THE INDEPENDENT VOICE OF HOSPITAL PHARMACY Xarelto Combi HPN A5(F):Layout 1 13/08/2012 16:28 Page 1
Xarelto : One Anticoagulant Protecting Against and Treating Many Clot Threats ®
Widely approved Prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery1 •
Licenced since 2008 in this indication
Proven superiority versus enoxaparin in RECORD trial programme2,3
Newly approved Prevention of stroke and systemic embolism in adult patients with non valvular atrial fibrillation (AF) with one or more risk factors, such as congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke or transient ischaemic attack4 Treatment of deep vein thrombosis (DVT), and preventionof recurrent DVT and pulmonary embolism (PE) following an acute DVT in adult patients4 Xarelto 10 mg film-coated tablets (Rivaroxaban). Please refer to full SmPC before prescribing. Presentation: Film-coated tablet containing 10mg rivaroxaban. Indication: Prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery. Dosage and Administration: Recommended dose is 10 mg rivaroxaban taken orally once daily. The initial dose should be taken 6 to 10 hours after surgery, provided that haemostasis has been established. Duration of treatment depends on the individual risk of the patient for VTE which is determined by the type of orthopaedic surgery. For patients undergoing major hip surgery, treatment duration of 5 weeks is recommended. For major knee surgery, treatment duration of 2 weeks is recommended. Renal impairment: No dose adjustment is necessary in patients with mild or moderate renal impairment. Use with caution in patients with severe renal impairment. Not recommended in patients with creatinine clearance <15 ml/min. Hepatic impairment: Contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk, including cirrhotic patients with Child Pugh B and C. Paediatric population: Xarelto is not recommended for use in children below 18 years of age, no data is available in this population. Contraindications: Hypersensitivity to the active substance or to any of the excipients; clinically significant active bleeding; hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C hepatic impairment; pregnancy and breast feeding. Warnings and Precautions: Not recommended: in patients receiving concomitant systemic treatment with strong CYP3A4 and P-gp inhibitors, i.e. azole-antimycotics or HIV protease inhibitors; patients with severe renal impairment (creatinine clearance <15 ml/min); patients below 18 years of age (due to lack of data); patients undergoing hip fracture surgery (due to lack of data), in patients treated concomitantly with dronedarone. Use with caution: in patients with severe renal impairment (creatinine clearance 15 - 29 ml/min) or moderate renal impairment (creatinine clearance 30 49 ml/min) or with renal impairment concomitantly receiving other medicinal products which increase rivaroxaban plasma concentrations; patients treated concomitantly with medicinal products affecting haemostasis (such as NSAIDs, acetylsalicylic acid, platelet aggregation inhibitors, other antithrombotic agents) or with strong CYP3A4 inducers; in patients with increased bleeding risk; when neuraxial anaethesisa or spinal/epidural puncture is employed; patients with congenital or acquired bleeding disorders, uncontrolled severe arterial hypertension, active ulcerative gastrointestinal disease, recent gastrointestinal ulcerations, vascular retinopathy, recent intracranial or intracerebral haemorrhage, intraspinal or intracerebral vascular abnormalities, recent brain, spinal or ophthalmological surgery, bronchiectasis or history of pulmonary bleeding. In patients at risk of ulcerative gastrointestinal disease prophylactic treatment may be considered. There is no need for monitoring of coagulation parameters during treatment with rivaroxaban in routine clinical situations. If clinically indicated rivaroxaban levels can be measured by calibrated quantitative antiFactor Xa tests. Xarelto contains lactose. Undesirable effects: Common: anaemia (incl. respective laboratory parameters), dizziness, headache, syncope, eye haemorrhage, tachycardia, hypotension, haematoma, epistaxis, gastrointestinal tract haemorrhage (incl. gingival bleeding and rectal haemorrhage), abdominal and gastrointestinal pain, dyspepsia, nausea, constipation, diarrhoea, vomiting, pruritus (incl. uncommon cases of generalised pruritus), rash, ecchymosis, pain in extremity, urogenital tract haemorrhage (incl. haematuris and menorrhagia), fever, peripheral oedema, decreased general strength and energy (incl. fatigue and asthenia), increase in transaminases, post-procedural haemorrhage (incl. post-operative anaemia and wound haemorrhage), contusion, wound secretion. Uncommon: thrombocythaemia (incl. platelet count increased), allergic reaction, dermatitis allergic, cerebral and intracranial haemorrhage, haemoptysis, dry mouth, hepatic function abnormal, urticaria, cutaneous and subcutaneous haemorrhage, haemarthrosis, renal impairment (incl. blood creatinine increased, blood urea increased), feeling unwell (incl. malaise), localised oedema, increases in: bilirubin, blood alkaline phosphatase, LDH, lipase, amylase and GGT. Rare: jaundice, muscle haemorrhage, bilirubin conjugated increased (with or without concomitant increased ALT.) Frequency not known: pseudoaneurysm formation following percutaneous intervention, compartment syndrome secondary to a bleeding, renal failure/acute renal failure secondary to a bleeding sufficient to cause hypoperfusion. Prescription only. Marketing Authorisation Holder: Bayer Pharma AG, D13342 Berlin, Germany. MA numbers: EU/1/08/472/006 - 008 Further information available from: Bayer Ltd., The Atrium, Blackthorn Road, Dublin 18. Tel: 01 2999313. Date of Preparation: 6/2012.
Xarelto 15mg and 20mg film-coated tablets (Rivaroxaban). Please refer to full SmPC before prescribing. Presentation: Film-coated tablet containing 15mg or 20mg of rivaroxaban. Indication: Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors, such as congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke or transient ischaemic attack. Treatment of deep vein thrombosis (DVT) and prevention of recurrent DVT and pulmonary embolism (PE) following an acute DVT in adults. Dosage and Administration: : Prevention of stroke and systemic embolism: The recommended dose is 20 mg once daily, which is also the recommended maximum dose. Treatment of DVT and prevention of recurrent DVT and PE: The recommended dose for the initial treatment of acute DVT is 15 mg twice daily for the first three weeks followed by 20 mg once daily for the continued treatment and prevention of recurrent DVT and PE. Renal impairment: No dose adjustment is necessary in patients with mild renal impairment. Patients with moderate or severe renal impairment, for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation, the recommended dose is 15mg once daily, and for the treatment of DVT and prevention of recurrent DVT and PE, treatment should be 15mg twice daily for the first 3 weeks, thereafter the recommended dose is 15mg once daily. Hepatic impairment: Contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C. Contraindications: Hypersensitivity to the active substance or any of the excipients; clinically significant active bleeding; hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C hepatic impairment; pregnancy and breast feeding. Warnings and Precautions: Not recommended: in patients receiving concomitant systemic treatment with strong concurrent CYP3A4- and P-gp-inhibitors, i.e. azole-antimycotics or HIV protease inhibitors; in patients with severe renal impairment (creatinine clearance <15 ml/min); in the treatment of acute pulmonary embolism; in patients below 18 years of age or with prosthetic heart valves or in patients concomitantly treated with dronedarone due to lack of data. Use with caution: in patients with severe renal impairment (creatinine clearance 15 - 29 ml/min) or with renal impairment concomitantly receiving other medicinal products which increase rivaroxaban plasma concentrations; patients concomitantly treated with medicinal products affecting haemostasis (such as NSAIDs, acetylsalicylic acid, platelet aggregation inhibitors, other antithrombotic agents) or with strong CYP3A4 inducers; in patients with increased bleeding risk; patients with congenital or acquired bleeding disorders, uncontrolled severe arterial hypotension, active ulcerative gastrointestinal disease, recent gastrointestinal ulcerations, vascular retinopathy, recent intracranial or intracerebral haemorrhage, intraspinal or intracerebral vascular abnormalities, recent brain, spinal or opthalmological surgery, bronchiectasis or history of pulmonary bleeding. In patients at risk of ulcerative gastrointestinal disease an appropriate prophylactic treatment may be considered. Clinical surveillance in line with anticoagulation practice is recommended throughout the treatment period. There is no need for monitoring of coagulation parameters during treatment with rivaroxaban in routine clinical situations. If clinically indicated rivaroxaban levels can be measured by calibrated quantitative anti-Factor Xa tests. Xarelto contains lactose. Undesirable effects: Common: anaemia, dizziness, headache, syncope, eye haemorrhage, tachycardia, hypotension, haematoma, epistaxis, gastrointestinal tract haemorrhage, gastrointestinal and abdominal pains, dyspepsia, nausea, constipation, diarrhoea, vomiting, pruritus, rash, ecchymosis, pain in extremity, urogenital tract haemorrhage, fever, peripheral oedema, decreased general strength and energy, increase in transaminases, post-procedural haemorrhage, contusion, wound secretion. Uncommon: thrombocythemia, allergic reaction, dermatitis allergic, cerebral and intracranial haemorrhage, haemoptysis, dry mouth, hepatic function abnormal, urticaria, cutaneous and subcutaneous haemorrhage, haemarthrosis, renal impairment, feeling unwell, localised oedema, increases in: bilirubin, blood alkaline phosphatase, LDH, lipase, amylase, GGT. Rare: jaundice, muscle haemorrhage and conjugated bilirubin increased. Frequency not known: pseudoaneurysm following percutaneous intervention, compartment syndrome or (acute) renal failure secondary to a bleeding. Prescription only. Marketing Authorisation Holder: Bayer Pharma AG, D-13342 Berlin, Germany. MA numbers: EU/1/08/472/011-21. Further information available from: Bayer Ltd., The Atrium, Blackthorn Road, Dublin 18. Tel: 01 2999313. Date of Preparation: 6/2012.
References: 1. Xarelto® 10mg Summary of Product Characteristics. 2.Eriksson et al, Oral rivaroxaban for the prevention of symptomatic venous thromboembolism after elective hip and knee replacement. J Bone Joint Surg [Br] 2009;91-B:636-44. 3. Turpie G et al.Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet 2009; 373: 1673–80. 4. Xarelto® 15/20mg Summary of Product Characteristics. L.IE.GM.07.2012.0030
IN THIS ISSUE: News: Caution expressed over generic drug substitution in solid organ transplant recipients Profile: We talk innovation and dynamics exclusively with the team at Letterkenny General Hospital Feature: Professor Moira O'Brien with an overview of the pharmacy role in Osteoporosis management Report: EAHP give HPN their view on clinical trial regulation and what it means for you CPD: The first module in our new series Pulmonary Arterial Hypertension in a Paediatric setting News: Coverage of the FIP centennial conference with a pharmacy technician first
Mercaptopurine oral suspension 20 mg/ml Xaluprine oral suspension offers your patients: n
Accuracy of dosing to 2 mg
Flexibility of dosage
A palatable alternative to tablets
Abbreviated Prescribing Information for Xaluprine (mercaptopurine) 20 mg/ml oral suspension: Please refer to the full Summary of Product Characteristics and the treatment protocol when prescribing Xaluprine. Presentation: Oral suspension, each 1 ml contains 20 mg mercaptopurine (as monohydrate), 3 mg aspartame, 1 mg methyl hydroxyl benzoate, 0.15 mg propyl hydroxybenzoate and sucrose (trace). Indications: For the treatment of acute lymphoblastic leukaemia (ALL) in adults, adolescents and children. Dose and administration: Treatment should be supervised by a physician or other healthcare professional experienced in the management of patients with ALL. The dose is governed by cautiously monitored haematotoxicity and should be carefully adjusted to suit the individual patient. Starting or target doses vary between 25 - 75 mg/m2 body surface area per day, but should be lower in patients with reduced or absent Thiopurine Methyl Transferase (TPMT) activity. Elderly: Monitor renal and hepatic function and if there is any impairment, consider reducing the dose. Renal impairment: Consider reduced starting doses. Monitor patients for dose related adverse reactions. Hepatic impairment: Consider reduced starting doses. Monitor patients for dose related adverse reactions. Switching between tablet and oral suspension and vice versa: The oral suspension and tablet are not bioequivalent. Intensified haematological monitoring is advised on switching formulations. Administration: Redisperse by shaking vigorously at least for 30 seconds. Xaluprine should be taken in the evening and may be taken with food or on an empty stomach. Standardise the method of administration. Xaluprine should not be taken with milk or dairy products but it should be taken at least 1 hour before or 2 hours after milk or dairy products. Water should be taken after each dose. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Concomitant use with yellow fever vaccine. Special Warnings and Precautions for Use: Cytotoxicity and haematological monitoring: Monitor haematological parameters.
Interrupt treatment immediately at the first sign of abnormally large fall in leucocyte and platelet counts. Bone marrow suppression is reversible if 6–mercaptopurine is withdrawn early. Patients with little or no inherited TPMT activity are at increased risk for severe toxicity and require substantial dose reduction. TPMT testing cannot substitute for haematological monitoring. Immunosuppression: Immunisations with live organism vaccines are not recommended. Hepatotoxicity: Monitor liver function weekly. More frequent monitoring may be advisable in those with pre-existing liver disease or receiving other potentially hepatotoxic therapy. Discontinue Xaluprine if jaundice becomes apparent. Renal toxicity: Monitor uric acid levels in blood and urine during remission induction. Hydration and urine alkalinisation may minimize potential renal complications. Mutagenicity and carcinogenicity: 6–mercaptopurine is potentially carcinogenic and consideration should be given to the theoretical risk of carcinogenesis. Excipients: Aspartame may be harmful for people with phenylketonuria. Methyl parahydroxybenzoate and propyl parahydroxybenzoates may cause delayed allergic reaction. Safe handling of the suspension: Avoid Xaluprine contact with skin or mucous membrane. For contact with skin or mucosa, wash immediately and thoroughly with soap and water. Interactions: When allopurinol and 6–mercaptopurine are administered concomitantly only a quarter of the usual dose of 6–mercaptopurine must be given. Other xanthine oxidase inhibitors should be avoided. Reinforced monitoring of INR is recommended in patients co-administered anti-coagulants. Aminosalicylate derivatives inhibit TPMT enzyme and should be administered with caution. Pregnancy and Lactation: Do not use during pregnancy unless expected benefits outweigh any possible risk. Do not use whilst breast-feeding.
and thrombocytopenia is the most common adverse reaction. Anaemia, anorexia, stomatitis, diarrhoea, vomiting, nausea hepatic necrosis, biliary stasis and hepatotoxicity are common adverse reactions. The following adverse reactions have also been reported from uncommonly to very rarely: arthralgia, skin rash, drug fever, pancreatitis, oral ulceration, hepatic necrosis, facial oedema, alopecia, transient oligospermia, secondary leukaemia, myelodysplasia and intestinal ulceration. Overdose: There is no antidote to Xaluprine. Monitor the blood picture and if necessary provide general supportive measures together with appropriate blood transfusion. Activated charcoal or gastric lavage can be undertaken within 60 minutes of ingestion. Pack size: 1 glass bottle containing 100 ml Xaluprine (mercaptopurine) 20mg/ml oral suspension. Shelf-life/Storage: 1 year; 28 days after first opening. Do not store above 25ºC. Legal category: POM. Marketing authorisation number: EU/1/11/727/001. Marketing authorisation holder: Nova Laboratories Limited, Martin House, Gloucester Crescent, Wigston, Leicester, LE18 4YL, UK. Date of latest revision of brief prescribing information: April 2012. Further information including full prescribing information is available from: Nova Laboratories Limited, Martin House, Gloucester Crescent, Wigston, Leicester, LE18 4YL, UK. Tel: +44 (0)116 223 0100.
Contraception: Sexually active men and women should use effective methods of contraception during treatment and for at least three months after receiving the last dose. Undesirable effects: Refer to the SPC for full list. Bone marrow suppression leading to leucopenia
Reference: 1. Mulla H, Leary A, White P, Pandya H. A Step Toward More Accurate Dosing for Mercaptopurine in Childhood Acute Lymphoblastic Leukemia. Journal of Clinical Pharmacology 0091270011423663, first published on December 15, 2011
Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk Adverse events should also be reported to: Nova Laboratories Limited, Martin House, Gloucester Crescent, Wigston, Leicester, LE18 4YL, UK. Tel: +44 (0)116 223 0100
David Preece appointed as new Hospital Pharmacy Advocate P4
First Pharmacy Technician symposium held at FIP Congress - Yvonne Sheehan reports P6
As Hospital Pharmacy News was going to press, a new pricing deal was unveiled by the Department of Health, with the objective of achieving €400m in savings in the State’s drugs bill as well as lowering costs for patients.
Kelly Jo Eastwood
Exclusive chat with the dynamic team at Letterkenny General Hospital P9 Waterford pharmacist Bernard Leddy addresses Malaysian Congress P14 EAHP's Richard Price gives us his view on the changes coming to clinical trial regulation P16 The debate on uncontrolled switching in solid organ transplant recipients P42 Intellectual property and the world of collaborative agreements P46
Regulars: The silent killer that is Osteporosis P18 CPD - The first in our new series of CPD Modules: Pulmonary Arterial Hypertension in a Paediatric setting P25 Current management of Ischaemic Heart Disease P30 Clinical profiles P49
Hospital Pharmacy News is Circulated to all independent, multiple and hospital pharmacist, pre reg pharmacists, students pharmacy student’s offi cial bodies, government officials and departments, Pharmacy Managers, Manufactures, Wholesalers. Buyers of pharmacy groups and healthcare outlets. Circulation is free to all pharmacists Subscription rate for Hospital Pharmacy News 60euro plus vat per year All rights reserved by Hospital Pharmacy News. All material published in Hospital Pharmacy News is copyright and no part of this magazine may be reproduced, stored in a retrieval system of transmitted in any form without written permission. Pharmacy Communication Ireland have taken every care in compiling the magazine to ensure that it is correct at the time of going to press, however the publishers assume no responsibility for any effects from omissions or errors.
PUBLISHER IPN Communications Ireland Ltd Carmichael House, Lower Baggot Street, Dublin 2 00353 (01) 6024715 MANAGING DIRECTOR Natalie Maginnis firstname.lastname@example.org EDITOR Kelly Jo Eastwood email@example.com ACCOUNTS Lorraine Moore firstname.lastname@example.org
SALES MANAGER Debbie Graham email@example.com CONTRIBUTORS Richard Price Yvonne Sheehan Laura Lyons Professor Moira O'Brien Anne Fitzpatrick Professor Frank Giles
The new deal involves an agreement between the DOH and the Irish Pharmaceutical Healthcare Association to ensure patients receive their medicines, and that the Minister shows moves towards cutting the huge deficit faced by his department. The €400m in savings to the State will be spread over three years and comes after criticism of the Minister for Health James Reilly cutting spending on services such as home help while failing to tackle the huge cost of drugs. On patent expiry, the price to the wholesaler of a medicine will be reduced to 70% of the original price. 12 months following this price reduction, the price to the wholesaler will be reduced to 50% of the original price. For existing patent expired medicines, the price to the wholesaler will be reduced to 60% of the original price on 1st November 2012. This will be followed by a further reduction to 50% of the original price to the wholesaler 12 months later. The Agreement will reduce State expenditure on medicines through the various state schemes and also providing patients who pay for their medicines with significant savings on hundreds of medicines. According to Business Monitor International Pharma Projections May 2012, expenditure on medicines has been falling since 2009 and is now fifth lowest in Europe at 11.7%- despite an increasing level of medicine usage. The level of savings delivered since 2006 has impacted on the Irish operations of pharmaceutical companies and these savings agreed will undoubtedly have further impact. Meanwhile Richard Price, Policy and Advocacy Officer at the European Association of Hospital Pharmacists, presents to us an exclusive, quick overview of new proposals from the European Commission on the regulation of clinical trials, and what this might mean for clinical trial management in Irish hospitals. The current system has faced criticism for quite some time now, and accepting these, the European Commission has spent the past two years and more consulting with clinical research stakeholders to formulate a set of proposals that will attempt to remedy the situation and construct a more proportionate and user-friendly set of regulations for conducting clinical research in Europe. Turn to page 16 for the full story.
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THE INDEPENDENT VOICE OF HOSPITAL PHARMACY HPN • Issue 6
Call for global pharmacy care indicators A new report has set out a series of proposals for the Irish Government, and allied European counterparts how to achieve more responsible medication use, including recommending global pharmaceutical care indicators. The report has been published by The European Directorate for Quality Medicines (EDQM). Entitled “Pharmaceutical care: Policies and Practices for a Safer and More Responsible and Costeffective Health System” the key recommendations are for every country, globally, to introduce
generally applicable quality indicators for pharmaceutical care “to provide themselves with valid information for policymaking and to set professional standards and best practices in the field."
7% of medication orders, 2% of patient days and 50% of hospital admissions.
Also contained within the report are an interesting mixture of statistics relating to hospital pharmacy, including references to studies suggesting that medicine administration errors are the most frequent type of medication error in hospital in the hospital setting and that prescribing errors affect up to
1. Number of pharmaceutical care interventions delivered per standardised denominator, such as 1000 prescriptions dispensed or 1000 patients
The report suggests 4 basic indicators for pharmaceutical care:
2. Number of patients counselled about their medicines per standardised denominator, such
as 1000 prescriptions dispensed or 1000 patients 3. Number of formal written feed-back responses from patients during treatment per 1000 prescriptions or 1000 patients about patients' specific medication-related literacy, concerns, life-quality needs/ expectations, and satisfaction. 4. Number of adverse drug event reports (to include both adverse drug reactions and medication errors) per year.
Marathon runners raise funds for Pharmacy Mairead and Deirdre from Our Lady's Hospice who took part in the mini marathon to raise funds for the pharmacy
Runners recently took place in the Mini Marathon, the biggest race in Europe to raise funds for expanding and improving the pharmacy facility at Our Lady's Hospice. In addition, the funds raised will help maintain services for the people in their care, initiate ward and family area refurbishment.
The Mini Marathon is the biggest race in Europe and this year's event was no exception. Yet again droves of women lace up their running shoes to show support for the hospice.
New advocate in hospital pharmacy The European Association of Hospital Pharmacists (EAHP) and the European Pharmaceutical Students Association (EPSA) have commenced a new collaboration with a full time EPSA intern joining the EAHP office. David Preece will work with
Issue 6 • HPN
EAHP assisting in both advocacy on behalf of hospital pharmacists, and in preparing EAHP’s next flagship Congress, taking place in Paris from 13th to 15th March 2013. Speaking about taking up the position, David said: “As the first EPSA intern within the
EAHP, it is a great pleasure to be strengthening the working relationship between the two organisations in this way. "I have a strong personal interest in the future role of the hospital pharmacist and hope this internship will enable me to learn more about hospital
pharmacy practise across Europe, to develop a greater understanding of the way pharmacy is governed at an EU level and more about the EAHP as an organisation. I would like to thank colleagues at both EPSA and EAHP for making this opportunity possible.”
Cancer research breakthrough gains medal University College Cork's Michael Bourke has received a medal for Best Original Research Paper for his research carried out at the Cork Cancer Research Centre at a symposium in Galway this month. His research, funded by Breakthrough Cancer Research, showed how reconditioning the tumour microenvironment with immunogene therapy suppresses tumour development and progression. There is a delicate balance inside the tumour environment between immune cells primed to kill the
cancer cells and other immune cells deployed to dampen down this effect. Dr. Bourke and his colleagues demonstrated that an immunogenetherapy using cytokine interleukin-21 evokes effective anti-tumour responses and has potential for clinical application.
This research project was awarded the Sir Peter Freyer Memorial Medal for Best Original Research Paper chosen from the plenary session of the Sir Peter Freyer Memorial Lecture and Surgical Symposium 2012 at NUI Galway and attended by over 300 delegates.
Excellence in Pharmaceutics Amy Whelan, recipient of the Servier Medal for Experienced Research is pictured with Yvonne Boland, joint winner of the Leo Medal for Excellence in Pharmaceutics; Dr. Judith Strawbridge, Programme Director for BSc in Pharmacy, RCSI and Karen Jordan, joint winner of Leo Medal for Excellence in Pharmaceutics and recipient of the Boots Medal for Excellence in Pharmacy Practice.
HPAI All Ireland Conference In association with the Hospital Pharmacists Association of Ireland, The 6th All Ireland Pharmacy Conference is being held this year on the 13th November 2012 at the Ballyscanlon House Hotel, Dundalk. The conference focus is
to share good practice in pharmaceutical care across the primary and secondary care sectors and is an important forum that enables pharmacists, pharmaceutical assistants and technicians to exchange ideas for pharmaceutical service development in the North and in
the Republic of Ireland. To facilitate networking, a conference dinner has been arranged for the evening of Monday 12th November 2012, the cost of which will be covered by sponsorship. The day delegate fee for the conference (Tuesday 13th
November 2012) is â‚Ź50, with the main proceedings starting at 10am and finishing at 4.30pm. Payment by cheque (to ICCPE) must accompany the application, which should be received by 12th October 2012. Further information can be obtained from www.iccpe.ie
HPN â€˘ Issue 6
Ist Pharmacy Technician symposium at FIP Congress The International Pharmaceutical Federation (FIP) held their centennial congress from 3-8 October in Amsterdam. With a theme of ‘Improving health through responsible medicines use’ the well structured programme provided delegates with learning opportunities in the form of presentations by experts, symposia, workshops, posters and exhibitors stands. The congress also provided networking opportunities between colleagues from all over the world. One of the aims of FIP’s centennial anniversary was to set the stage for the future of pharmacy. Recognizing, the invaluable role of pharmacy technicians in the pharmacy and the healthcare team, FIP offered for the first time, a special two day symposium for pharmacy technicians. The symposium was facilitated by Susanne Engstrom (Denmark) president of the European Association of Pharmacy Technicians (EAPT). The sessions on day one highlighted the current roles of pharmacy technicians around the world, highlighting the differences in regulation and the challenges facing pharmacy technicians. Future job roles and developments in education were also discussed at these sessions.
On day two, the sessions focused on how pharmacy technicians could decrease medication errors and improve patient safety through quality management in areas such as dispensing and OTC counselling. Attention was also drawn to how pharmacy technicians and pharmacists could best work together in a ‘Dream Team’ collaboration to improve patient safety. Presenters from the USA demonstrated how pharmacy technicians can be best utilized in the prevention of medication errors in hospital pharmacies. One case study reminded us that the only real mistake is the one from which we learn nothing. Delegates learnt how a young child who had survived cancer died a result of a medication error. The error occurred when a pharmacy technician who did not have sufficient training used the incorrect strength of sodium chloride when diluting a product for intravenous use. The error was not picked up the pharmacist when checking the product before dispensing. A new law was later introduced into that state requiring pharmacy technicians to be certified and registered. To date there have been no studies published on the role of the pharmacy technician in improving
patient safety but the EAPT are currently looking for opportunities to get involved in such a project. The 73rd FIP World Congress 2013 will be held in Dublin from 31 August until 5 September. Hope to see you there.
Yvonne Sheehan President of the National Association of Hospital Pharmacy Technicians NAHPT Committee member of the European Association of Pharmacy Technicians EAP
Regulation of medical device proposals Proposals have been published for the future regulation of medical devices with the aim of improving assessment procedures, access to information and traceability procedures. In relation to healthcare professionals, it is the European Commission’s expressed hope that the proposals will enable better provision of information on the benefits of particular devices to patients as well as residual risks. This will be provided by an extension of the existing database on medical
Issue 6 • HPN
devices (Eudamed), with access to non-confidential data provided to patients, healthcare professionals and the public at large. The Commission hope this will help healthcare professionals in making the best use of medical equipment in their treatment and care of patients. Other key aspects of the Commission proposals are: > Medical Device Assessment procedures: The Commission’s proposals will enable stronger supervision of independent assessment bodies by national
authorities, with new details to be given on how notified bodies must carry out their evaluations before and after market release (eg the documents to be provided, the scope of verification, the obligation to carry out unannounced on-thespot inspections, checks of samples). > New rules for high risk devices: The Commission proposals introduce a new “scrutiny procedure” for very risky products (Class III). Under this procedure, notified bodies – which authorise the placing on
the market of devices qualifying for the CE label – will be obliged to inform a pan-European Medical Device Coordination Group when they receive a new request for market authorisation for a risky device. > Traceability: The Commission’s proposals will introduce a Unique Device Identification system to enhance post-market safety of medical devices, to help to reduce medical errors and to fight against counterfeiting.
INCIVO®, in combination with peginterferon alfa & ribavirin, for treatment of genotype 1 chronic hepatitis C in adult patients with compensated liver disease (including cirrhosis)1: n who are treatment‑naïve; n who have previously been treated with interferon alfa (pegylated or non‑pegylated) alone or in combination with ribavirin, including relapsers, partial responders and null responders INCIVO® is the only PI to prospectively demonstrate superior SVR rates vs standard therapy for all Genotype 1 patient types2,3,4
INCIVO® 375mg film-coated tablets ACTIVE INGREDIENT(S): Telaprevir Please refer to Summary of Product Characteristics (SmPC) before prescribing. INDICATION(S): Only in combination with peginterferon alfa and ribavirin, for treatment of genotype 1 chronic hepatitis C in adult patients with compensated liver disease (including cirrhosis): treatment naïve or previously treated with interferon alfa (pegylated or nonpegylated) alone or combination with ribavirin, including relapsers, partial and null responders. DOSAGE & ADMINISTRATION: Adults: Two 375 mg tablets, orally every 8 hours with food, swallowed whole (total daily dose: 6 tablets) for 12 weeks, in combination with peginterferon alfa-2a or -2b and ribavirin. Refer to peginterferon alfa and ribavirin SmPC for specific dosage instructions. Total treatment duration of peginterferon alfa and ribavirin either 24 or 48 weeks refer to INCIVO SmPC All patients: Patients with HCV RNA > 1,000 IU/ml at week 4 or 12 should discontinue all therapy. In case of 48 weeks treatment, discontinue peginterferon alfa and ribavirin if HCV RNA detectable at week 24 or 36. Do not reduce or interrupt INCIVO treatment. Do not restart INCIVO treatment if discontinued for ADRs or insufficient virologic response. Missed dose can be taken within 4 hours; otherwise skip dose. Children: <18 years old - no data available. Elderly: Limited data ≥ 65 years old. Renal impairment: No dose adjustment . No data on moderate/severe renal impairment (CrCl < 50 ml/min) or haemodialysis. Hepatic impairment: Dose modifications not required in mild hepatic impairment (Child-Pugh A, score 5-6). Not recommended in moderate to severe impairment (Child-Pugh B or C, score ≥ 7) or decompensated liver disease. Peginterferon alfa and ribavirin are contraindicated in Child Pugh score ≥ 6. CONTRAINDICATIONS: Hypersensitivity to INCIVO tablets. Combinations with strong inducers of CYP3A and active substances highly dependent on CYP3A for clearance where resulting elevated plasma concentrations associated with serious and/or life-threatening events. Do not use with medicines such as: alfuzosin, amiodarone, bepridil, quinidine, astemizole, terfenadine, cisapride, pimozide, ergot derivatives, lovastatin, simvastatin, atorvastatin, sildenafil or tadalafil (only when used for treatment of pulmonary arterial hypertension), oral midazolam and triazolam, rifampicin, St. John’s wort, carbamazepine, phenytoin, phenobarbital. Concomitant Class Ia or III antiarrhythmics, except IV lidocaine. Refer to SmPCs for peginterferon alfa and ribavirin for their contraindications SPECIAL WARNINGS & PRECAUTIONS: Rashes: Severe rashes reported with INCIVO combination treatment; inform patients. Monitor all rashes for progression. Consider consultation with dermatology specialist for moderate rash (< 50% of body surface area). If rash severe (> 50% of body surface area), discontinue INCIVO immediately; consult dermatology
specialist; peginterferon alfa and ribavirin may need to be discontinued. Discontinue INCIVO, peginterferon alfa and ribavirin if generalised bullous eruption, Drug Rash with Eosinophilia and Systemic Symptoms (DRESS), Stevens-Johnson syndrome/toxic epidermal necrolysis, acute generalised exanthematous pustulosis, erythema multiforme suspected/ diagnosed; consult dermatology specialist. Do not restart INCIVO if discontinued. Anaemia: Incidence and severity of anaemia increased with INCIVO combination treatment. Regularly monitor haemoglobin prior to and during treatment. Management of anaemia, see SmPC for ribavirin. If ribavirin permanently discontinued, INCIVO must also be permanently discontinued. If INCIVO discontinued for anaemia, may continue treatment with peginterferon alfa and ribavirin. Do not reduce dose of INCIVO or restart if discontinued. Pregnancy and contraception: see ‘Pregnancy’ below, see also SmPC for ribavirin. Cardiovascular: Significance of modest increase in QTcF interval uncertain. Use with caution with Class Ic antiarrhythmics propafenone and flecainide and other QT prolonging medicines. Avoid in patients with congenital QT prolongation, or family history of congenital QT prolongation or sudden death. Caution in patients with: history of acquired QT prolongation; persistent heart rate < 50 bpm; history of heart failure with reduced left-ventricular ejection fraction; with medicinal products known to prolong QT interval. Clinical and ECG monitoring required. Monitor and correct electrolyte disturbances. Laboratory tests: Monitor HCV RNA levels at least at weeks 4 and 12. Prior to treatment, monitor complete blood count with white blood cell differential counts, electrolytes, serum creatinine, liver function tests, TSH, uric acid and at least at weeks 2, 4, 8 and 12. Combination with peginterferon alfa-2b: No clinical data on treatment-experienced patients and limited data in treatment-naïve patients. Thyroid disease: Risk of increased TSH. Monitor TSH levels before and during treatment. Possible dose adjustment of thyroid replacement therapy. No clinical data on retreating patients who have failed HCV NS3-4A protease inhibitor-based therapy; in pre/peri/post-liver or other transplants; with HCV/HBV coinfection. Limited data in HIV/HCV co-infection. Tablets contain sodium. SIDE EFFECTS: Very common (> 1/10): anaemia, nausea, diarrhoea, vomiting, haemorrhoids, proctalgia, pruritus, rash. Common (> 1/100 to < 1/10): oral candidiasis, thrombocytopenia, lymphopenia, hypothyroidism, hyperuricaemia, hypokalameia, dysgeusia, syncope, anal pruritus, rectal haemorrhage, anal fissure, hyperbilrubinaemia, eczema, swelling face, exfoliative rash, oedema peripheral, product taste abnormal. Serious side effects: DRESS, Stevens-Johnson syndrome, retinopathy. Refer to INCIVO SmPC for other side effects. Refer to peginterferon alfa and ribavarin SmPC for associated side effects. PREGNANCY: Not recommended. Males and females (of childbearing potential) and their partners must use 2 effective non-hormonal contraceptives during treatment and for 2 months after INCIVO
treatment ended. Refer to peginterferon alfa and ribavirin SmPC. LACTATION: Discontinue breast-feeding prior to therapy. INTERACTIONS: Co-administration with CYP3A and/or P-gp inducers may decrease telaprevir plasma concentrations; avoid use with mild/ moderate CYP3A inducers. CYP3A and/or P-gp inhibitors may increase telaprevir plasma concentrations. INCIVO may increase systemic exposure to substrates of CYP3A or P-gp. Refer to C/Is. Avoid domperidone. Rifabutin, darunavir/ritonavir, fosamprenavir/ritonavir, lopinavir/ritonavir, salmeterol, vardenafil not recommended. Inhaled/ nasal fluticasone/budesonide not recommended unless benefit/risk positive. Avoid colchicine in renal or hepatic impairment. Caution with: Class Ic antiarrhythmics propafenone and flecainide, IV lidocaine, digoxin, clarithromycin, erythromycin, telithromycin, troleandomycin, warfarin, dabigatran, trazodone, ketoconazole, itraconazole, posaconazole, voriconazole, parenteral midazolam, amlodipine, diltiazem, felodipine, nicardipine, nifedipine, nisoldipine, verapamil, systemic dexamethasone, bosentan, atazanavir/ritonavir, tenofovir disoproxil fumarate, abacavir, zidovudine, ethinylestradiol/norethindrone, cyclosporine, tacrolimus, sirolimus, methadone, tadalafil (for erectile dysfunction). Use telaprevir 1,125 mg q8h with efavirenz. Clinical relevance of changes unknown for alprazolam, escitalopram, zolpidem. LEGAL CATEGORY: Prescription only medicine. PRESENTATIONS, PACK SIZES, PRODUCT LICENCE NUMBERS- 375mg film coated tablets; pack of 42 tablets (1 week) EU/1/11/720/002 MARKETING AUTHORISATION HOLDER: JANSSENCILAG INTERNATIONAL NV, Turnhoutseweg 30, B-2340 Beerse, Belgium. FURTHER INFORMATION IS AVAILABLE FROM: Janssen-Cilag Ltd, 50100 Holmers Farm Way, High Wycombe, Buckinghamshire HP12 4EG UK. © Janssen-Cilag Ltd 2011 Prescribing information last revised: October 2011 PIVER1011 References 1. INCIVO® Summary of Product Characteristics. 2. Jacobson IM et al. ADVANCE Study team. Telaprevir for previously untreated chronic hepatitis C infection. N Engl J Med 2011; 364 (25): 2405-2416. 3. Sherman et al. ILLUMINATE study team. N Engl J Med. 2011; 365: 1014-24. 4. Zeuzem et al, REALIZE Study team, N Engl J Med. 2011;364(25)2417-2429. Date of preparation: March 2012. IRE/TPV/2012/0055
The evoluTion of Generics The evolution of Generics
Gemcitabine 100 mg/ml concentrate for solution for infusion Accord has developed a ready to use formulation of Gemcitabine: Gemcitabine 100 mg/ml Concentrate for Solution for Infusion which allows to calculate a more precise total volume of concentrate required to prepare a given dose, as shown in the table:
100 mg/ml formulation (Accord)
Aware of the higher concentration of the product before the preparation of solution for infusion (concentration 100 mg/ml as compared to 38 mg/ml after the preparation of solution for infusion in the originator) warning texts have been included in product cartons and labels to avoid any potential confusion by personnel dispensing, handling and preparing Gemcitabine concentrate for solution for infusion.
”: Concentration must be noticed
Warning text “caution, new concentration overdose may occur.
Text “Must be diluted before use”: Gemcitabine concentrate for solution for infusion must be diluted. The total quantity of the Gemcitabine concentrate for solution for infusion required for an individual patient should be diluted into at least 500 ml of sterile sodium chloride 9 mg/ml (0.9%) solution to a final concentration of 0.1 to 5 mg/ml.
100 mg/ml highlighted: 100 mg/ml concentration is highlighted by a coloured box on both main faces of carton, on top flap and on product label. This is highlighted across the different product presentations.
1000 mg/10 ml “Must be diluted before use” This text has been made more prominent on the main face of the carton and on label. Bold text has been applied.
“100 mg/ml” coloured box “caution, notice new concentration (100 mg/ml)” This text has been included in carton and label, right below the name of the product and it’s repeated on both main faces of the carton. Bolded text has been applied.
Concentrate for Solution for Infusion is available in different presentations:
Each presentation is differentiated by: •
including horizontal running lines: one line represents the lowest fill volume and for each next fill volume there is one additional bolded line.
each presentation has a different colour strip alongside the product name box, matching with the same colour of boxed text also included.
1500 mg/15 ml 2000 mg/20 ml
Accord Gemcitabine Solution SPC available on IMB database
200 mg/2 ml Accord Healthcare Ireland Ltd, 24-26 Bullford Business Campus, Kilcoole, County Wicklow, Ireland Tel. +353 (0)1 2592020
Innovation and communication is key at Letterkenny Hospital Pharmacy Department "We have increased our confidence in product quality and patient safety. Moreover, the system has already paid for itself several times over by helping us avoid significant product loss. We recovered our costs within a year saving in excess of €40,000.” Tom Ferrie, Chief Pharmacist
With thousands of medications making their way through hospital and to patients every day, the medication management process is complex, and medication errors and inefficiencies are unfortunately inevitable. The team within the pharmacy department of Letterkenny General Hospital counteracted this problem with an innovation designed to streamline the medication process. Under the leadership of Chief Pharmacist Tom Ferrie, they became the first hospital pharmacy department in Ireland to introduce a Pyxis Medication Management Station, and hence greatly enhanced their safety profile. The innovation has enabled the team to significantly reduce medication errors, help free up staff time to focus on patient care, increase the predictability of medication availability and reduce inefficiencies in the medication use process. At almost every point in this
process, safety and efficiency can be increased with the comprehensive capabilities of the medication management system. Tom tells HPN: “The system ensures staff have to log into the unit with a biometric ID to withdraw medication and this ensures not only far greater accountability but increases patient safety. The start-up was slow and after evaluating different automation solutions on the market, we decided to switch from Pyxis to Omnicell.” LOWERING COSTS AND DELIVERY CARE Undoubtedly, says Tom, the system has helped lower costs and better enable the team to deliver the right care to their patients at the right time. The automated supply cabinet product lines empower hospital supply chain management to effectively control inventory costs, accurately capture charges for reimbursement, and
improve the reorder process for drug supplies. By enabling all of a patient’s medications to be managed through the automated dispensing cabinet, the system creates a closed-loop distribution process that greatly reduces the risk of medication errors and streamlines medication management. The latest system has been introduced into the new Emergency Department within Letterkenny General Hospital. Within the next four weeks it will be in place for the four new wards in the recently opened extension. Tom continues: “Due to the enhanced storage system we have been able to save between 10-15% on our medicines bills. While the system has been costly to introduce, we estimate making back our investment with the savings made.” Additional benefits include significant decrease in medication returns; Less time
spent pulling, checking, and restocking medication and improved pharmacy staff satisfaction. Tom Ferrie has worked within the pharmacy department of Letterkenny General Hospital for over thirty years. During that time he has witnessed many changes, both within the hospital setting and within the pharmacy profession itself. “We have come a long way,” he tells us. “From a staff of one-two pharmacists to approximately 25 full and part-time members of the team. However, staffing levels is always an issue we are re-visiting as I would love to have more staff on board to even further enhance the service we are providing. “We have also moved into a different aspect of pharmacy. Rather than the label of pharmacists simply buying and supplying medicines we are now very much an integral part of the clinical team. The role of the hospital pharmacist, and the
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10 Profile hospital pharmacy technician is now to help reduce a patient’s stay and re-admission rate. “We are continually moving into more specialised areas such as oncology, palliative care, anti-microbials and renal clinical work. The technicians here are also more deeply involved in the purchasing of drugs and sourcing best value.”
General Hospital has formal links with University of Eastern Finland in Kuopio and the Medical University of Gdansk in Poland. “We have been taking students into the department on work placements for over fifteen years from all around the world,” Tom continues.
It is quite clear innovation is rife amongst the team. Tom tells us; “Approximately seven years ago we were concerned about the cold storage here of medicines. By chance, I noticed a local company who had developed a temperature monitoring system within the food industry.
“Our formal education links serve as yet another benchmark for our department. The team at Gdansk chose us as a partner as they realised their potential for learning from our working. They are currently very much in the position we were in a decade ago and they can see how far we have progressed. We, in turn can relate to where they are as we’ve been there.
“A meeting led to them developing a system, specifically for our pharmacy department for the cold storage of drugs. Now, if any fridge goes above a certain temperature I get a text alert and from this money saved has been immense.”
In addition to learning about pharmacy these students have been introduced to Irish life, made friends and in turn have contributed to the local economy during their visit and subsequent visits by them, their family and friends.
Pharmaceutical storage needs to be monitored at all times to maintain the integrity of drugs, including clinical trial materials, and temperature monitoring is used to keep a constant and up to date record of fridge and room temperatures.
“We are immensely proud of our student involvement and links. I feel education and co-operation are hugely important and one of the key aspects to our success as a pharmacy team is our levels of communication. We meet regularly for clinical discussion, to share ideas and promote innovation.”
In line with regulatory requirements and good practice guidelines hospital pharmacies carry out temperature mapping of storage units upon commission and on a continuous basis. With the Kelsius system, users are empowered to carry out their own mapping activities in a cost-effective and time saving manner. An additional feature of that users can enjoy is the ability to automatically capture any door opening events during the mapping process which can be used to explain potential temperature spikes. The Kelsius mapping system cuts costs from day one. It provides an easy to use customisable reporting system and ensures mapping reports can easily be shared with colleagues, clients and verification authorities. The system is now used in many Irish and British hospital. EDUCATION IS KEY An area Tom is passionate about is education. The Pharmacy Department in Letterkenny
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Letterkenny General Hospital (LGH) is an acute general and maternity Hospital, which forms an integral part of the Health Service Executive North West Region. The Hospital aims to deliver a patient-centred, quality-driven focused service and provides a wide range of diagnostic and support services. LGH is also a teaching hospital with links to the National University of Ireland Galway, the Royal College of Surgeons and the Letterkenny Institute of Technology. Recently contract work was completed on site at the new Emergency Department and Medical Wards at the Hospital. The new Emergency Department incorporates an 11 bedded Medical Assessment Unit and X-Ray room and has19 treatment spaces The new facility also provides 3 medical floors which consist of a total of 72 beds, two thirds of which are provided in single rooms, The catchment area incorporates
patients residing in the County Donegal north of Laghey/Pettigo with a population of 140,000.
Not just in terms of their education but their all-round adaptability.
THE FUTURE OF PHARMACY SERVICES
“In addition I would like to see an increase in the provision of pharmacy staff. We continually look to the services provided at some of the major Dublin hospitals who enjoy greater staffing levels and the amount that could be accomplished is tremendous.
Whilst the team at Letterkenny Pharmacy Department continue to strive towards providing optimum patient care, what does Tom feel the future holds for the profession as a whole? “The quality of our pharmacists recently have been really incredible,” he says. “It is such a tragedy that we produce such high calibre professionals and then lose them as the calibre of students has been exceptional.
“Pharmacists are of economic and clinical importance and if the money was available we could expand greatly.”
1 1) Annalise Murphy 2) Tom Ferrie 3) Caitriona Devlin 4) Caitriona Devlin & Annalise Hegarty
We are immensely proud of our student involvement and links. I feel education and co-operation are hugely important and one of the key aspects to our success as a pharmacy team is our levels of communication. We meet regularly for clinical discussion, share ideas and promote innovation.
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Cell communication research funding Dr Lorraine O’Driscoll of the School of Pharmacy and Pharmaceutical Sciences at Trinity College Dublin is the lead principal investigator for an international research consortium that has recently been granted funding of more than €500,000 to work together to shed light on how cells communicate.
Dr Lorraine O’Driscoll
The field of study is in its infancy but the research has implications for the study of cancer, macular degeneration, neurodegenerative and cardiovascular diseases. The research will look at tiny packages of information spurted out from cells called microvesicles and exosomes. “Our research on cancer cells initially suggested that these microvesicles and exosomes may be useful bundles of biomarkers, as micromaps of their cell of origin. More intriguingly –and somewhat more worryingly – our more recent studies suggest that, in cancer, they may also be involved in cellto-cell communication and the transfer of adverse information from cancer cells, contributing to cancer spread to secondary sites throughout the body,” Dr O’Driscoll explains. MICROVESICLES AS KEY PLAYERS Scientists and clinicians from 16 European countries, Australia, three American universities, and five industry partners will be
Issue 6 • HPN
involved in the project. Among the participants are Harvard University, the University of Oxford and INSERM Institut Curie Paris. Industry partners include Nanosight in England, Diagnostic Technologies in Israel and Danone in the Netherlands. The field of microvesicles and exosomes research is in its infancy, but emerging data suggests they are key players in health and disease. Their involvement has been associated with a broad range of events from stem cell communication in embryo development and the body’s education of the immune system, protecting itself, to conditions such as neurodegenerative disease, cardiovascular disease and cancer. Dr O’Driscoll is highly respected in field. Following her BSc(pharmacology) and MSc(clinical pharmacology), her PhD studies in Dublin City University focused on multiple drug resistance in cancer. She worked in research for industry
before returning to academic research and teaching. Since 2001, as collaborator or principal investigator, she has secured research and capital funding approaching €40 million from such authorities as the EU. She also sits on a number of national and international boards and acts as editorial board member and reviewer for key scientific journals. “While the funding of €536,000 is relatively modest compared to some large EU programmes in which Trinity College Dublin is involved, it allows the collaborators to adopt a multidisciplinary approach to enhance basic understanding of and the translational potential of microvesicles and exosomes. Furthermore, a substantial focus here is on training young European researchers in this new area, through workshops, summer schools and exchange programmes and helping to prepare them for future leadership roles in biomedical research,” adds Dr O’Driscoll. IRELAND PLAYING A PIVOTAL ROLE Funding for the European Network on Microvesicles
and Exosomes in Health and Disease (ME-HAD) consortium was granted under the Seventh Framework programme for Research and Technological Development(FP7). This is the EU’s main instrument for funding research in Europe and it will run until 2013. “As initiator and lead institute, Trinity College Dublin will play a pivotal role in ME-HAD. A number of factors have enabled us to be in a position to take this lead,” says Dr O’Driscoll. These include essential support for the research from Science Foundation Ireland, the Marie Keating Foundation, the Irish Research Council for Science, Engineering & Technology (IRCSET), Health Research Board, Trinity Foundation and the Danish Council for Strategic Research. The Higher Education Authority’s support of the Trinity Biomedical Sciences Institute and its stateof-the-art facilities, through the Programme for Research in Third-Level Institutions, means that it is able to host ME-HAD meetings, workshops and summer schools.
in association with: Supported by LEO PHARMA
LEO® © LEO Pharma June 2012. IE/AK/2012/08. ALL TRADEMARKS MENTIONED BELONG TO THE LEO GROUP
A lifetime exposed to the sun, even in Ireland, could mean that you’re at risk from sun-damaged skin1
What do you know about Actinic Keratosis (AK)? Rash-like patches of skin that feel different to the surrounding area could be a serious pre-cancerous skin disease called Actinic Keratosis. Don’t ignore them. Check your skin and ask your GP today about AK.1-3
Summer holidays 1963
, Co Wexford
feel the differeNce, kNow the risk
www.checkyourskin.ie References: 1. Stockfleth E and Kerl H. Eur J Dermatol. 2006; 16:599-606 2. Berman B et al. Supplement to the: The Journal of Family Practice. 2006; 3. Primary Care Dermatology Society. Actinic keratosis. Available at http://www.pcds. org.uk/component/content/article/50-image-atlas-detailed-articles/73-actinic-keratosis. [Last accessed May 2012]
Scan with your smartphone to learn more about AK today Date of preparation: May 2012
HSE Programme works to reduce errors Tim Delaney, HSE
An important aim in the HSE’s Medication Safety Programme is to implement medication reconciliation at 'transitions of care' (such as between hospitals, GPs and the home), in order to reduce errors at 'handover of care'. The Executive also plans to work towards the introduction of technology
to underpin safe, efficient work practices in medication management. According to Tim Delaney, programme lead for medication safety at the HSE’s Quality and Patient Safety Directorate, who was addressing delegates at the recent Retail Excellence Ireland Retreat, bar-code technology in pharmacy can enhance patient safety in both prescribing and dispensing. As of now, the current transcription burden has the potential to cause considerable harm in many areas.
“With regard to transcription and medication reconciliation at hand-over of care, the HSE’s Primary Care Reimbursement Service (PCRS) processed over 17.5 million prescriptions for patients in the General Medical Services (GMS), Drugs Payment Scheme and Long-Term Illness Scheme in 2009,” said Delaney. “With an average of three items per prescription, the total number of individual items processed was 54.3 million. “Bar-coding would facilitate the transition to e-prescribing,” continued Delaney.
New ways of drug discovery Waterford Pharmacist Dr Bernard Leddy is to address the Malaysian Chemical Congress in Kuala Lumpur next month. Dr Leddy, a former President of the pharmacy regulator, the Pharmaceutical Society of Ireland, will address the prestigious Congress on new ways of organising drug discovery. His paper for the Congress is titled “In the Footsteps of Robert Boyle New Ways of Organising Drug Discovery”. "I am honoured to be giving this paper in Malaysia. The great Irish scientist Robert Boyle of Boyle's law fame and a fellow Waterford
man is revered in Malaysia as the father of chemistry. I will be making the link between he, Ireland and Malaysia when I give my research. The Malaysian Government rightly see the potential of science for socioeconomic development and I hope to work for Ireland and Waterford's job creation benefit while I am there." The Malaysian Chemical Congress is the flagship biennial scientific meeting of South East Asia since 1986. Academics, educators and chemistry professionals gather at it to present the latest scientific research. It runs from October
Dr Bernard Leddy
15th for three days. The 17th Congress next month is one of the largest of its kind and is held in conjunction with six Asian universities. Dr Leddy's paper to the Congress will be submitted for publication in the Malaysian Journal of Chemistry next year.
Dr Leddy runs his own consultancy business. He is a former Director and General Manager of pharmacy chain Mari Mina Pharmacies. He graduated with a PhD in pharmacy in the UK. He undertook postdoctoral work in the chemistry department of UCC.
Pharmacy students welcomed at RCSI The Royal College of Surgeons in Ireland (RCSI) welcomed 477 new students to the College to study Medicine, Physiotherapy and Pharmacy during Orientation Week earlier this month. This year's undergraduate intake includes 49 pharmacy students within a total of 337 medical students and 29 physiotherapy studentsfrom Ireland and 23 other countries across Europe, North America, the Middle East, Asia and Africa. Pictured is Dr. Judith Strawbridge, Programme Director for BSc in Pharmacy (centre) with Mary Hopkins and William Whyte, Servier Novice Reseracher Medal winners.
Issue 6 • HPN
Did you know?
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Change is coming to clinical trial regulation in Irish Hospitals: what will it look like? Richard Price, Policy and Advocacy Officer at the European Association of Hospital Pharmacists, presents a quick overview of new proposals from the European Commission on the regulation of clinical trials, and what this might mean for clinical trial management in Irish hospitals. Clinical trial regulation in Europe is sub-optimal. It is not simply external detractors saying this, even the European Commission is prepared to publicly acknowledge the facts: 1. Divergent application of the existing European Clinical Trials Directive, largely due to inconsistent interpretation across different Member States, has made it increasingly difficult to undertake multi-national clinical trials. 2. The 2001 Clinical Trials Directive has led to a greater administrative burden for clinical trials, with associated costs and delays. The assessment undertaken by the Impact on Clinical Research of European Legislation (ICREL) found that non-commercial sponsors required an increase from 1.5 to 2.8 FTE (full-time equivalent) staff to manage administrative tasks associated with a Clinical Trial Authorisation, and that there was an increase in time between finalisation of protocol and first patient recruited from 144 to 178 days. 3. The ‘one size fits all’ regulatory requirements of the Clinical Trials Directive has meant that trials on well-understood drugs are regulated in the same way as trials of completely new drugs, where the risks are unknown. This has increased the difficulties in conducting low-risk clinical trials. Accepting these criticisms, the European Commission has spent the past two years and more consulting with clinical research stakeholders to formulate a set of proposals that will attempt to remedy the situation and construct a more proportionate and user-friendly set of regulations for conducting clinical research in Europe. The Commission published their proposals in July 2012. Key aspects of reform are: 1. The new framework for trial regulation in Europe
Issue 6 • HPN
will no longer be governed by a Directive, but by a Commission Regulation, a device that removes much of the potential for Member States to make widely divergent interpretations of requirements, or to “gold plate” requirements with national level add-on requirements. 2. A new single application portal for conducting a multinational trial will be created, circumventing the need to make multiple applications to every country the trial expects to be conducted in. This new application portal is also expected to increase transparency with much of the information submitted to be made publicly available. 3. The Commission will now allow multi-national clinical trials to be “co-sponsored”. This will be of great assistance to organisations across Europe by allowing those who could not otherwise run clinical research to share responsibilities associated with trials. This measure is important for many academic trials which are conducted through a partnership between universities and hospitals. 4. A new risk-based approach to clinical trial regulation will be put in place, introducing the concept of a “low-interventional trial”. Clinical trials encompass a wide range of medicines from those which are being tested in humans for the first time to those which have already been in established clinical practice for many years. A risk proportionate approach would recognise that the requirements associated with application and monitoring processes of a trial can be reduced depending on the established profile of the medicine. If the intention behind the Commission proposals are successfully realised then the
outcome of the changes should be a more flexible, lower burden and more transparent scheme for clinical trial application, assessment and reporting across Europe. The Commission’s proposals for reforming clinical trial regulation will now be scrutinised over the next year by both the European Parliament and the European Council of Ministers (the relevant Government Departments of each EU Member State). The European Association of Hospital Pharmacists, in conjunction with other organisations, such as Cancer Research UK, the European Science Foundation, and the European Clinical Research Infrastructures Network, is reviewing the proposals in detail and currently seeks more clarity from the European Commission on such issues as: • The detailed specifications and useability features of a new single electronic portal for clinical trials in Europe; • Whether scope will be given to Member States to develop their own risk based approaches to trial regulation; and. • The extent to which reporting requirements for trials using medicines with established safety profiles will actually be reduced. Furthermore EAHP has overarching concerns about clinical trials, including: • How the participation of key under-represented patient groups in clinical trials can be improved (e.g. the elderly, children and females); • How the results, procedures and evidence associated with observational trials can be made more transparent (these currently fall outside the scope of the clinical trials directive); and,
Richard Price • What improvements may be available to improve the systems by which hospitals are compensated for their participation in trials. Advocacy activity by EAHP on the issue of clinical trials will therefore continue through the year ahead. However, the Association has already given a cautious welcome to the intent of the Commission’s proposals and will generally seek to aid their passage into European legislation. EAHP always welcomes contributions to its policy work from hospital pharmacists and others in practice. If you would like to be part of the EAHP’s advocacy team on clinical trial regulation please contact email@example.com for more information. If you would like to receive updates on the progress of these reforms to clinical trial regulation, and other key initiatives relevant to hospital coming from the European Commission, you can sign up to the EAHP’s weekly “EU Monitor” on its website www.eahp.eu
New in Osteop Male orosis 1
Protelos is proven to be an effective long term 1st line osteoporosis treatment option in postmenopausal women, to reduce the risk of vertebral and hip fractures, and in men at increased risk of fracture1
Protelos (strontium ranelate) abbreviated prescribing information: Please refer to the Summary of product Characteristics before prescribing. Presentation: Sachet containing 2g of strontium ranelate granules for oral suspension. Indication: Treatment of postmenopausal osteoporosis to reduce the risk of vertebral and hip fractures. Treatment of osteoporosis in men at increased risk of fracture. Dosage and Administration: The recommended daily dose is one 2g sachet once daily by oral administration at bedtime, preferably at least two hours after eating. The granules in the sachets must be taken as a suspension in a glass of water. Due to the nature of the treated disease, strontium ranelate is intended for long-term use. Patients treated with strontium ranelate should receive vitamin D and calcium supplements if dietary intake is inadequate. Elderly (>65): No dosage adjustment is required in relation to the elderly. Renal Impairment: No dosage adjustment is required in patients with mild-to-moderate renal impairment (30-70 ml/min creatinine clearance). Strontium ranelate is not recommended for patients with severe renal impairment (creatinine clearance below 30 ml/min). Hepatic Impairment: As strontium ranelate is not metabolised, no dosage adjustment is required in patients with hepatic impairment. Paediatric Population: The safety and efficacy of Protelos in children aged below 18 years have not been established. No data are available. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Current or previous venous thromboembolic events (VTE), including deep vein thrombosis and pulmonary embolism. Temporary or permanent immobilisation due to e.g. post-surgical recovery or prolonged bed rest. Precautions: VTE: Protelos is associated with an increased risk for VTE. The cause of this finding is unknown. Protelos should be used with caution in patients at risk of VTE. When treating patients over 80 years at risk of VTE, the need for continued treatment with PROTELOS should be re-evaluated. Skin reactions: Life-threatening cutaneous reactions (Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug rash with eosinophilia and systemic symptoms (DRESS)) have been reported with the use of Protelos. Patients should be advised of the signs and symptoms and monitored closely for skin reactions.Interaction with laboratory test: Strontium interferes with colorimetric methods for the determination of blood and urinary calcium concentrations. Therefore, in medical practice, inductively coupled plasma atomic emission spectrometry or atomic absorption spectrometry methods should be used to ensure an accurate assessment of blood and urinary calcium concentrations. Excipient: Protelos contains a source of phenylalanine which could be harmful for people with phenylketonuria. Interactions: Food, milk and derivative products, and medicinal products containing calcium may reduce the bioavailability of strontium ranelate, therefore, administration of Protelos and such products should be separated by at least two hours. It is preferable to take antacids at least two hours after Protelos, however, when this dosing regimen is impractical due to the recommended administration of Protelos at bedtime, concomitant intake remains acceptable. Protelos therapy should be temporarily suspended if a patient is on a course of oral quinolone or tetracycline antibiotics as it may hinder their absorption. Fertility, pregnancy and lactation: There are no data from the use of strontium ranelate in pregnant women. Physicochemical data suggest excretion of strontium ranelate in human milk. Protelos should not be used during breast-feeding. No effects were observed on males and females fertility in animal studies. Undesirable effects: Overall incidence rates for adverse events with strontium ranelate did not differ from placebo and adverse events were usually mild and transient. Adverse reactions, defined as adverse events considered at least possibly attributable to strontium ranelate treatment in phase III studies are listed below using the following convention (frequencies versus placebo): very common (>1/10); common (>1/100, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). Common: nausea (7.1% vs. 4.6%), and diarrhoea (7.0% vs. 5.0%), headache (3.3% vs. 2.7%), memory loss (2.5% vs. 2.0%), disturbance of consciousness (2.6% vs. 2.1%), dermatitis (2.3% vs. 2.0%), eczema (1.8% vs. 1.4%), venous thromboembolism (2.7% vs. 1.9%), increases in blood creatinine phosphokinase (1.4% vs. 0.6%), Rare: DRESS Very rare: Severe cutaneous adverse reactions- SJS and TEN. Frequency was unknown include: alopecia; oral mucosal irritation; bronchial hyperreactivity, hepatobiliary disorders, hepatitis, bone marrow failure, insomnia, dyspepsia, gastroesophageal reflux, constipation, flatulence. Undesirable effects associated with hypersensitivity skin reactions include pyrexia, lymphadenopathy and eosinophilia. See Summary of Product Characteristics for further details. Presentation: Box containing 28 sachets. Legal Category: POM. Marketing Authorisation Numbers and Holder: EU/1/04/288/001-006, Les Laboratoires Servier, 50, rue Carnot 92284 Suresnes cedex France. Date of Preparation or Last Review: June 2012. Full prescribing information is available from: Servier Laboratories, Block 2, West Pier Business Campus, Old Dunleary Road, Dun Laoghaire, Co. Dublin. Tel: (01) 6638110, Fax: (01) 6638120. Date of Preparation of item: July 2012. 1. Protelos Summary of Product Characteristics PRTPA004
Osteoporosis - The Silent Killer
Professor Moira O Brien FRCPI,FFSEM, FFSEM(UK), FTCD. Preident Irish Osteoporosis Society EU Osteoporosis Charities panel.
early detection is economically essential. One fragility fracture significantly increases the risk of a second fracture occurring, if it is not diagnosed and treated. 20% of people who fracture their hip 60+ will die from the secondary complications within one year. 50% will have difficulty washing, dressing and walking across a room unaided. Only 30% aged 60+ who fracture their hip will regain their independence. 8
Osteoporosis is the commonest bone disease worldwide and is known as “the silent disease”. Osteoporosis is a systemic skeletal disease characterized by low bone mass, micro architectural deterioration of bone tissue and compromised bone strength, with a consequent increase in bone fragility and susceptibility to fracture, particularly of the wrist, hip and spine, which consist mainly of trabecular or spongy bone, however any bone can be affected.(fig 1a,b) The clinical significance of osteoporosis is the fractures that occur. Risk of fractures is increased in patients with low bone density and with each additional risk factor. Osteoporosis can affect all age groups. It is not just an old lady’s
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disease. 1 in 5 men over 50 and 1 in 2 women over 50 will develop an osteoporotic fracture in their lifetime. It is never too late to treat a person or too young to be diagnosed. The first sign is usually a low trauma fracture (fragility fracture), or loss of height. Osteoporosis usually does not cause pain, unless the person has had a fracture, which in many cases could have been prevented. Osteoporosis is a major Public Health Hazard, with a high morbidity, mortality and social costs, because of the high risk of fractures.2 Osteoporosis is a complication of many medical conditions and/ or their treatment. €402 million was spent in 2010 just on falls and fractures in senior citizens, this is why prevention and
It is important to determine the cause or causes. Example: undiagnosed gluten sensitive patient, if not diagnosed, will not improve on oral osteoporosis medication due to malabsorption. Each patient must be treated as an individual and their treatment should be based on: their risk of fracture/ re-fracture, DXA results of spine and hips, their age, their medical history, especially menstrual status in females, and testosterone levels in males. The risk of developing a fragility fracture (breaking a bone as a result of a minor fall) depends on the strength and amount of bone and the rate at which bone is lost and replaced and the type of fall. The most common cause of osteoporosis in females is oestrogen deficiency and low levels of testosterone in males. Prevention should start in early childhood and continue throughout life. Sex hormones play a vital role in determining the onset of osteoporosis. Both testosterone in males and the
female hormone, oestrogen have a protective effect on bones and help prevent the breakdown of bone. Lifestyle choices especially in childhood; lack of exercise, low calcium and vitamin D can have detrimental affects on bone health. These occur in both males and females. Some of the drugs that cause increased bone loss Long-term use of Corticosteroids (e.g. Cortisone, Prednisolone, Dexamethasone etc). Corticosteroids, are used for the treatment of many conditions, and are the most common cause of secondary osteoporosis. Main bone loss occurs in the first six months of treatment. Corticosteroids 7.5 mg a day for more than 3 months in a year. Bone loss may occur at lower doses in some people, particularly if there are other risk factors5 or if they already have undiagnosed low bone density. Thyroxine, if serum levels are high, if it is not monitored Anticonvulsant therapy, Anti- epileptic medications – (phenytoin, phenobarbitone) when taken over a long time, they can interfere with calcium absorption and the production of vitamin D. Prolactin raising drugs, Antipsychotic medication, e.g. some SSRI and Long term lithium therapy
Chronic heparin or Warfarin – there are many medications that cause bone loss. Aromatase inhibitors for the treatment of Prostatic or Breast Cancer- loss is in first six months of treatment. Arimidex for breast cancer. Chemotherapy or radiation or Post organ transplant therapy LHRH analogues; testosterone suppression Diuretics such as Burinex, Lasix. Proton Pump Inhibitors eg omeprazole etc Depot-provera, particularly in adolescents Tranquillizers and sedatives may increase the risk of a fall fig 1a
Osteoporotic bone above, below normal trabecular bone fig 1b
Genetics; A family history of osteoporosis is a very strong risk factor, as 80% of a persons bone is genetic, particularly if it includes a history of hip fracture/s. Age, Senior citizens are more at risk, as they are more likely to have low oestrogen and testosterone levels, low vitamin D levels, have poor nutrition, take less exercise and have other medical conditions or be on a medication that can increase bone loss. Previous fractures after minor trauma. Low bone mineral density by DXA of spine and hips. Loss of height – more than 2cm. Undiagnosed upper, middle or low back pain or undiagnosed hip pain. Low body weight for height. People with osteoporosis or moderate to marked osteopenia are at risk of low trauma fractures (fragility fractures). These are fractures that occur as a result of mechanical forces that would not ordinarily cause a fracture, such as a cough, a sneeze, turning over in bed or from a trip and fall. WHO has quantified this as “forces equivalent to a fall from standing height or less” 38. Research shows that the majority of people who fracture have moderate to marked osteopenia. The risk of a subsequent fracture is much higher in postmenopausal women who already have had a fracture. 4 It is the result of the negative balance between bone formation and bone resorption, i.e. more bone is lost than is formed. Bones require normal levels of sex hormones, adequate caloric intake, protein, calcium and vitamin D and regular weight bearing exercise. The rate of bone turnover is determined by hormonal and local factors. Osteoporosis is the result of the negative balance between bone
formation and bone resorption, i.e. more bone is lost than formed. 60% of bone` is laid down during a child’s growth spurt. When oestrogen declines it affects calcium metabolism and there is increased bone loss. The main bone loss in women occurs in the perimenopausal or first year post menopausal. Some women lose at a faster rate than others. The most common cause of osteopenia or osteoporosis in females is oestrogen deficiency, a late menarche, after age of 15, irregular periods or loss of periods – other than pregnancy. Negative factors include low body mass: under weight for height, past or present eating disorders. Depo-Provera contraceptive can cause bone loss, particularly high risk if given during adolescence when bone is being laid down. Years post menopause: usual menopause occurs in early fifties, a premature menopause is before the age of 45, either natural or surgical. Early menopause is often genetic, it is rare but menopause can happen even as early as the 20’s age group. TREATMENTS All medications prescribed have potential side effects, but the risk of fractures usually far out weights the risk of side effects. So it is essential to discuss which medication is the most suitable for each individual patient. All treatments are aimed at reducing the risk of fracture preventing bone loss or increasing bone formation. MEDICATIONS ARE CLASSIFIED INTO THREE GROUPS Anti-resorptive prevent bone removal • Calcium & Vitamin D for everybody, HRT, Testosterone, SERMS
Bisphosphonates, Denosumab; Human monoclonal antibody targeting RANK Ligand Increase Bone formation • Parathyroid Hormone (1-34 Forsteo) Preotect (1-84) Increase Bone formation and Prevent Bone Removal • Protelos In certain cases, the medication could be contraindicated and specific tests must be carried out to see if the patient is suitable to go on the treatment. The patient must follow the exact instructions on how to take the medication. If a patient has a problem with a medication or develops side effects, it is essential that they contact the doctor who prescribed the medication, as there are other alternatives. Patients should be told of possible side affects, that they are rare however it is important that they report this if they occur, versus stop taking their medications. The various options of treatments should be explained to the patient as well as the importance of taking the medication correctly. What treatment suits the individuals’ life style should also be taken into consideration. In most cases the patient will not feel their bones getting stronger; this is why it is essential to explain this to the patient, to help improve compliance. The treatment prescribed should depend on a number of factors: age, sex, risk of fracture or refracture, cause or causes of their osteoporosis, DXA scan results of their spine and hips and medical history. The patient’s ability to swallow tablets and to sit upright for periods of time or ability to self-inject. Compliance of patient with medications and the patient’s cognitive ability. Discovering the cause or
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causes of the osteoporosis and addressing each one is hugely important for the treatment to be effective. Ideally all Osteoporosis medications should always be used in combination with a well balanced diet with adequate calories, calcium and vitamin D, 30 minutes weight bearing exercise daily (60 minutes for children), suitable for the person’s age, medical history and ability. The 30 minutes can be divided into segments of 3-5 minutes such as marching or running on the spot, stair climbing and dancing. Walking is weight bearing however; the speed and path should be altered to get the most benefit. SERMs are a group of drugs that have a positive effect on the oestrogen receptors in the bone and cardiovascular system and have a negative effect on the oestrogen receptors in the breast (Prevent oestrogen dependent breast cancer) and some may or may not increase the endometrium or lining of the uterus –Tamoxifen. • Contraindications are; Premenopausal women or pregnant women. • People who are experiencing hot flushes due to menopause, as it can increase flushes. • Patient who has a history of venous thromboembolic events, including deep vein thrombosis (DVT) and pulmonary embolism (a blood clot). Bisphosphonates are poorly absorbed, must be taken on an empty stomach, with water, 30 to 60 minutes before breakfast, must stay upright and ideally no upper GI problems, oesophageal abnormalities, hiatus hernia or gastritis and have normal renal function. Osteonecrosis of jaw is extremely rare, it is commoner in patients who have poor dental hygiene and also patients with cancer; incidence is less than
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one per 100 000 patient years. Atypical femoral fractures are also rare; they tend to occur in patients who have been on bisphosphonates for long period of time, 5-10 years. It is recommended that patients should be switched to a non bisphosphonate treatment after five years. Oral Bisphosphonates can be taken once weekly, alendronate , Fosamax 75mg or Fosavance combined with vitamin D3; risedronate, Actonel 35mg or combined with calcium and vitamin D Once monthly: Ibandronate 150mg, Bonviva once monthly or available as IV as every three months. Zoledronic acid: Aclasta is an intravenous infusion. 5mg/100ml by at least a 15 minute infusion once a year. The patient must have normal vitamin D levels, normal calcium and renal function, precaution if patient has auricular fibrillation. Denosumab: Prolia is an anti Rank Ligand monoclonal antibody, which reduces the formation Rank ligand and as a result osteoclasts, which remove bone; two subcutaneous injections a year, patients must have normal levels of vitamin D, it is particularly suitable for people who have been prescribed aromatase inhibitors for cancer of the breast or prostate and those who have absorption problems and reduced renal function. Strontium Ranelate: Protelos has a dual action, it reduces bone resorption, prevents bone loss and increases bone formation and bone mineral density (BMD) through the formation of new normal strong bone37. Protelos is taken daily, one 2G Sachet with water, no calcium containing food should be taken 2 hours before or 2 hours after taking the medication, as it competes with
calcium. Protelos can be taken during the day, at bedtime or during the night. Protelos can help decrease pain of vertebral fractures and osteoarthritis. Anabolic agents: PTH 34 (Forsteo) or PTH 84 (Preotact) are the most effective anabolic agents and the most expensive, as a result they are high tech drugs , and can only be prescribed by a consultant. Forsteo is given daily, dose is 20mcg, as a subcutaneous injection for a maximum of 2 years, must take calcium and vitamin D and do 30 minutes weight bearing exercise. Stop smoking, and other osteoporotic medication must have normal levels of parathyroid hormone, serum vitamin D and normal renal function. Patients who have had radiation, are unable to receive this treatment. Monitor by blood tests and DXA. To maintain the increase in BMD in most cases patient needs to go on an osteoporotic medication at the end of the course of PTH. Forsteo is effective in relieving the pain of vertebral fractures. HRT - OESTROGEN/ HORMONE THERAPY HRT (oestrogen and a prosgestogen) for people, who have had an early menopause before 45, particularly if they have menopausal symptoms or are very thin, provided there are no contraindications. HRT is determined on individual basis, must take into account the patients age, years post menopause, history, menopausal symptoms and risk factors. Oestrogen only for patients with no uterus. Teenagers with an eating disorder usually have very low oestrogen and progesterone levels and are often diagnosed with osteopenia or osteoporosis15, those with eating disorders, past or present, male or female, should have a DXA scan urgently. The earlier this disease is diagnosed the more
effective recovery in dealing with the cause as well as their reduced bone density. Lifestyle factors: Stopping smoking and reducing alcohol intake, decreasing fibre if more than 40 grams a day and cutting down on caffeine. Adequate fluid intake is essential for over all heath. Calcium and Vitamin D: The daily recommended amounts of calcium and vitamin D are essential for the prevention and treatment of Osteoporosis. The amounts required depend on the patient’s age. Calcium and vitamin D should be taken preferably in food as it is easier to absorb, however many people will require calcium and vitamin D supplements. Calcium and vitamin D should be taken throughout life to help protect bone. Calcium and vitamin D are an essential part of the prevention and treatment of osteoporosis, particularly in housebound and nursing home elderly. Bone is a major store of calcium and phosphate. Vitamin D is necessary for adequate absorption of calcium and is important for normal muscle and nerve action. There may be inadequate amounts of Vitamin D in the diet, and supplementation is necessary when dietary intake of vitamin D is inadequate. Normal levels of oestrogen and testosterone are required to form vitamin D. It is important also to determine whether there is lack of absorption of vitamins D. Many people think that bloating of the stomach after food, is because they have eaten too much or eaten to fast. Ireland has one of the highest rates of Coeliac disease/gluten sensitivity in the world, therefore every patient should be asked regarding the symptoms. Gluten intolerance is very common and is associated with low levels of vitamin D, particularly if people avoid
any sun exposure. A history of irritable bowel, bloating, constipation or loose stools associated with eating bread, pasta, drinking beer, wheat or gluten products or a family history of Coeliac disease should be investigated. Often when people are stressed they increase their intake of bread, biscuits and cakes, similar to carbohydrate loading in athletes, which may give them symptoms of Malabsorption, affecting calcium and vitamin D. If low levels of vitamin D persist for a period of time it may cause secondary hyperparathyroidism resulting in increased bone loss and prevents absorption of medications and increased risk of falls. NOTE: Reducing stress should also be encouraged, as stress can affect sex hormones, which can affect bone. The major source of vitamin D is from the action of sunlight on the skin. About 15 minutes of sunlight a day on the face and arms during the summer helps to increase vitamin D levels. However their needs to be sun, to avail of vitamin D, which unfortunately Ireland lacks. The amount formed depends on the age of the person and the amount of sun block and/ or make up used. It is very important to avoid over exposure resulting in sunburn, as we are all aware of the damaging effects of the sun also (especially skin cancer). Therefore sun block should be applied after 15 minutes. If a person has very light skin, 2-3 minutes, several times a day to equal the 15 minutes, followed by sun block being put on.
Calcium absorption Parathyroid hormone Appropriate neuromuscular function
Bone mineral density
Risk of fracture
bone turnover and an increased risk of fractures, especially in older people (â‰Ľ65 years) and those with osteoporosis. Low levels of vitamin D will also increase the risk of falls and as a result, the risk of fractures increases.28-38 All the above are an essential part for the prevention and treatment for all patients along with their osteoporosis medication.
Compliance is one of the major problems in treating patients with osteoporosis. If a patient has not fractured, if the results of the DXA scan has been explained to them and also the consequences of not taking medication and implementing life style changes, poor compliance is evitable. Patients should be monitored by DXA to see if they are improving, which also improves compliance.
Fall Prevention programmes by a Chartered Physiotherapist for those with a prior fall or at risk to fall.
The Irish Osteoporosis Society does not recommend heel scanning for the diagnosis of Osteoporosis.
It is usually never too late to treat osteoporosis. However early detection is essential and all the cause/s should be found and addressed to prevent further problems. Treatment of osteoporosis should if possible have a multidisciplinary approach. Osteoporosis is preventable and treatable in the majority of people. Pharmacists are respected by the public and are on the front line with patients. By being pro active, pharmacists can significantly decrease the amount of people ending up losing their independence.
Osteoporosis skeletal progression
PROLONGED LOW LEVELS OF VITAMIN D Prolonged Low levels of vitamin D may lead to sub-optimal calcium absorption, which may increase the levels of Parathyroid Hormone i.e. secondary hyperparathyroidism, with a high
HPN â€˘ Issue 6
Figures reveal free statins too high in costs Cllr Kieran Dennison
places in care homes. A total of £1.3billion is spent annually on cardiovascular drugs alone. Cllr Dennison asked: “To ask the estimated cost of prescribing statins on the GMS to all those over the age of 50 in the Dublin North East region and what the savings might be based on the recent trial published in the Lancet. Figures from the HSE show: • Cost of Statins on GMS scheme 2011 for patients aged 50 & over in Dublin North East €18,215,568 • No of unique patients treated with Statins 2011 aged 50+ in Dublin North East 59,313 • Eligible Medical Card Population 2011 Dublin North East aged 50+ 122,600 • Cost per patient €307.11
Following a question by Fine Gael Councillor Kieran Dennison, at the May meeting of the DNE Regional Health Forum, figures have been revealed which show potentially providing statins free of charge to all those over the age of 50 would cost the HSE may be presently unachieveable in the current economic climate.
A report published in the Lancet earlier this year demonstrated that benefits to people with no history of heart disease with the use of statins. The risk of a heart attack or stroke was shown to reduce by a fifth. Treatment guidelines should be reviewed in light of the findings, the report experts said, and the NHS should impose a blanket policy
of prescribing up to 20 million people statins at a potential cost of £240million a year. The cost of statins, which can cost as little as £1 for a month’s course, would also be offset by the savings they would bring to the NHS in preventing costly operations, rehabilitation and by freeing ward space and
> Estimated cost of Statins for patients aged 50 yrs + in Dublin North East €37,651,686.00 Commenting on the findings, Cllr Dennison said: “The evidence is compelling but obviously the cost in the present climate may be prohibitive.”
Medicine prices to drop in deal worth over €400 million The Irish Pharmaceutical Healthcare Association (IPHA) has announced a very significant new Supply Agreement which will ensure that new medicines are made available to Irish patients. The Agreement was reached with the Department of Health and the Health Service Executive. According to David Gallagher, outgoing President who led the negotiations on behalf of IPHA: “Ireland has a strong record in ensuring that patients can
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access new advanced therapies. This new Agreement provides assurance for Irish patients that they will be able to get new medicines when they become available. Medicines are a key pillar of any advanced health system and medical innovation has extended life expectancy through reducing illness and death. Many patients are in need of new, advanced medicines in areas such as Alzheimer’s Disease, arthritis, cancer, stroke prevention, multiple sclerosis
and cystic fibrosis.” The Agreement will provide over €400 million in savings, reducing State expenditure on medicines through the various state schemes and also providing patients who pay for their medicines with significant savings on hundreds of medicines. This is in addition to reductions of €600 million provided by pharmaceutical companies since 2006. Orlaith Brennan, Commercial
Affairs Director of the IPHA said “We understand the enormous fiscal challenges facing the country, but it is important to ensure that patient’ needs and expectations can continue to be met. This deal offers value and savings to the State and patients, and ensures that the full range of modern therapeutically advanced medicines continue to be available to Irish patients in spite of current economic difficulties”.
- INTRODUCING -
B ONASOL Once Weekly Oral Solution 70mg Alendronic Acid
The optimal solution for Alendronate. The iSSue:
Alendronate tablets are highly acidic, and must be taken before food and with at least 200ml of water, due to the risk of them causing ulceration and oesophagitis this an lead to poor compliance.
The SOluTiOn: BONASOL is a liquid formulation of alendronate, 70mg/100ml in a pleasant sugar-free solution, thus avoiding these complications. Bonasol Once Weekly is a unique medicine, developed and made in Ireland, for Europe and the world. Rx 100ml once weekly, before breakfast.
PACKAGE QUANTITIES: 4* 100ml clear plastic bottle with a tamper-evident closure POM. GMS MAH: XEOLAS PHARMACEUTICALS LIMITED PA 1572/1/1 MARKETED IN IRELAND BY: FANNIN LTD, FANNIN HOUSE, LEOPARDSTOWN, DUBLIN 18 For a copy of the SmPC or further medical information, please contact MedInfo@fannin.eu Adverse events should be reported to Fannin Ltd at 01 2907000 or firstname.lastname@example.org FN2012-10-005
It's not what you do but the way you do it! The APTUK 2012 conference was held in the NEC, Birmingham on September 29th and 30th co-located with the Pharmacy Show. Laura Lyons, Vice President of the National Association of Hospital Pharmacy Technicians attended and gives Hospital Pharmacy News an overview of the event. During the Saturday it was fascinating to gain an overview of what it takes to be involved in the pharmacy olympic family. Despite there being a lage number of interesting sessions, I chose a talk by Trudy Thomas, Head of Clinical and Professional Practice, University of Kent. She spoke about her experience of being a pharmacist in the Olympic Pharmacy and outlined what it takes to look after all the athletes and the Olympic family of both the Olympic and Paralympic games. Following on from this I attended a session on New Medicines Service(NMS). Its purpose is to follow up with patients when they have been started on new medication to ensure they are taking it correctly and to answer any questions they have.
Delegates at the APTUK conference
Trudy Thomas and Nimo Ahmed
Kevin Ratcliffe, consultant pharmacist with Birmingham and Solihull addictions team spoke about needle exchange programmes and the importance of understanding and supporting drug addicts. The final session of the day was a talk from Derek Redmond, retired Olympic Athlete. He concentrated on one particular race in his career, the 1991 Tokyo World Championship 4x400m relay final. The GB team managed to beat the USA team against all odds by simply changing the order in which the four team members ran. His message was “its not what you do but the way you so it”. He produced the gold medal at the end of the talk.
Save the Date
The first session on Sunday was on Ethical Dilemmas. The talk was given by Chris Chapman, Chemist and Druggist. He spoke about ethical dilemmas facing both pharmacists and technicians. Nimo Ahmed, Acting Head of Enforcement, MHRA spoke about fake medicines and how prevalent they are. He mentioned a case they had worked on for a number of years that had eventually ended in a conviction.
The National Association of Hospital Pharmacy Technicians annual conference will take place
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Saturday 27th of April 2013 in the Crowne Plaza, Santry, Dublin.
Pharmacy Technicians from all sectors are welcome. More details to follow!
CPD 1: PULMONARY ARTERIAL HYPERTENISON IN A PAEDIATRIC SETTING Biography - Anne Fitzpatrick qualified from TCD in 2006 and began working at Our Lady's Children's Hosptial, Crumlin. She has been working there as a pharmacist in various specialities since 2007. In 2010, she completed an MSc in Clinical Pharmacy from UCC.
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.
Pulmonary Arterial Hypertenison in a Paediatric Setting BACKGROUND Pulmonary arterial hypertension (PAH) is a chronic disorder of the pulmonary vasculature. It is characterised by a progressive increase in pulmonary vascular resistance which, if left untreated, may be fatal. Death may occur as a result of both acute and chronic right heart failure and its associated arrhythmias.1 The normal value for mean pulmonary artery pressure is 15mmHg (systolic 22mmHg, diastolic 10mmHg).2 By definition, paediatric idiopathic PAH exists when mean pulmonary artery pressure is >25mmHg at rest with normal capillary wedge pressure and when any associated causes of pulmonary hypertension have been ruled out. Secondary / Associated causes of pulmonary hypertension include portal hypertension, systemic lupus erythematous and certain types of congenital heart disease.2,3According to the UK pulmonary hypertension association PAH is estimated to affect between 15 and 50 people per million of the population4. In a healthy individual, the pulmonary artery carries blood from the right ventricle of the heart to the lungs, where the blood is oxygenated. This oxygenated blood is carried back to the heart into the left ventricle and is pumped through the aorta all around the body. The body’s organs and muscles
use the oxygen and the blood is passed back to the right side of the heart. During exercise the body’s demand for oxygen increases. This in turn causes increased heart rate. The pulmonary artery widens and blood flow through the lungs is increased.
Other symptoms include:
However in pulmonary hypertension, the vessel walls are thicker and less flexible, making it harder for the right ventricle to pump blood through the lungs. Over a period of time, the right ventricle enlarges and works less efficiently. The heart muscle then weakens and loses the ability to pump enough blood for the body’s needs. Heart failure may then result.4
• Swelling in the legs and ankles
A number of tests are used to help diagnose PAH. A chest X-ray may reveal abnormalities of the heart and lungs that are characteristic of PAH. An electrocardiogram (ECG) will show evidence of right ventricular dilatation and hypertrophy. An echocardiogram is used to estimate pulmonary arterial systolic and diastolic pressures. Lung function tests, exercise testing, MRI scanning may also be useful. Cardiac catheterisation confirms diagnosis, assesses severity and accurately determines pulmonary arterial pressures.4
• Tiring easily • Palpitations • Syncope • Near syncope
Unfortunately there is presently no cure for this disease. Before treatment with vasodilator therapy was available, the expected survival time was less than two years for children. With treatment, survival has improved. However, morbidity and mortality still remains high and varies depending on the age of the patient, the degree of pulmonary hypertension and the response to vasodilator therapy. The United Kingdom Pulmonary Hypertension Service for Children reported survival rates of 85.6% at 1 year, 79.9% at 3 years, and 71.9% at 5 year5.
• Bluish colour lips. However, symptoms are often non-specific making the diagnosis of PAH more difficult. Symptoms may be associated with a variety of other conditions e.g. asthma. Pulmonary hypertension should be suspected where there is no evidence of heart or lung disease.
PAH can be classified according to the severity of the symptoms.The WHO functional assessment6 is shown in Table 1 below.
1: adapted from Rubin LJ. Diagnosis and management of TableTable 1: adapted from Rubin LJ. Diagnosis and management of pulmonary arterial 6 pulmonary arterial hypertension:Clinical ACCP Evidence-Based Clinical hypertension: ACCP Evidence-Based Practice Guidelines 6 Practice Guidelines
Class I: Class II:
Shortness of breath and fatigue are two of the most common complaints, which may occur either at rest or during exercise.
Patients with PAH but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnoea or fatigue, chest pain, or near syncope. Patients with PAH resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnoea or fatigue, chest pain, or near syncope. Patients with PAH resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnoea or fatigue, chest pain, or near syncope. Patients with PAH with inability to carry out any physical activity without symptoms. These patients manifest signs of right-heart failure. Dyspnoea and / or fatigue may even be present at rest. Discomfort is increased by any physical activity.
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CPD 1: PULMONARY ARTERIAL HYPERTENISON IN A PAEDIATRIC SETTING Table 1: adapted from Rubin LJ. Diagnosis and management of pulmonary arterial hypertension: ACCP Evidence-Based Clinical Practice Guidelines6 Patients with PAH but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnoea or fatigue, chest pain, or near syncope. Patients with PAH resulting in slight limitation of physical Class II: activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnoea or fatigue, chest pain, or near syncope. Patients with PAH resulting in marked limitation of physical Class III: activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnoea or fatigue, chest pain, or near syncope. Patients with PAH with inability to carry out any physical Class IV: activity without symptoms. These patients manifest signs of right-heart failure. Dyspnoea and / or fatigue may even be 8 present at Discomfort is increased by any physical Figure 1 Mechanism ofrest. action of sildenafil . cGMP, cyclic guanosine activity. monophosphate; GTP, guanosine triphosphate; GMP, Class I:
TREATMENT The main aims of treatment are to
• Delay disease progression and prolong survival • Increase exercise tolerance and quality of life • Reduce severity of symptoms These goals may be adapted depending on co-morbidities, underlying disease, patient priorities and the disease stage at diagnosis.
2. Endothelin 3. Prostacyclin • Functional class II - Sildenafil •
Functional class III Endothelin-receptor antagonists (bosentan), sildenafil, IV epoprostenol, or inhaled iloprost
• Functional class IV Intravenous epoprostenol (treatment of choice) 1. NITRIC OXIDE Sildenafil Sildenafil is a selective inhibitor of phosphodiesterase type 5 (PDE-5). High concentrations of PDE-5 are found in the lungs. Cyclic guanosine monophosphate (cGMP), involved in the nitric oxide signalling pathway, increases blood flow and promotes relaxation of vascular smooth muscle and vasodilation. cGMP is broken down by PDE-5. By inhibiting PDE-5, Sildenafil enhances the vasodilator effects of nitric oxide.7 Figure 1 above illustrates the mechanism of action of sildenafil8.
Bosentan is currently not licensed for use in children. However, the pharmacokinetic profile in children appears to be similar to that in adults and studies have suggested a role for bosentan in this population.11 The current dosing guidelines are as follows: <10kg: 1mg/kg orally every twelve hours for four weeks then increase to 2mg/kg every twelve hours
Three main pathways are targeted: 1. Nitric Oxide
increased cardiac output without increased heart rate.11,12
Sildenafil must be initiated by a consultant cardiologist. The initial dose is 0.25 – 0.5mg/kg every four to eight hours, which can be adjusted according to response, up to a usual maximum dose of 2mg/kg every four hours.9 It is recommended to start with a lower dose and frequency especially if it is used in combination with other vasodilators. The main side effects are headache, facial flushing, systemic hypotension, gastritis, cough, nasal congestion and visual disturbances.10 Sildenafil is available as 20mg tablets (Revatio®). In 2012, a licensed version of Sildenafil liquid (Revatio® 10mg/ml) became available in Ireland. Liquid preparations mean smaller doses can be easily measured and doses can be titrated upwards in smaller increments. Potential drug interactions need to be borne in mind. Bosentan, carbamazepine, phenytoin and phenobarbitone all speed up the clearance of sildenafil. Enzyme inhibitors such as itraconazole and clarithromycin slow the clearance of sildenafil. In August 2012 a safety alert was issued by the US Food
and Drug Administration. This occurred following the outcome of a trial which demonstrated a direct dose related effect on mortality in patients treated with high doses of sildenafil. However, the full implications of this trial remain to be seen and limited treatment options mean clinicians have little choice. 2. ENDOTHELIN RECEPTOR ANTAGONISTS • Bosentan (Tracleer® 62.5mg & 125mg tablets) Bosentan is an endothelin receptor antagonist with affinity for both endothelin A and B receptors. Endothelin-1, a neurohormone, is one of the most potent vasoconstrictors, which mediates its effects by binding to ETa and ETb receptors in the endothelium and vascular smooth muscle. It is pro-inflammatory and can also promote fibrosis, cell proliferation, cardiac hypertrophy and remodelling. In patients with PAH levels of endothelin-1 are raised. Several studies have suggested a correlation between ET-1 levels and severity of disease. By blocking the action of ET-1, Bosentan decreases both pulmonary and systemic vascular resistance resulting in
10 – 20kg: 31.25mg orally once daily for four weeks then increase to target dose of 31.25mg eve twelve hours. 20 – 40kg: 31.25mg every twelve hours orally for four weeks then increase to target dose of 62.5mg every twelve hours. >40kg: 62.5mg every twelve hours orally for four weeks, then increase to 125mg twelve hourly. Maximum dose 250mg twelve hourly. The main adverse effects are elevations in liver aminotransferases and a dose related decrease in haemoglobin concentration. Haemoglobin concentrations must be checked prior to initiation of treatment, every month during the first 4 months, and quarterly thereafter. Liver aminotransferase levels must be measured prior to initiation of treatment and subsequently at monthly intervals for the duration of treatment. Liver aminotransferase levels must be measured 2 weeks after any dose increase.12 Bosentan is an inducer of cytochrome P450 isoenzymes CYP2C9 and CYP3A4. Consequently, it reduces plasma concentrations of drugs metabolised by these isoenzymnes. Bosentan is
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CPD 1: PULMONARY ARTERIAL HYPERTENISON IN A PAEDIATRIC SETTING
also metabolised by CYP2C9 and CYP3A4. The use of enzyme inhibitors such as azole antifungals should be avoided. Enzyme inducers such as rifampicin may decrease bosentan levels. The use of bosentan is contraindicated with ciclosporin. For those patients on warfarin no dose adjustment is needed, but the INR should be monitored closely, especially when bosentan is initiated and during the uptitration period. There is a also a potential for increased bosentan concentration and decreased sildenafil concentration when the two drugs are co-administered.12 Bosentan is currently only available as 62.5mg and 125mg tablets (Tracleer®). It has potential teratogenic effects and therefore handling precautions are necessary. Splitting tablets or the handling of split tablets should not be performed by women who are / may be pregnant.11 Instructions for cutting tablets: To obtain a dose of 31.25mg, a commercial tablet cutter should be used to cut a 62.5mg tablet in half. The tablet cutter should be cleaned before and after use to avoid cross-contamination of other medicines. The occupational exposure limit for bosentan is very low and it is classified as being moderately toxic. It is recommended that a mask and gloves be worn. Dissolving tablets For doses less than 31.25mg, a tablet should be dissolved in water. There is no need to crush bosentan tablets as they will dissolve readily in water. Fruit juices and other acidic drinks should not be used as they hinder dissolution. The required dose may then be drawn up and any remaining solution discarded. • Sitaxentan (Thelin®) Sitaxentan is a potent and highly
selective entothelin receptor antagonist. It has a much greater affinity for ETa receptors than ETb. It is licensed for use in patients with WHO functional class III pulmonary hypertension. It is not approved for use in paediatrics.13 3. PROSTACYCLIN Epoprostenol Epoprostenol (Flolan® 0.5mg and 1.5mg vials - powder with diluent for reconstitution) Prostacyclin is a steroid made naturally in the body which relaxes blood vessels in the lungs. Patients with PAH have lower levels of prostacyclin which leads to constriction of blood vessels. Epoprostenol relaxes blood vessels in lungs, slows scarring and cell growth within vessels preventing further vessel narrowing. It increases cardiac output and oxygen saturation. Epoprostenol is a potent vasodilator but it is also the most potent inhibitor of platelet aggregation known.1 It is administered as a continuous intravenous infusion. The half-life is three to five minutes. Ideally, it is administered via a permanently placed Hickman line (irritant if administered peripherally) Patient education on central line and catheter site care is important as complications such as catheter related sepsis may occur. The pump that delivers epoprostenol is portable. Sudden drug interruption may be life threatening. The solution must be made up fresh every twelve hours. For home administration the prepared solution is stored in a specially designed cassette and attached to a pump. The final solution must be filtered via a 0.22micron filter. It is recommended to start at a low dose i.e. 2nanogram/ kg/min and titrate slowly, up to 20-40nanogram/kg/min.
Doses are titrated according to response and tolerance. It is important that blood pressure and heart rate are monitored during epoprostenol infusion, until the patient is stabilised on a dose, as heart rate may be affected and hypotension can occur. Dose reductions or discontinuation of the drug may be required if excessive hypotension occurs.14 Epoprostenol has been shown to improve exercise tolerance, symptoms, heamodynamics and survival in children and in adults. The main side effects are jaw pain, headache, diarrhoea, flushing, leg pain, and nausea. Side effects tend to be mild and dose related.1 Due to its platelet aggregation inhibition the risk of bleeding may be increased if NSAIDs are used concomitantly.14 Inhaled prostacyclin analogues are an alternative to parenteral formulations. Iloprost is licensed for use in adults with WHO class I PAH15. It is not currently used as part of the treatment regime for paediatric patients. It has a longer half life (1530 mins) than epoprostenol. Frequent nebulisations are necessary, as the duration of action is approximately 60mins. Treprostinil is another inhaled formulation approved for use in adults. The nebulised route is less invasive and without the risks associated with central venous lines. Systemic side effects are reduced. Studies are lacking in chidren. Sick children may not be able to cope with the mask, nebuliser device or frequency of nebulistaion required1. Inhaled formulations are not routinely used as part of the treatment regime for paediatric patients in Ireland. OXYGEN THERAPY For many patients oxygen therapy at night is used as part of the treatment regime. It is recommended to give
supplemental oxygen in patients with resting or exercise-induced hypoxemia3. FUTURE THERAPIES All treatment options at the moment provide symptomatic relief. There are no disease modifying treatments available. Clinical trials are currently under way investigating the safety and efficacy of several new therapies for PAH. Work is focused on prostacyclin analogues, newer endothelin antagonists and PDE5 inhibitors. Research is also underway investigating Tyrosine Kinase Inhibitors (TKI) as disease modifying agents. However, even if TKIs have a role in the inflammatory and remodelling process they won’t be a cure for the disease. CASE STUDY A 12 year old girl (32kg) presented to OLCHC in June 2012. She had been a previously healthy child with no significant past medical history. She had never been keen for exercise or sport. Approximately six months prior to presentation she began to complain of being tired all the time. Her mother noted that she needed to sit down and rest on walks with her family. She began to develop palpitations and shortness of breath with minimal amount of physical activity. Her parents then noted her lips had a bluish colour and she was brought to her GP who referred her to Our Lady’s Children’s Hospital, Crumlin. Investigations were carried out at OLCHC, where a diagnosis of severe PAH was made. The patient was commenced on the following medicines • Sildenafil 20mg tds •
Bosentan was initiated at 31.25mg bd. This was increased after four weeks to a maintenance dose of 61.25mg bd
• She also began warfarin
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CPD 1: PULMONARY ARTERIAL HYPERTENISON IN A PAEDIATRIC SETTING
therapy to maintain an INR of 1.5 – 2. • Due to the severity of the disease and following another cardiac catheterisation 2/52 later she was commenced on Epoprostenol at an initial rate of 2ng/kg/min. She experienced some facial flushing and dizziness but was otherwise tolerant Epoprostenol was increased daily by 0.25ng/kg/min every 12 hours as tolerated. MONITORING • Liver function tests. One month following the initiation of bosentan there was a slight elevation in transaminases. As per the SPC, dose reductions are not required unless LFTs rise to greater than three times the upper limit of normal. Therefore, no dose reduction was warranted.
epoprostenol continuous infusion. To reduce the risk of error the standard rate of infusion of epoprostenol is 1ml/hour. Calculations are required prior to each dose increment to make a final concentration of solution that delivers the required dose when infused at 1ml/hour. PARENT EDUCATION 1) Bosentan – The initial dose was 31.25mg (half a tablet). The patient’s mother needed to be educated on the safety points – to wear a mask and gloves when handling and splitting tablets, to have a designated tablet cutter for bosentan only. 2) The patient needed to be advised regarding symptoms of liver damage e.g. abdominal pain, jaundice, myalgia. In such circumstances bosentan may need to be discontinued.
• Haemoglobin levels were monitored closely. No dose related decrease was noted.
3) Warfarin counselling. Monitor for signs of bleeding / bruising etc.
• Since bosentan can decrease the plasma concentration of warfarin close monitoring was required until a stable INR was achieved. It was important to closely monitor INR again when the dose of bosentan was increased.
4) Weeks of preparation, education and counselling were necessary before the patient could be discharged home on a continuous infusion of epoprostenol. Education prior to each dosage increment is vital as the volume of concentrate and diluent required to make the final concentration will change. Dose adjustments will be necessary as the patient gains weight. Parents also need to be educated on how to set up the infusion and run the infusion at the correct rate. A preparation and administration sheet is provided by the pharmacist.
• Depending on tolerability the dose of epoprostenol was titrated upwards every day. For the first few days no adverse effects were noted. As the higher doses were reached the patient experienced some discomfort with jaw pain and facial flushing. The dose was increased every two days from then on. Prior to discharge home the target maintenance dose of ~30ngkg/min was reached. • Pharmacy instruction is necessary for the preparation and administration of
5) Epoprostenol is stable in solution for twelve hours only. The infusion will need to be freshly prepared twice daily. It is important that suitable times are decided prior to discharge, for example, in the evening time and early in the morning when both parents are at home.
6) Approval needed to be sought from the HSE for two CADD-legacy PLUS infusion pumps, medication cassettes for CADD-Legacy PLUS pumps (50ml), CADD extension sets with 0.2micron filter and antisiphon valve (76cm length) 7) Lisiaon with community pharmacy is needed to provide availability details on all of the medicines. Discussions about the number of epoprostenol vials required per month are needed. A certain amount of overage is required – at present using 2 x 1.5mg vials / 24hours. Each vial costs approximately 250euro. 8) Medication safety issue: Flolan 0.5mg and 1.5mg vials look very similar so it was decided to keep one strength only at a time. 9) Parents need to be aware of how to react to emergencies relating to the Hickman line. These include loss of line, suspected line infection and line blockage. Sudden interruption to the infusion may have detrimental consequences. FOLLOW UP • As weight is gained, the dose of epoprostenol will need to be adjusted • The patient is likely to need a wheelchair in order to attend secondary school in the coming year • If O2 saturations drop the patient will need home oxygen supply • Heart and lung transplant may be considered if the condition continues to deteriorate despite pharmacological intervention. Quality of life and life expectancy can be moderately to substantially improved by transplant. Unfortunately this is still not a cure for the condition.
REFERENCES 1. Ford K. Pulmonary artery hypertension: new drug treatment in children. Archives of Disease in Childhood and Practice Edition 2005;90:ep15-ep20 2. Wanstall J, Jeffery T. Recognition and Managemnet of Pulmonsry Hypertension. Drugs 1998Dec;56(6):989-1007 3. Berger S. Paediatric Pulmonary Arterial Hypertension. Available online at: http://emedicine.medscape.com/ article/1004828-overview#aw2aab6b2b4aa 4. Pulmonary Arterial Hypertension. Pulmonary Hypertension Association UK. Available online at: http://www. phassociation.uk.com/downloads/PHA_ background_information.pdf 5. Haworth SG. Idiopathic pulmonary arterial hypertension in childhood. Cardiol Rev. Mar-Apr 2010;18(2):64-6. [Medline]. 6. Rubin LJ. Diagnosis and management of pulmonary arterial hypertension: ACCP Evidence-Based Clinical Practice Guidelines5) Introduction. Chest. 2004;126:7S-10S. 7. Buck M. Sildenafil for the treatment of Pulmonary Hypertension in Children. Paediatric Pharmacy. 2004; 10(20) 8. Abrams D, Schulze-Neick I, Magee AG. Sildenafil as a selective pulmonary vasodilator in childhood primary pulmonary hypertension.Heart 2000;84:e4 doi:10.1136/heart.84.2.e4 9. The hospital formulary and prescribing guide. Our Lady’s Children’s Hospital, Crumlin 10. Datapharm Communications Ltd 2012, Summary of product characteristics for Revatio® (sildenafil). [online] Surrey. Datapharm Communications Ltd. Available at www.medicines.org.uk 11. Buck M. Use of bosentan in pediatric pulmonary hypertension. Paediatric Pharmacy. 2011;17(11). 12. Datapharm Communications Ltd 2012, Summary of product characteristics for Tracleer® (bosentan). [online] Surrey. Datapharm Communications Ltd. Available at www.medicines.org.uk 13. Datapharm Communications Ltd 2012, Summary of product characteristics for Thelin® (sitaxentan). [online] Surrey. Datapharm Communications Ltd. Available at www.medicines.org.uk 14. Datapharm Communications Ltd 2012, Summary of product characteristics for Flolan® (epoprostenol). [online] Surrey. Datapharm Communications Ltd. Available at www.medicines.org.uk 15. Datapharm Communications Ltd 2012, Summary of product characteristics for Iloprost). [online] Surrey. Datapharm Communications Ltd. Available at www. medicines.org.uk 16. Oudiz RJ, Primary Pulmonary Hypetension. Available online at: http:// emedicine.medscape.com/article/301450overview
ABBREVIATED PRESCRIBING INFORMATION
Please refer to the Summary of Product Characteristics (SmPC) before prescribing Rapilysin 10 U Powder and Solvent for Solution for Injection Indications: Thrombolytic treatment of suspected myocardial infarction with persistent ST elevation or recent left Bundle Branch Block within 12 hours after the onset of acute myocardial infarction AMI symptoms. Dosage: Treatment with reteplase should be initiated as soon as possible after the onset of AMI symptoms. Reteplase is supplied as a freeze-dried substance in vials. The lyophilisate is reconstituted with the contents of the accompanying syringe. Rapilysin should be injected preferably through an intravenous line whose sole purpose is the injection of Rapilysin (no other medicines should be injected through the line reserved for Rapilysin). In those patients where the same line has to be used, this line (including Y-line) must be flushed thoroughly with 0.9 % sodium chloride or 5 % dextrose solution prior to and following the Rapilysin injection. Dosage of Rapilysin: Rapilysin is administered as a 10 U bolus dose followed by a second 10 U bolus dose 30 minutes later (double bolus). Each bolus is administered as a slow intravenous injection within 2 minutes. Heparin and acetylsalicylic acid should be administered before and following the administration of Rapilysin to reduce the risk of rethrombosis. Heparin: 5000 I.U. given as a bolus injection prior to reteplase therapy followed by an infusion of 1000 I.U. per hour starting after the second reteplase bolus. Heparin should be administered for at least 24 hours, preferably for 48 – 72 hours, aiming to keep a PTT values 1.5 to 2 times normal. Acetylsalicylic Acid: at least 250 mg (250 – 350 mg) prior to thrombolysis followed by 75 – 150 mg/day at least until discharge. Contraindications: Hypersensitivity to reteplase, polysorbate 80 or any of the other ingredients. Because increases the risk of bleeding, is contra-indicated in the following situations: - known haemorrhagic diathesis - patients concomitantly treated with oral anticoagulants (e.g. warfarin sodium) - intracranial neoplasm, arteriovenous malformation or aneurysm neoplasm with increased bleeding risk - history of cerebrovascular accident - recent (< 10 days) prolonged and vigorous external heart massage - severe uncontrolled hypertension - active peptic ulceration - portal hypertension (oesophageal varices) - severe liver or renal dysfunction - acute pancreatitis, pericarditis, bacterial endocarditis - within 3 months of severe bleeding, major trauma or major surgery (e.g. coronary artery bypass graft, intracranial or intraspinal surgery or trauma), obstetrical delivery, organ biopsy, previous puncture of non-compressible vessels. Warnings and precautions: The most common complication encountered is bleeding. The risks may be increased and should be weighed against the anticipated benefits in: cerebrovascular disease, systolic blood pressure at entry > 160 mmHg, gastrointestinal or genitourinary bleeding (within 10 days), high likelihood of left heart thrombus (mitral stenosis with atrial fibrillation), septic thrombophlebitis or occluded arteriovenous cannula at seriously infected site, age over 75 years, any other condition in which bleeding constitutes a significant hazard or would be particularly difficult because of its location. Concomitant use of heparin anticoagulation may contribute to bleeding. Bleeding from recent puncture sites may occur: attention to all possible bleeding sites (including catheter insertion sites, arterial and venous puncture sites, cut down sites and needle puncture sites). The use of rigid catheter as well as intramuscular injections and nonessential handling of the patient should be avoided during treatment with reteplase. Caution when used with heparin, low-molecular-weight heparins, heparinoids, oral anticoagulants and antiplatelet agents other than acetylsalicylic acid, such as dipyridamole, ticlopidine, clopidogrel or glycoprotein IIb/IIIa receptor antagonists. Should serious bleeding, any concomitant heparin should be terminated immediately. The second bolus of reteplase should not be given if the serious bleeding occurs before it is administered. Protamine should be considered if heparin has been administered within 4 hours of the onset of bleeding. Coronary thrombolysis may result in arrhythmias associated with reperfusion; antiarrhythmic therapy for bradycardia and/or ventricular tachyarrhythmias (e.g. ventricular tachycardia or fibrillation) should be available when reteplase is administered. Readministration is not recommended as there is no experience. Interactions: Heparin, vitamin K antagonists and medicinal products that alter platelet function (such as acetylsalicylic acid, dipyridamole and abciximab) may increase the risk of bleeding if administered prior to, during or after reteplase therapy. Attention should be paid to this effect especially during periods of low plasma fibrinogen (up to about 2 days after fibrinolytic therapy of AMI). Pregnancy and Lactations: Pregnancy: Should not be used, except in life-threatening situations. Lactation: Breast milk should be discarded within the first 24 hours after thrombolytic therapy. Side Effects: Bleeding at injection site (haematoma); Gastrointestinal (haematemesis, melena), gingival or genitourinary bleeding; Recurrent ischaemia / angina; Hypotension and Heart failure / Pulmonary oedema; Arrhythmias (AV block, atrial fibrillation/flutter, ventricular tachycardia/fibrillation, electromechanical dissociation (EMD)); Cardiac Arrest; Cardiogenic shock and reinfarction. Shelf Life: Unopened: 3 years. Reconstituted: 8 hours between 2°C and 30°C. Pack size: Each pack contains: 2 colorless vials of 10 U of powder with a rubber closure, 2 prefilled syringes with 10 ml solvent for single use, 2 reconstitution Spikes, 2 needles 19 G1. Marketing Authorisation Holder (MAH): Actavis Group PTC ehf., Reykjavíkurvegi 76-78, 220 Hafnarfjordur, Iceland. Marketing Authorisation Number: EU/1/96/018/001. Legal Category: Medicinal product subject to medical prescription. Date of Generation of API: November 2011 Full prescribing information including the SmPC is available on request from Actavis Ireland Limited, Euro House, Little Island, Co. Cork or email email@example.com. Information about adverse event reporting can be found on the IMB website (www. imb.ie) or by contacting Actavis Ireland Limited PLRPfirstname.lastname@example.org.
Date of Preparation: October 2012 FADHCP-015-01 1. Rapilysin SmPC 2. Wilcox RG. et al. For the International Joint Efficacy Comparison of Thrombolytics (INJECT) Trial Group. Randomised, double-blind comparison of reteplase doublebolus administration with streptokinase in acute myocardial infarction (INJECT): trial to investigate equivalence. The Lancet 346: 329-336 (1995). 3. Topol E. et al. For the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO III) Investigators. A comparison of reteplase with alteplase for acute myocardial infarction. N Engl J Mad. 337: 1118-1123 (1997). 4. Richards C. et al. Reducing medication errors: potential benefits of bolus thrombolytic agents. Acta Erner Mad 7: 1285-1289 (2000). Wilcox RG. et al. Stroke and intracranial haemorrhage after reteplase or alteplase: results from GUSTO-III trial. Circulation 96: 1-330 (1996). 5. Keintsch-Engel R. et al. No induction of antibodies in patients treated with the recombinant plasminogen activator reteplase (BM 06.022) Fibrinolysis & Proteolysis: 11 (5/6):259-264 (1997).
30 Cardiovascular Disease
Current management of Ischaemic Heart Disease Cardiovascular disease cost the European economy €192 billion in 2006, with an estimated 57% directly linked to healthcare, 21% to productivity losses and 22% to the cost of informal care provided by relatives and friends (European Heart Network, 2008). Evaluation of EU health spending on cardiovascular health suggests that Ireland fares poorly relative to its EU counterparts in the proportion of its total spend attributed to cardiovascular disease. A 2006 comparison of the 27 EU Member States reported that, on average, 10% of the total healthcare budget was spent on cardiovascular diseases and that the comparative Irish figure was 6% (European Heart Network, 2008).
Deaths from ischemic heart disease including heart attack increased up to the 1970s when it peaked at 54% of deaths in 1974. Since then the trend has been moving towards a reduction in deaths from cardiovascular disease. According to the National Cardiovascular Health Policy 2010-2019, cardiovascular disease remains the most common cause of death in Ireland, currently accounting for one-third of all deaths and one in five premature deaths. However, there has been substantial progress. Age-standardised death rates from cardiovascular disease have decreased by two-thirds over the past 30 years. Despite improvements, Ireland still ranks below the EU15 average for life expectancy for both men and women. As mortality rates have reduced, demand on health services has intensified.Without changes in prevalence and practice, hospital bed use can be expected to increase substantially over the next decade as the number of people aged over 65 in Ireland is predicted to increase by 41%. In primary care, prescriptions for cardiovascular medication have increased two- to four-fold. At population level, the current lifestyle-related risk factor profile of the Irish population is a major concern: levels of smoking have not changed in the last 5 years, while levels of obesity and physical inactivity have increased.
Issue 6 • HPN
If these patterns continue, they threaten to reverse the declining trend in cardiovascular disease mortality of recent decades. There is thus considerable scope for improvement. This challenge is an intersectoral one – involving and being driven by those responsible for health and healthcare, but supported and enabled by sectors such as education, transport and agriculture. Apart from the human cost, the cost of cardiovascular disease to the Irish economy – which includes the costs of healthcare, loss in productivity and informal care – is a significant burden. Spending on cardiovascular health, while substantial, accounts for only 6% of the Irish healthcare budget – lower than the EU27 average of 10%. A much greater level of analysis of the costs of cardiovascular disease is needed to inform discussions about service investments and value for investment over the 10-year timeframe of this new policy. According to the Irish Heart Foundation, Ireland is still above average for premature deaths from CVD for the EU member countries before 2004. Last available figures show that Ireland has 52 premature deaths per 100,000 in comparison with the (pre 2004) EU average of 42. However, with the inclusion of the Eastern European accession states, the average EU figure for the equivalent period rises to 101 premature deaths per 100,000.
As recently as this year, pharmacists warned that Ireland is facing a crisis in heart disease and have called on the Government to introduce a National Cardiovascular Screening Service. The call was made at the IPU National Pharmacy Conference. The Conference heard from Bernard Duggan, a pharmacist from Dublin and Chairman of the Community Pharmacy Committee, that approximately 10,000 people die each year from cardiovascular disease, including coronary heart disease, stroke and other circulatory diseases. Bernard Duggan said: “The introduction of screening for heart disease and other chronic diseases through pharmacies could directly reduce the number of deaths from heart disease each year in Ireland. This will not only save lives but will save money as well by reducing the need for expensive hospital care for those who are struck down with heart disease.” ACUTE CORONARY SYNDROMES It is now preferable to classify ACS by the presence or absence of ST elevation on the initial 12lead electrocardiogram (ECG) as: 1. ST elevation myocardial infarction (STEMI), or 2. non-ST elevation ACS (subclassified as non-STEMI if cardio biomarkers are elevated or as unstable angina if there is no biomarker elevation).
An assessment of the initial ECG guides appropriate acute therapy (as opposed to the previous classification based on the presence or absence of Q waves on th discharge ECG). STEMI The primary goal of acute therapy in STEMI is establishing reperfusion in the culprit artery. This may be attempted by primary percutaneous coronary intervention (PCI) or fibrinolytic therapy. Although primary PCI is potentially more effective, in most clinical scenarios it incurs an additional (‘PCI-related’) delay compared with immediate fibrinolytic therapy. The acceptable limit for PCI-related delay, beyond which outcomes may be less favourable than with immediate fibrinolytic therapy, istypically around 110–120 minutes, although this is influenced by time from pain onset, infarct location and patient age. The 2008 European STEMI guideline recommends PCI as the preferred treatment strategy where feasible (class 1a recommendation), provided the expected time from first medical contact to balloon/ device is <120 minutes (and <90 minutes for those presenting early with large infarcts but low bleeding risk). Primary PCI is also indicated, irrespective of the time delay, for patients in shock or with contraindications to fibrinolytic therapy. Otherwise, in the absence of contraindications, fibrinolytic
31 Table 1: Comparison of in-hospital mortality (1998 and 2008)
CHD 6% 3.2% Heart Failure
PVD 12.4% 7.9% Stroke
Source: HIPE and NPRS Unit, ESRI, for all acute and non-acute HIPE-reporting hospitals1
therapy is the recommended reperfusion method, given ideally pre-hospital, as a bolus fibrinspecific agent. Even with a fully developed UK primary PCI service, it is estimated that at least 20% of patients may be better treated initially by fibrinolytic therapy. Following fibrinolytic therapy, serial ECG analysis is essential to identify the ~25% of patients who at 90 minutes have failed to show ≥50% resolution of ST elevation (as measured at the J point) and thus need to be considered for ‘rescue’ PCI. Interestingly, an immediate pre-hospital fibrinolytic plus consistent rescue PCI strategy has been shown to yield similar outcomes to a primary PCI strategy in the recent FAST-MI registry. Even in patients with successful ECG resolution after fibrinolytic therapy, urgent cardiac catheterisation +/– revascularisation is recommended after three but within 24 hours. ADJUNCT ANTITHROMBOTIC THERAPY IN STEMI Patients undergoing primary PCI require rapid loading with antiplatelet therapy and intravenous/arterial anticoagulation. Currently, oral antiplatelet loading is typically undertaken with aspirin (non-enteric coated)
300 mg and clopidogrel600 mg (which achieves acceptable platelet inhibition at ~2 hours, compared with ~6 hours following the conventional 300 mg loading dose). The recently approved P2Y12 receptor blocker prasugrel, given as a 60 mg loading dose, followed by 10 mg once daily, shows faster onset of action and greater platelet inhibition than clopidogrel and appears preferable in the primary PCI setting (TRITON-TIMI 38). Intravenous antiplatelet therapy remains indicated in the presence of conventional anticoagulation, that is unfractionated heparin (UFH) or low molecular weight heparin (LMWH). The HORIZONS trial showed that intravenous (IV) direct thrombin inhibition was preferable to the conventional combination of UFH plus glycoprotein IIb/ IIIa blocker with respect to 30-day net clinical adverse events (including a reduction in 30-day cardiac death). The benefit was driven largely by reduced major bleeding. Fondaparinux, the new factor Xa blocker, has been associated with an excess of catheter thrombosis (thought to be due to the absence of antiIIa activity +/– lower levels of anti-Xa activity) and is thus contraindicated as the sole anticoagulant during PCI, with additional unfractionated heparin being recommended.
At present, patients receiving fibrinolytic therapy are given adjunct antiplatelet therapy with aspirin loading (300 mg) and clopidogrel (300 mg if ≤75 years; 75 mg if >75 years). While UFH was conventionally used for adjunct anticoagulation to reduce the risk of reocclusion following successful fibrinolysis, the ExTRACT-TIMI 25 trial established the LMWH enoxaparin as the anticoagulant of choice given its significant improvementin efficacy and net clinical benefit compared with UFH. If using enoxaparin, the use of the trial dosing regimen is strongly recommended, that is patients ≤75 years: 30 mg IV bolus, then 1 mg/ kg/12h (maximum 100 mg) subcutaneously; patients >75 years: no initial IV bolus, subcutaneous dose 0.75 mg/kg (maximum 75 mg); patients with creatinine clearance <30 ml/min (dose reduced to 1 mg/kg/24h). In contrast, bivalirudin and fondaparinux have not shown any clear benefit over UFH as adjuncts to fibrinolytic therapy. GENERAL MEASURES For those who stop smoking, mortality in subsequent years is less than half that of those who continue to smoke. Smoking cessation is thus potentially the most effective of all secondary prevention measures. Cardiac rehabilitation and moderate exercise (to the
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32 Cardiovascular Disease
Consensus opinion recommends beta blockers indefinitely after MI,
point of slight breathlessness) for 20–30 minutes on most days is associated with a significant improvement in outcome.
Congestive heart failure
ASPIRIN Aspirin irreversibly inhibits cyclo-oxygenase (COX)-1 in platelets, thereby limiting the formation of thromboxane A2 and reducing platelet aggregation. The Antiplatelet Trialists’ Collaboration showed a 25% reduction in death and MI in post-infarction patients. In both general and post-PCI patients, no benefit has been demonstrated for high dose (i.e. ≥ 300 mg) aspirin. The conventional dose in the UK is 75 mg lifelong. CLOPIDOGREL/P2Y12 BLOCKADE Adenosine diphosphate (ADP) pathway-induced platelet activation may be blocked by specific inhibition of the P2Y12 ADP receptor. NICE guidelines recommend clopidogrel in addition to aspirin for up to one year after non-STEMI, based on CURE trial data, but only for 30 days after STEMI (since this was the treatment duration in CLARITY). However, the European Society of Cardiology STEMI guideline recommends clopidogrel for one year after STEMI. Maintenance dosage is usually 75 mg once daily, although pre-discharge platelet inhibition assessment may guide higher doses, e.g. 150 mg once daily in the future. The GRAVITAS trial is under way to assess this strategy. BETA BLOCKERS Consensus opinion recommends beta blockers indefinitely after MI, with the strongest evidence in patients with left ventricular (LV) dysfunction. Multiple studies suggest that elevated resting
Issue 6 • HPN
heart rate predicts adverse risk, and titrating the dose to achieve a resting heart rate at least <70 beats per minute and, if tolerated, ~60 beats per minute is considered desirable. STATINS/LIPID THERAPY Statin therapy is recommended for all patients with coronary artery disease. Early initiation following MI may be beneficial through mechanisms of plaque stabilisation, anti-inflammatory effects and restoration of endothelial function. The PROVE-IT trial in patients with recent MI showed that use of an intensive statin strategy (atorvastatin 80 mg; median ontreatment low-density lipoprotein cholesterol (LDL-C) 1.6 mmol/l) compared with a moderate statin strategy (pravastatin 40 mg; median on-treatment LDL-C 2.5 mmol/l) resulted in a 16% relative reduction at two years in death/MI/unstable angina/
revascularisation or stroke. Low levels of highdensity lipoprotein (HDL) cholesterol (<1.0 mmol/l) also predict increased future risk. The independent predictive value of elevated triglycerides is less certain. ACE INHIBITORS Angiotensin-converting enzyme (ACE) inhibitors reduce remodelling and improve survival in patients with reduced LV systolic dysfunction post MI. Additionally, ramipril and perindopril have shown improved cardiovascular outcome in patients with risk factors for or established atherosclerotic disease, irrespective of LV function and apparently beyond effects on blood pressure. Thus ACE inhibitors are recommended lifelong for all post-MI patients. Doses should be titrated to the relevant study targets (for example, ramipril 10
mg once daily and perindopril 8 mg once daily). Angiotensin receptor blockers are not routinely recommended post MI, but in individuals known to be intolerant to ACE inhibitors, valsartan is licensed for patients post MI with heart failure (based on the VALIANT study). ACE INHIBITORS Angiotensin-converting enzyme (ACE) inhibitors reduce remodelling and improve survival in patients with reduced LV systolic dysfunction post MI. Additionally, ramipril and perindopril have shown improved cardiovascular outcome in patients with risk factors for or established atherosclerotic disease, irrespective of LV function and apparently beyond effects on blood pressure. Thus ACE inhibitors are recommended lifelong for all post-MI patients. Doses should
NEW oral anti-platelet treatment for a broad range of ACS patients
BRILIQUE saves more lives than clopidogrel as measured by CV deaths (PLATO study)1
BRILIQUETM 90MG FILM-COATED TABLETS (ticagrelor) Abridged Prescribing Information (For full details see Summary of Product Characteristics (SmPC)) Use: Adults aged 18 years and older, co-administered with acetylsalicylic acid (ASA) daily: for the prevention of atherothrombotic events in patients with acute coronary syndromes (unstable angina, non-ST-segment elevation myocardial infarction [NSTEMI] or ST-segment elevation myocardial infarction [STEMI]); including patients managed medically, and those who are managed with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). Presentation: 90mg ticagrelor film-coated tablets. Dosage and administration: Treatment should be initiated with a single 180mg loading dose (two tablets of 90mg) and then continued at 90mg twice daily. Following an initial dose of ASA, patients should also take a daily maintenance dose of 75-150mg of ASA with Brilique, unless ASA is specifically contraindicated. Treatment is recommended for up to 12 months unless discontinuation is clinically indicated. Premature discontinuation of treatment or lapses in therapy should be avoided. Patients treated with clopidogrel can be directly switched to Brilique. For oral use. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Active pathological bleeding. History of intracranial haemorrhage. Moderate-to-severe hepatic impairment. Co-administration with strong CYP3A4 inhibitors (e.g. ketoconazole). Precautions: Due to the increased risk of non-fatal or non-life threatening bleeding, use with caution in patients at an increased risk for bleeding (e.g. recent trauma or surgery, bleeding disorders or recent gastrointestinal bleeding) or those on concomitant medication that may increase bleeding risk (e.g. NSAIDs, anticoagulants) within 24 hours of taking Brilique. Brilique should be stopped 7 days prior to elective surgery if the antiplatelet effect is not desired. Use with caution in patients with an increased risk of bradycardic events (e.g. patients on digoxin), as asymptomatic ventricular pauses have been observed with Brilique, a history of asthma and/or COPD, a history of hyperuricaemia or gouty arthritis. Creatinine levels may increase during treatment with Brilique. Renal function should be checked after one month and thereafter according to routine medical practice, paying special attention to patients ≥ 75 years, patients with moderate-to-severe renal impairment and those receiving concomitant treatment with an ARB. Co administration of Brilique is not recommended with a high maintenance dose of ASA (> 300mg) or with doses of simvastatin > 40mg. Co administration of ticagrelor with strong CYP3A4 inducers is discouraged, as this may lead to a decrease in exposure and efficacy of ticagrelor. Co-administration with CYP3A4 substrates with narrow therapeutic indices is not recommended. Concomitant use of ticagrelor with doses of simvastatin or lovastatin > 40mg not recommended. Caution with concomitant use of P-gp inhibitors or P-gp substrates with narrow therapeutic indices e.g. verapamil, quinidine and cyclosporin. Caution with concomitant administration of SSRIs. Brilique is not recommended during pregnancy and breastfeeding. Undesirable effects: Common: Dyspnoea, epistaxis, gastrointestinal haemorrhage, subcutaneous or dermal bleeding, bruising and procedural site haemorrhage. Other undesirable effects include intracranial bleeding, elevations of serum creatinine and uric acid levels. Consult SmPC for a full list of undesirable effects. Legal category: POM. Marketing Authorisation Number: EU/1/10/655/004. Market Authorisation Holder: AstraZeneca AB, S 151 85, Södertälje, Sweden. Further information on request from: Freephone 1800 800 899 or contact AstraZeneca UK Limited, Horizon Place, 600 Capability Green, Luton, Bedfordshire, LU1 3LU, United Kingdom. Abridged prescribing information prepared: 04/12. BRILIQUE is a trade mark of the AstraZeneca group of companies. Reference 1: Brilique Summary of Product Characteristics. URN: 12/0266. Date of preparation: May 2012
34 Cardiovascular Disease
Insufficient blood ďŹ‚ow to the heart muscle from narrowing of coronary artery may cause chest pain
Plaque in coronary artery
be titrated to the relevant study targets (for example, ramipril 10 mg once daily and perindopril 8 mg once daily). Angiotensin receptor blockers are not routinely recommended post MI, but in individuals known to be intolerant to ACE inhibitors, valsartan is licensed for patients post MI with heart failure (based on the VALIANT study).
NO0912654 Date of Preparation: September 2012
a Novartis company
Introducing Biosimilars: New horizons in affordable healthcare
Pioneering the future
For further information contact Alison Henderson on Alison.email@example.com or 087 6858069 5065 - Novartis Biosimiliars H&IPN Ad v2.indd 1
Issue 6 â€˘ HPN
Novartis Ireland Ltd., Beech House, Beech Hill Office Campus, Clonskeagh, Dublin 4 Tel: 01 260 1255 Fax: 01 260 1263 11/10/2012 13:45
In bipolar disorder, find the right balance
The first* tetracyclic antipsychotic for bipolar I disorder1,2 Rapid efficacy with a fast-dissolving sublingual tablet3,4
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: Not recommended. 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: Discontinue Sycrest 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, 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, 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: July 2012.
References: 1. Shahid M, et al. Asenapine: a novel psychopharmacologic agent with a unique human receptor signature, J Psychopharmacol 2009: 23(1) 65-73. 2. http://www.psychotropics.dk/About/default.aspx 3. 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. 4. Sycrest Summary of Product Characteristics. * Licensed
e ements We provide a full procurement service of all Exempt Medicinal Products and operate in line with IMB regulations and HSE reimbursement. We provide a Specialty Ordering Service where we will source, price, supply and deliver unusual and once-off products.
For further details contact: United Drug Telesales Dublin - 01 463 2300 /2307 /2311 Limerick - 061 315 411 Ballina - 096 72 555 Leonora Kinsella Customer Services Development Manager Telephone 01 463 2308 Mobile 087 251 3021 Fax 01-463 2525 www.united-drug.ie
Seeing the human side of Lucentis® Written by Eamonn Brady (MPSI), a community pharmacist who owns Whelehans Pharmacy in Mullingar. The tour of the Novartis facility took place on June 26th 2012.
Eamonn Brady MPSI graduated from the Robert Gordon University in Aberdeen in 2000 with a Masters in Pharmacy. He worked for Boots in the UK before moving back to Ireland in 2002. He bought Whelehans Pharmacy in Mullingar in 2005. He undertakes clinical training for nurses in the midlands. Last month kicked off the first part of our series of articles following Eamonn’s trip to the Novartis facility in Basle. We follow-on in this issue with a look at Lucentis, logisitics and investment. Lucentis® (Ranibizumab) is part of a class of drugs called anti-VEGF drugs developed in recent years for wet age related macular degeneration (ARMD). Vascular endothelial growth factor (VEGF) is a chemical involved in the formation of new abnormal blood vessels in the macula, a cause of wet ARMD. Blocking the action of this chemical prevents the formation of the abnormal blood vessels. Wet ARMD generally causes severe visual loss over a short time period, sometimes only months. It accounts for about 1 in 10 cases of ARMD. The other 9 out of 10 cases are called dry ARMD which develops more slowly (over ten years) and does not cause rapid sight loss like wet ARMD. ARMD generally affect people over 60. Both wet and dry ARMD are classified according to severity. Early, intermediate or advanced types refer to the degree of damage to the macula. 6 out of 10 cases of intermediate/ advanced ARMD are due to wet ARMD.
Lucentis® is one of the first successful treatments developed to treat wet ARMD; it was launched by Novartis in 2006. Ranibizumab improves vision in about 1 in 3 people treated. However, treatment in most people will maintain vision and prevent the condition from getting worse. About 1 person in every 10 does not respond to anti-VEGF drugs at all. In 2011, Lucentis® received approval for a new indication, the treatment of Diabetic Macular Edema, a leading cause of blindness in diabetics. We were given an overview of the condition by Professor Christian Prunte, one of Switzerland’s top ophthalmologists. We were then given an insight into the condition from a patient perspective. 59 year old German businessman, Detlef Plass, described how he was diagnosed with Diabetic Macular Edema by an ophthalmologist two years ago after his eye sight started to deteriorate rapidly. Prior to this diagnosis, he hadn’t realised he was diabetic. His eyesight deteriorated to the extent that glasses no longer improved his vision and his livelihood and ability to live a normal life was threatened. His ophthalmologist suggested he be treated with Lucentis®, and he went on to describe
how his eyesight has improved immeasurably since treatment began. From a situation were he faced certain blindness, his vision has gone back to the way it was over 10 years ago. LUCENTIS® IN IRELAND Lucentis® has been available in Ireland since 2007 and is now licensed here for wet ARMD and Diabetic Macular Edema. It can only be prescribed by a consultant ophthalmologist. It costs about €1000 per injection but is covered by many health insurance policies. It is not allowed on the GMS scheme so it does not have a GMS code. It is administered in hospital, therefore community pharmacies do not typically need to order Lucentis® for patients. LOGISTICS AT STEIN The next part of our tour was the logistics facility at Stein. The Stein site acts as the logistics nerve centre for all Novartis products. Therefore, as well as products manufactured at Stein, products manufactured at all other Novartis sites throughout the world are transported to Stein’s state of the art logistics warehouse for distribution to Novartis customers in 140 countries worldwide.
In 2011, 105 million packages passed through the logistics centre in Stein. Novartis estimated in 2011 that their vaccines and medicines reached 1 billion people. Their warehouse is fully automated meaning that this vast facility which takes 22, 000 customer orders of various sizes per year is operated by less than 100 staff. We were given a tour of the warehouse by the logistics manager of the facility, Pascal Degen. We noticed that whilst there were a small number of workers driving forklifts, most of the packages and boxes were being moved by computer operated robots which moved around the warehouse floor independent of human operators. These robots had sensors which not only enabled them to move around but also to stop when some of the group from our tour got in their way. We viewed massive automated material handling systems that retrieve palettes and boxes of products from towers of shelves. Conveyer belts were also used to move some of the products. Warehouse management systems have been developed at Stein by using barcodes, scanners, and complex logistics software which enables thousands of packages to be moved efficiently and accurately. The warehouse is temperature controlled and
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each product is fully traceable down to the finest detail. The products are transported by sea or air to Novartis’s “1 billion customers” around the world. Example of products familiar to Irish pharmacists which I viewed being transported from the Stein facility were Exelon®, Exforge®, Femara®, Foradil®, Lamisil®, Lucentis®, Neoral®, Onbrez®, Sandostatin®, Tegretol®, Voltarol® and Xolair®. CONTINUED INVESTMENT Many pharmaceutical companies have cut back heavily on research and development in recent years as profits falls due to patent loss and weak economic conditions. Novartis has also been hit by patent loss in recent years including the loss of patent for Diovan®, Femara® and Lamisil®. In addition, the fact that their new anti-hypertensive, Rasilez® has shown less than favourable results in clinical trials recently has been another major hit for Novartis. Whilst Novartis has had some job losses, it continues to invest heavily in research and innovation. Andrew Jack of the Financial Times claims the four pharmaceutical companies coping best with “avoiding the fall off the patent cliff” are GSK, Johnson and Johnson, Sanofi and Novartis; he explains this is due to their continued investment in research, despite patent loss. In 2011, Novartis announced $58 billion in sales (second only to Pfizer in the pharmaceutical sector) and of this, $9.6 billion was reinvested in research and development. We saw an example of this continued investment during our trip to the Novartis facilities; the day before our visit to Novartis’s Stein facility, the “sod was turned” on the construction of a new state-of-the-art facility
for solid dosage forms in Stein with an investment of over €400 million. This new facility will replace an older one which will be partially demolished by 2016. According to a Novartis press release, Stein will be a technological competence centre for both sterile and solid dosage forms within Novartis’s global production network. Novartis plans to expand the site’s strategic role as a key platform for global launches of new pharmaceuticals. Novartis state that the flexible and modular set-up of this new facility will help it meet its future product portfolio requirements while focusing on difficult to make products in the area of inhalation and highly active solids. A Novartis spokesman stated that the new set-up will allow Novartis to adapt its production capacity more quickly depending on an evolving portfolio and market demand. In addition to the cost of this new build at Stein, a further €50 million is being spent on a production line for freezedried medicines, opening in 2014, with another €105 million investment on a data centre scheduled for completion next year. Novartis are also aiming to reduce the impact of patent loss by investing in generics. It created a generics division in 2003 under the name of its predecessor, Sandoz, it’s a bit of a “if you can’t beat them join them” attitude with Novartis in relation to generics. Since 2003 they have purchased a number of generic companies including Hexal and Eon labs and earlier in 2012 they purchased Fougera, an American generic dermatology company, a move that will make them the biggest manufacturer of generic dermatology products in the
Frank Gehry designed building located at Novartis Headquarters
Issue 6 • HPN
world. As an example of their move into generics, Novartis actually manufacture generic valsartan for Rowex under the brand name Vatan®; therefore Irish pharmacists and patients will notice that Vatan® tablets look visually identical to Diovan®. NOVARTIS INSTITUTE OF BIOMEDICAL RESEARCH (NIBR) The Novartis Institutes for BioMedical Research (NIBR) is the global pharmaceutical research organisation of Novartis. NIBR has approximately 6 000 scientists and doctors at different 9 locations throughout the world with Basel being the largest. The research is focused on
discovering innovative new drugs that will change the practice of medicine. On the afternoon of our visit, we toured the NIBR (Basel) which is located at their headquarters. Research at NIBR Basel focuses primarily on drug discovery. Novartis are currently transforming their headquarters into what they call an “attractive high quality workplace where they create high quality medicines for patients” They believe “Inspiring working environments have concrete business benefits”. They are changing their headquarters from an “industrial complex to a place of innovation, knowledge and encounter”. The multispace work area concept aims
to enhance communication and effectiveness. Indoor and outdoor common spaces are designed to promote interaction between employees, improving teamwork and knowledgesharing. Over the last few years, older buildings have been demolished and replaced by newer more inspiring buildings designed by artists and architects of international stature, including their unique “glass” human resources building designed by world famous architect Frank Gehry. The NIBR Basel site we toured is open plan and is not what many would expect a lab to look like. NIBR doesn’t have the traditional lab bench. The lab has more of a relaxed feel than traditional labs, giving more of a modern “café like” environment than a lab. Dr Mark Fisherman, the founder and head of NIBR said regarding traditional labs that “benches are designed for the way the work was done 50 years ago…the space isn’t used well; at the same time, it’s not enough space.” In the NIBR lab, scientists of different disciplines use the same lab for a project; Novartis feels this creates more sharing of knowledge and ideas. The building has a “just in time” inventory system so scientists can order and receive lab supplies promptly from a central location meaning the lab is used only for research and not storage creating a very uncluttered environment and ultimately uncluttered minds to help harness ideas. Scientists have access to innovative
video conferencing technology which allows them to contact and work with colleagues in other Novartis labs around the world. Drug discovery in NIBR in Basel focuses on autoimmunity, transplantation, inflammation as well as musculoskeletal diseases, neuroscience and oncology.
drug’s safety and effectiveness) to help find and advance the most promising drug candidates. These proof-of-concept studies often focus on treating a rare, but genetically well-defined disease. Novartis has more than 134 projects in clinical development, many of which are new molecular entities.
“FOCUS ON THE PATIENT, FOLLOW THE SCIENCE”
COMPUTER AIDED DRUG DESIGN
Scientists we spoke to on the tour explained they prioritise their work based on unmet medical need and strong scientific understanding of disease, not the size of the potential commercial market.
Novartis use a technique called computer aided drug design. Scientists especially designed computer software to design compounds that they hope someday will become drugs. Scientists in NIBR use the “lock and key” analogy to describe how they develop drugs. Put simply they see diseases as a locks on doors that need to be opened or closed. The lock represents the biological target that needs to be turned on or off, the drug researchers try to design molecules which act as keys. In the old days, drug discovery was much more trial and error with new drugs tending to be discovered by accident without really understanding how they worked. Nowadays, scientists can use specialised computer programmes to analyse millions of molecules and points of data which allows the scientists see which will give the best chance of success. This streamlines the drug discovery process and enables scientists to more accurately predict likely outcomes before deciding to commence clinical trials. It also enables scientists view more molecules at one time and get faster answers.
Novartis researchers aim to map complex protein signaling networks known as molecular signaling pathways inside of cells. These molecular pathways are highly controlled and interconnected signalrelay systems, similar to communication networks, and are responsible for normal cell function. When a protein in a pathway does not function properly, the result can be abnormal signaling and disease. Scientists at the Novartis Institutes for BioMedical Research (NIBR) develop small molecule drugs or antibodies to target key nodes within pathways that, when defective, lead to disease. To translate scientific discoveries from the lab bench to the clinic, Novartis uses proof-of-concept clinical trials (small scale studies used to get an early read on a
Interior view of Labs of the future at NIBR
By streamlining the drug discovery and development process, Novartis can reduce the risk of failures in late stage clinical trials, failures which can turn out costly in financial terms. An interesting aspect of Novartis research is that they invite scientists who are not directly employed by them to use their facilities; this enhances the culture of innovation and openness.
INSIGHT TO OPHTHALMOLOGY RESEARCH IN NOVARTIS Our final part of the NIBR tour was to speak to Dr Ted Dryja, the global head of Ophthalmology for Novartis. Dr Dryja is based in Novartis’s research facility in Cambridge Massachusetts, so we spoke to him by video conference. Dr Dryja specialises in ophthalmology and is recognized for his 1986 discovery of the Rb tumor suppressor gene, mutations in which lead to an eye cancer known as retinoblastoma. As well as his role as the head of ophthalmology research at Novartis, he is also a professor of ophthalmology at Harvard Medical School. Dr Dryja described how his team aim to discover drugs that will treat and hopefully eradicate common (and not so common) eye conditions. He claims that financial reward is not the key motivator for him and his team’s work. Novartis give him a free hand and he never has to worry about how viable a drug will be on the market when he discovers it. He said he leaves the “financial worries” to the chief executive. When a Turkish journalist asked him what the budget is for his department, he said that he genuinely had no idea. I asked him if a drug he discovered could only treat a very rare eye condition meaning it is not economically viable to bring to the market, would Novartis bring it to market nevertheless?. He claimed that Novartis would bring a drug to market even though it would cost them money to do so if it was going to improve patients’ quality of life and save lives. He said that Novartis have in the past brought drugs to market for very rare conditions (only a few hundred potential patients worldwide) at their own cost. I asked him if he checks on what his competitors are doing in other companies? He answered that he never does, he only focuses on what he can do.
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First Treatment for Rare Cancer receives Irish licence treatment development, Dr Eibhlin Conneally, Consultant Haematologist at St James’ Hospital, who has extensive experience in clinical trials and clinically manages many of these patients said: “Ruxolitinib is specifically directed at an abnormally active enzyme or kinase that has been recently defined as a key driver of myelofibrosis. This kinase, called Jak-2, has emerged as a key target for therapy in myelofibrosis.
Frank Giles, Professor of Cancer Therapeutics
For the first time outside of clinical trials, a treatment for a rare haematologial malignancy myelofibrosis (MF) will be available. MF is severely debilitating in some patients as it disrupts the body's normal production of blood cells resulting in extensive scarring in the bone marrow, leading to severe anemia, weakness, fatigue, and often, an enlarged spleen and liver. However, despite having its EU license, the drug is currently under HSE review for reimbursement before it can be made available to patients who need it. Dr Conneally concluded on this point stating “this treatment development is of huge importance to Irish patients so it is vital that it be made available to the Irish patients who need it as soon as possible. Irish patients have a right to this treatment that can improve their quality of life and give them a previously unavailable treatment option in an area with
Issue 6 • HPN
previously extremely limited treatment options.” Myelofibrosis is a type of chronic leukemia and can occur on its own (primary myelofibrosis) or as a result of another bone marrow disorder (secondary myelofibrosis). Most patients are older than 60 years at diagnosis, with 33% of patients are asymptomatic at presentation. The new treatment, which is the first of its kind, is manufactured by Novartis. The drug, called ruxolitinib, recently received European approval and means that the unmet needs of Irish MF patients can now be addressed. This is the first and only specific therapy for MF, a particularly important development as some patients with MF are impacted by multiple severe complications such as grossly enlarged spleen, fatigue, shortness of breath, appetite loss and shortened survival. Specifically, MF may result in serious complications including
splenic pain, early satiety, anemia, bone pain, fatigue and night sweats. Median survival varies, but can be considerably reduced in high-risk patients. People over the age of 60 are most likely to have this disease. Irish expert on the condition, Frank Giles, Professor of Cancer Therapeutics at NUI Galway and Trinity College Dublin, welcomed the announcement on the drug’s license saying: “Myelofibrosis is a rare and devastating cancer with a poor prognosis and limited treatment options for those that suffer from it. While supportive and palliative therapies, including blood transfusions and radiotherapy, have been used to manage some of the individual symptoms of MF, we have had no prior FDA or EMEA-approved specific MF treatment option available to patients. This is a unique exciting development that will begin to address the unmet needs of Irish patients with MF.” Further commenting on this
"It is a central driver of the disease and inhibiting its function with ruxolitinib directly improves many patients’ symptoms and reduces their spleen swelling. It is the latest big success in our move away from non-specific cell-killing drugs towards safer, more targeted drugs that are really directed at the fundamental drivers of cancer.” Primary MF is characterized by splenomegaly, immature peripheral blood granulocytes and erythrocytes, and teardropshaped red blood cells. In its early phase, the disease is characterized by elevated numbers of CD34-positive cells in the marrow, while the later phases involve marrow fibrosis with decreasing CD34 cells in the marrow and a corresponding increase in splenic and liver engorgement with CD34 cells. Commenting further on this breakthrough treatment, Prof Giles said: “Bringing a compound from early pre-clinical discovery to the patient is a complex and costly process that can take more than a decade. For every 5,000-10,000 compounds that enter the early R&D pipeline, only one will receive regulatory approval, although this ratio is improving as molecular biology becomes increasingly of clinical relevance. The success of bringing Ruxolitinib, a first in class, first on target, first specific anti-MF agent to market provides a unique and vital theraepeutic improvement for Irish patients.”
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The debate rages on uncontrolled switching There is considerable debate regarding generic drug substitution in solid organ transplant recipients, and various European transplant associations and societies have expressed caution about the potential adverse consequences from uncontrolled switching between the different narrow therapeutic index drug (NTID) formulations now available to the physician and pharmacist.
Professor Atholl Johnston
This issue was discussed the 17th Congress of the EAHP, Milan, Italy. The Astellassponsored symposium, chaired by Professor Atholl Johnston (Professor of Clinical Pharmacology, Barts and The London School of Medicine and Dentistry, UK), explored the risks and benefits of switching between alternative NTID formulations, and outlined current European recommendations. Professor Johnston introduced the symposium, highlighting the severe shortage of organ donors across all organ categories in Europe, and the fact that every donated organ represents a gift, either by the family of the deceased or by the living donor. Consequently, it is essential to make optimal use of organs and not waste this precious resource. Transplant recipients need to be responsible for their transplanted organ. However, there may be a lack of knowledge about drug interactions within both the
Issue 6 â€˘ HPN
patient community and primary care. Transplant recipients need to be well informed, and this should be a collaborative responsibility of the transplant centre, the pharmacist and the patient. Professor Johnston discussed the issues around the generic drug approval process and bioequivalence. Health expectations must be matched with available
resources, and generic prescribing is promoted by health authorities and health maintenance organisations because of the potential cost savings that can accrue. Many generic formulations are of excellent quality and can be substituted for the original product. However, the substitution of branded pharmaceutical products requires regulatory oversight to ensure that generic drug formulations are equivalent to the innovator's drug in terms of efficacy and safety. Otherwise, any immediate monetary gains may be offset by additional healthcare costs. In conclusion, multiple formulations of NTIDs are now available. It is not clear how these products compare to existing formulations, particularly in terms of the risk of treatment failure and side-effects. Therefore, it is not advisable for patients to change formulations except under close supervision and monitoring by a transplant specialist, and unless effective pharmacovigilance procedures are in place. The costs of this must be borne in mind when
evaluating potential cost savings made by generic substitution. Professor Johnston concluded the symposium by highlighting that NTIDs exhibit a narrow range of exposure between therapeutic and toxic thresholds, and switching between NTID formulations should only be done under the close supervision of a transplant specialist. The focus should not be on drug cost alone, but instead on patient needs, safety and quality of life, the overall healthcare burden and optimising immunosuppression to improve long-term outcomes. Next month's issue of Hospital Pharmacy News will feature an exclusive clinical feature authored by Kathryn Feeley on liver transplantation, with specific reference to tacrolimus.
44 Out and About New treatment launched for rare cancer
Intervention service now available A home-based intervention developed by St James’s Hospital and the Regional Oncology Programme Office, Dublin has now been made available to regional oncology centres nationwide by Roche. The intervention helps cancer survivors manage cancer related fatigue, one of the most common, distressing and disabling difficulties people face after cancer treatment.
The Royal College of Physicians, Ireland was the setting for the launch of a new treatment for rare cancer. Jakavi is now available for the treatment of the rare bone cancer myelofibrosis and was launched by Novartis. Speaking at meeting Professor Claire Harrison said: “This new treatment is fantastic news – a great thing for patients. We are at a pivotal point in this disease” She continued: “This is a very debilitating illness – patients really are quite ill. This new treatment is a radical step forward and is very meaningful. Some of the drug’s effects are seen literally overnight.” 1) Dr Gerard Crotty, Tullamore Hospital and Diarmuid Mackey, Novartis. 2) Dr Eibhlin Conneally, St.James’s Hospital, and Jo O’Sullivan, Novartis. 3) Prof Claire Harrison, Guys and St Thomas’ NHS.
Entitled Understanding and Managing Persistent Cancer-Related Fatigue, the easy-to-use innovative manual and accompanying DVD, is structured on cognitive behavioural therapy (CBT) techniques and is made up of eight different chapters tackling issues such as inactivity, low mood, sleep problems, worry and reclaiming life after cancer. Pictured are Dr Sonya Collier and Dr Anne-Marie ODwyer from the St James’s Hospital, Psychological Medicine Service. Further information on the programme visit www.roche.ie or call 01 6452946.
Launch of i360medical
Richard Stack, Synecor; Minister Richard Bruton; Derek Young, CEO of i360medical; Professor Oscar Traynor, RCSI; Dominic Considine, i360medical and Eunan Friel, RCSI, are pictured at the launch of i360medical, a new healthcare solutions and medical device innovation company launched in Dublin by Richard Bruton TD, Minister for Jobs, Enterprise and Innovation.
The company, which taps into Ireland’s growing medical device expertise, has joined with some of the world leaders in healthcare innovation to help generate and commercialise new world-class healthcare technology solutions. i360medical is a spin-out company from the Royal College of Surgeons in Ireland where it was formerly known as The Centre for Innovation in Surgical Technology (RCSI-CIST). The company is positioned to provide new ‘start up’ deal flow to multinational’s and SMEs which will help safeguard existing jobs and create new jobs in the industry in Ireland.
Issue 6 • HPN
Treatment for Pulmonary Arterial Hypertension classified as WHO functional class III, to improve exercise capacity.
Treatment should only be initiated and monitored by a physician experienced in the treatment of pulmonary arterial hypertension. In case of clinical deterioration in spite of Revatio treatment, alternative therapies should be considered. Please consult the Summary of Product Characteristics before treatment, particulary in relation to side-effects, precautions and contraindications. Further information is available on request from Pfizer Healthcare Ireland, 9 Riverwalk, National Digital Park, Citywest Business Campus, Dublin 24, Ireland. PH: 01 467 6500. Legal Category: S1A. Marketing Authorisation holder: Pfizer Limited, Sandwich, Kent CT13 9NJ, United Kingdom REV/2012/001
46 LK Shields
INTELLECTUAL PROPERTY: The best of both worlds? will be owned by the university and not by the spin-out body. Carrying out some legal due diligence before an agreement is negotiated can save a lot of time. AGREEING THE SCOPE Defining what the parties want to achieve is the backbone of any collaboration agreement. At the outset, it is worth considering whether the development plan is to be fluid in nature and pitched in terms of ‘reasonable endeavours’ to reach an end point or to be more rigid, with fixed key milestones, target timeframes, defined project phases and quality standards. It is worth considering what should happen if the development plan is not adhered to: for instance, what should happen if regulatory approvals are not obtained or commercial launch deadlines are not met? Either party may wish to include a right to terminate the agreement if certain goals aren’t met. MANAGING THE PROJECT Rachel Spencer of LK Shields Solicitors
In the field of pharmaceuticals and biotechnology, collaboration agreements are increasingly being used to get products from pipeline to target market in the most cost-effective way. Rachel Spencer of LK Shields Solicitors gives an overview of collaboration agreements and highlights some major concerns. Collaboration agreements can turn competitors into contractually-controlled allies.
Issue 6 • HPN
Whether the scope of the project spans from initial lab scaleup, formulation development and stability testing through to obtaining regulatory approval; or to the much more focused compilation and on-licensing of technical files for use in registration dossiers, a wellstructured Collaboration Agreement should allow for a dynamic alliance, while protecting valuable product rights and market access.
CONTRACTING PARTIES It is vital that the collaboration agreement is entered into between the correct contracting parties – that is to say, between the entities that actually own (or have full rights to use and exploit) the relevant intellectual property. A good example of where this can become an issue is when partnering with a university spin-out: in most cases, the intellectual property
It is not uncommon for joint steering committees to be appointed to manage the project. The drawback with such decision making is that development can grind to a halt because of the need for unanimity or the lack of clarity as to who controls which elements. To avoid this, it is worth considering the right to a casting vote in certain circumstances. INTELLECTUAL PROPERTY Intellectual Property is of critical importance. The parties generally agree to bring together their existing knowhow, intellectual property and technology (known as ‘background IP’) with a view to creating new know-how, IP or technology (‘foreground IP’). This
is typically a complex area, but here some of the issues to bear in mind: Licensing background IP: In many cases, one party will need a full and ongoing licence from an IP-owning party to use and exploit the background IP for the project and also to make full use of foreground IP (which is usually dependent on background IP). It is essential to consider the nature of such a licence: should it be royalty bearing? exclusive? transferable? Should there be restrictions in terms of duration, territories and use? Ownership of foreground IP: Where parties are jointly responsible for creating foreground IP, the key question is: who owns it? Joint ownership is generally to be avoided. In practice, it is
preferable that one party has outright ownership and grants a full and ongoing licence to the other party. The issue of ownership will invariably be dictated by the respective bargaining positions and the nature of the project. REGULATORY AND PATENTS Collaboration agreements should be clear about what happens, for example, in the case of an adverse event report, and in the allocation of responsibility and costs in respect of obtaining and maintaining regulatory approval. Similarly, there should be clear allocation of responsibility and costs in respect of filing and maintaining patents for new developments, and for the prosecution, settlement and enforcement of patent and other IP rights, and infringement claims.
LOOKING TO THE FUTURE It is not unusual for a party to a collaboration agreement to be acquired or to be the subject of future inward investment during the lifetime of the agreement. The agreement should be structured in such a way that potential mergers and acquisitions can be explored. It is sensible to address ‘change of control’ issues and whether this will have a bearing on the project, particularly in the case where an acquirer or investor happens to be a competitor. It is worth noting that anti-bribery provisions in collaboration agreements are becoming ever more complex. This reflects the multi-jurisdictional nature of such projects, where the more stringent anti-bribery regulations will generally prevail. A good
example of this is where an Irish company enters into a collaborative venture with a UK counterpart: it is generally the case that the Irish company will have to comply with the standard anti-bribery provisions of the UK partner. WHAT SHOULD YOU DO? Having dealt with many collaboration agreements across a wide range of industries, we find that anticipating and dealing with these key terms appropriately in a formal agreement can be critical to the success of a project. We have experience in helping clients to identify their key issues and our advice would be to plan ahead, anticipate the ‘road-bumps’ and thrash out the difficult issues before you begin!
HPN • Issue 6
BuTrans Patches ®
…effective analgesia helping 2,4 to improve quality of life
Butrans® patches contain an opioid analgesic BuTrans® 5 µg/h, 10 µg/h and 20 µg/h vasodilatation, dyspnoea, constipation, dry Transdermal Patch. Prescribing mouth, nausea, vomiting, abdominal pain, Information. Republic of Ireland. Please diarrhoea, dyspepsia, sweating, tiredness, read the Summary of Product pain, peripheral oedema, application site Characteristics before prescribing. pruritus, application site reaction, application Presentation: BuTrans 5 µg/h, 10 µg/h, 20 site erythema, application site rash, chest pain, µg/h. Transdermal beige patches containing pruritus, erythema, rash, exanthema, asthenia. buprenorphine. Indications: Treatment of Uncommon but potentially serious (≤ 1/100): non-malignant pain of moderate intensity anaphylactic reaction, anaphylactoid reaction, when an opioid is necessary for obtaining restlessness, agitation, depersonalisation, adequate analgesia. BuTrans is not suitable for euphoric mood, affect lability, hallucinations, the treatment of acute pain. Dosage and psychotic disorder, decreased libido, drug Administration: BuTrans should be admin- dependence, mood swings, sedation, istered every 7 days. Elderly and adults over 18 migraine, balance disorder, speech disorder, years only: Use the 5 µg/h patch for at least blurred vision, visual disturbance, eyelid the first 3 days of treatment, before increasing oedema, vertigo, angina pectoris, palpitations, the dose if necessary. Do not use more than tachycardia, hypotension, circulatory collapse, two patches at a time. Contra-indications: hypertension, asthma aggravated, hypoxia, Known buprenorphine or excipient wheezing, hyperventilation, respiratory hypersensitivity, opioid dependent patients, depression, respiratory failure, diverticulitis, use for narcotic withdrawal treatment, dysphagia, ileus, biliary colic, muscular respiratory depression, use of MAO inhibitors weakness, urinary retention, erectile within the past 2 weeks, myasthenia gravis, dysfunction, sexual dysfunction, oedema, delirium tremens. Precautions and drug withdrawal syndrome, alanine aminoWarnings: Convulsive disorders, head injury, transeferase increased, accidental injury, fall. shock, reduced consciousness of uncertain Please consult the SPC for details of other sideorigin, intracranial lesions or increased effects. Legal category: CD (Sch2) POM intracranial pressure, severe hepatic Package quantities: 5 µg/h transdermal impairment, history of drug abuse. Not patch: 2 individually sealed patches 10 µg/h recommended immediately postoperatively or transdermal patch: 4 individually sealed for situations characterised by a narrow patches 20 µg/h transdermal patch: 4 therapeutic index or for rapidly varying individually sealed patches. Marketing analgesic require-ments. May affect ability to Authorisation numbers: PA 913/24/1-3. drive or use machinery. As with all opioids, Marketing Authorisation holder: chronic use may result in the development of Mundipharma Pharmaceuticals Limited, physical dependence. Interactions: Mono- Millbank House, Arkle Road, Sandyford, amine oxidase inhibitors (MAOIs), CNS Dublin 18. Tel: +353 (0)1 2063800. One of depressants (e.g. benzodiazepines, opioid the Mundipharma / Napp independent derivatives, antidepressants, sedatives, associated companies. Date of preparation: alcohol, anxiolytics, neuroleptics, clonidine). August 2011 (UK/BUTR-11033). References: CYP 3A4 inhibitors and inducers, products 1. Butrans® SPC. 2. James IGV, O'Brien CM reducing hepatic blood flow (e.g. halothane). and McDonald CJ. J Pain Sympt Manage Pregnancy and lactation: BuTrans should not 2010; 40(2):266-278. 3. MIMS Ireland. 4. be used during pregnancy or in women of Karlsson M. et al: Efficacy and Safety of Low childbearing potential who are not using dose Transdermal Buprenorphine Patches effective contraception. The use of BuTrans (5,10 & 20ug/h) versus prolonged release during lactation should be avoided. Side tramadol tablets (75, 100, 150 and 200mgs) Effects: Very common (≥ 1/10) or common in patients with chronic osteoarthritis pain: a (≥ 1/100) side-effects: anorexia, confusion, twelve week, randomized open label, depression, insomnia, nervousness, headache, controlled, parallel-group non inferior study. dizziness, somnolence, paraesthesia, Clinical Therapeutics /Vol 31 No3, 2009. Adverse events should be reported to Mundipharma Pharmaceuticals Limited on 1800 991830 ® BuTrans and the Mundipharma device (logo) are Registered Trade Marks. © 2011 Mundipharma Pharmaceuticals Limited. IRE/BU-12001a. Date of Item: April 2012
BuTrans® 5mg: 7 days continuous pain relief 1 The lowest dose opioid analgesic patch 3 available in Ireland Reduces the burden of daily tablet use 2
A joint effort… good news for your patients and good news for you
Pfizer receives EU Marketing Authorization for INLYTA® (axitinib)
Pfizer Healthcare Ireland announced recently that the European Commission (EC) has granted marketing authorization for INLYTA® (axitinib) for the treatment of adult patients with advanced renal cell carcinoma (RCC), a type of kidney cancer, after failure of prior treatment with sunitinib or a cytokine. INLYTA®, a kinase inhibitor, is an oral therapy that was designed to selectively inhibit vascular endothelial growth factor (VEGF) receptors 1, 2 and 3,1 which are proteins that can influence tumor growth, vascular angiogenesis
PHURENET online resource launched
Sycrest® 5 & 10mg sublingual tablets - a new treatment option for moderate to severe manic episodes associated with bipolar I disorder
and progression of cancer (tumor spread)2. "INLYTA® offers physicians and their patients with advanced kidney cancer a new treatment option following prior treatment with sunitinib or a cytokine. INLYTA® data demonstrated statistically significant improvement in progression free survival compared with sorafenib, and supports the continued role for VEGFR-targeted therapy, following the first-line standard of care, SUTENT®," said Dr. Ray McDermott, Consultant Medical Oncologist at St Vincent’s
A new, online education and support resource for healthcare professionals, called PHURENET, has been launched. PHURENET (the PHURE standing for Pelvic Health and Urology Resources for Education) is Pfizer’s first website that provides healthcare professionals with tools, educational materials and services to optimise patient management in pelvic health and urology.
healthcare professionals with an interest in pelvic health enhance their clinical skills in areas such as overactive bladder (OAB) and urinary incontinence.
Created in partnership with a faculty of leading urology and gynaecology professionals from eight European countries, PHURENET is designed to help
• Patient communications tools – that aim to help the healthcare professional and patient consultation
Lundbeck have announced that they have received notification from the HSE that Sycrest® (asenapine) it is to be added to the list of medicines available to patients under the GMS and DPS schemes. Sycrest® is available in Ireland from 3rd September 2012.
disorder.1 Sycrest is a tetracyclic antipsychotic derived from a chemical template that is different to currently available atypical antipsychotics, and has a distinct receptor signature compared to these agents.2
Sycrest has been approved for the treatment of moderate to severe manic episodes associated with bipolar I disorder (BD-I) in adults.1 The approval for Sycrest was based on a review of efficacy data from studies involving more than 1300 patients with manic or mixed episodes of bipolar I
Key features of the resource include: • Pelvic health insights – including presentations and discussion highlights on the management of pelvic health disorders
“Bipolar I disorder can be very difficult to manage. Individuals can respond very differently to treatment, so having a number of options is important," said Professor Timothy Dinan, Consultant Psychiatrist, Professor of Psychiatry at University College Cork.
University Hospital and The Adelaide Meath & National Children’s Hospital, Tallaght. The approval is based on data from the Phase 3 AXIS trial, which demonstrated that INLYTA® significantly extended progression free survival (PFS) [HR=0.67, 0.560.81, P<0.0001] with a median PFS of 6.8 months (95% CI: 6.4, 8.3) compared with 4.7 months (95% CI: 4.6, 6.3) for those treated with sorafenib, a current secondline standard of care for this patient population, representing a 45 percent improvement in median PFS compared to sorafenib1.
• Video highlights – demonstrating some surgical techniques and procedures in urology and gynaecology “PHURENET is an invaluable resource that gives the clinician up to date information on a variety of aspects of urogynaecology with particular emphasis on urinary incontinence and OAB”, comments Dr Paul Byrne, Consultant Gynaecologist, Beaumont Hospital. Healthcare professionals can access the website for free by visiting: www.PhUREnet.ie
Sycrest has demonstrated superior efficacy to placebo in the reduction of manic symptoms associated with bipolar I disorder in monotherapy and as adjunct to a mood stabiliser over three weeks.3-6 Sycrest is available as a fast dissolving sublingual tablet and efficacy versus placebo is evident as early as Day 2 in monotherapy.1,3-4 Sycrest has shown a favourable safety and tolerability profile in clinical trials7 with a mean weight change in Sycrest treated patients of 0.8 kg.1
HPN • Issue 6
50 Clinical Profiles
XALUPRINE (MERCAPTOPURINE) 20MG/ML Oral Suspension
Xaluprine ( Mercaptopurine) 20mg/ ml Oral Suspension has been granted a European license , EU/1/11/272/001, and is indicated for the treatment of acute lymphoblastic leukaemia (ALL) in adults, adolescents and children.
Xaluprine is distributed in Ireland by all the major wholesalers. Full prescribing information is available on request. This product is subject to medical prescription.
Xaluprine is available as a 100ml bottle at a list price of €252.97 and is GMS reimbursable from September 2012. Dosing can be accurately and consistently achieved using the 1ml & 5ml oral syringes supplied with the product.
New Xiapex® Safety and Efficacy Data
New data presented recently at the annual congress of the American Society for Surgery of the Hand (ASSH) show that the clinical success rate following treatment of Dupuytren’s contracture with Xiapex® (collagenase clostridium histolyticum (CCH) was greater for joints treated when fixed flexion contracture (FFC) was between 5 and 20 degrees, compared with FFC equal to or more than 20 degrees. The study examined treatment with CCH in patients who participated in one of two Phase 3 studies (CORD I or CORD II). It compared results in joints where FFC was
Less than 2 years after the publicatio Accord Healthcare have brought to market 2 strengths of Midazolam solution for injection. Trade Licence Holder Name
Issue 6 • HPN
between 5 and 20 degrees with results in joints (in the same 65 target patients) that had FFC equal to or greater than 20 degrees.
degrees and those who only had an injection to a joint with FFC equal to or greater than 20 degrees.
Results from the 5 to 20 degree FFC group were also compared with results from all other patients (n=297) who received injections only when FFC was equal to or more than 20 degrees.
Commenting on the study results, Mr. Jack Kelly, Consultant Plastic Surgeon, University Hospital Galway noted, “These results are encouraging and suggest that when treating Dupuytren’s contracture patients who have a palpable cord with collagenase clostridium histolyticum, earlier intervention may help to improve outcomes both in terms of safety and efficacy.”
Patients injected with CCH when FFC was between 5 and 20 degrees experienced fewer and less severe adverse events, compared with the same patients after an injection to a joint with FFC equal to or greater than 20
1mg/ml is available in a pack size of 10 x 5ml ampules and the 5mg/ ml comes in 10 x 10ml ampules.
Midazolam is indicated for use in both adults and children for sedation or anaesthesia.
Licence Strength Dosage Form Number
MIDAZOLAM Accord Healthcare Limited
Solution for Injection
MIDAZOLAM Accord Healthcare Limited
Solution for Injection
ch to op a io o r id p p
Targin® tablets contain an opioid analgesic
Targin® (oxycodone hydrochloride/naloxone hydrochloride) 5mg/2.5mg, 10mg/5mg, 20mg/10mg and 40mg/20mg prolonged release tablets Prescribing Information Republic of Ireland Please read the Summary of Product Characteristics (SmPC) before prescribing. Indications: Severe pain, which can be adequately managed only with opioid analgesics. Naloxone is added to counteract opioidinduced constipation by blocking the action of oxycodone at opioid receptors locally in the gut. Dosage and administration: Adults over 18 years: Usual starting dose for opioid naïve patients: 10 mg/5 mg taken orally at 12hourly intervals. Patients already receiving opioids may be started on higher doses depending on their previous opioid experience. Targin® 5 mg/2.5 mg is intended for dose titration when initiating opioid therapy & individual dose adjustment. The dosage is dependent on the severity of the pain and the patient’s previous history of analgesic requirements. Maximum daily dose of Targin is 80 mg oxycodone hydrochloride & 40 mg naloxone hydrochloride. Targin is not intended for the treatment of breakthrough pain. Please refer to SmPC for further details. Targin must be swallowed whole & not be broken, chewed or crushed. Children under 18 years: Not recommended. Contra-indications: Hypersensitivity to active substances or excipients, any situation where opioids are contra-indicated, severe respiratory depression with hypoxia and/or hypercapnoea; severe COPD, cor pulmonale, severe bronchial asthma, non-opioid induced paralytic ileus, moderate to severe hepatic impairment. Precautions and warnings: Respiratory depression, elderly or infirm, opioid-induced paralytic ileus, severely impaired pulmonary function, myxoedema, hypothyroidism, adrenocortical insufficiency, toxic psychosis, cholelithiasis, prostate hypertrophy, alcoholism, delirium tremens, pancreatitis, hypo- or hyper-tension, pre-existing cardiovascular diseases, head injury, epileptic disorder, predisposition to convulsions, patients taking MAO inhibitors, history of alcohol/drug abuse, galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorption, renal impairment, mild hepatic impairment, pre-operative use or within the first 12 - 24 hours post-operatively. Not suitable for treatment of withdrawal symptoms. Not recommended in cancer associated with peritoneal carcinomatosis or sub-occlusive syndrome in advanced stages of digestive & pelvic cancers. Concomitant use of alcohol and Targin may increase the undesirable effects of Targin and should be avoided. Tolerance and dependence may occur. It may be advisable to taper dose when stopping treatment to prevent withdrawal symptoms. Interactions: Substances having a CNS-depressant effect (e.g. other opioids, sedatives, hypnotics, anti-depressants, sleeping aids, phenothiazines, neuroleptics, anti-histamines and antiemetics) may enhance CNS-depressant effect of Targin (e.g. respiratory depression). Alcohol may enhance the pharmacodynamic effects of Targin; concomitant use should be avoided. Interaction with coumarin
anticoagulants may increase/decrease INR. Pregnancy and lactation: Not recommended. Side-effects: Common: decreased/loss of appetite, restlessness, dizziness, headache, vertigo, decrease in blood pressure, abdominal pain, diarrhoea, dry mouth, constipation, flatulence, vomiting, nausea, dyspepsia, increased hepatic enzymes, hiccups, altered mood, personality change, decreased activity, psychomotor hyperactivity, agitation, dysuria, pruritus, skin reactions, hyperhidrosis, drug withdrawal syndrome, feeling hot & cold, chills, asthenic conditions. Uncommon but potentially serious: hypersensitivity, confusion, depression, euphoric mood, hallucinations, paraesthesia, speech disorder, convulsions, sedation, syncope, visual disturbances, palpitations, angina pectoris, tachycardia, increase in blood pressure, dyspnoea, respiratory depression, biliary colic, erectile dysfunction, urinary retention, peripheral oedema, tooth disorder, chest pain and injuries from accidents. Refer to SmPC for further details of other uncommon side-effects and oxycodone class-effects. Legal category: CD (Sch2) POM. Package quantities: Blisters of 56 tablets. Marketing Authorisation numbers: PA913/025/001-4. Marketing Authorisation holder: Napp Pharmaceuticals Limited, Cambridge Science Park, Milton Road, Cambridge CB4 0GW, UK. Member of the Napp Pharmaceutical Group. Further information is available from: Mundipharma Pharmaceuticals Limited, Millbank House, Arkle Road, Sandyford, Dublin 18, Tel: +353 (0)1 2063800. Date of preparation: August 2011. References: 1. Nadstawek J, et al. Int J Clin Pract, August 2008; 62 (8): 1159–1167. 2. Simpson K, Leyendecker P, Hopp M, et al. Fixed-ratio combination oxycodone/naloxone compared with oxycodone alone for the relief of opioid-induced constipation in moderate-tosevere noncancer pain. Curr Med Res Opin 2008;24(12):3503-3512. 11144TRG
Adverse events should be reported to Mundipharma Pharmaceuticals Limited on 1800 991830
® The Napp device (logo) is a Registered Trade Mark. ® Targin is a Registered Trade Mark. © 2011-2012 Napp Pharmaceuticals Limited.
educedriskof r opioid-induced constipation
Targin® provides pain relief that is as effective as oxycodone alone2 Targin® reduces the risk of opioid-induced constipation when compared to oxycodone alone2 Targin® is indicated for severe pain, which can be adequately managed only with opioid analgesics. The opioid antagonist naloxone is added to counteract opioid-induced constipation by blocking the action of oxycodone at opioid receptors locally in the gut.
The power to reduce cardiovascular events1
ABBREVIATED PRESCRIBING INFORMATION. Product Name: Atorvas 10mg, 20mg, 40mg and 80mg Film-coated Tablets. Composition: Each film-coated tablet contains 10mg, 20mg, 40mg or 80mg atorvastatin respectively. Description: 10mg, 20mg and 40mg tablets: Light yellow, dappled, glossy, round biconvex film-coated tablets, debossed with ‘HLA 10’, ‘HLA 20’ and ‘HLA 40’ on one side respectively. 80mg tablets: Light yellow, dappled, glossy, oval biconvex film-coated tablets, debossed with ‘HLA 80’ on one side. Indication(s): Hypercholesterolaemia and prevention of cardiovascular disease. Dosage: Adults and elderly: Usual starting dose is 10mg daily with or without food. Primary hypercholesterolaemia and mixed hyperlipidaemia: 10mg daily, maintained for chronic therapy. Maximum therapeutic response seen after 4 weeks. Heterozygous familial hypercholesterolaemia: Initially 10mg daily. Adjust every 4 weeks to 40mg daily. Dose may still be increased to 80mg daily, or add a bile acid sequestrant with 40mg Atorvas as daily dose. Homozygous familial hypercholesterolaemia: Limited data available. Dose is 10mg to 80mg daily or as an adjunct to other lipid lowering treatments (i.e. LDL apheresis). Prevention of cardiovascular disease: Dose of 10mg daily may be increased to attain (LDL-) cholesterol levels in line with guidelines. Renal impairment: No adjustment of dose. Hepatic impairment: Caution. Paediatric use: Only by a specialist. Experience is limited to age group 4-17 years with severe dyslipidaemias at a starting dose of 10mg increased to 80mg daily. Contraindications: Hypersensitivity to the active or excipients. Active liver disease or unexplained persistent elevations of serum transaminases exceeding 3 times the upper limit. Pregnancy, breast-feeding and women of childbearing potential not using adequate contraception. Warnings and Precautions for Use: Liver effects: Monitor liver
function tests regularly. Caution in patients with liver disease or high alcohol intake. Stroke prevention by aggressive reduction in cholesterol levels: Increase in incidence of stroke with 80mg dose in prior haemorrhagic stroke or lacunar infarct. Caution as risks and benefits of 80mg dose is uncertain. Skeletal muscle effects: In rare occasions: myalgia, myositis, myopathy that may lead to rhabdomyolysis characterised by elevated creatine kinase (CK) levels, myoglobinaemia and myoglobinuria. Caution in predisposing factors for rhabdomyolysis; measure CK levels before treatment in the following situations: renal impairment, hypothyroidism, personal or familial history of muscular disorders, previous history of muscular toxicity with a statin or fibrate, previous history of liver disease or high alcohol intake, where an increase in plasma levels may occur, such as possible interactions, special populations. Increased CK levels 5 times higher than normal and if confirmed after 5 to 7 days; unsuitable for treatment. If patients complain about muscle pain, cramps, weakness with malaise, measure CK levels and act accordingly. Caution when taking drugs that may increase plasma concentration of atorvastatin (potent inhibitors of CYP3A4 or transport proteins, e.g. ciclosporin, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors). Higher risk of myopathy with gemfibrozil, other fibric acid derivatives, erythromycin, niacin, ezetimbe. Adjust dose of atorvastatin if use is necessary. Interstitial lung disease: Have been reported with long term therapy, discontinue atorvastatin. Interactions: Caution: CYP3A4 inhibitors: See above if given with potent inhibitors of CYP3A4. Moderate CYP3A4 inhibitors, e.g. erythromycin, verapamil, fluconazole: Monitor patients and give lower dose of atorvastatin. CYP3A4
inducers: Lower plasma levels of atorvastatin with efavirenz, rifampicin, St John’s Wort. Transport protein inhibitors: Ciclosporin can increase systemic exposure of atorvastatin. Gemfibrocil/fibric acid derivatives, Ezetimbe: Higher risk of muscle related events. Colestipol: Lower atorvastatin plasma levels, but lipid effects were greater when given in combination. Fusidic acid: Avoid. Digoxin: Monitor as digoxin levels may increase. Oral contraceptives: Increased plasma levels of norethindrone and ethinyl estradiol. Warfarin: Monitor prothrombin time. First 4 days of an 80mg dose gave a slight decrease in prothrombin time that normalised after 15 days of atorvastatin treatment. See SPC for recommended dosage schedules in combination with other drugs. Pregnancy and Lactation: Contraindicated. Ability to Drive and Use Machinery: Negligible influence. Undesirable Effects: Nasopharyngitis, allergic reactions, hyperglycaemia, headache, constipation, pharyngolaryngeal pain, epistaxis, flatulence, dyspepsia, nausea, diarrhoea, myalgia, arthralgia, pain in extremity, muscle spasms, joint swelling, back pain, liver function tests abnormal, and blood creatine kinase increased. Marketing Authorisation Holder: Rowex Ltd, Bantry, Co. Cork. Marketing Authorisation Numbers: PA 711/180/1-4. Further information and SPC are available from: Rowex Ltd, Bantry, Co. Cork. Freephone: 1800 304 400 Fax: 027 50417 E-mail email@example.com Legal Category: Subject to medical prescription. Date of Preparation: April 2012. Ref 1: PMID:21873710. Edition 1 05/12
Manufacturing in Ireland from our Bantry base, we believe in investing in the best medicines for your patients Medicinal products subject to prescription. Further information and SPC available from Rowex Ltd., Bantry, Co. Cork.
CCF No: 14111
Published on Oct 31, 2012
Published on Oct 31, 2012
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