ireland as a whole.

Sponsored in conjunction with the Jack and Jill Foundation – the HPN Awards nominated charity – we are looking for Visit us during HPAI Conference someone who’s pioneering influence and unique approach to the delivery of sophisticated patient care and enhancement is worthy of the Lifetime Achievement title. The group’s vision is to be involved in all the aspects of bringing pharmaceuticals to patients. Our activities today encompass the entire pharmaceutical value chain and so create a truly integrated offering.

Accord Healthcare Ltd. 24-26 Bullford Business Campus Kilcoole, County Wicklow - Ireland E-mail: info@accord-healthcare.ie Tel. +353 (0)1 2592020

The Lifetime Achievement Award is the most prestigious of The Evolution of Generics all awards presented at the HPN Awards. It does not merely signify the superior achievement embodied in a single work. Instead, it is an acknowledgement of superior achievement in an entire career. So, to prevent unseemly competition and to prevent the impression that there are any losers in this category, this is the only award that is not decided by a vote of our judging panel. www.accord-healthcare.ie

Instead, a special sub-committee of our judging panel - a Lifetime Achievement Award Committee has been established consisting of five members from across a diverse area within pharmacy. This committee will consider all the recommendations made for this award. Examples:  Made a positive impact on the pharmacy industry  25 years, or more, of sustained service to pharmacy  Earned recognition by other industry, training, education or academic groups;  The respect of professional peers

HPN • Issue 9


IN ADVANCED RENAL CELL CARCINOMA 1

O

THE FIRST VEGFR-TKI FAILURE 2,3

The only once-daily mTOR inhibitor 1

AFINITOR doubled median PFS after the first failure with VEGFR-TKI, sunitinib or sorafenib.2,3 ABBREVIATED PRESCRIBING INFORMATION Refer to the Summary of Product Characteristics (SmPC) before prescribing. Afinitor 5 mg Tablets, Afinitor 10 mg Tablets. Presentation: tablets containing 5 mg or 10 mg of everolimus. Indications: adult patients with advanced renal cell carcinoma (RCC), whose disease has progressed on or after treatment with VEGF-targeted therapy. Treatment of unresectable or metastatic, well- or moderately-differentiated neuroendocrine tumours of pancreatic origin in adults with progressive disease. Afinitor is indicated for the treatment of hormone receptor-positive, HER2/neu negative advanced breast cancer, in combination with exemestane, in postmenopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor. Dosage: Adults: one 10 mg dose once daily at the same time every day, with or without food. Dose adjustment may be required due to side-effects or when used with moderate CYP3A4 or PgP inhibitors or strong CYP3A4 inducers Children: Afinitor is not recommended for use in children or adolescents. Patients with hepatic impairment: Mild hepatic impairment (Child-Pugh A) – the recommended dose is 7.5 mg daily. Moderate hepatic impairment (Child-Pugh B) – the recommended dose is 5 mg daily. Severe hepatic impairment (Child-Pugh C)–Afinitor is only recommended if the desired benefit outweighs the risk. In this case, a dose of 2.5 mg daily must not be exceeded. Contraindications: Hypersensitivity to the active substance, to other rapamycin derivatives or to any of the excipients. Warnings/Precautions: Non-infectious pneumonitis: Cases have been described in patients taking Afinitor, some of these have been severe and on rare occasions, a fatal outcome was observed. In case of shortness of breath, pleural effusion, cough or dyspnoea not due to infection or malignancy, radiologic assessment for pneumonitis is indicated. In some cases, management of pneumonitis may require dose adjustment and/or interruption, or discontinuation of Afinitor and/or addition of corticosteroid therapy Infections: Afinitor is immunosuppressive. Localised and systemic infections have been described in patients taking Afinitor, some of these have been severe (e.g. leading to respiratory failure) and occasionally fatal. In case of fevers and chills, signs of a potential bacterial or invasive fungal infection should be looked for and appropriate treatment promptly instituted; Treat pre-existing invasive fungal infections prior to starting treatment with Afinitor; If a diagnosis of invasive systemic fungal infection is made, discontinue Afinitor and treat with appropriate antifungal therapy. Hypersensitivity reactions manifested by symptoms including but not limited to, anaphylaxis, dyspnoea, flushing, chest pain or angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus (see section 4.3). Oral ulceration: Mouth ulcers, stomatitis and oral mucositis have been seen in patients treated with Afinitor (see section 4.8), topical treatments are recommended, but alcohol- or peroxide- containing mouthwashes should be avoided. Anti-fungal agents should not be used unless fungal infection has been diagnosed ( see section 4.5) Laboratory tests and monitoring: Renal function, blood glucose, and complete blood counts are recommended prior to initiation and periodically during treatment Hepatic

The only once-daily mTOR inhibitor, AFINITOR doubled median Impairment: Not recommended in patients with severe hepatic impairment (Child-Pugh class C) Vaccination: Avoid use of live vaccines Fertility: The potential for everolimus to cause infertility in male and female patients is unknown, however, secondary PFS after the first failure with VEGFR-TKI, sunitinib or andsorafenib. amenorrhoea associated LH/ FSH imbalance has been observed in female patients. Pregnancy: should not be given to

NO0713418 Date of Preparation: July 2013.

pregnant women unless the potential benefit outweighs the potential risk to the foetus. The potential risk for humans is unknown. Women of childbearing potential: Use effective contraception methods while receiving Afinitor, and for up to 8 weeks after ending treatment Breast-feeding: Women taking Afinitor should not breast feed Interactions: avoid concurrent treatment with strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, ritonavir, clarithromycin, telithromycin) and strong PgP inhibitors caution with moderate inhibitors of CYP3A4 and/or PgP (e.g. erythromycin, verapamil, diltiazem, fluconazole, ciclosporin, amprenavir, fosamprenavir, aprepitant) avoid concurrent treatment with strong inducers of CYP3A4 or PgP (e.g. rifampicin, rifabutin) St. John’s Wort (Hypericum perforatum), carbamazepine, phenobarbital, phenytoin, efavirenz, nevirapine, dexamethasone, prednisone, prednisolone avoid grapefruit juice, grapefruit and other foods affecting CYP3A4 or PgP. Co-administration of everolimus and exemestane increased exemestane Cmin and C2h by 45% and 64%, respectively. However, the corresponding oestradiol levels at steady state (4 weeks) were not different between the two treatment arms. No increase in adverse events related to exemestane was observed in patients with hormone receptor-positive advanced breast cancer receiving the combination. The increase in exemestane levels is unlikely to have an impact on efficacy or safety. Adverse reactions: ♦ Very common (≥10%): Stomatitis, rash, fatigue, asthenia, diarrhoea, anorexia, nausea, mucosal inflammation, vomiting, cough, infections, peripheral oedema, dry skin, epistaxis, pneumonitis, pruritus anaemia, thrombocytopenia, dyspnoea, dysgeusia, pyrexia, hyperglycaemia, hypercholesterolaemia, hypertriglyceridaemia; ♦ Common (≥1 to <10%): Headache, dry mouth, pyrexia, weight decreased, hand-foot syndrome, abdominal pain, erythema, insomnia, dyspepsia, creatinine increased, dysphagia, hypertension, increased daytime urination, dehydration, chest pain, haemoptysis, exacerbation of diabetes mellitus, leukopenia, lymphopenia, neutropenia, pulmonary embolism, skin lesion, mild alopecia, Diabetes mellitus, hypophosphataemia, hypokalaemia,,hyperlipidaemia, hypocalcaemia; ♦ Uncommon (<1%): Pure red cell aplasia, ageusia, congestive cardiac failure, deep vein thrombosis, new onset diabetes mellitus, impaired wound healing, grade 1 haemorrhages, cases of Hepatitis B reactivation have been observed. Legal Category: POM Product Authorisation Numbers: EU/1/09/538/001-003 EU/1/09/538/004-006 Pack Sizes: 30 Tablets. Date of Revision of Text: March 2013. Full prescribing information is available on request from Novartis Ireland Ltd, Beech Hill Office Campus, Clonskeagh, Dublin 4 or at www.medicines.ie Tel: 01 260 1255 Fax: 01 260 1263. Afinitor® is a registered Trade Mark. References: 1. Afinitor Summary of Product Characteristics. 2. Motzer et al. Cancer. 2010 Sep 15;116(18):4256-65 3. Calvo E et al. Ann Oncol. 2010;21(suppl 8):viii285.


CPD 4: RENAL CELL CARCINOMA Biography - Dr Ray McDermott commenced his training in Medical Oncology at the Mater Hospital, Dublin during which time he completed an MBA in Health Services Management. He went on to The Institut Curie, Paris (2000-2002) where he completed a PhD in Tumour Immunology. He subsequently completed his clinical training at Fox Chase Cancer Center, Philadelphia (2002-2004), where he furthered an interest in Genito-Urinary Oncology. During this training period, he published over twenty peer reviewed articles and Book Chapters. He took up a post as Consultant Medical Oncologist at the Adelaide Meath & National Childrens Hospital, Tallaght in July 2004. In 2006, Dr McDermott was instrumental in establishing Ireland as a main member of the Eastern Co-Operative Group, the largest clinical trials group in the USA with over 70 active studies. Dr McDermott is the Principal Investigator for Ireland in this initiative and is involved in twice yearly meetings with ECOG to develop this relationship. Dr McDermott is currently Vice-Chair of ICORG, the Irish Clinical Oncology Research Group.

60 Second Summary Renal cell carcinoma is the second most common urological malignancy and accounts for up to 3% of all new cancer diagnoses worldwide. Up to 40% of cases are at an advanced stage at the time of diagnosis. The median age at diagnosis is 66 years, with a male preponderance of two to one. It is estimated that 10% to 40% of RCCs present with one of a wide range of paraneoplastic syndromes. These include constitutional symptoms such as cachexia or pyrexia; specific metabolic and biochemical abnormalities such as hypercalcaemia; hypertension or polycythaemia; or Stauffer's syndrome, a syndrome of nonmetastatic hepatic dysfunction. RCCs are highly resistant to conventional cytotoxic chemotherapy. With early stage disease, radical nephrectomy is the treatment of choice. There is currently no role for adjuvant therapy in resected RCC although studies are ongoing. Pharmacologic intervention is reserved for recurrent or advanced disease, where the aim of treatment is predominantly palliative and non-curative in nature. Axitinib is another anti-VEGF TKI recently licensed for use in the second-line setting based on the Phase III AXIS study. This study randomized 723 previouslytreated patients to receive either axitinib or sorafenib. Axitinib demonstrated superior progression-free survival of 8.3 months compared to 5.7 months for sorafenib. As RCC is a highly vascular malignancy, an anti-angiogenic approach still remains as the most efficacious strategy to date. Other anti-VEGF TKIs in various stages of clinical investigation included dovitinib, tivozanib and nintedanib.

1. REFLECT - Before reading this module, consider the following: Will this clinical area be relevant to my practice. 2. IDENTIFY - If the answer is no, I may still be interested in the area but the article may not contribute towards my continuing professional development (CPD). If the answer is yes, I should identify any knowledge gaps in the clinical area. 3. PLAN - If I have identified a knowledge gap - will this article

satisfy those needs - or will more reading be required? 4. EVALUATE - Did this article meet my learning needs - and how has my practise changed as a result? Have I identified further learning needs? 5. WHAT NEXT - At this time you may like to record your learning for future use or assessment. Follow the 4 previous steps, log and record your findings.

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

Written by: Dr Min Yuen Teo, Research Registrar, Medical Oncology and Dr Ray McDermott, Medical Oncologist

Management of Advanced Renal Cell Carcinoma INTRODUCTION Renal cell carcinoma is the second most common urological malignancy and accounts for up to 3% of all new cancer diagnoses worldwide1. Up to 40% of cases are at an advanced stage at the time of daiagnosis2. The median age at diagnosis is 66 years, with a male preponderance of two to one3. The Irish National Cancer Registry recorded 405 cases of RCC in 20074 and the incidence of the disease has been gradually increasing over the last three decades. Although some of this increase may be accounted for by earlier detection of asymptomatic tumours through advanced imaging modalities, it would appear that other factors are also implicated5. Traditionally this has been a difficult disease to treat, with many patients diagnosed succumbing to their illness due to a lack of effective therapies. This situation is now changing as we gain understanding of the underlying disease process. CLINICAL PRESENTATION The classic triad of haematuria, flank pain and a palpable mass

occurs in less than 10% of cases6. An increasing percentage of RCCs are now diagnosed at an early-stage, often picked up incidentally during radiological assessment for other reasons5. More advanced cases may present with non-specific constitutional symptoms such as weight loss, or pyrexia of unknown origin7. Other manifestations depend on the sites of metastatic disease. It is estimated that 10% to 40% of RCCs present with one of a wide range of paraneoplastic syndromes. These include constitutional symptoms such as cachexia or pyrexia; specific metabolic and biochemical abnormalities such as hypercalcaemia; hypertension or polycythaemia; or Stauffer’s syndrome, a syndrome of nonmetastatic hepatic dysfunction8 STAGING AND PROGNOSIS RCCs are staged according to the AJCC classification of malignant tumours (TNM)9. Fiveyear survival ranges from 90% in stage I disease (disease confined to kidneys) to 20% in stage IV (metastatic disease) RCCs.4

AJCC TNM-staging, tumour size, nuclear grade and the presence of a sarcomatoid component are significantly associated with poorer outcomes in all renal cancer histologic subtypes. In the metastatic setting, Motzer el al devised a prognostic model based on the presence or absence of certain variables, namely poor performance status, a time from diagnosis to treatment of less than one year, haemoglobin level less than normal, serum lactate dehydrogenase (LDH) over 1.5 times normal, and an elevated serum calcium. Patients were stratified into one of three groups depending on the number of risk factors present. (Good risk – no risk factors; Intermediate risk – one to two risk factors; Poor risk – three or more risk factors). They demonstrated substantial differences in survival between these groups, ranging from five months in the poor risk group to 30 months in the good risk group10. Their findings were subsequently validated by Mekhail et al who added prior nephrectomy and the number of metastatic sites as independent prognostic factors11.

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


CPD 4: RENAL CELL CARCINOMA

standard of care in metastatic RCC. However, treatment with sunitinib is not without its toxicities. Higher rate of grade 3 or 4 fatigue, diarrhoea, hypertension and hand-foot syndrome have been reported. An expandedaccess study of sunitinib included patients who would otherwise have been excluded from clinical trials and demonstrated similar efficacy in cytokine-treated patients, and patients over 65 years. Less marked benefits were seen in patients with poor performance status, brain metastases and nonclear cell histology.17

PHARMACOLOGIC MANAGEMENT OF ADVANCED RCC – PAST AND PRESENT RCCs are highly resistant to conventional cytotoxic chemotherapy. With early stage disease, radical nephrectomy is the treatment of choice. There is currently no role for adjuvant therapy in resected RCC although studies are ongoing. Pharmacologic intervention is reserved for recurrent or advanced disease, where the aim of treatment is predominantly palliative and non-curative in nature. Historically, immunotherapy has been the mainstay of therapy but it has proven to be beneficial only in a small number of patients. A Cochrane review of immunotherapy in RCC showed an overall response rate of only 12.4% and median survival of 13 months12. Interferon-alfa (IFN-α) offers modestly improved survival of three months over control although the survival benefit may be preferentially imparted to patients without adverse prognostic factors. More importantly, patients treated with IFN-α experience quite significant toxicity, notably flu like symptoms and fatigue.

High-dose interleukin-2 (IL2) has demonstrated a superior response rate of 20% compared to interferon and has been associated with some durable remissions, however, there is substantial treatment-related toxicity, meaning that it can only be administered in selected specialist centres. Until relatively recently, patients who did not have a response or whose disease progressed after first-line cytokine therapy had no other viable options for treatment. Capitalising on the elucidation of molecular pathways important in the pathogenesis of clear cell RCC, a number of targeted agents have been developed. Table 1 outlined the ESMO recommendation for treatment of advanced RCC. ANTI-ANGIOGENIC AGENTS A paradigm-shifting phase III trial was reported in 2006 comparing sunitinib, an orally-administered small-molecule tyrosine-kinase inhitor (TKI) targeting VEGF with IFN-α. The trial recruited 750 patients and demonstrated a significant improvement in progression-free survival of 11 months versus five months, and overall response rate of 40% versus 8%,16 thus firmly establishing sunitinib as the

Pazopanib is another anti-VEGF TKI with significant activity in the first-line setting. In a Phase III study with over 435 patients, pazopanib demonstrated superior progression-free survival compared to placebo in both treatment-naive and cytokinepretreated patients, at 9.2 – 11.1 months. Numerically, these figures were comparable to sunitinib, and this led to the subsequent COMPARZ study. Only recently reported, this study showed that pazopanib was similar to sunitinib in terms of efficacy, with a more tolerable toxicity profile. Sorafenib is also an oral small-molecule TKI but with a different range of targets and toxicity profile. Escudier et al compared sorafenib to bestsupportive care in 904 cytokine pre-treated patients, showing a statistically-significant increment in progression-free surival of 5.5 months versus 2.8 months, albeit with increased toxicity.18 This led to approval of sorafenib as secondline treatment. Benefits again appear limited to the clear cell population. Axitinib is another anti-VEGF TKI recently licensed for use in the second-line setting based on the Phase III AXIS study. This study randomized 723 previously-treated patients to receive either axitinib or sorafenib. Axitinib demonstrated superior progression-free survival of 8.3 months compared to 5.7 months for sorafenib. However, the gain in progression-free survival was more marked in patients who received prior cytokines than patients who received previous anti-VEGF TKI (predominantly sunitinib). This study was notable

for the feasibiliy of up-titrating dosage of axitinib in the absence of toxicity (Reference). Bevacizumab, a monoclonal antibody targeting VEGF is administered intravenously. Two trials with more than 1,300 patients collectively compared the efficacy of interferon-alfa with and without bevacizumab. The results significantly favoured bevacizumab with a median progression-free survival between 8.5 and 10.2 months 20,21 closely resembling that of sunitinib and reaffirming the role of anti-angiogenic agents in the treatment of advanced renal cell cancer. mTOR INHIBITORS Mammalian target of rapamycin (mTOR) kinase is a component of intracellular signalling pathways involved in the growth and proliferation of cells and the response of such cells to hypoxic stress.22 Temsirolimus an inhibitor of mTOR admistered intravenously on a weekly basis. In a phase III trial, Hudes et al divided 626 patients with poor-risk RCC to receive either interferon-alfa alone, temsirolimus alone, or interferon-alfa in combination with temsirolimus. The results demonstrated a statistically significant improvement in progression-free survival at 1.9, 3.9 and 3.9 months respectively, and median survival of 7.3, 10.9 and 8.4 months respectively.22 Furthermore, more than 20% of the patients had non-clear cell histologic subtype. Temsirolimus has thus been recognised as an acceptable first-line option for poor-risk patients and non-clear cell subtypes. Everolimus / RAD001 is an orallyavailable mTOR inhibitor. The phase III RECORD-I trial involving 416 patients compared everolimus to placebo in patients previously treated with a VEGF TKI, and showed progression-free survival of five months compared to less than two months for placebo.23 mTOR inhibitors are generally quite well tolerated, Most commonly reported severe adverse effects are predominantly fatigue, anaemia and hyperglycaemia MANAGEMENT STRATEGIES The availability of such a range of

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


CPD 4: RENAL CELL CARCINOMA

therapeutic options has translated into better outcomes for patients, although many will still die of their disease. In a recent report by Heng et al on survival in metastatic RCC in the era of targeted therapy, the median overall survival for the good and intermediate risk groups had not yet reached after a median follow-up of 24.5 months, while the median overall surival for the poor risk group remained sub-optimal at 8.8 months.24 Various strategies and approaches have been adopted to improve outcomes of these patients. These include newer and more efficacious agents, combination of currently available agents and optimising sequencing of available therapies. NEW AGENTS As RCC is a highly vascular malignancy, an anti-angiogenic approach still remains as the most efficacious strategy to date. Other anti-VEGF TKIs in various stages of clinical investigation included dovitinib, tivozanib and nintedanib. Interests in immunotherapy were recently reignited following data from early phase trials of nivolumab, a monoclonal antibody against Programmed Death-1 (PD-1), an immune checkpoint protein found on immune cells and tumour cells. In a dosefinding phase I study, 33 of 296 enrolled patients had advanced RCC and were heavily pre-treated. Objective response rates from 24 â&#x20AC;&#x201C; 31% were observed, with some patients experiencing prolonged response to treatment. This had led to a phase III study comparing nivolumab to everolimus in the second or third line setting. The study is currently open in a number of Irish centres. COMBINATION The three main classes of drugs used in the management of advanced renal cell carcinoma - immunotherapy, anti-VEGF agents and mTOR inhibitors, have differing modes of action. This knowledge has led to interest in combination therapies, exemplified by recent success of such a strategy in breast cancer13. Attempts at combination of VEGF blockade and mTOR inhibition have met with limited success due to overlap in their toxicity

profiles. The TORAVA study was a three-arm randomized phase 2 study pitting bevacizumab plus temsirolimus against sunitinib or bevacizumab plus interferon. The experimental arm reported inferior progression-free survival. Over 40% of patients stopped treatment secondary to toxicity, with a rate of grade 3 & 4 toxicity in excess of 70%14. During the ESMO Congress 2012, two other combination studies were reported in abstract form. The INTORACT study investigated temsirolimus plus bevacizumab while the RECORD-2 examined everolimus plus bevacizumab. Both studies had interferon plus bevacizumab as the control arm, and neither demonstrated superiority of the novel combinations. SEQUENCING Although new therapeutic options for patients with advanced RCC are in use, and more are likely to become available in the coming years, the optimal way to these agents sequentially remain underinvestigated. Amongst anti-VEGF TKIs, the ideal sequencing of existing agents is not clear. Although the target is the same, these drugs differ in their affinity for this target and also in their promiscuity for other targets. This is manifest in the toxicities associated with each VEGF TKI which vary significantly. In addition to targeting VEGF, Sorafenib also targets RAF kinase which may be important in other cancer types. Retrospective data have indicated that within a sequential regimen, progression-free survival can be improved by using Sorafenib as first-line therapy followed by sunitinib15-17 rather than the other way around. Data is more limited on sequential use of other VEGF TKIs. The AXIS study compared axitinib with sorafenib as second line therapy and recruited over 700 patients. Fifty-four percent of patients on each arm received prior sunitinib and reported progression-free survival of 4.8 and 3.4 months, respectively18, which was comparable to retrospective sorafenib data17, 19, 20. Other anti-VEGF molecules which have shown activity as second-

line therapy included linifanib21 and pazopanib22, the latter is also the subject of an current phase 2 ICORG investigation (NCT01566747). The largest dataset for mTOR inhibitors in sequence comes from the RECORD-1 study23. Preplanned subgroup analysis from the RECORD-1 study showed that everolimus demonstrated activity following either one or two lines of VEGF blockade24 with progression free survival similar to that seen with Axitinib in second line use. More recently, RECORD-3 was reported in abstract form at the 2013 ASCO Annual Meeting. Patients were randomised to either sunitinib or everolimus, with a planned switch to the other agent on disease progression. Everolimus demonstrated significantly shorter progression-free survival in first line treatment. Second-line sunitinib was not able to make up for lost time and although the data was still immature, everolimus as first-line treatment showed a trend towards inferior overall survival. This supports the VEGF-mTOR sequence in clinical practice. For the proportion of patients who retain a good performance status, management upon progression beyond available agents poses a significant challenge. Small retrospective studies suggest that anti-VEGF rechallenge following everolimus resistance may be effective28, 29, however, new agents with alterantive mechanisms of action are required. ADJUNCTIVE THERAPIES Skeletal metastases affect up to one third of all patients with metastatic renal cell carcinoma. In an analysis of over 800 patients, 32% of patients were afflicted with osseous metastasis, half of which were present at diagnosis and the remainder of which developed bony involvement during the course of their illness30. It was estimated that each patient with bone metastasis experienced 2.4 skeletal-related events, most commonly bony pain necessitating radiotherapy (60.9%), fractures (20%) and malignant cord or nerve root compression (11%)30. Indeed, it has been suggested -based on analysis of over 200 cases of

advanced disease- that osseous involvement by metastatic renal cell carcinoma is a poor prognostic indicator, predicting shorter progression-free survival and poorer overall survival31. Bisphophonates such as zoledronic acid have been shown in multiple tumour types to reduce skeletal-related events. In a subset analysis of renal cell cancer cases which constituted 10% of the entire cohort, zoledronic acid reduced the average rate of skeletal-related events and significantly prolonged time to first event32, 33. Keizman and colleagues also reported that biphosphonates in renal cell carcinoma might improve progression-free and overall survival in a retrospective study34. CONCLUSION The landscape of renal cell carcinoma has changed significantly since 2004, with the introduction of several active targeted therapies. As we move beyond the initial phase of familiarising ourselves with these new agents, their cytostatic properties and different sideeffects profiles, larger questions have begun to present themselves. Adjuvant therapy has historically been ineffective in renal cell carcinoma, and the reproducibility of the activity of targeted therapies in the adjuvant setting remains to be elucidated. In the management of metastatic renal cell carcinoma, combination approaches have been confounded by limited efficacy and substantial toxicity. Sequential monotherapy has become the mainstay of day-to-day clinical practice. Primary refractory disease and osseous metastases have been recognised as poor prognostic indicators. The treatment of advanced renal cell carcinoma appears set to become more complex with further anti-VEGF agents at an advanced stage, and new agents with different targets in development. While the goal of cure remains elusive, trials examining optimisation of existing agents and efficacy of new therapies represent a critical step forward.

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


CPD 4: RENAL CELL CARCINOMA

Histology and Setting

Risk Group

N

Standard

Option

Clear Cell Good or Intermediate Risk Sunitinib 1st Line

Bevacizumab + Interferion

Cytokines (including high-dose IL2) Sorafenib

Pazopanib

Poor Risk

Temsirolimus

Sunitinib

Sorafenib

Sunitinib

Clear Cell Post-cytokines 2nd Line

Sorafenib

Pazopanib

Axitinib

Post-TKIs

Everolimus

Sorafenib

Axitinib

Clear Cell Post-2 TKIs Everolimus 3rd Line Non-Clear Cell

Temsirolimus

Sunitinib

Sorafenib

REFERENCES 1. Lipworth L, Tarone RE, McLaughlin JK. The epidemiology of renal cell carcinoma. The Journal of urology 2006;176:2353-8. 2. SEER Cancer Statistics Review, 1975 2006, National Cancer Institute. Bethesda, MD. Based on November 2008 SEER data submission, poster to the SEER web site., 2009. (Accessed at http://seer.cancer.gov/ csr/1975_2006/.) 3. Pantuck AJ, Zisman A, Belldegrun AS. The changing natural history of renal cell carcinoma. The Journal of urology 2001;166:1611-23. 4. National Cancer Registry Ireland. (Accessed at httpL//ncri.ie/ncri/index.shtml.) 5. Chow WH, Devesa SS, Warren JL, Fraumeni JF. Rising incidence of renal cell cancer in the United States. JAMA 1999;281:1628-31. 6. Casciato DA, Territo MC. Manual of Clinical Oncology, 6th Edition. 7. Zell J, Chang J. Neoplastic fever: a neglected paraneoplastic syndrome. Supportive Care in Cancer 2005;13:870-7. 8. Palapattu G, Kristo B, Rajfer J. Paraneoplastic syndromes in urologic malignancy: the many faces of renal cell carcinoma. Reviews in Urology 2002;4:163. 9. Storkel S, Eble JN, K. A, al. e. Classification of Renal Cell Carcinoma: Workgroun Union Internationale Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC). . Cancer 1997. 10. Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. Journal of Clinical Oncology 2002;20:289.

11. Mekhail T, Abou-Jawde R, BouMerhi G. … prognostic factors model for survival in patients with previously untreated metastatic renal …. Journal of Clinical Oncology 2005. 12. Coppin C. Immunotherapy for renal cell cancer in the era of targeted therapy. Expert Rev Anticancer Ther 2008;8:907-19. 13. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormonereceptor-positive advanced breast cancer. N Engl J Med 2012;366:520-9. 14. Negrier S, Gravis G, Perol D, et al. Temsirolimus and bevacizumab, or sunitinib, or interferon alfa and bevacizumab for patients with advanced renal cell carcinoma (TORAVA): a randomised phase 2 trial. Lancet Oncol 2011;12:673-80. 15. Merseburger AS, Simon A, Waalkes S, Kuczyk MA. Sorafenib reveals efficacy in sequential treatment of metastatic renal cell cancer. Expert Rev Anticancer Ther 2009;9:1429-34. 16. Porta C, Szczylik C, Escudier B. Combination or sequencing strategies to improve the outcome of metastatic renal cell carcinoma patients: A critical review. Critical reviews in oncology/hematology 2011. 17. Porta C, Tortora G, Linassier C, et al. Maximising the duration of disease control in metastatic renal cell carcinoma with targeted agents: an expert agreement. Medical Oncology 2011. 18. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 2011;378:1931-9. 19. Dudek AZ, Zolnierek J, Dham A, Lindgren BR, Szczylik C. Sequential therapy with

sorafenib and sunitinib in renal cell carcinoma. Cancer 2009;115:61-7. 20. Sablin MP, Negrier S, Ravaud A, et al. Sequential Sorafenib and Sunitinib for Renal Cell Carcinoma. The Journal of urology 2009;182:29-34. 21. Tannir N, Wong Y, Kollmannsberger C, et al. Phase II trial of linifanib in patients with advanced renal cell cancer (RCC) after sunitinib failure. . Journal of Clinical Oncology 2010;28, No 15 Suppl (May 20 Supplement), 2010: Abstr 4527. 22. Reeves JA, Spigel D, Daniel DB, Friedman EK, Burris HA, Hainsworth JD. Pazopanib in patients with metastatic renal cell carcinoma previously treated with sunitinib or bevacizumab: A Sarah Cannon Research Institute phase II trial. . Journal of Clinical Oncology 2011;29, No 15 Suppl (May 20 Supplement), 2011: Abstr 4659. 23. Motzer RJ, Escudier B, Oudard Sp, et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma. Final results and analysis of prognostic factors 2010;116:4256-65. 24. Calvo E, Escudier B, Motzer RJ, et al. Everolimus in metastatic renal cell carcinoma: Subgroup analysis of patients with 1 or 2 previous vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapies enrolled in the phase III RECORD-1 study. European Journal of Cancer 2012;48:333-9. 25. Gerullis H, Bergmann L, Maute L, et al. Feasibility of sequential use of sunitinib and temsirolimus in advanced renal cell carcinoma. Medical Oncology 2009;27:373-8. 26. Grundbichler M, Mlineritsch B, Ressler S, et al. Efficacy of Temsirolimus after Previous Treatment with Sunitinib, Sorafenib or Everolimus in Advanced Renal Cell Cancer. Oncology 2011;80:34-41.

27. MacKenzie MJ, Rini BI, Elson P, et al. Temsirolimus in VEGF-refractory metastatic renal cell carcinoma. Annals of Oncology 2010;22:145-8. 28. Grünwald V, Seidel C, Fenner M, Ganser A, Busch J, Weikert S. Treatment of everolimusresistant metastatic renal cell carcinoma with VEGF-targeted therapies. British Journal of Cancer 2011;105:1635-9. 29. Zama IN, Hutson TE, Elson P, et al. Sunitinib rechallenge in metastatic renal cell carcinoma patients. Cancer 2010;116:5400-6. 30. Woodward E, Jagdev S, McParland L, et al. Skeletal complications and survival in renal cancer patients with bone metastases. Bone 2011;48:160-6. 31. Beuselinck B, Oudard S, Rixe O, et al. Negative impact of bone metastasis on outcome in clear-cell renal cell carcinoma treated with sunitinib. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO 2010. 32. Lipton A, Zheng M, Seaman J. Zoledronic acid delays the onset of skeletal-related events and progression of skeletal disease in patients with advanced renal cell carcinoma. Cancer 2003;98:962-9. 33. Rosen LS. Zoledronic Acid Versus Placebo in the Treatment of Skeletal Metastases in Patients With Lung Cancer and Other Solid Tumors: A Phase III, Double-Blind, Randomized Trial--The Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group. Journal of Clinical Oncology 2003;21:3150-7. 34. Keizman D, Ish-Shalom M, Pili R, et al. Bisphosphonates combined with sunitinib may improve the response rate, progression free survival and overall survival of patients with bone metastases from renal cell carcinoma. European Journal of Cancer 2012.

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


COMBINATION

NEW

Rapid onset* and long lasting efficacy**

50/5 µg 125/5 µg 250/10 µg

The NEW asthma maintenance treatment

INNOVATION

Modern aerosol device with a patient-facing dose counter1 * Open label study, significant increase in FEV1 5 mins after dosing (p=o.oo1) (Aalbers et al: Onset of Bronchodilation with fluticasone/formoterol combination versus fluticasone/salmeterol in an open-label, randomised study; Adv Ther 2012) ** 6-12 month open label study, significant improvement in spirometric secondary endpoints vs baseline (Mansur et al, Long Term Safety and Efficacy of fluticasone/formoterol combination therapy in Asthma; JAMP -Vol 25, No0, 2012 p1-10)

flutiform is indicated for the regular treatment of asthma in adults and adolescents (12 years and over), where use of a combination product (inhaled corticosteroid [ICS] and long-acting ß2-agonist [LABA]) is appropriate. flutiform 250/10µg indicated in adults only. flutiform® (FLUTICASONE PROPIONATE AND FORMOTEROL FUMARATE) PRESSURISED INHALATION SUSPENSION. Prescribing Information Ireland. Please read the Summary of Product Characteristics before prescribing. Presentation: Pressurised inhalation suspension, in a pressurised metered dose inhaler (pMDI), containing fluticasone propionate and formoterol fumarate dihydrate at strengths of 50 µg/5 µg, 125 µg/5 µg or 250 µg/10 µg per actuation. Indications: Regular treatment of asthma where the use of a combination product (inhaled corticosteroid and long-acting ß2-agonist) is appropriate: For patients not adequately controlled with inhaled corticosteroids and ‘as required’ inhaled short-acting ß2-agonist (SABA), or for patients already adequately controlled on both an inhaled corticosteroid and a long-acting ß2-agonist (LABA). flutiform 50 µg/5 µg and 125 µg/5 µg per actuation are indicated for use in adults and adolescents 12 years and above. flutiform 250 µg/10 µg per actuation is only indicated for use in adults. Dosage and administration: For inhalation use. The patient should be shown how to use the inhaler correctly by a physician or other healthcare professional. Patients should be given the strength of flutiform containing the appropriate fluticasone propionate dose for their disease severity (note that flutiform 50 µg/5 µg per actuation is not appropriate in patients with severe asthma). The appropriate strength should be taken as two inhalations, twice-daily (normally in the morning and evening) and used every day, even when asymptomatic. flutiform should not be used in children under 12 years. Prescribers should be aware that in asthmatics, fluticasone propionate is as effective as some other inhaled steroids when administered at approximately half the total daily microgram dose. Total daily dose can be increased if asthma remains poorly controlled by administering a higher strength inhaler. Appropriate doses of the ß2-agonist and inhaled corticosteroid (ICS) in separate inhalers, or the ICS alone, should be prescribed if a patient requires doses outside the recommended dose regimens. Patients should be assessed regularly and once asthma is controlled, treatment should be reviewed and stepped down to the lowest effective dose, or an ICS alone. It is extremely important to regularly review patients as their treatment is stepped down. ICSs alone are first line treatment for most patients. flutiform is not intended for initial treatment of mild asthma. For patients with severe asthma the ICS therapy should be established before prescribing a fixed-dose combination product. Patients on flutiform must not use an additional LABA. An inhaled SABA should be taken for immediate relief of asthma symptoms arising between doses. The AeroChamber Plus® spacer device is recommended in patients who find it difficult to use inhalers; re-titration should always follow the introduction of a spacer device. Patients should be advised to contact their prescriber when the flutiform dose indicator is getting near zero.Contra-indications: Hypersensitivity to any of the active substances or excipients. Precautions and warnings: flutiform should not be used for the first treatment of asthma, to treat acute asthma symptoms or for prophylaxis of exercise-induced asthma. It should not be initiated during an exacerbation, during significantly worsening or acutely deteriorating asthma, and should not be stopped abruptly. Patients should use their flutiform maintenance treatment as prescribed, even when asymptomatic. If a patient experiences serious asthma-related adverse events or exacerbations, they should continue treatment but also seek medical advice. Patients should be reviewed as soon as possible if there is any indication of deteriorating asthma control. In the case of sudden and progressive deterioration, which is potentially life-threatening, an urgent medical assessment should be carried out. Use with caution in patients with: pulmonary tuberculosis; quiescent tuberculosis; fungal, viral or other infections of the airway; thyrotoxicosis; pheochromocytoma; diabetes mellitus (consider additional blood sugar controls); uncorrected hypokalaemia; predisposition to low levels of serum potassium; impaired adrenal function (monitor HPA axis function regularly) ; hypertrophic obstructive cardiomyopathy; idiopathic subvalvular aortic stenosis; severe hypertension; aneurysm or other severe cardiovascular disorders. There is risk of potentially serious hypokalaemia with high doses of ß2-agonists or concomitant treatment with ß2-agonists and drugs that can induce or potentiate a hypokalaemic effect. Particular caution is recommended in unstable or acute severe asthma and other conditions when the likelihood for hypokalemia adverse effects is increased. Monitoring of serum potassium levels is recommended during these circumstances. Formoterol may induce prolongation of the QTc interval. Caution must be observed when treating patients with existing prolongation of QTc interval. flutiform should be discontinued immediately if there is evidence of paradoxical bronchospasm. Systemic effects with an ICS may occur, particularly at high doses for prolonged periods or when combined with potent CYP3A4 inhibitors, but are less likely than with oral corticosteroids. Use of a spacer device may also cause an increased systemic exposure. Increased exposure can be expected in patients with severe hepatic impairment. Prolonged

NEW

fluticasone propionate/formoterol A POWERFUL PARTNERSHIP

treatment with high doses of corticosteroids may result in adrenal suppression and acute adrenal crisis, particularly in adolescents and children or potentially as a result of trauma, surgery, infection or rapid dose reduction. Patients should be advised that flutiform contains a small amount of ethanol; however this negligible amount does not pose a risk to patients. flutiform is not recommended in children under 12 years of age. Interactions: Caution is advised in long-term co-administration with strong CYP3A4 inhibitors (e.g. ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nelfinavir, saquinavir, ketoconazole and telithromycin); co-administration should be avoided if possible. Ritonavir in particular should be avoided, unless the benefits outweigh the risks of systemic side-effects. Caution is advised with use of non-potassium sparing diuretics (e.g. loop or thiazide), xanthine derivatives, glucocorticosteroids, L-Dopa, L-thyroxine, oxytocin, alcohol or other adrenergic drugs. There is an increased risk of arrhythmias in patients receiving concomitant anaesthesia with halogenated hydrocarbons. Hypokalaemia may increase the risk of arrhythmias in patients being treated with digitalis glycosides. Concomitant use of ß-adrenergic drugs can have a potentially additive effect. Extreme caution should be taken when using formoterol fumarate with drugs known to prolong the QTc interval, such as tricyclic antidepressants or MAOIs (and for two weeks following their discontinuation), as well as antipsychotics (including phenothiazines), quinidine, disopyramide, procainamide and antihistamines. Concomitant use of an MAOI or a similar agent, such as furazolidone or procarbazine, may precipitate hypertensive reactions. ß-blockers and formoterol fumarate may inhibit the effect of each other. ß-blockers may produce severe bronchospasm in asthma patients, and they should not normally be treated with ß-blockers including those that are used as eye drops to treat glaucoma. Under certain circumstances, e.g. as prophylaxis after myocardial infarction, cardioselective ß blockers could be considered with caution Pregnancy and lactation: flutiform is not recommended during pregnancy. It should only be considered if benefits to the mother outweigh risks to the foetus. It is not known whether fluticasone propionate or formoterol are excreted in breast milk; a risk to the breast feeding infant cannot be excluded. A decision should be made on whether to discontinue breastfeeding or discontinue/abstain from flutiform. Side-effects: Potentially serious side-effects: hyperglycaemia; depression; aggression; behavioural changes (predominantly in children); paradoxical bronchospasm; agitation; vertigo; palpitations; ventricular extrasystoles; angina pectoris; tachycardia; hypertension; dyspnoea; peripheral oedema; Cushings Syndrome; adrenal suppression; growth retardation; cataract and glaucoma; hypersensitivity reactions and QTc interval prolongation. Please consult the SPC for details of non-serious side-effects and those reported for the individual molecules. Legal category: POM Package quantities: One inhaler containing 120 actuations 50 µg/5 µg, 125 µg/5 µg, 250 µg/10 µg Marketing Authorisation numbers: PA 1688/13/1-3 Marketing Authorisation holder: Mundipharma Pharmaceuticals Limited, Millbank House, Arkle Road, Sandyford, Dublin 18, Ireland. Member of the Mundipharma Pharmaceutical Group. For medical information enquiries, please contact info@mundipharma.ie Date of preparation: January 2013 Reference: 1. flutiform Summary of Product Characteristics ® FLUTIFORM is a registered trademark of Jagotec AG, and is used under licence. ® AEROCHAMBER and AEROCHAMBER PLUS are registered trade marks of Trudell Medical International. © 2012 Mundipharma Pharmaceuticals Limited. Adverse events should be reported. Reporting forms and information can be found at http://www.imb.ie/EN/Safety--Quality/Online-Forms/Human- Medicine-Adverse-Drug-Reaction.aspx Adverse events should also be reported to Mundipharma Pharmaceuticals Limited on 01 206 3800/1800 991830 (outside office hours). IRE/FL-12042


32 Acquired Immune Deficiency Syndrome

H.I.V and the role of the pharmacist Author Biography: Written by Paul Knox. Paul is a Pharmacist with Cloughjordan Pharmacy and a Research Student at Trinity College School of Pharmacy, Dublin.

In Ireland, it is estimated that the diagnosed prevelance of HIV in adults aged 17-78 is approximately 1 in 1000, rising to 2 in 1000 in Dublin. In 2012, 341 people were diagosed with HIV in Ireland, an increase of 7% compared with 2011 figures. To the end of 2012, 6,629 people have been diagnosed with HIV in Ireland since its discovery, but this number does not accurately represent the number of people living with HIV in Ireland, as it does not take factors such as death and migration into account. The number of people living with HIV in Ireland is, thus, not known. A recent study found that 3,254 patients accessed HIV outpatient care in six centres in Ireland over a twelve-month period from 2009-2010. The approximate male-female ratio of newly diagnosed patients for 2011 and 2012 is 2.5.2 3 While it is imprudent to categorise HIV patients, knowledge of the method of contraction may allow subsequent counselling and education to be tailored to the patient’s circumstance. Male to male transmission is the predominant mode of transmission in Ireland, accounting for 49% of the total number of diagnoses in 2012, as the figure below illustrates.

Issue 9 • HPN

Figure 1

Figure 1 Probable Mode of Transmission of HIV in Newly Diagnosed Patients in 2011/12 in Ireland 8

Unknown

Mode of Transmission

The global impact of AIDS (Acquired Immune Deficiency Syndrome) and its causative agent HIV (Human Immunodeficiency Virus),since their discovery in 1981 and 1983 respectively, has been well documented. Needless to say, HIV infection/AIDS is a global pandemic, with an estimated 34.2 million people living with HIV in 2011, of which 2.5 million people were newly diagnosed.i

Mother to Child

1 1 4

IDU

17

2012 2011

5

He terosex ual

34

38

MSM

43 0

10

20

30

40

49

50

60

% Patients

Note

1) MSM – Men who have sex with men 2) IDU – Intravenous drug users 1) MSM – Men who have sex with men 3) Of the five Mother to child transmission (MTCT) cases newly diagnosed, 2) IDU – Intravenous drug users the probable countries of infection for all cases were in sub‐ Saharan Africa. No 3) Of the five Mother to child transmission (MTCT) cases newly diagnosed, the probable countries of infection for all cases were MTCT cases were identified in children born in Ireland in 2012. Error! Bookmark in sub-Saharan Africa. No MTCT cases were identified in children born in Ireland in 2012. not defined. The recent advent of highly active antiretroviral therapy (ART), first touted in 1996, has rendered the disease a chronic medical Note

condition; the majority of patients living with HIV in developed countries can live relatively normal lives.i

The recent advent of highly active antiretroviral therapy (ART), first touted in 1996, has rendered the disease a chronic medical condition; the majority of patients living with HIV in developed countries can live relatively normal lives.i


33 Disease Overview: The pharmacist’s role in HIV treatment shouuld extentd beyond the pharmacology of the antiretrovial drugs used in clinical practice. A hollistic approach to the patient’s needs should be adopted. The pharmacist should first be cognizant of the clinical particulars of HIV, including pathophysiology, clinical presentation and diagnosis. HIV is a single stranded RNA retrovirus. Extracellular virions enter their target cell via a three step process – Attachment to the CD4 receptor, Binding to the CCR5/CCXCR4 co-reeptors, or both, Membrane fusion.4 The hallmark of HIV is a profound immunodeficiency resulting primarily from a progressive quantitative and qualitative deficiency of the subuset of T lymphocytes. This cell mediated immune deficiency renders the host vulnerable to infections with intracellular pathogens, while the concurrent coexisting antibody abnormalities predispose to infections with encapsulated bacteria. The risk of HIV transmission is highest – in the first few weeks of infection, before and around seroconversion (the development of detectable antibodies to microorganisms in the blood serum), when plasa RNA levels are high. In older patients, rapid progression may occur, the virus continues to replicate and the person remains infectious; in advance disease as the viral loada increases.1 In this case, CD4 cell count may fall from normal values of 500-1000 cells/µL to below 350 cells/µL.5(A CD4 count of fewer than 200 cells/mm3 is one of the criteria for a diagnosis of AIDS: As the CD4 cell count falls, there is a corresponding risk in HIV-associated diseases such as cytomegalovirus infection, Kaposi’s sarcoma, HIV encephalopathy, herpes simples, pneumocystis pneumonia, and cerebral toxoplasmosis.) In other words, a patient can be HIV positive, without evincing or developing any AIDS like symptoms. The viral load estimates the amount of circulating virus in the blood plasma. This has been proven to to correlate with prognosis, with a high viral load prediciting faster disease progression.6 a

Presentation: Primary HIV infection is often asymptomatic, with the majority of patients oblivious to seroconversion. Up to 50% of patients may experience flu-like symptoms 2-4 weeks after infection, but these tend to resolve

spontaneously. Upon resolution of theses primary symptoms, the infected patient enters a clinically asymptomatic phase, which may persist for a median of 10 years.1

involvement; those with HIV presenting with either and AIDS defining infection, a serious bacterial infection, and a CD4 cell count < 200 cells/µL.10 1

Diagnosis: Early diagnosis is imperative, as late diagnosis has been assoicated with increased morbidity and mortality, impaired response to antiretrovial therapy, and increased cost to the healthcare system.1 There were approximately 175,000 HIV tests carried out in Ireland in 2012 in 10 locations nationwide, (under the purview of the National Virus Reference Laboratory – NVRL) corresponding to 38 tests per 1000 population, compared with 8.3 in Poland (lowest) and 98.3 in Austria (highest). It is important to note that the calculated testing rates are likely to over-estimate the true rate of testing in the population as the numbers reported are not of individuals who have been tested but of tests performed. This includes repeated tests on the same individual. The number of female patients tested was almost double that of male patients as this reflects the HIV voluntary antenatal screening programme, which is in place in all maternity units in Ireland, introduced in 1999.2

Life expectancy of HIV patients being treated with ARTs: A UK study has demonstrated that life expectancy for those with HIV has increased by 15 years since the advent of ART in 1996, but remains 13 years less than those not afflicted with the condition. The study concludes that ART intervention at the earliest possible time will further increase life expectancy.11

HIV is diagnosed by a positive result of HIV antibody screening test or a combined screening test (HIV antibody and HIV p24 antigen), and confirmed by a more specific antibody test such as the Western blot.1 An HIV test may yield a false-negative result in the acute infection phase (1-3 weeks post exposure), thus, repeat test at 6 and 12 weeks should be conducted. Confirmation of HIV requires two positive results on two separate samples, and the Department of Public Health must be notified of all newly diagnosed HIV cases.7 Pharmacological management: healthcare of only one patient with HIV, and that related to a non-HIV health issue. Recovering IDU who require methadone therapy may indeed be HIV positive, but this fact may not necessarily be disclosed to the pharmacist. The pharmacist, however, should have a working knowledge of the drugs that comprise HAART, and the pharmacological, pharmacodynamic and practical issues associated with such therapy. The British HIV association currently recommend the initiation of HAART therapy for patients with a CD4 count ≤ 350 cells/µL; those presenting with an HIV-associated disease, regardless of CD4 cell count;, those presenting with a HIV infection with neurological

Pregnancy: ART during pregnancy has effectively eliminated mother to child transmission in the developed world.1 The therapy should be initiated at least by the second trimester, and therapy continued after birth.10 Serodiscordant relationships: This defines a relationship where one partner is HIV positive, and the other HIV negative. WHO now recommends that HIV positive partners in such couples should receive ART for regardless of their respective CD4 T-cell count.12 ART intervention in this regard reduces the rate of transmission of HIV by 96%.13 Treatment Failure: Virological treatment failure is generally defined as persistent detectable plasma HIV-RNA concentrations 16-24 weeks post treatment. Treatment failure can nominally be attributed to non-adherence or inherent drug resistance1, and should trigger a full review and/ or overhaul of the entire treatment regimen. ART agents and their practical implications: HIV treatment is an ever-evolving facet of medicine, but treatment principles should, where possible, adhere to the following paradigm – A combination of three or more antiretroviral agents should be prescribed to optimise efficacy and minmise the risk of resistance. Include a drug that penetrates the central nervous system and confers protection against HIV related encephalopathy/dementia. The regimen should be tailored to the lifestyle of the patient, where optimum adherence be prioritised. ART drugs are classified according to the stage at which they inhibit the viral life-cycle. To limit resistance, three active drugs are prescribed concurrently. Over the past decade, there have been numerous advances in HIV therapy, with 6 drug classes comprising 24 individual antiretroviral agents now available. Conventionally the patient is

commenced on a combination of two nucleoside/nucleotide reductase inhibitors (NRTIs – e.g. abacaivir, didanosine) and a third drug, a protease inhibitor (PI – e.g. atazanavir, indinavir), a non-nucleoside reductase inhibitor (NNRTIs – e.g. efavirenz, etravirine) or an integrase inhibitor (raltegravir). Recent studies have touted the use of three NRTI therapy9, but the treatment can be tailored to the individual patient depending on initial viral load, optimum adherence, minimum adverse events, and limit resistance. The aim of the initial therapy is to achieve viral load suppression in the plasma to levels below the detection limits of available assays. The list of ART agents is evolving and certainly not exhaustive. Newer agents such as CCR5 inhibitors (maraviroc), or entry inhibitors (enfuvirtide) have been introduced and highlight the advancement being made in HIV therapy. The latter has been recommended as a second-line treatment for those who have failed or cannot tolerate other regimens. The expanding HIV formulary gives hope to patients upon diagnosis that a treatment can be determined to allow them to live relatively full lives, albeit with a chronic medical condition requiring their full attention. The radiostation Newstalk conducted an interview with a HIV patient on their breakfast show of 24rd June. The patient, a middle-aged, professional gay man, recalls his life expectancy was estimated at two years upon initial diagnosis in the mid 90s, but this ‘deathsentence’ has been stayed, his life reprieved as a result of the advent of ARTs, and their relative ease of access in Ireland. Education played a role in his survival and relative vitality since his diagnosis, but this will be touched upon later. Drug Interactions: HIV patients may be managed by non-HIV healthcare professionals for co-morbid conditions, hence it behoves the pharmacist to become cognizant of all medicines the patient is prescribed (including herbal remedies). The pharmacist should educate themselves and the patient on the possibility of interactions, and foster good communication with the entire healthcare team. The patient should be advised on the dangers of interactions with OTC medicines and recreational drugs also. Clinically important drug interactions to consider when co-administering with ART (whether CYP-mediated or otherwise) include methadone, oral contraceptives, antiepileptics, antidepressants, lipid-

HPN • Issue 9


34 Acquired Immune Deficiency Syndrome

lowering agents, proton-pum inhibitors, antimicrobials such as clarithromycin, antiarrhythmics, TB therapies, anticancer drugs, immunosuppressants, phospodiesterease inhibitors and hepatitis C virus therapy.1 The majority of these interactions may be considered minor, but such is the nature of the interaction, co-administration of the following should be avoided – ribavarin/ zidovudine; atazanavir/proton pump inhibitors; protease inhibitors/rifampicin; protease inhibitors/dabigatran/rivaorxaban; protease inhibitors/triazoloam. In this manner, it is imperative that the pharmacist maintains clinical vigilance when presented with a HIV patient. Pharmacists’ involvement in the care of HIV-positive patients has been associated with improved patient outcomes, including enhanced adherence, reduced bill burden and dosing frequency, greater increases in CD4 cell count, higher rates of viral suppression, and decrease in medication errors.14 Pharmacists should adhere to the old adage ‘treat the patient, not the disease’ when presented with a HIV patient. Patients have specific needs, characteristics and idiosyncrasies to consider, such as the sexual preference, recreational drug use, drug addiction, blood disorders, asylum seekers, pregnancy and/ or paediatric considerations. The patient may require medication to cope with the trauma of diagnosis, hence the pharmacist should approach this delicately, form both a pharmacological and emotional perspective. The pharmacist may be the first health professional to which the patient discloses their condition, so the pharmacist must render practical, psychosocial, and emotional support. Firstly, the pharmacist should set aside any entrenched negative views he/ she may have regarding HIV and the stigma attached to it, lending professional, objective, nonjudgemental support to the patient. The patient should be immediately linked to the nearest, most appropriate HIV clinic. The patient should be educated about lifestyle factors, and their responsibilities. The patient must be empowered to participate in their own health care decision-making, but also be aware of the wider impact of neglecting their disease or treating it with undue respect. The patient has a responsibility and obligation

Issue 9 • HPN

to protect their loved ones and how must be informed how their actions may have consequences for the society at large. Pharmaceutical Care: The pharmaceutical care of patients with HIV, as mentioned above, pertains to polypharmacy, adverse drug reactions, new drugs, drug interactions, and adherence. Paediatric patients: Setting aside normal pharmacological, formulation and taste related issues, a potential barrier to adherence within this subpopulation is the uniquely paediatric concept that some patients may not be aware of their HIV diagnosis. This presents practical and ethical issues to the pharmacist. Disclosure is typically a gradual process, initiated by the parents (at their discretion) and incremented and staggered over time until the patient’s parent or caregiver deems that the child is sufficiently mature to grasp the full significance of the diagnosis. While being oblivious to a serious, chronic illness may be beneficial to the child, allowing them to enjoy relatively normal formative years, there may in turn be a negative impact on adherence, as the child not acutely aware of the disease. However, to prevent disclosure of diagnoses to people outside the family through identification of medications, practical dosing schedules need to be designed that avoid administration of ARTs

during daycare or school hours, if appropriate.14 • Become more engaged in therapeutic dosage monitoring in the pharmacy. This may be more consigned to the HIV clinic, but the longer opening hours make the community pharmacy a more attractive and convenient treatment centre. Pharmacists should engage in suitable education programmes, especially relating to the implications of exposure, and post-exposure prophylaxis. • Become more proactive in the provision of education and literature in the community, such as hosting educational evenings, or lectures in the area. • Be informed on all new HIV therapies and their role within treatment regimens, interactions and adverse effects. References 1. National Medicines Information Centre Publication 2012 Human Immunodeficiency Virus Infection Vol 18, number 4 2. HPSC Report 2012 HIV in Ireland, published May 2013 3. HSPC Report 2011 HIV in Ireland, published May 2012 4. Volberding P, Deeks S 2010 Antiretroviral therapy and the management of HIV infection Lancet 376: 49-62 5. Official U.S. government publication www.aids.gov/hiv-aidsbasic; last revised Nov 2010

6. Mellors J, Munoz A, Girogi J V 1997 Plasma viral load and CD4 lymphocyctes as prognostic markers of HIV-1 infection Annals of Internal Medicine 126: 946-954 7. A working group for the National AIDS Strategy Committee, HIV notification – information for professionals June 2012. Sourced from www.hpsc.ie 8. National AIDS Strategy Committee’s HIV and AIDS Education and Prevention Plan 2008- 2012 Living with HIV in Ireland: A self-help guide 1: 6-7 9. Walker R, Edwards C 2004 Clinical pharmacy and therapeutics Churchill Livingston 3rdEdition 39: 597-622 10. Thompson M, Aberg J, Cahn P et al 2012 Antiretroviral treatment of adult HIV infection Journal of the American Medical Association 304(3): 321-333 11. Mat M et al 2011 Impact of late diagnosis and treatment of life expectancy in people with HIV-1 UK Collaborative HIV Cohort (UK CHIC) Study, BMJ Oct 2011; 343: d6106 12. World Health Organization April 2012 Guidance on Couples HIV Testing and Counselling, Including Antiretroviral Therapy for Treatment and Prevention in Serodiscordant Couples. 13. Cohen M 2011 Prevention of HIV-1 infection with early antiretroviral therapy New England Journal of Medicine 365(6): 493-505 14. Tseng A, Foisy M, Hughes C A, et al 2012 Role of the Pharmacist in Caring for Patients with HIV/AIDS: Clinical Practice Guidelines Canadian Journal of Hosptial Medicine 65(2): 125–145


NEW

A NEW FACE IN

2nd-LINE mRCC TREATMENT

MONTHS MEDIAN PFS VS 4.7 MONTHS FOR SORAFENIB1 INLYTA® is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) after failure of prior treatment with sunitinib or a cytokine 1 PRESCRIBING INFORMATION Inlyta (axitinib) Film-Coated Tablets Please refer to the Summary of Product Characteristics (SmPC) before prescribing Inlyta 1 mg or 5 mg film-coated tablets. Presentation: Each 1 mg and 5 mg film-coated tablets contain 1 mg and 5 mg of axitinib. Indications: For the treatment of adult patients with advanced renal cell carcinoma (RCC) after failure of prior treatment with sunitinib or a cytokine. Dosage: Treatment should be initiated by a physician experienced in the use of anticancer therapies. The recommended starting oral dose is 5 mg twice daily (approximately 12 hours apart) taken with or without food. Dose increase or reduction is recommended based on individual safety and tolerability. Patients who tolerate the starting dose of 5 mg twice daily with no adverse reactions > Grade 2 according to Common Terminology Criteria for Adverse Events (CTCAE) for two consecutive weeks may have their dose increased to 7 mg twice daily unless BP > 150/90 mmHg or patient is receiving anti-hypertensive medication. Subsequently, using the same criteria, patients who tolerate a dose of 7 mg twice daily, may have their dose increased to a maximum of 10 mg twice daily. Management of some adverse drug reactions may require temporary or permanent discontinuation and/or dose reduction. When dose reduction is necessary, the dose may be reduced to 3 mg twice daily and further to 2 mg twice daily. Co-administration with strong CYP3A4/5 inhibitors or inducers may increase or decrease axitinib plasma concentrations respectively. Selection of an alternative concomitant medicine with no or minimal CYP3A4/5 inhibition or induction potential is recommended. If a strong CYP3A4/5 inhibitor must be coadministered, a dose decrease of axitinib to approximately half the dose (e.g. from a starting dose of 5 mg twice daily to a reduced dose of 2 mg twice daily) is recommended. If co-administration of the strong inhibitor is discontinued, a return to the axitinib dose used prior to initiation of the CYP3A4/5 inhibitor should be considered. If a strong CYP3A4/5 inducer must be co-administered, a gradual dose increase is recommended with careful monitoring for toxicity. If coadministration of the strong inducer is discontinued the axitinib dose should be immediately returned to the dose used prior to initiation of the strong CYP3A4/5 inducer. No dose adjustment is required in elderly patients or patients with renal impairment or with mild hepatic impairment (Child Pugh class A). A dose decrease is recommended in patients with moderate hepatic impairment (ChildPugh class B) (e.g. the starting dose should be reduced from 5 mg twice daily to 2 mg twice daily). Axitinib has not been studied in patients with severe hepatic impairment (Child-Pugh class C) and should not be used in this population Dose adjustment is not required on the basis of patient age, race, gender, or body weight. The safety and efficacy of axitinib in children (<18 years) have not been established. Contra-indications: Hypersensitivity to axitinib or to any of the excipients. Special warnings and precautions for use: Blood pressure should be well-controlled prior to initiation. Patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In the case of persistent hypertension despite use of anti-hypertensive medicinal products, the axitinib dose should be reduced. For patients who develop severe INL/2012/004 Date of Preparation: October 2012

hypertension, temporarily interrupt axitinib and restart at a lower dose once the patient is normotensive. If axitinib is interrupted, patients receiving antihypertensive therapy should be monitored for hypotension. In case of severe or persistent arterial hypertension and symptoms suggestive of posterior reversible encephalopathy syndrome, a diagnostic brain MRI should be considered. Thyroid function should be monitored before initiation of, and periodically throughout, treatment. Hypothyroidism and, to a lesser extent, hyperthyroidism were reported in clinical studies and should be treated as per standard medical practice to maintain a euthyroid state. Arterial embolic and thrombotic events (including transient ischaemic attack, myocardial infarction, cerebrovascular accident and retinal artery occlusion) and venous embolic and thrombotic events (including pulmonary embolism, deep vein thrombosis, and retinal vein occlusion/thrombosis) were reported in clinical studies and axitinib should be used with caution in patients at risk of or who have a history of these events. Increases in haemoglobin or haematocrit, reflective of increase in red blood cell mass may occur during treatment and should be monitored before initiation of, and periodically throughout, treatment and treated as per standard medical practice. An increase in red blood cell mass may increase the risk of embolic and thrombotic events. Haemorrhagic events (most commonly epistaxis, haematuria, rectal haemorrhage and gingival bleeding) were reported in clinical studies. Axitinib has not been studied in patients who have evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. Temporarily interrupt treatment if any bleeding requires medical intervention. Events of gastrointestinal perforation and fistulas were reported in clinical studies and symptoms for these should be monitored periodically throughout treatment. Treatment with axitinib should be stopped at least 24 hours prior to scheduled surgery and the decision to resume therapy after surgery should be based on clinical judgment of adequate wound healing. Events of posterior reversible encephalopathy syndrome, PRES (a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances; mild to severe hypertension may be present) were reported in clinical studies. MRI is necessary to confirm diagnosis. In patients with signs or symptoms of PRES, temporarily interrupt or permanently discontinue axitinib treatment. The safety of reinitiating therapy in patients previously experiencing PRES is not known. Proteinuria, including that of Grade 3 severity, was reported in clinical studies. Monitoring for proteinuria before initiation of, and periodically throughout, treatment with axitinib is recommended. In moderate to severe proteinuria reduce the dose or temporarily interrupt treatment. Increases in ALT, AST and bilirubin have been reported. Liver function tests should be monitored before initiation of, and periodically throughout, treatment. Systemic exposure to axitinib was approximately two fold higher in subjects with moderate hepatic impairment (Child-Pugh class B) compared to subjects with normal hepatic function. In these patients dose decrease is recommended (see Dosage section). Axitinib has not been studied in patients with severe hepatic impairment (Child Pugh class C) and should not be used in these patients. Contains lactose and patients with rare hereditary problems of

galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. Other interactions: Axitinib is metabolised primarily by CYP3A4/5 and, to a lesser extent, CYP1A2, CYP2C19, and uridine diphosphate-glucuronosyltransferase (UGT) 1A1. If a strong CYP3A4/5 inhibitor (e.g. itraconazole, clarithromycin, erythromycin) or inducer (rifampicin, dexamethasone phenytoin, and Hypericum perforatum [St. John’s wort]) must be co-administered, a dose adjustment of axitinib is recommended (see Dosage section). In patients taking strong inhibitors of CYP1A2 and CYP2C19 caution should be exercised due to the risk of increased axitinib plasma concentrations. Smoking is a CYP1A2 inducer and the risk of decreased axitinib plasma concentrations should be considered. Fertility, pregnancy and lactation: Axitinib may cause foetal harm when administered to a pregnant woman. Studies in animals have shown reproductive toxicity including foetal malformations. Axitinib should not be used during pregnancy unless the clinical condition of the woman requires treatment. Axitinib should not be used during breast-feeding and women of childbearing potential must use effective contraception during and up to 1 week after treatment. Fertility may be impaired during treatment. Driving and operating machinery: No studies have been performed. Advise patients that they may experience dizziness and/or fatigue during treatment. Undesirable effects: The most important serious adverse reactions reported in patients receiving axitinib were arterial embolic and thrombotic events, venous embolic and thrombotic events, haemorrhage (including gastrointestinal haemorrhage, cerebral haemorrhage and haemoptysis), gastrointestinal perforation and fistula formation, hypertensive crisis, and PRES. Very common (≥ 1/10) adverse events are hypothyroidism, decreased appetite, headache, dysgeusia, hypertension, haemorrhage (epistaxis, haematuria, rectal haemorrhage, gingival bleeding), dysphonia, diarrhoea, vomiting, nausea, stomatisis, constipation, palmar-plantar erythrodysaesthesia (hand-foot syndrome), rash, dry skin, proteinuria, fatigue, asthaenia, mucosal inflammation, weight decreased. Common (≥ 1/100 to < 1/10) reported adverse events are anaemia, thrombocytopenia, dehydration, dizziness, tinnitus, venous and arterial embolic and thrombotic events, dyspnoea, cough, oropharyngeal pain, abdominal pain, upper abdominal pain, dyspepsia, flatulence, haemorrhoids, pruritus, erythema, alopecia, myalgia, arthralgia, pain in extremity, renal failure, thyroid stimulating hormone increased, lipase increased, and ALT, AST, alkaline phosphatase and amylase increased. Refer to SmPC for information on other adverse effects. Legal Category: S1A Marketing Authorisation Number: EU/1/12/777/002 - 1 mg (56 tablets); EU/1/12/777/005 - 5 mg (56 tablets) Marketing Authorisation Holder: Pfizer Limited, Sandwich, Kent, CT13 9NJ, United Kingdom. Further Information is available on request from: Pfizer Healthcare Ireland, 9 Riverwalk, CityWest Business Campus, Dublin 24, Ireland. Last revised: September 2012. Ref: IL 1_0. References: 1. INLYTA® Summary of Product Characteristics. September 2012.


36 Arthritis

New developments on psoriasis and psoriatic arthritis Written by, Kay McNamee PhD; Fiona McCann PhD The Kennedy Institute of Rheumatology - Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, UK.

Taking cues from the largely successful treatment of rheumatoid arthritis (RA) with tumor necrosis factor alpha (TNFα) blockade, the treatment of psoriasis and psoriatic arthritis (PsA) has been vastly improved in recent years with the development of biologic therapies that target important inflammatory proteins pivotal for disease progression. Whilst efficacious for a substantial number of patients, a number of drawbacks with this course of therapy prevail. High on the list is the necessary route of administration; biologics must be delivered either intravenously or subcutaneously, mostly requiring regular visits to the clinic for dosing. This inconvenience to the patient, coupled with the relatively high manufacturing costs of biologics, drives continued research and the development of improved, orally available therapies that limit disease progression without impacting on patient lifestyle and well-being. This review provides an overview of the current therapies for psoriasis and PsA, and the future prospects for new drugs in the pipeline, with special attention given to apremilast (Celgene Corporation, Summit, NJ, USA), a novel, orally available phosphodiesterase 4 (PDE4) inhibitor, which is now in Phase III clinical trials. Psoriasis is a chronic immune skin disorder that affects 1%–3% of the world’s population. Often linked with genetic and environmental triggers,1,2 it is characterized by hyperpro-liferation of the skin’s epidermal layer, which is attributed to premature maturation of keratinocytes and dermal inflammatory infiltrates comprising dendritic cells, macrophages and T cells.1,2 Affecting 85%–90% of patients, the most prevalent form of psoriasis (psoriasis vulgaris) results in the occurrence of raised plaques with silvery scales that can present on any part of the skin, but are most

Issue 9 • HPN

FIGURE 1

commonly found on the scalp, back, and the extensor surfaces (elbows and knees) (Figure 1).2,3 While approximately one-third of patients go on to develop PsA, up to 20% of PsA sufferers develop arthritic symptoms prior to plaque formation.4,5 PsA presents additionally with joint inflammation and synovitis, but it is distinct from related joint disorders like RA through the inclusion of enthesitis, dactylitis, and spinal involvement (Figure 1), and it is better characterized as a spondyloarthropathy disorder.4,6 Psoriasis and PsA patients often have a poor quality of life,2 and both diseases have a considerable impact on the economy, with the National Psoriasis Foundation (USA) estimating the direct and indirect costs at over US $11 billion annually.7 Unsurprisingly, the effective management of psoriasis and PsA is largely dependent on the severity of the disease. Mild psoriatic plaques can be successfully treated topically, with corticosteroids, emollients, coal tar preparations, or vitamin D analog.5 For moderate to severe disease, systemic treatments are employed. Initially, patients are often treated with oral therapies such as methotrexate, cyclosporine, and sulfasalazine.5,6,8 Failure to respond to these agents can lead to the patient being placed on a biologic, most commonly an anti-TNFα inhibitor (Table 1). Anti-TNFα biologics have been highly successful in the treatment of psoriasis and PsA, with efficacy measured using the Psoriasis Area and Severity Index (PASI). The PASI assesses psoriatic disease by assigning an ascending score to plaques of increasing severity (thickness, redness, and scaling) and the extent of the plaque spread. Psoriasis patients

typically achieve a 75% reduction compared to baseline PASI (PASI75) in ~70%–80% of cases that are treated with either adalimumab or infliximab. Similarly, ~59%–68% of PsA patients receiving either agent reach PASI-75.5,6,8,9 Despite the clear efficacy of anti-TNFα biologics, not all patients respond adequately to treatment. New biologic targets are now being evaluated in the clinic to address this, with a recent focus on targeting Th17 cells (Table 1). Th17 cells are T helper cells defined by their production of interleukin (IL)-17 and require IL-23 for their maintenance.10 Brodalumab (Amgen Inc, Thousand Oaks, CA, USA), ixekizumab (Eli Lilly and Company, Indianapolis, IN, USA), and secukinumab (Novartis Corporation, Basel, Switzerland) are antagonistic antibodies that target IL-17. All have demonstrated efficacy in their initial drug trials, and they are currently being studied in Phase III trials for the treatment of psoriasis and PsA.11–14 Targeting related pathways, briakinumab (Abbot Laboratories, Abbott Park, IL, USA) and ustekinumab (Janssen Biotech, Inc, Horsham, PA, USA) inhibit the IL-12/IL-23p40 subunit, and have completed Phase III trials for psoriasis and are currently being evaluated in PsA.15–19 Notably, results

from an additional 12-week trial suggested that psoriasis patients receiving either ustekinumab or briakinumab had a higher clinical response than patients receiving etanercept,20–22 suggesting that these emerging biologics may challenge the dominance of anti-TNFα in psoriasis and PsA if their long-term safety profile is acceptable. A major disadvantage with biologic therapies is that they must be delivered either subcutaneously or intravenously, and they are expensive, with the cost per patient ranging between US $15,000–$30,000+ per year.23 Thus, there is a significant need for more cost-effective drugs that can be orally administered that influence proinflammatory cytokines. Small molecular weight inhibitors (SMI compounds with a molecular weight of less than 1 kDa), have been much explored for their potential to treat autoimmune disorders, with manufacturing costs projected to be significantly less expensive than biologics.24 The SMI currently being investigated in inflammatory diseases are largely targeted to intracellular signaling pathways, the most explored of which target kinases. Imperative for cellular processes, kinases are attractive


37

targets as they often act upstream of inflammatory mediators such as TNFα, and hence selective blockade can regulate multiple inflammatory processes.25 Although many novel kinase inhibitors have been developed in recent times, few have progressed through the clinic. Of these, tofacitinib (Pfizer, Inc, New York, NY, USA) is an oral Janus kinase (JAK) inhibitor that has proven to be efficacious in moderate to severe plaque psoriasis over a 12-week treatment period and is currently in Phase III trials.26,27 Tofacitinib is also in Phase IIb trials for PsA after its success in trials with RA patients who had previously failed to respond to biologics;28 however, concerns were raised over toxicity when four patients enrolled in the RA Phase III multicenter studies died, where one of these deaths due to respiratory failure was attributed to the drug.29 Adding to the concern, a recent study has suggested a link between tofacitinib and reactivation of tuberculosis in a mouse model, further highlighting the need for more thorough investigation into its safety.30 Another oral JAK1/2 inhibitor, baricitinib (Eli Lilly and Company; Incyte Corporation, Wilmington, DE, USA), is currently being evaluated in a Phase IIb study for patients with moderate to severe psoriasis, and primary results are expected in 2013.31 PDE4 INHIBITION AND APREMILAST Although research for oral treatments has been largely dominated by kinase targets, other SMI-targeting alternative pathways are in development, including those designed to inhibit PDE4. Phosphodiesterases comprise a family of enzymes that uniquely hydrolyse and degrade cyclic adenosine monophosphate (cAMP). One of eleven subtypes, PDE4, is widely expressed in numerous cell types, including hematopoietic cells, keratinocytes, endothelial cells, as well as muscle and nerve cells.32,33 Amongst its various cellular functions, including roles in apoptosis and lipid metabolism, PDE4 regulates immune and inflammatory processes through

control of intracellular cAMP levels and downstream protein kinase A pathways.34 In turn, the production of a number of key inflammatory cytokines by myeloid and lymphoid cells is affected, shaping the immune response accordingly. Specific inhibition of PDE4 in human peripheral monocytes by a number of agents causes decreased production of LPSinduced TNFα.35 Monocytes and macrophages chronically treated with ethanol showed increased expression of PDE4B, reduced expression of cAMP, and increased nuclear factor kappa beta (NFκB) signaling, ultimately leading to an increase in lipopolysaccharidestimulated TNFα production. This effect was abolished by the addition of the classical PDE4 inhibitor, rolipram, highlighting the potential of this class of drug to control NFκB-mediated immune processes.36 Intriguingly, such effects are not restricted to the control of proinflammatory mediators. Inhibition of PDE4 has been demonstrated to elevate the anti-inflammatory cytokine IL-10 via protein kinase A-mediated protein interactions with cAMP response elements in the promoter and enhancer regions of the IL-10 gene.37,38 Thus, the outcome of limiting PDE4 activity is contextually dependent on effector gene expression and the proximity of NFκB or cAMP response elements in promoter regions. Additionally, PDE4 activity augments effector function in lymphocytes and neutrophils. Inhibition with rolipram suppresses antigen-induced T cell proliferation and cytokine production,39 while PDE4 inhibition decreases the production of IL-8, a major chemoattractant for neutrophils. Furthermore, PDE4 increases expression of the B2-integrin Mac-1 on neutrophils, associated with activation and extravasation across endothelial linings.33 Thus, the potential of a selective PDE4 inhibitor to control unwarranted immune responses, pertinent to autoimmunity, is clear. Many of the cytokine mediators of psoriasis and PsA are influenced by PDE4 activity; therefore, specific inhibitors could be beneficial, as previously

reviewed.40,41 Celgene has developed apremilast (CC-10004; Celgene Corporation), a novel, orally available small molecule that specifically targets PDE4. Effects on lipopolysaccharidestimulated human peripheral blood mononuclear cells demonstrated the attenuation of a number of cytokines including IFNγ, TNFα, IL12, and IL-23, and the chemokines CXCL9 and CXCL10.41 Importantly, this study has also demonstrated the potential of apremilast to restrict TNFα production from keratinocytes and natural killer cells, the major constituent of psoriatic skin lesions.40,42 Recently, in vivo experiments conducted in a classical preclinical model of psoriasis, using normal human skin xeno-transplanted onto severe combined immunodeficiency mice, injected with human natural killer cells from psoriatic donors, strongly support a therapeutic role for PDE4 blockade. Orally administered apremilast significantly reduced epidermal thickness and decreased histopathological features of psoriasis plaques.41 While many mouse models of psoriasis have been described,43 an equivalent model for PsA combining skin lesions and spondyloarthropathies has not been described. However, the therapeutic effect of apremilast and other PDE4 inhibitors has been tested in human rheumatoid synovial cells and in animal models of arthritis.44,45 Inhibitory effects on the spontaneous production of TNFα, IL-1b, and chemokines MCP-1, MIP-1α, MIP-1β, and RANTES from RA synovial cells were observed in the presence of roflumilast (Takeda Pharmaceutical Company Limited, Osaka, Japan) and two novel PDE4 inhibitors (INH0061 and INH0062; GlaxoSmithKline Inc, London, UK). Similarly, at 0.25 nM to 100 nM concentrations, apremilast dose-dependently inhibited the spontaneous production of TNFα from RA synovial membrane cultures, showing a similar efficacy to the classic PDE4 inhibitor, rolipram.45 In classical collageninduced arthritis in dilute brown non-agouti/1 (DBA/1) mice, clinical and histopathological signs of

disease were reduced with daily intraperitoneal injections of 5 mg/ kg or 25 mg/kg. Such effects were reproduced in an alternative model of collagen antibodyinduced arthritis in BALB/c mice, receiving an oral dose of 25 mg/kg apremilast daily. ASSESSMENT OF APREMILAST IN THE CLINIC Having demonstrated the capacity to suppress TNFα in vivo, and indications that it was well tolerated by naïve mice in terms of lethargy relative to those dosed with rolipram,45 apremilast held significant promise when entering Phase II clinical trials. Since the early development of PDE4 inhibitors, one of the main concerns has been the associated adverse events (AE). These side effects tend to primarily affect the gastrointestinal system, resulting in nausea and emesis, as well headaches.34 It has been shown that these AE are a result of the inhibition of the PDE4D isoform.46 Interestingly, apremilast does not selectively inhibit any specific isoform of PDE4,47 but it does appear to be void of these typical complications, and the majority of reported AE are classed as “mild to moderate” by investigators. The total number of clinical trials involving apremilast currently stands at 39. These include small Phase I trials and pilot studies investigating efficacy in a number of conditions including atopic dermatitis, erythematotelangiectatic rosacea, acne, acute gout, uveitis, vulvodynia, and prurigo nodularis.48 Nine studies have published their results and are summarized in Table 2. There are a total of four published trials assessing the efficacy of apremilast in psoriasis or PsA, which we will look at in this review. Amongst the completed Phase II trials, three stand out due to the substantially higher number of enrolled participants, exceeding 200 in each study. These trials were well conducted and contained patients displaying similar demographic and baseline characteristics between the randomized groups. Strikingly, all three have yielded positive

HPN • Issue 9


38 Arthritis Table 1 Summary of current biological therapies for the treatment of moderate to severe psoriasis and PsA

Drug

Treatment

Mechanism of action

Efficacy

Safety

Anti-TNF

Adalimumab

PsA 40 mg SC every other week, psoriasis 80 mg SC at week 0; 40 mg SC every other week thereafter5

Fully human monoclonal antibody

PASI-75 achieved in 71% of psoriasis and 59% of PsA patients. PsA ACR20 achieved in 58%5

Etanercept

PsA 25 mg SC twice a week. Psoriasis 50 mg SC twice weekly for 3 months, 50 mg/week thereafter5

Fusion protein to link TNF receptor to the Fc component of human IgG

PASI-75 achieved in 49% of psoriasis and 26% of PsA patients. PsA ACR20 achieved in 59%5

Golimumab

PsA 50 mg SC every month5

Human monoclonal antibody (2-week half-life) Phase II trials for psoriasis

PASI-75 achieved in 58% of psoriasis and 58% of PsA patients. PsA ACR20 achieved in 5I%5

Infliximab

PsA and psoriasis 5 mg/kg Chimeric (mouseat weeks 0, 2, and 6, and at human) monoclonal every 8 weeks thereafter5 antibody

PASI-75 achieved in 80% of psoriasis and 68% of PsA patients. PsA ACR20 achieved in 58%5

Association with increased prevalence of bacterial, viral, and fungal infections. Reactivation of hepatitis B. Increased tuberculosis recurrence5,6

Anti-IL-17

Brodalumab

Subcutaneous injection

Anti-IL-17 receptor monoclonal antibody

PASI-75 achieved in up to 82% of PsA patients at 12 weeks (placebo, 0%)13

AE reported include nasopharyngitis, injection, nausea, and arthralgia13

Ixekizumab

Subcutaneous injection

Monoclonal anti-IL17 antibody

Up to 82% PASI-75 improvement at 12 weeks (placebo 7.7%)11

AE include infections, headaches, and nasopharyngitis11

Secukinumab Subcutaneous injection

Monoclonal anti-IL-

81.5% achieved PASI-75 ( 150 mg) at 12 weeks

AE include pharyngitis, fatigue, and

Drug

Treatment

Mechanism of action

Efficacy

Safety

17 antibody

(placebo, 9.1%)12

peripheral edema12

Subcutaneous injection

Human monoclonal antibody anti-p40 subunit

Up to 82% achieved PASI 75 (placebo 6%–7%)20,21

AE include nasopharyngitis headache and infections20,21

Ustekinumab Subcutaneous injection

Human monoclonal antibody anti-p40 subunit

Up to 67% achieved PASI75 (placebo 3.1%)17

AE include headache, myocardial infarction, and stroke. Potential increase of latent infection5,17

Anti-IL-12/ IL-23

Briakinumab

Anti-T cell activation

Abatacept

Subcutaneous injection

Fully human CTLA-4- Up to 48% of PsA patients AE include dizziness, headache, and lgG 1 fusion protein achieved ACR20 in Phase II hypertension. Increased risk of that binds trial (placebo, 19%)5 infection5 CD80/CD86

Alefacept

Intramuscular injection 15 mg once weekly for 12 weeks6,34

Inhibits T cell activation and proliferation

Phase III trial; 33% achieved No increased incidence for PASI-75 versus with 13% infections6 placebo. PsA (plus MTX) 54% ACR20 versus MTX alone6,34

Abbreviations: PsA, psoriatic arthritis; SC, subcutaneous; PASI, Psoriasis Area and Severity Index; ACR20, American College of Rheumatology-20; TNF, tumor necrosis factor; IgG, immunoglobulin G; IL, interleukin; AE, adverse events; CTLA-4, cytotoxic T-lymphocyte antigen 4; MTX, methotrexate.

Issue 9 • HPN

results when testing apremilast against placebo, as well as displaying a dose-dependent effectiveness in both psoriasis and PsA.49–51 The first trial of apremilast in the treatment of psoriasis was published in 2008.52 Eight out of the 19 patients receiving apremilast achieved the primary endpoint of a reduction in epidermal thickness of ≤20% (classified as responders), with one other patient reaching a 19.9% reduction. Four other patients experienced reductions of <20%. Accompanying the positive clinical response, a decreased number of T cells and CD11c-expressing cells in the dermis and epidermis was observed in responders, thus illustrating apremilast’s potential biological activity. In this study, 14 of the 19 patients (73.7%) saw an improvement in their disease state according to their PASI score. At least one AE (the most common being nausea and headaches) was observed in 14 patients (73.7%), but most of these were classified as mild by the investigators. While this study involved only a small number of patients, it demonstrates the ability of apremilast to successfully and safely treat psoriasis in some patients. The two largest Phase II trials investigating the effectiveness of apremilast in psoriasis treatment were led by Dr Kim Papp et al.49,50 Each trial has been double-blinded and involved a robust number of participants, 259 and 352 respectively, across multiple sites. The first study was conducted between April 2006 and May 2007 across 30 sites in Canada,50 as well as in the Czech Republic and Germany. The investigators compared apremilast at doses of 20 mg once daily (SID), 20 mg twice daily (BID), and a placebo. Employing the endpoint of PASI-75, only the higher dose (20 mg BID) was significantly more effective than placebo, with efficacy observed in 21 out of 86 patients (24.4%), compared to nine out of 87 patients (10.3%) for both the apremilast 20 mg SID and placebo group. When applying a PASI-50 endpoint, the results of the apremilast 20 mg BID group improved to 49 out of 86 patients (57.0%), and the apremilast 20 mg

SID group to 24 out of 87 patients (27.6%) meeting the target, suggestive of a dose-dependent response. Both treatment regimens provided enhanced efficacy over the placebo where 20 out of 87 patients (23.0%) reached PASI50. No serious AE were seen, and both doses of apremilast were well tolerated. The most common AE recorded were headaches, nasopharyngitis, diarrhea, and nausea. This study clearly demonstrated that apremilast is effective at treating moderate to severe psoriasis. Given that no serious AE were seen with a dose of 20 mg BID, and considering the dose-dependent results that were indicated, Papp et al50 suggested a higher dose could be used in future trials. Following on, the second of Papp et al’s clinical trials,49 which was also conducted across multiple sites in the USA and Canada, investigated a dosing regimen of 10 mg, 20 mg, and 30 mg BID versus placebo in a total of 352 patients suffering from moderate to severe psoriasis. Again, the primary endpoint was PASI-75, but this time the study was extended from 12 to 16 weeks. A total of 6% of the placebo group reached PASI-75 compared to 11%, 29%, and 41% of the 10 mg, 20 mg, and 30 mg groups, respectively. The two highest doses were significantly efficacious when compared to placebo, unequivocally illustrating the dose-dependent characteristics of apremilast as suggested in the first of Papp’s clinical trials. An additional dimension to this trial involved the placebo group being placed on either 20 mg or 30 mg BID of apremilast at week 16 for a further 8 weeks. The improvement in PASI score in these patients was rapid and by week 24 the mean change from baseline was on par with patients that had started treatment with 20 mg or 30 mg BID of apremilast at week 0. Apremilast was effective in reducing disease severity in a number of other measurements, including Dermatology Life Quality Index scores and the Short Form36 mental component summary scores. During the first 16-week period of the trial, 255 out of 352 patients (72.4%) suffered at least


39

one AE, and during the period of weeks 16–24 the ratio changed to 121 out of 280 (43.2%). Of these, most were considered to be mild to moderate. Another encouraging Phase II clinical trial investigating the effect of apremilast in the treatment of PsA was led by Professor Georg Schett in Germany.51 In this trial, 204 patients received either 20 mg BID, 40 mg SID, or placebo. The primary endpoint was the achievement of a 20% reduction in disease according to the American College of Rheumatology criteria (ACR20). In all, 165 patients completed the treatment phase (12 weeks) and 11.8% of the placebo group reached ACR20, compared to 43.5% of the 20 mg BID group and 35.8% of the 40 mg SID group. Further to this, patients that were receiving placebo were then rerandomized at week 12 to receive either 20 mg BID or 40 mg SID of apremilast for another 12 weeks. By week 24 in both apremilast groups > 40% had achieved ACR20. While this data is positive, more trials in PsA are required to assess the limitations of apremilast. When evaluating ACR20, the ratio of success was 11.8%:43.5%:35.8% (placebo:apremilast 20 mg BID: apremilast 40 mg SID) after the treatment phase. Although it is difficult to conclude until a direct comparison is conducted, the success rate of apremilast in this study is less than that observed for anti-TNFα treatment of PsA (51%– 59% meet ACR20; see Table 1), thus highlighting that more needs to be done to establish whether apremilast confers overall benefits compared to currently available biologics.

To date, there are nine Phase III clinical trials underway at several sites, which are due for completion from 2014 onwards (listed in Table 3); the majority of these trials are assessing the effects of multiple doses of apremilast in treating patients with PsA, psoriasis, ankylosing spondylitis (AS), sarcoidosis, and cutaneous sarcoidosis. While this review is focusing on the treatment of psoriasis and PsA, the documented effects of apremilast in the treatment of related autoimmune diseases such as RA and AS are noteworthy. Although three Phase II trials have been registered to assess the safety and effectiveness of apremilast in RA patients, none have so far yielded results. Two trials that were initiated in 2010 (NCT01285310 and NCT01204138) have not yet published the results. Recruitment is ongoing for a third Phase II trial (NCT01250548), and therefore it remains too early to ascertain the efficacy of apremilast in RA.48 Perhaps more akin to PsA is the related spondyloarthropathy, AS. Genetic studies have revealed an association between psoriasis and AS with common susceptibility genes IL-23R, IL-12B, STAT3, and CARD9.53,54 Due to the similarities in genetics and clinical manifestations, it was therefore pertinent to investigate whether apremilast could also be beneficial to AS patients. Most recently, Pathan et al55 published a wellexecuted, but small, study to evaluate the efficacy and safety of apremilast in AS treatment. While the 19 patients assigned to the apremilast group (30 mg BID) failed to reach the primary endpoint (a significant change

in the mean Bath Ankylosing Spondylitis Disease Activity Index), the investigators did report general improvement in all clinical assessments; however, none of these clinical improvements reached statistical significance. Investigators also looked at certain biomarkers associated with osteoporosis in patient serum. They reported a significant decrease in serum receptor activator of nuclear factor kappa-B ligand (RANKL) and sclerostin. RANKL inhibition is known to reduce bone erosion in arthritis models.56 There was also an observed decrease in the RANKL: osteoprotegerin ratio, reported to be associated with reduced bone mineral density.57 Along with tolerable AE, these interesting findings support the rationale for a larger study in AS to be conducted Discussion Data from three large-scale, multicenter Phase II clinical trials report apremilast to be both efficacious and well tolerated in the treatment of psoriasis and PsA. It has proven successful in achieving PASI-75 in some patients (the most widely used clinical assessment for psoriasis) in these studies, and has been consistently more effica-cious than placebo in each case. However, the percentages of patients reaching PASI-75 or ACR20, even at higher doses of apremilast, are not on par with those treated with biologics. Apremilast treatment sees a maximum of 41% psoriasis patients reach PASI-75,48 compared to 71% treated with adalimumab, and 80% of those treated with infliximab (Table 1). It is also worth noting that emerging biological therapies are proving to be effective. AntiIL-17 therapies see 75%–86% of psoriasis patients reach PASI75, and anti-IL-12/23 therapies are successful in reaching the same endpoint in 67%–82% of psoriasis patients. Apremilast has consistently displayed a dosedependent profile; the difference in efficacy between doses warrants the investigation of higher doses. While many patients treated with apremilast still suffer AE, they tend to be mild in severity. The ongoing Phase III trials will go some way

to thoroughly determine whether efficacy outweighs the AE profile, to qualify apremilast to be the first PDE4 inhibitor licensed for treatment of psoriasis and PsA. At present, the data available indicates that apremilast is not as effective as the biological therapies currently in use. However, the only fair test is a side-by-side comparison, such as the phase III trial currently underway in North America, Belgium, and Netherlands (NCT01690299), which is directly comparing the effects of apremilast with etanercept for treatment of psoriasis.58 It is the only Phase III trial that included a biologic as a comparator, as opposed to just a placebo. In addition to efficacy, this head-to-head comparison will be crucially informative on the relative intensity of AE and tolerability. At present, biologics are the leading treatment for moderate to severe psoriasis and PsA. Provided that AE remain mild and well tolerated, and given the lower costs and oral availability, the further clinical development of apremilast seems assured if efficacy proves to be on par with TNF inhibitors. That has yet to be proven, and until the ongoing Phase III trials can be evaluated, the future of apremilast for the treatment of psoriasis and PsA is uncertain. Figure 1: Psoriasis and PsA. (A) Psoriasis is associated with a hyperproliferative epidermal layer, abnormal keratinocyte growth, and an inflammatory cell infiltrate including T cells and macrophages. This manifests in inflamed skin and raised plaques with silvery ... Table 1: Summary of current biological therapies for the treatment of moderate to severe psoriasis and PsA REFERENCES: 1. Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med. 2009;361(5):496–509.[PubMed] 2. Gottlieb AB. Psoriasis: emerging therapeutic strategies. Nat Rev Drug Discov. 2005;4(1):19–34.[PubMed] 3. Griffiths CE, Barker JN. Pathogenesis and clinical features of psoriasis. Lancet. 2007;370(9583):263–271.[PubMed] 4. Gladman DD. Psoriatic arthritis. Dermatol Ther. 2009;22(1):40–55.[PubMed] 5. Chang CA, Gottlieb AB, Lizzul PF. Management of psoriatic arthritis from

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40 Arthritis

the view of the dermatologist. Nat Rev Rheumatol. 2011;7(10):588–598.[PubMed]

chronic plaque psoriasis. Br J Dermatol. 2011;165(3):652–660.[PubMed]

cyclase. Mol Pharmacol. 1995;48(4):747–757. [PubMed]

6. Myers WA, Gottlieb AB, Mease P. Psoriasis and psoriatic arthritis: clinical features and disease mechanisms. Clin Dermatol. 2006;24(5):438–447.[PubMed]

22. Lin VW, Ringold S, Devine EB. Comparison of ustekinumab with other biological agents for the treatment of moderate to severe plaque psoriasis: a Bayesian network meta-analysis. Arch Dermatol. 2012:1–8.[PubMed]

36. Gobejishvili L, Barve S, Joshi-Barve S, McClain C. Enhanced PDE4B expression augments LPS-inducible TNF expression in ethanol-primed monocytes: relevance to alcoholic liver disease. Am J Physiol Gastrointest Liver Physiol. 2008;295(4):G718– G724. [PMC free article][PubMed]

7. Melnikova I. Psoriasis market. Nat Rev Drug Discov. 2009;8(10):767–768.[PubMed] 8. Weger W. Current status and new developments in the treatment of psoriasis and psoriatic arthritis with biological agents. Br J Pharmacol. 2010;160(4):810–820. [PMC free article][PubMed] 9. Gottlieb A, Korman NJ, Gordon KB, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 2. Psoriatic arthritis: overview and guidelines of care for treatment with an emphasis on the biologics. J Am Acad Dermatol. 2008;58(5):851–864.[PubMed] 10. Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 Cells. Annu Rev Immunol. 2009;27:485–517.[PubMed] 11. Leonardi C, Matheson R, Zachariae C, et al. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N Engl J Med. 2012;366(13):1190–1199. [PubMed] 12. Papp KA, Langley RG, Sigurgeirsson B, et al. Efficacy and safety of secukinumab in the treatment of moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled phase II dose-ranging study. Br J Dermatol. Oct 27, 2012. Epub. [PubMed] 13. Papp KA, Leonardi C, Menter A, et al. Brodalumab, an anti- interleukin-17-receptor antibody for psoriasis. N Engl J Med. 2012;366(13):1181–1189.[PubMed] 14. Garber K. Anti-IL-17 mAbs herald new options in psoriasis. Nat Biotechnol. 2012;30(6):475–477.[PubMed] 15. Gottlieb A, Menter A, Mendelsohn A, et al. Ustekinumab, a human inter-leukin 12/23 monoclonal antibody, for psoriatic arthritis: randomised, double-blind, placebo-controlled, crossover trial. Lancet. 2009;373(9664):633–640.[PubMed] 16. Papp KA, Langley RG, Lebwohl M, et al. PHOENIX 2 study investigators Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebocontrolled trial (PHOENIX 2) Lancet. 2008;371(9625):1675–1684.[PubMed] 17. Leonardi CL, Kimball AB, Papp KA, et al. PHOENIX 1 study investigators Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebocontrolled trial (PHOENIX 1) Lancet. 2008;371(9625):1665–1674.[PubMed] 18. Goldminz AM, Gottlieb AB. Ustekinumab for psoriasis and psoriatic arthritis. J Rheumatol Suppl. 2012;89:86–89.[PubMed] 19. Gordon KB, Langley RG, Gottlieb AB, et al. A phase III, randomized, controlled trial of the fully human IL-12/23 mAb briakinumab in moderate-to-severe psoriasis. J Invest Dermatol. 2012;132(2):304–314.[PubMed] 20. Strober BE, Crowley JJ, Yamauchi PS, Olds M, Williams DA. Efficacy and safety results from a phase III, randomized controlled trial comparing the safety and efficacy of briakinumab with etanercept and placebo in patients with moderate to severe chronic plaque psoriasis. Br J Dermatol. 2011;165(3):661–668.[PubMed] 21. Gottlieb AB, Leonardi C, Kerdel F, Mehlis S, Olds M, Williams DA. Efficacy and safety of briakinumab vs etanercept and placebo in patients with moderate to severe

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23. Liu Y, Wu EQ, Bensimon AG, et al. Cost per responder associated with biologic therapies for Crohn’s disease, psoriasis, and rheumatoid arthritis. Adv Ther. 2012;29(7):620–634.[PubMed] 24. Stanczyk J, Ospelt C, Gay S. Is there a future for small molecule drugs in the treatment of rheumatic diseases? Curr Opin Rheumatol. 2008;20(3):257–262.[PubMed] 25. Bonilla-Hernán MG, Miranda-Carús ME, Martin-Mola E. New drugs beyond biologics in rheumatoid arthritis: the kinase inhibitors. Rheumatology (Oxford) 2011;50(9):1542– 1550.[PubMed] 26. Papp KA, Menter A, Strober B, et al. Efficacy and safety of tofacitinib, an oral Janus kinase inhibitor, in the treatment of psoriasis: a Phase 2b randomized placebocontrolled dose-ranging study. Br J Dermatol. 2012;167(3):668–677.[PubMed] 27. Pfizer A one-year study to evaluate the effects and safety of CP-690,550 in patients with moderate to severe chronic plaque psoriasis ClinicalTrialsgov [website on the Internet] Bethesda, MD: US National Library of Medicine; 2011. [updated December 24, 2012]. Available from: http://www.clinicaltrials.gov/ct2/show/ NCT01276639?term = tofacitinib + psoriasis &recr = Recruiting&phase = 2 & rank = 1. NLM identifier: NCT01276639Accessed February 8, 2013. 28. Fleischmann R, Cutolo M, Genovese MC, et al. Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs. Arthritis Rheum. 2012;64(3):617–629.[PubMed] 29. Garber K. Pfizer’s JAK inhibitor sails through phase 3 in rheumatoid arthritis. Nat Biotechnol. 2011;29(6):467–468.[PubMed] 30. Maiga M, Lun S, Guo H, Winglee K, Ammerman NC, Bishai WR. Risk of tuberculosis reactivation with tofacitinib (CP-690550) J Infect Dis. 2012;205(11):1705– 1708. [PMC free article][PubMed] 31. Eli Lilly and Company A study in participants with rheumatoid arthritis on background methotrexate therapy ClinicalTrialsgov [website on the Internet] Bethesda, MD: US National Library of Medicine; 2010. [updated September 18, 2012]. Available from http://www. clinicaltrials.gov/ct2/show/NCT01185353 ?term=baricitinib&rank=7. NLM identifier: NCT01185353Accessed February 8, 2013. 32. Conti M, Beavo J. Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling. Annu Rev Biochem. 2007;76:481–511.[PubMed] 33. Houslay MD, Schafer P, Zhang KY. Keynote review: phosphodiesterase-4 as a therapeutic target. Drug Discov Today. 2005;10(22):1503–1519.[PubMed] 34. Page CP, Spina D. Phosphodiesterase inhibitors in the treatment of inflammatory diseases. Handb Exp Pharmacol. 2011;204:391–414.[PubMed] 35. Seldon PM, Barnes PJ, Meja K, Giembycz MA. Suppression of lipopolysaccharideinduced tumor necrosis factor-alpha generation from human peripheral blood monocytes by inhibitors of phosphodiesterase 4: interaction with stimulants of adenylyl

moderate to severe psoriasis: a randomised controlled trial. Lancet. 2012;380(9843):738– 746.[PubMed] 51. Schett G, Wollenhaupt J, Papp K, et al. Oral apremilast in the treatment of active psoriatic arthritis: results of a multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum. 2012;64(10):3156– 3167.[PubMed]

37. Eigler A, Siegmund B, Emmerich U, Baumann KH, Hartmann G, Endres S. Antiinflammatory activities of cAMP-elevating agents: enhancement of IL-10 synthesis and concurrent suppression of TNF production. J Leukoc Biol. 1998;63(1):101–107.[PubMed]

52. Gottlieb AB, Strober B, Krueger JG, et al. An open-label, single-arm pilot study in patients with severe plaque-type psoriasis treated with an oral anti-inflammatory agent, apremilast. Curr Med Res Opin. 2008;24(5):1529–1538.[PubMed]

38. Platzer C, Fritsch E, Elsner T, Lehmann MH, Volk HD, Prösch S. Cyclic adenosine monophosphate-responsive elements are involved in the transcriptional activation of the human IL-10 gene in monocytic cells. Eur J Immunol. 1999;29(10):3098–3104.[PubMed]

53. Burton PR, Clayton DG, Cardon LR, et al. Wellcome Trust Case Control Consortium; Australo-Anglo-American Spondylitis Consortium (TASC), Biologics in RA Genetics and Genomics Study Syndicate (BRAGGS) Steering Committee Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet. 2007;39(11):1329–1337. [PMC free article][PubMed]

39. Essayan DM, Huang SK, KageySobotka A, Lichtenstein LM. Differential efficacy of lymphocyte- and monocyteselective pretreat-ment with a type 4 phosphodiesterase inhibitor on antigen-driven proliferation and cytokine gene expression. J Allergy Clin Immunol. 1997;99(1 Pt 1):28–37. [PubMed] 40. Bos JD, de Rie MA, Teunissen MB, Piskin G. Psoriasis: dysregulation of innate immunity. Br J Dermatol. 2005;152(6):1098–1107. [PubMed] 41. Schafer PH, Parton A, Gandhi AK, et al. Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis. Br J Pharmacol. 2010;159(4):842–855. [PMC free article][PubMed] 42. Cameron AL, Kirby B, Fei W, Griffiths CE. Natural killer and natural killer-T cells in psoriasis. Arch Dermatol Res. 2002;294(8):363–369.[PubMed] 43. Wagner EF, Schonthaler HB, GuineaViniegra J, Tschachler E. Psoriasis: what we have learned from mouse models. Nat Rev Rheumatol. 2010;6(12):704–714.[PubMed] 44. Crilly A, Robertson SE, Reilly JH, et al. Phosphodiesterase 4 (PDE4) regulation of proinflammatory cytokine and chemokine release from rheumatoid synovial membrane. Ann Rheum Dis. 2011;70(6):1130–1137. [PubMed] 45. McCann FE, Palfreeman AC, Andrews M, et al. Apremilast, a novel PDE4 inhibitor, inhibits spontaneous production of tumour necrosis factor-alpha from human rheumatoid synovial cells and ameliorates experimental arthritis. Arthritis Res Ther. 2010;12(3):R107. [PMC free article][PubMed] 46. Cherry JA, Davis RL. Cyclic AMP phosphodiesterases are localized in regions of the mouse brain associated with reinforcement, movement, and affect. J Comp Neurol. 1999;407(2):287–301.[PubMed] 47. Schafer P. Apremilast mechanism of action and application to psoriasis and psoriatic arthritis. Biochem Pharmacol. 2012;83(12):1583–1590.[PubMed] 48. ClinicalTrialsgov [webpage on the Internet] Search of: Apremilast -List Results Bethesda, MD: US National Library of Medicine; Available from: http://www.clinicaltrials.gov/ ct2/results?term=Apremilast&Search=Search Accessed November 26, 2012. 49. Papp KA, Kaufmann R, Thaçi D, Hu C, Sutherland D, Rohane P. Efficacy and safety of apremilast in subjects with moderate to severe plaque psoriasis: results from a phase II, multicenter, randomized, double-blind, placebo-controlled, parallel-group, dosecomparison study. J Eur Acad Dermatol Venereol. 2012 Oct 3; Epub. [PubMed] 50. Papp K, Cather JC, Rosoph L, et al. Efficacy of apremilast in the treatment of

54. Reveille JD, Sims AM, Danoy P, et al. Australo-Anglo-American Spondyloarthritis Consortium (TASC) Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nat Genet. 2010;42(2):123–127. [PMC free article] [PubMed] 55. Pathan E, Abraham S, Van Rossen E, et al. Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in ankylosing spondylitis. Ann Rheum Dis. Sep 14, 2012. Epub. [PubMed] 56. Schett G, Hayer S, Zwerina J, Redlich K, Smolen JS. Mechanisms of disease: the link between RANKL and arthritic bone disease. Nat Clin Pract Rheumatol. 2005;1(1):47–54. [PubMed] 57. Kim HR, Lee SH, Kim HY. Elevated serum levels of soluble receptor activator of nuclear factors-kappaB ligand (sRANKL) and reduced bone mineral density in patients with ankylosing spondylitis (AS) Rheumatology (Oxford) 2006;45(10):1197–1200.[PubMed] 58. ClinicalTrialsgov [webpage on the Internet] Search of: apremilast: Phase 3 - List Results Bethesda, MD: US National Library of Medicine; Available from: http://www. clinicaltrials.gov/ct2/results?term=apremila st&recr=&rslt=&type=&cond=&intr=&outc= &spons=&lead=&id=&state1=&cntry1=&sta te2=&cntry2=&state3=&cntry3=&locn=&gn dr=&phase=2&rcv_s=&rcv_e=&lup_s=&lup_ e=Accessed November 26, 2012. 59. Samrao A, Berry TM, Goreshi R, Simpson EL. A pilot study of an oral phosphodiesterase inhibitor (apremilast) for atopic dermatitis in adults. Arch Dermatol. 2012;148(8):890–897. [PMC free article][PubMed] 60. Paul J, Foss CE, Hirano SA, Cunningham TD, Pariser DM. An open-label pilot study of apremilast for the treatment of moderate to severe lichen planus: A case series. J Am Acad Dermatol. 2013;68(2):255–261.[PubMed] 61. Volf EM, Au SC, Dumont N, Scheinman P, Gottlieb AB. A phase 2, open-label, investigator-initiated study to evaluate the safety and efficacy of apremilast in subjects with recalcitrant allergic contact or atopic dermatitis. J Drugs Dermatol. 2012;11(3):341– 346.[PubMed] 62. De Souza A, Strober BE, Merola JF, Oliver S, Franks AG., Jr Apremilast for discoid lupus erythematosus: results of a phase 2, open-label, single-arm, pilot study. J Drugs Dermatol. 2012;11(10):1224–1226.[PubMed] 63. Bren L. Psoriasis: more than cosmetic. FDA Consumer. 2004 Sept-Oct Available from: http://permanent.access. gpo.gov/lps1609/www.fda.gov/fdac/ features/2004/504_psoriasis.htmlAccessed February 8, 2013.


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42 Report

Learning from excellence Most recent Hospital Pharmacy Survey The European Association of Hospital Pharmacists (EAHP) has announced the publication of a new booklet which provides a detailed summary of the largest ever survey undertaken of hospital pharmacy practice in Europe. EAHP survey national member co-ordinator for Ireland was Joan Peppard, former President of the Hospital Pharmacist Association of Ireland. EAHP Survey 2010: Hospital Pharmacy Practice in Europe is the collected analysis of a comprehensive survey, conducted throughout 2010, which investigates the many facets of current practice in hospital pharmacies across 30 different countries. The booklet, published by BMJ, contains the full series of articles that were originally published in The European Journal of Hospital Pharmacy. The articles scrutinise the survey’s findings across a number of themed areas, including: • hospital pharmacy staffing; • procurement and distribution practices; • production of medicines within hospital pharmacies; • the extent of clinical service development; and, • the role of hospital pharmacies in the conduct of clinical trials and research. The articles observe the differences of practice between countries, as well as prevailing common trends in practice, with the intention of providing thought-provoking stimulus for any reader involved in hospital pharmacy service development. The results of the survey will also guide future work by EAHP in delivering its mission of developing the hospital pharmacy profession across Europe.

Issue 9 • HPN

Speaking on the publication of the booklet, EAHP President Dr Roberto Frontini said; “EAHP Survey 2010: Hospital Pharmacy Practice in Europe is a tool for hospital pharmacy service development right across Europe. Hospital pharmacists can see where their country fits within the overall European picture and better direct their improvement efforts. I therefore hope all my professional colleagues will take time to read this new publication, digest the results, and reflect on what the achievements of other countries might mean for practice within their own national systems. “EAHP sets itself the mission of continuously improving hospital pharmacy practice in Europe for the benefit of patients. The data collected by the survey supports EAHP in taking decisions on effective actions to achieve this, especially in terms of education and exchange of experience. However, for every individual hospital pharmacist the survey offers the opportunity to compare practice in their own country or hospital with that in other European countries. In this respect, the survey results are designed to provide an effective benchmarking tool for selfdirected practice improvement in every European health system. There is no such thing as perfect practice but there are certainly centres of excellence from which we can all learn. “It is impossible to report all of the survey information in this booklet and we recognise that colleagues may be interested in additional details. It is for this reason that we have included the original questionnaire in this booklet. A range of information about, and from, the survey is also available on the EAHP website at www.eahp.eu/ publications/surveys. Individuals with further queries are invited to contact the EAHP office and ask for additional analysis of the responses to a specific question. It should be understood that due to the complexity and sensitivity

Joan Peppard, EAHP national member for Ireland

of the original data EAHP is not able to make available the primary data. “EAHP has always aimed to create a continuously improving survey. So now, with over 15 years of experience acquired in this project area, further refinements and modifications to future surveys are planned. These changes will aim to ensure that both the rigour and the usefulness of the exercise are maintained and built upon. Although still subject to discussion, one suggestion under consideration is for more regular, but shorter, survey activity. This could increase the precision of the survey as a tracking mechanism of practice improvement and innovation in Europe. In whatever event, as EAHP’s membership and reach continues to extend, and as information technology opens up new avenues for data collection previously not possible, I am confident that EAHP surveys will continue to benefit of all those who draw inspiration and conclusions from their findings.” PROCUREMENT AND DISTRIBUTION Hospital pharmacists are responsible for the procurement of medicines, which are commonly restricted to those listed in a formulary (77.4% of pharmacies, n=990). In a few countries (Croatia, former Yugoslav Republic of Macedonia, Greece, Ireland, Serbia and Slovenia) there are no formularies in <50% of hospitals. The average number of products in formularies is 1006 (median 960) with no significant changes since 2005 (average 1031) but with a large range from 246 (Bosnia and Herzegovina) to 1982 (UK). Price information is shown in 43.6% of formularies (n=748) and formularies are updated by 75.2% of pharmacies each year (n=747).

Medical devices are selected by 55.8% and purchased by 56.2% of hospital pharmacies (n=975). Few hospital pharmacies in Denmark and The Netherlands are involved in this activity, while more than 90% of pharmacies in Slovakia, Belgium and Luxembourg are responsible for selecting and purchasing these products. Most medical supplies are procured from wholesalers (51%) or direct from industry (46%), with only 2% being sourced from other hospitals and 1% from own production (n=892). Large hospitals purchase less from wholesalers and more from industry, with small hospitals exhibiting the opposite trend; some large hospitals produce their own supplies. There is a clear difference between northeastern and southwestern Europe, with the latter being industry orientated and the former wholesale oriented (figure 1). Own production is significant only in Denmark (17.2% of purchasing volume). Sources of procurement have not changed significantly since 2000 in most European countries.2 Just under half of European pharmacies (45.7%) do not participate in group purchasing, ranging from 28.7% of hospitals in the UK having no alliance to 50% in eight other countries.


43

Figure 1

pharmacies answered the questionnaire (table 1). Very good response rates above 50% were also found in Austria, Croatia, Estonia, Latvia, Luxembourg, Slovakia and Slovenia. The poorest response rates were in France, Lithuania, Poland and the UK.

DISCUSSION Roughly half the hospital pharmacies in Europe have responsibility for medical devices, so hospital pharmacists should promote their competence and expertise in this field. Interestingly, eastern Europe pharmacies purchase medicines significantly more through wholesalers than western countries, perhaps because of the concentration of the pharmaceutical industry in western Europe and the fact that prices of medicines are almost identical for hospitals and ambulatory care in eastern Europe where there are also fewer large hospitals with a huge turn-over. Compared with the results of a similar survey in the USA,3 it seems that distribution in Europe is more centralised (70%) than in the USA (37%). This is also apparent when unit-dose services are examined: almost every hospital in the USA offers this service compared to only 23% in Europe. EAHP Survey 2010: Hospital Pharmacy Practice in Europe is available to download here: GENERAL FRAME AND STAFFING The pan European survey on hospital pharmacy practice is an important source in understanding the future challenges and needs for

development in Europe. In 2002, the European Association of Hospital Pharmacists (EAHP) General Assembly, in Portorozˇ,Slovenia, decided to run the survey every 5 years. In 1995, 18 countries participated, in 2000, 16 countries, in 2005, 22 countries and in 2010, 30 countries participated. The 2010 survey was based on a questionnaire with 87 questions covering the following major topics: 1. General frame and staffing 2. Procurement and distribution 3. Production and quality assurance 4. Clinical services 5. Patient safety

Each single question was answered by a median of 960 (74.8%) of the 1283 responding pharmacists (minimum 64 (5.0%), maximum 1168 (91.0%)). The number of responding pharmacists to a specific question is indicated as n (number) and all results (in %) are related to the n of the single question. DISCUSSION The results of the 2010 survey on hospital pharmacy practice in Europe are reliable because of the good response rate by most countries, with only a few having an unacceptable response rate. The data from France, Lithuania, Poland and the UK should be interpreted with caution. Nevertheless, we can still have an overview of pharmacy practice in Europe: on average, a hospital pharmacy in Europe is providing hospital pharmacy

services to a hospital with 606 beds with complete hospitalisations. The average number of hospital pharmacists in these hospital pharmacies is 4.7 (0.9 pharmacists for 100 beds) and 5.5 PT (1.0 PT/100 beds). On average, since 2005, we have seen only a small increase in the number of beds served for complete and partial hospitalisations, as well as in the number of staff. Therefore, it is interesting to look at the development of services in terms of increasing efficiency. Comparing staffing in hospital pharmacies in Europe and the USA highlights some important differences: a hospital pharmacy in USA has, on average, 19fold the pharmacists in Europe (17.5 to 0.9 FTE/100 beds complete hospitalisations).3 Similar differences can also be observed for PT: in USA, on average, 15-fold greater numbers (1.0 to 15.0 PT FTE/100 beds complete hospitalisations). Even taking into account the different educational systems between the USA and Europe—which could have different staffing as a consequence—direct comparisons between hospital pharmacy services in the USA and Europe are problematic.

6. Education and research. The average response rate was 27.0% (1283/4748). As not all of the questions were answered in the questionnaires, we also calculated a weighted response rate, which is the ratio between the total number of answered questions and the total number of questionnaires sent out in that country, multiplied by 87 (total number of questions). The total weighted response rate was 16.7%. Response rates varied substantially across the member states. The highest response rate was achieved in FYROM (Former Yugoslav Republic of Macedonia) were all hospital

Figure 2

HPN • Issue 9


44 News

NAHPT Annual Conference The National Association of Hospital Pharmacy Technicians recently held their Annual Conference in the Crowne Plaza, Santry, Dublin 9 on Saturday 27th April 2013. The theme of the event this year was â&#x20AC;&#x2DC;Leaning towards best practice. The programme included presentations and workshops that focused on best practice guidelines and standards in various areas of pharmacy.

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1: David O'Brien, Tony Twoomy, Brendan O'Connell Allphar and Jennifer Mackey Tallaght Hospital 2: Bill Proctor and A.J.Cotter BBraun 3: Damien MacKenna Ricesteel, Seana Hogan Boots, Lila Hogan and Diane Patterson AIT 4: Daniel Byers and Paul Nash KRKA 5: Dawn Johnston, Muireann Ryan, Laura Cannon Medisource, Yvonne Sheehan, Paul Boland and Aoife O'Brien, Medisource 6: Winner of the ¤100 Actavis gift voucher Emily Tracy Letterkenny General with Yvonne Sheehan and Caroline Fitzgerald Actavis 7: Elizabeth Collis recieving her highly commended prize in the Actavis Poster Competition with Caroline Fitzgerald from Actavis 8: Fran Glynn Naas Hospital, Padraig Cahill Pfizer, Anne McCarthy United Drug and Rosemary Dwyer Our Ladies Hospital 9: Gillian Colford and Bairbre Hickie Fresenius Kabi 10: Liz Devlin Mount Carmel Hospital, Conor Sadler and Caroline Fitzgerald Actavis, Ann O’Brien, Caitriona Wyer, Mater Hospital 11: Maria Rosko St Brendans Hospital Yvonne Kavanagh Teva and Louise Dempsey St Brendans Hospital 12: Martina Rudden MercuryPharma Pauline Kavanagh Kinbara Pharmacy and Helen Heenan MercuryPharma 13: Michelle Smyth and Mark Kelly Hospira with Aine O'Byrne Sports Injury Clinic Santry 14: Sheena Brennan Novartis Melissa Carthy Beaumont Hospital and Louise Duggan Novartis

HPN • Issue 9


46 Zelboraf Report Zelboraf® (vemurafenib) is now reimbursed in Ireland as monotherapy for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma Dr Paul Donnellan - Zelboraf

was most commonly treated by local excision. Patients generally continued on treatment without dose modification1. ABOUT METASTATIC MELANOMA AND BRAF

Roche is pleased to announce that Zelboraf® (vemurafenib) is now reimbursed in Ireland as monotherapy for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma1.

commercially available targeted therapy to show efficacy in the treatment of metastatic melanoma, with response rates that are truly phenomenal (57%), and a definite improvement in otherwise-dismal survival.

The welcome approval of the first personalised medicine to extend the lives of patients with BRAF V600 mutation positive unresectable or metastatic melanoma to over a year1 is a celebratory milestone for the melanoma community.

“The significant overall survival benefit over the previous 1st line preferred option, establishes the product as the new standard of care in stage IIIC and IV melanoma patients harbouring the BRAF V600 mutation. This treatment will be a major boon to the 40% to 60% of my patients with unresectable or metastatic melanoma whose tumours harbour a BRAF V600 mutation, so there is an urgent need to screen all metastatic melanoma patients upfront to check if they are harbouring that specific mutation.”

Vemurafenib, an oral therapy that targets the activity of the faulty BRAF V600 gene present in 40 to 60% of patients with inoperable metastatic melanoma2, is the only approved medicine in its class shown to improve survival rates and stall the growth or spread of cancer.1,2 The phase III clinical trial (BRIM3) has shown:3  an significant increase in median overall survival of 3.9 months vs dacarbazine, the standard chemotherapy (median 13.6 months compared to 9.7 months with dacarbazine)  an significant increase in median progression free survival (PFS) of 5.3 months vs dacarbazine (median 6.9 months compared to 1.6 months with dacarbazine)  an objective response rate of 57%, compared to 8.6% with dacarbazine Welcoming the announcement, Dr Paul Donnellan, Consultant Medical Oncologist at University College Hospital Galway said: "I am delighted to hear that vemurafenib is now reimbursed and fully available in Ireland. Vemurafenib is the first

Issue 9 • HPN

In February 2012, Zelboraf received European approval for use as a monotherapy for the treatment of adult patients with BRAFV600 mutation-positive unresectable or metastatic melanoma1. Zelboraf is designed to target and inhibit mutated forms of the BRAF protein found in about half of all cases of stage IIIC or IV melanoma. Zelboraf is approved in more than 38 countries and more than 4000 patients worldwide have now been treated with vemurafenib in clinical trials. ZELBORAF SAFETY The most common adverse drug reactions (ADR) (> 30%) reported with vemurafenib include arthralgia, fatigue, rash, photosensitivity reaction, nausea, alopecia and pruritus. CuSCC was very commonly reported and

When melanoma is diagnosed early, it is generally a curable disease. However, when it spreads to other parts of the body, it is the deadliest and most aggressive form of skin cancer. A person with metastatic melanoma typically has on average a short life expectancy that is measured in months. Only around one in four people with metastatic melanoma are expected to be alive one year after their diagnosis.4 The BRAF protein is a key component of the RAS-RAF pathway involved in normal cell growth and survival. Mutations that keep the BRAF protein in an active state may cause excessive signalling in the pathway, leading to uncontrolled cell growth and survival. These mutations of the BRAF protein are thought to occur in approximately 40% to 60% of cutaneous melanomas2. ABOUT BRIM3 BRIM3 is a global, randomised, open-label, controlled, multicentre, phase III study that compared Zelboraf to dacarbazine chemotherapy, a standard of care, in 675 patients with previously untreated BRAF V600E mutation-positive, unresectable or metastatic melanoma2. ABOUT ZELBORAF Zelboraf is an oral, small molecule, kinase inhibitor indicated for the monotherapy treatment of adult patients with BRAF V600 mutation positive unresectable or metastatic melanoma. Zelboraf is not recommended for use in melanoma patients with wildtype BRAFV600 unresectable or metastatic melanoma. Zelboraf is being co-developed under a 2006 license and collaboration agreement between Roche and Plexxikon, a member of the Daiichi Sankyo Group. ABOUT ROCHE Headquartered in Basel,

Switzerland, Roche is a leader in research-focused healthcare with combined strengths in pharmaceuticals and diagnostics. Roche is the world’s largest biotech company with truly differentiated medicines in oncology, virology, inflammation, metabolismrld leader in in-vitro diagnostics, tissue-based cancer diagnostics and a pioneer in diabetes management. Roche’s personalized healthcare strategy aims at providing medicines and diagnostic tools that enable tangible improvements in the health, quality of life and survival of patients. In 2011, Roche had over 80,000 employees worldwide and invested over 8 billion Swiss francs in R&D. The Group posted sales of 42.5 billion Swiss francs. Genentech, United States, is a wholly owned member of the Roche Group. Roche has a majority stake in Chugai Pharmaceutical, Japan. For more information: www.roche.com. For more information, please contact: Communications Department Roche Products (Ireland) Limited Ireland.communications@roche. com Tel: 01-469 0700 Fax: 01-469 0790 REFERENCES 1. Zelboraf* Summary of Product Characteristics, 17th January 2013 2. Chapman, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 2011;364(26):2507-2516. 3. Chapman et al. Updated overall survival results for BRIM-3, a Phase III randomized, open-label, multicenter trial comparing the BRAF inhibitor, vemurafenib with dacarbazine in previously untreated patients with BRAFV600E-mutated metastatic melanoma. Presentation at 48th Annual Meeting of the American Society of Clinical Oncology (ASCO) Abstract #8502 4. Korn EL, et al. Meta-analysis of phase II cooperative group trials in metastatic stage IV melanoma to determine progression-free and overall survival benchmarks for future phase II trials. J Clin Oncol 2008;26(4):527-34. *Legal classification: Product subject to prescription which may not be renewed.


Out & About

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Irish Pharmacy Awards 2013 Irish Pharmacy News, sister publication to Hospital Pharmacy News, recently hosted the second Irish Pharmacy Awards 2013 at the Burlington Hotel, Dublin. The event was an astounding success as over 500 of the community pharmacy industry descended upon Dublin for the biggest night in the pharmacy calendar.

With 10 categories up for grabs, the winners on the night included: Community Pharmacist of the Year – Oonagh O’Hagan, Meaghers Pharmacy Pharmacy Team of the Year – Brennans Pharmacy, Buncrana

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OTC Retailer of the Year – LloydsPharmacy, Blackrock Business Development of the Year (Independent) – Burren Pharmacy, Lisdoonvara

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Business Development of the Year (Chain) – Healthwise Pharmacy Group 5

Young Pharmacist of the Year – Aaron Carlyle, Brennans Pharmacy, Buncrana Pharmacy Representative of the Year – Helen Taylor, McLernon Computers Pharmacy Manager of the Year – Mairead Tobin, Hanleys Pharmacy 2

Innovation and Service Development (Independent) Award – Brennans Pharmacy

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Innovation and Service Development (Chain) Award – Bradleys Pharmacy The People’s Pharmacist Award – Anne Marie Walsh, DocMorris, Donnybrook

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Pharmacy Manager of the Year Award – Jason Duffy, Healthwise Pharmacy, Sligo

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1: Brian O'Donnell and Suzanne McCarthy - UCC School of Pharmacy. 2: Left to right: Diane Patterson, Athlone Institute of Technology and Yvonne Cummins - Mater Hospital Pharmacy. 3: 3971 Left to right: Jean and Colin Smith - Roches Pharmacy. 4: 3896 Left to right: Nicola Kenny and Stacey Sheridan - Lloyds Pharmacy Blackrock who were winners on the night of the OTC Retailer of the Year Award. 5: Left to right: Clare McDonagh, Seana Hogan, Aideen McInerney, Pat Laffey, Malachy O'Donaghue and Colm Walsh - Boots Pharmacy. 6: Left to right: Johan, Brigid, Shirley, Eimear, Niall and Susan - Mulligans Pharmacy. 7: Left to right: Kim Darcy, Eleanor Murphy, Leo Pike and Mary Magner - United Drug. HPN • Issue 9


48 Out & About Patient focused website launch

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The National Cancer Control Programme (NCCP), in cooperation with the NET Patient Network, hosted a joint event in St. Vincent’s Hospital to announce Prof Dermot O’Toole as the National Clinical Lead of the Irish Neuroendocrine Tumour (I-NET) group. The NET Patient Network took this opportunity to officially launch their new patient focused website, www.netpatientnetwork.ie. This website will help to put Irish NET patients in touch with each other and provides a great reference point for those searching for information on their disease. 1: Professor Kieran Sheahan, Dr Susan O’Reilly, Professor Donal O’Shea, Lisa Cullen, NeuroEndocrine Nurse Specialist in St Vincents Hospital, Dr Gadintshware Gaoatswe, St Vincent’s Hospital, Dr.Dermot O’Toole, Mark McDonnell & Justin Geoghegan. 2: Aran O’Loughlin, Novartis, Dr Dermot O’Toole and Mark McDonnell.

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Cardiology Bursary

Campaign to target arthritis sufferers

Dr. Jim Crowley, Consultant Cardiologist/National Specialty Director for Cardiology, with Dr. George Mak, Cardiology SPR AMNCH, winner of the 2013 MSD Cardiology Bursary in partnership with the Irish Board for Training in Cardiovascular Medicine and Mr Bobby Nolan MSD. This bursary exposes Irish doctors to new concepts and ideas which will ultimately lead to the benefit of Irish cardiac patients in the future. This bursary also allows a fellow in cardiology the opportunity to train and develop research in their chosen subspecialty.

Dr. Jim Crowley, Consultant Cardiologist/National Specialty Director for Cardiology, with Dr. George Mak, Cardiology SPR AMNCH, winner of the 2013 MSD Cardiology Bursary in partnership with the Irish Board for Training in Cardiovascular Medicine and Mr Bobby Nolan MSD. This bursary exposes Irish doctors to new concepts and ideas which will ultimately lead to the benefit of Irish cardiac patients in the future. This bursary also allows a fellow in cardiology the opportunity to train and develop research in their chosen subspecialty. Above: Michael Stewart, Pfizer Healthcare Ireland; Professor David Kane, Consultant Rheumatologist, AMNCH, Tallaght; Anne Marie Gannon; Emma Coyle, Pfizer Healthcare Ireland; John Church, CEO Arthritis Ireland.

Issue 9 • HPN


49 PSI opens smoke-free headquarters The Minister for Health, Dr James Reilly TD, has officially opened the new building for the pharmacy regulator, the Pharmaceutical Society of Ireland(PSI) at Fenian Street, Dublin. The PSI is the first health agency to declare its new building tobacco free as part of a Government initiative to have all campuses and hospitals tobacco free by 2015. The PSI’s new premises is a 1980s office building which has been refurbished to make it sustainable with low energy consumption. Pictured with the minister is immediate past PSI Vice-President Eoghan Hanly and Acting PSI Registrar Ciara McGoldrick.

Caps and gowns at the ready 15 candidates were conferred with degrees of Masters in Pharmacy (MPharm) at the recent Royal College of Surgeons graduations annual conferring ceremony in the National Concert Hall, Dublin. RCSI operates the largest medical school in Ireland, and it provides undergraduate courses in pharmacy and physiotherapy. The College provides an extensive range of postgraduate training and education programmes in the medical sciences, surgery, medical and nursing specialties, international health, tropical medicine and leadership and healthcare management. Pictured are Sarah Pilon, Nur Hafizah, Dhanhanasekaran Thanapal, Vivienne Sullivan and Art Malone.

Targeted therapies for Melanoma Pictured are some of those who recently attended the recent Royal Academy of Medicine In Ireland Dermatology Meeting. The meeting title was “Targeted therapies for melanoma”, and was sponsored by Pfizer Healthcare Ireland. Pictured are Hensin Tsao MD Phd, Mass General Hospital and Harvard Medical School, Boston with Dr Patsy Lenane, Consultant Dermatologist, Mater Misericordiae University Hospital and John Thompson, Pfizer Healthcare Ireland.

HPN • Issue 9


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Clinical Profiles MAJOR MILESTONE IN A NEW ERA OF LOWERCOST BIOLOGIC THERAPIES

PREDNISOLONE 5MG TABLETS NEW 98 BLISTER PACK

ACTAVIS LAUNCHES RAPORSIN (DOXAZOSIN) TO IRISH MARKET

XTANDI™ (ENZALUTAMIDE) AUTHORISED IN THE EUROPEAN UNION (EU) FOR ADVANCED PROSTATE CANCER

Hospira , the world’s leading provider of injectable drugs and infusion technologies, has received a positive opinion from the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP), recommending the European Commission (EC) approval of Inflectra (infliximab) for rheumatoid arthritis, inflammatory bowel disease and plaque psoriasis.

51 review via the EMA biosimilars regulatory pathway. A biosimilar developed in-line with EU requirements can be considered a therapeutic alternative to an existing biologic, with comparable quality, efficacy and safety to the reference product.[1] Remicade® had European sales of over USD 2bn in 2012.[2]

Inflectra (infliximab) is a biosimilar medicine to the reference medicinal product, Remicade® (infliximab), and is the first monoclonal antibody therapy to reach a positive opinion following

Inflectra specifically targets tumour necrosis factor (TNF) alpha, a protein in the body that contributes to the painful inflammation seen in rheumatoid arthritis, inflammatory bowel disease and plaque psoriasis. The drug›s safety, efficacy and

Clonmel Healthcare would like to advise that Prednisolone 5mg Tablets are now available in blister packs of 98. These replace the previous tubs of 1000.

with cross-shaped breaking notch and imprint “5” on one side. The break line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

The formulation has also changed. The tablet will now be white, round

Full prescribing information for Prednisolone is available on

Actavis Ireland is pleased to announce the launch of Raporsin (Doxazosin) 4 mg and 8mg x 28 prolonged-release tablets to Ireland. The launch of Raporsin 8 mg is significant for Actavis, as it is the first and only generic 8mg sku of Doxazosin available on the Irish market.

symptomatic treatment of benign prostatic hyperplasia, Raporsin is subject to medical prescription.

Indicated for the treatment of essential hypertension and the

Delivering key products continues to be an important focus for

Enzalutamide authorised in European Union (EU) for the treatment of adult men with metastatic castration-resistant prostate cancer whose disease has progressed on or after docetaxel therapy1

daily, oral androgen receptor signalling inhibitor.3 It inhibits multiple steps in the androgen receptor (AR) signalling pathway, which has been shown to decrease cancer cell growth and induce cancer cell death (apoptosis).3 The EU authorisation is based on results from the phase III AFFIRM study. The phase III AFFIRM trial was a randomised, double-blind, placebo-controlled, multinational trial evaluating enzalutamide (160 mg/day) versus placebo in 1,199 men with progressive metastatic castrationresistant prostate cancer who were previously treated with docetaxelbased chemotherapy.4

Astellas Pharma Europe Ltd., Medivation, Inc.; the European Commission (EC) has now granted the marketing authorisation for XTANDI (enzalutamide) capsules for the treatment of adult men with metastatic castrationresistant prostate cancer whose disease has progressed on or after docetaxel therapy.1 Xtandi had previously received a positive opinion by the European Medicines Agency (EMA) and a positive Committee for Medicinal Products for Human Use (CHMP) opinion on 25th April 2013.2 Enzalutamide is a novel, once-

Raporsin 4 mg x 28 prolongedrelease tablets is available at the trade price of ¤8.48 and Raporsin 8 mg is available at a trade price of ¤7.71.

AFFIRM confirmed that enzalutamide demonstrated a statistically significant improvement (p<0.0001) in overall survival compared to placebo, with a median survival of 18.4

tolerability have been established through a comprehensive clinical trial programme. In a phase III randomised, double-blind study, Inflectra met its primary endpoint of therapeutic equivalence to the reference product. In the study, 73.4% of patients receiving Inflectra achieved a greater than 20% improvement in RA symptoms after 30 weeks of treatment (using the ACR20 scoring system), compared with 69.7% treated with reference infliximab. The safety and tolerability of Inflectra was also demonstrated to be comparable to Remicade, supporting its approval. [4]

request or go to www.clonmel-health.ie . This Product is subject to medical prescription. If you require any further information, please contact Clonmel Healthcare on 01 6204000

Actavis Ireland and this latest launch continues to underline Actavis’ position as the fastest growing pharmaceutical company on the Irish market1. For further information on the Actavis portfolio please contact Actavis on 1890 33 32 31 or email on contact@actavis.ie

months in the enzalutamide group versus 13.6 months in the placebo group, an advantage of 4.8 months [hazard ratio (HR) = 0.631]. The study also concluded that enzalutamide was generally well tolerated by patients and met all secondary endpoints.4 Professor John Mc Caffrey, Mater Misericordiae University Hospital comments: “Enzalutamide is an important development in prostate cancer therapeutics providing a critically important, orally available and well tolerated new option to the armamentarium of active drugs in advanced prostate cancer. Enzalutamide has a significant impact on quality of life and survival from this disease, this is good news for Irish patients and their families”

HPN • Issue 9


52 Clinical Profiles DATA REVEALS CHANGES IN MANAGEMENT OF PATIENTS LIVING WITH ATRIAL FIBRILLATION

Daiichi Sankyo Europe GmbH has announced the first presentation of baseline results from the PREFER in AF (The PREvention oF thromboembolic events – European Registry in Atrial Fibrillation) registry.1 PREFER in AF has been designed with a unique patient focus, collating ‘real life’ data from 7,243 atrial fibrillation patients (AF) across 461 centers in Austria, France, Germany, Italy, Spain, Switzerland and UK. Baseline data illustrate a change in management of patients with AF following the publication of the 2010 ESC guidelines.2 The

PREFER in AF registry shows that anticoagulant therapies are widely used, but also highlights that further advances in this field are required in order to achieve better outcomes for patients and European healthcare systems.

mono-therapy, 720 patients a VKA and Antiplatelet Agents (AP) in combination (9.9%). New oral anticoagulant drugs (NOAC, dabigatran, rivaroxaban or apixaban) were already being used in 442 patients (6.1%).

In patients with a CHA2DS2VASc score of 2 or higher, more than 85% received oral anticoagulants according to current guidelines, illustrating that evidence and guidelines are followed. The majority of patients (n=4799, 66.3%) received a Vitamin K Antagonist (VKA) as

PREFER in AF will inform about anticoagulation and rhythm control therapy. The registry is a multicentre, prospective observational disease registry, with a one-year follow up – monitoring AF management over a 12 month period.

SERVIER ANNOUNCES NEW CARDIOVASCULAR COLLABORATION WITH AMGEN

Servier has just announced a new collaboration agreement with the leading biotechnology company Amgen (NASDAQ:AMGN) enhancing each company’s commitment to cardiovascular diseases.

excluding the U.S. Already more than 6 million patients worldwide benefit from Procoralan.

and elevated heart rate1.

Amgen has gained the commercial rights in the U.S. to Servier’s innovation, Procoralan® (Ivabradine), for the treatment of chronic heart failure and stable angina patients. Procoralan is currently the only drug in its class (If inhibitor) and was discovered and developed by Servier, and registered in 100 countries worldwide, currently

PHARMACONEX ON THE MOVE

PharmaConex Ireland’s premium locum and recruitment agency for Pharmacy are delighted to announce that they are moving to new offices in Dublin City Centre from 1st of July. The new offices are located in the landmark Capel Building on the Luas line between the Jervis Centre and the Four Courts. PharmaConex are really looking forward to the move to the prestigious new location which boasts a host of amenities both internally and nearby – we hope that both candidates and clients will feel free to drop in for a coffee and a chat anytime they are in the area. Pictured are the Dublin team from PharmaConex in the reception area of their new offices.

Issue 9 • HPN

The clinical benefits and safety profile of Procoralan are supported by an extensive development program performed in more than 40,000 patients in randomized controlled trials. Clearly a major advance in Procoralan’s ongoing development program was accomplished with the Shift trial presented at the ESC congress in 2010 and published in the Lancet: Procoralan demonstrated a significant 18 % reduction in cardiac deaths and hospitalizations for heart failure in patient in sinus rhythm, NYHA II to IV, LVEF < 35%

Professor Ken McDonald, National Clinical Lead for Heart Failure in Ireland and Consultant Cardiologist at St Vincent’s Hospital commented: “This news demonstrates great recognition of Procoralan. We now have good experience in Ireland of the benefits of using ivabradine in suitable patients in combination with long standing treatments for heart failure. This Agreement will no doubt be a beneficial addition to US prescribers for the management of heart failure.”


53 ANOTHER DAY ONE LAUNCH FROM ACTAVIS!

Actavis Ireland is delighted to announce the launch of Zoledronic Acid 4mg/5ml x 1 Vial on Day One following patent expiry. Zoledronic Acid is indicated for the prevention of skeletal related events (pathological fractures, spinal compression, radiation or bone surgery) in adult patients with advanced bone malignancies. It is also indicated for the treatment of adult patients with tumour-induced hypercalcaemia (TIH). Commenting on this important Day One launch, Actavis Ireland Hospital Business Manager, Caroline Fitzgerald said “Actavis is

KRKA LAUNCHES MARUXA 10MG IN 28 AND 56 PACK

KRKA ANNOUNCE 5 ADDITIONAL MOLECULES TO THEIR RANGE

committed to bringing value and choice to the Irish Market. Actavis offers fast access to a wide choice of Hospital Pharmaceuticals across all therapeutic areas. We operate contemporary GMP approved manufacturing facilities in Europe, with meticulous in house quality standards and rigorous regulatory environments ensuring the highest quality at all times. We will continue to expand our product portfolio throughout 2013 in order to provide the highest quality pharmaceuticals possible.”

Maruxa is subject to medical prescription and is GMS reimbursable.

Maruxa is indicated for the treatment of moderate to severe Alzheimer’s disease1.

MARUXA 10mg x 28 film coated tablets ¤23.37

The arrival of Maruxa brings the KRKA portfolio to 27 molecules launched in under 2 years.

MARUXA 10mg x 56 film coated tablets

KRKA are delighted to announce the launch of 5 additional products available with GMS reimbursement from 1st July 2013.

Trade Price:

Diacronal MR (gliclazide) prolonged release tablets are indicated for treatment of patients with non insulin dependent diabetes. Trade Price: Diacronal MR 30mg prolonged release tablets x 60 ¤3.98 Diacronal MR 60mg prolonged release tablets x 30 ¤3.98 (the only generic version of the 60mg currently available in Ireland) Icorvida SR (indapamide) prolonged release tablets are indicated for the treatment of patients with hypertension.

For further information on the Actavis portfolio please contact us in Cork today on 1890 33 32 31 or email on contact@actavis.ie

Zoledronic Acid 4mg/5ml is available to order from the Allphar/

KRKA Pharma Ireland are pleased to announce the launch of Maruxa 10mg (Memantine) on the Irish market. Maruxa is available in both a 28 and 56 pack presentation.

Diacronal MR (gliclazide) 30mg and 60mg, Icorvida SR (indapamide) 1.5mg, Kamiren (doxazosin) 4mg, Venlafex XL (venlafaxine) 37.5mg, 75mg and 150mg, Vizarsin FCT and ODT (Sildenafil) 25mg, 50mg and 100mg.

Uniphar network.

Maruxa Trade price

¤46.72

Icorvida SR 1.5mg prolonged release tablets x 30 ¤2.95 (the only generic version currently available in Ireland) Kamiren (doxazosin) prolonged release tablets are indicated for the treatment of patients with hypertension. Trade Price: Kamiren (doxazosin) 4mg prolonged release tablets x 28 ¤8.48 Venlafex XL (venlafaxine) prolonged release tablets are indicated for the treatment and prevention of major depressive episodes. Trade Price: Venlafex XL 37.5mg prolonged release tablets x 28 ¤8.06 Venlafex XL 75mg prolonged release tablets x 28 ¤11.56 Venlafex XL 150mg prolonged release tablets x 28 ¤19.48

Should you require any further information about Maruxa please contact KRKA on (01) 293 9180

Vizarsin (sildenafil) film coated and orodispersible tablets are indicated for the treatment of men with erectile dysfunction. Trade price Vizarsin 25mg film coated tablet x 4 ¤12.31 Vizarsin 50mg film coated tablet x 4 ¤14.35 Vizarsin 100mg film coated tablet x 4 ¤17.44 Vizarsin 25mg orodispersible tablet x 4 ¤12.31 (the only orodispersible sildenafil currently available in Ireland) Vizarsin 50mg orodispersible tablet x 4 ¤14.35 (the only orodispersible sildenafil currently available in Ireland) Vizarsin 25mg orodispersible tablet x 4 ¤17.44 (the only orodispersible sildenafil currently available in Ireland) For further information on these products or the rest of KRKA’s portfolio please contact our Dublin office on 01 293 9180 or email info.ie@krka.biz

HPN • Issue 9


54 Appointments

Dr Stephen Byrne Dr Stephen Byrne was recently appointed Chair in Clinical Pharmacy Practice along with the post of Head of the School of Pharmacy at UCC. He will take up his post in October of this year. Current Head Professor Caitriona O’Driscoll congratulated Dr Byrne not only for his work to date but his engagement with the profession and his colleagues in both hospital and community pharmacy practice.

Paul Reid Paul Reid has been appointed as the new Managing Director of Pfizer Healthcare Ireland. Paul will be responsible for the performance of Pfizer’s commercial subsidiary in Ireland and is also head of Pfizer’s Specialty Care Business Unit which is responsible for many of Pfizer’s leading medicines in inflammation, vaccines, haemophilia and infective diseases. Paul has over 18 years of pharmaceutical experience, 12 of these at Pfizer where he has held a number of different roles in sales and marketing, including Sales Director/Head of Learning & Development and Marketing Director. Prior to joining Pfizer, he worked with Aventis Pharma, Nutricia Ireland and Rowa Pharmaceuticals.

Brendan McAtamney United Drug plc has announced the appointment of Brendan McAtamney as Chief Operating Officer with effect from 1 September 2013. Brendan will be based at United Drug’s headquarters in Dublin. He joins from Abbott Laboratories Inc. (NYSE:ABT) where he has worked for the last seventeen years in a variety of Global and European leadership positions. In his role, Brendan will focus on enhancing business performance across the three divisions within United Drug; Sales, Marketing and Medical, Healthcare Supply Chain and Packaging and Specialty.

Professor Dermot O’Toole Professor Dermot O’Toole has been appointed as the National Clinical Lead of the Irish Neuroendocrine Tumour Group. Professor O’Toole is Consultant Gastroenterologist/Pancreatologist and Associate Professor St James's Hospital & Trinity College Dublin.

Cllr. Tim Lombard Cllr. Tim Lombard has been elected as the new Chairperson of the Regional Health Forum for the HSE South at its annual general meeting in Cork.The functional area of the Regional Health Forum in the HSE South covers the city councils of Cork and Waterford and the county councils of Carlow, Cork, Kerry, Kilkenny, South Tipperary, Waterford and Wexford.

Richard Simmonds Richard Simmonds has been appointed head of global marketing at medical devices firm Owen Mumford from July 1, 2013. The appointment is a promotion for Simmonds who is currently general manager of the company's international non-group business unit, responsible for international business development. In his new role, Simmonds will lead the newly formed global marketing team, which is to be formed as part of a restructure at Owen Mumford that will see the company work in five new regional management structures.

Peter Guenter Sanofi has announced a new commercial organisation to better align with its business priorities. The past four years have seen a significant shift within the company to become an integrated global healthcare leader focused on patients’ needs with increasingly diversified businesses. The new organisation and subsequent appointments are effective July 1st, 2013. Two new units will be created, Global Commercial Operations and Global Divisions & Strategic Commercial Development to replace the former Global Operations. Peter Guenter, currently Senior Vice President, Europe, Sanofi, has been appointed Executive Vice President, Global Commercial Operations.

Issue 9 • HPN


Benetor

®

Olmesartan medoxomil

Benefit from Benetor® For the Effective Management of Essential Hypertension Greater BP reduction vs. other ARBs*1-7 Effective BP control maintained over 24 hours1,8 Proven achievement of recognised BP targets9,10 * vs. losartan, valsartan and candesartan

ABBREVIATED PRESCRIBING INFORMATION. Benetor 10, 20, 40mg film-coated tablets (olmesartan medoxomil). Refer to Summary of Product Characteristics (SPC) before prescribing. Presentation: Film-coated tablets containing 10mg, 20mg, 40mg olmesartan medoxomil. Contains lactose. Uses: Treatment of essential hypertension. Dosage: Adults: Recommended starting dose 10mg daily. If required the dose may be increased to 20mg daily. Maximum dose 40mg daily. Elderly: No dose adjustment generally required. Patients with moderate renal or hepatic impairment: Maximum daily dose is 20mg. Children, adolescents (below 18 years) and patients with severe hepatic impairment or severe renal impairment: Not recommended. Contra-indications: Hypersensitivity to any component. Second and third trimesters of pregnancy. Patients with biliary obstruction. Warnings and Precautions: Correct intravascular volume depletion before administering. In patients with other conditions associated with stimulation of renin-angiotensin-aldosterone system, possible side effects include acute hypotension, azotaemia, oliguria or, rarely, acute renal failure. Increased risk of severe hypotension and renal insufficiency in patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney. Periodic monitoring of serum potassium and creatinine levels is recommended in patients with impaired renal function. No experience in kidney transplantation or end-stage renal impairment. Hyperkalaemia (which may be fatal), risk factors include diabetes, renal impairment, age (> 70 years), combination with medicines which increase potassium potassi levels, potassium supplements, intercurrent events. Close monitoring of serum potassium in at risk patients is recommended. Not recommended for combination use with lithium. Special caution is recommended in patients suffering from aortic or mitral valve stenosis, or obstructive hypertrophic cardiomyopathy. Not recommended in patients with primary aldosteronism. The blood lowering effect of olmesartan medoxomil is somewhat less in black patients than non-black patients. Do not initiate during pregnancy. Excessive blood pressure decrease in patients with ischaemic heart disease or ischaemic cerebrovascular disease could result in a myocardial infarction or stroke. Interactions: Concomitant use with potassium supplements, potassium sparing diuretics and drugs that increase serum potassium levels (e.g. heparin) is not recommended. The blood pressure lowering effect of olmesartan medoxomil can be increased by concomitant use with other antihypertensive medications. Risk of acute renal failure with concomitant use of NSAIDs and angiotensin II antagonists. Monitoring of renal function and regular hydration of the patient is recommended. Use with NSAIDs can reduce the effect of olmesartan maedoxomil. Coadministration of warfarin and digoxin had no significant effect on the pharmacokinetics of olmesartan, warfarin or digoxin. Use in combination with lithium not recommended. If necessary, careful monitoring of serum lithium levels recommended. No clinically relevant interactions between olmesartan and drugs metabolised by cytochrome P450 enzymes 1A1/2, 2A6, 2C8/9, 2C19, 2D6, 2E1 and 3A4 are expected. Pregnancy and Lactation: Contraindicated in second and third trimesters of pregnancy. Not recommended in first trimester and during breast feeding. Discontinue as soon as possible if pregnancy occurs during therapy. Undesirable Effects: Market experience: The following have been reported very rarely (<1/10,000): Thrombocytopenia, hyperkalaemia, dizziness, headache, cough, abdominal pain, nausea, vomiting, pruritus, rash, allergic conditions such as angioneurotic oedema, dermatitis allergic, facial oedema, urticaria, muscle cramp, myalgia, acute renal failure, renal insufficiency, asthenia, fatigue, malaise, lethargy, abnormal renal function tests, increased hepatic enzymes. Clinical Trials: Common side effects include dizziness, bronchitis, cough, pharyngitis, rhinitis, abdominal pain, diarrhoea, dyspepsia, gastroenteritis, nausea, arthritis, back pain, skeletal pain, haematuria, urinary tract infection, chest pain, fatigue, influenza-like symptoms, peripheral oedema, pain, increased creatinine phosphokinase, hypertriglyceridaemia, hyperuricaemia, and liver enzyme elevations. Less common side effects include vertigo, hypotension, angina pectoris, rash, hyperkalaemia. Overdosage: Most likely effect is hypotension. In the event of overdosage, monitor the patient carefully and give symptomatic and supportive treatment. Pack Sizes: Blister containing 28 film-coated tablets. Legal Category: POM. Product Authorisation Numbers: PA 1595/1/1-3. Product Authorisation Holder: Daiichi Sankyo Ireland Ltd., Riverside One, Sir John Rogerson’s Quay, Dublin 2. Additional information is available on request from: Daiichi Sankyo Ireland Ltd., Telephone: (01) 489 3000, Fax: (01) 489 3033, E-mail: medinfo@daiichi-sankyo.ie Date of Preparation: November 2009. References: 1. Smith D et al. Am J Cardiovasc Drugs 2005; 5(1):41-50. 2. Oparil S et al. J Clin Hypertens 2001;3;283−291,318. 3. Brunner HR et al. Clin Drug Invest 2003;23(7):419−430. 4. Brunner H and Arakawa K. Clin Drug Invest 2006;26(4):185−193. 5. Ball KJ et al. J Hypertens 2001;19(Suppl 1):S49−S56. 6. Stumpe KO and Ludwig M. J Hum Hypertens 2002;16(Suppl 2):S24−S28. 7. Giles TD et al. J Clin Hypertens 2007;9:187−195. 8. Fabia M J et al. J Hypertension 2007, 25:1327-1336. 9. Püchler J et al. J Hypertension 2001, 19(Suppl 1):S41-48. 10. Barrios V et al. Vascular Health and Risk Management 2009:5 723-729. Date of item: July 2013 DSIE/BEN54

HOSPITAL PHARMACY NEWS - ISSUE 9 - 2013  

IN THIS ISSUE: News: Recognition for Kerry hospital pharmacists - Report: Revised biosimilar guideline released - Profi le: Tony Hynds on Ac...

HOSPITAL PHARMACY NEWS - ISSUE 9 - 2013  

IN THIS ISSUE: News: Recognition for Kerry hospital pharmacists - Report: Revised biosimilar guideline released - Profi le: Tony Hynds on Ac...

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