SEPTEMBER 2014 HPRA DRUG SAFETY NEWSLETTER 63RD EDITION
In this Edition Health Products Regulatory 1 Health Products Authority (HPRA) Transdermal fentanyl: 2 Reminder about the potential Regulatory for life-threatening harm from accidental exposure to transdermal fentanyl Authority Denosumab (Prolia): 3 Updated information to minimise the risk of (HPRA) osteonecrosis of the jaw and hypocalcaemia Ferumoxytol (Rienso): 5 New important advice to
mitigate the risk of serious hypersensitivity reactions.
Beta interferons: 6 Risk of thrombotic
microangiopathy and nephrotic syndrome
Adverse Reaction 7 Reporting during 2013
Direct Healthcare Professional 8 Communications published on the HPRA website since the last Drug Safety Newsletter
As highlighted in the 62nd edition To continue to receive the DSN, of the Drug Safety Newsletter (DSN) please register on the HPRA website published in June 2014, the Irish (www.hpra.ie) to receive an alert Medicines Board (IMB) changed when a new issue is published, or Figure 1. its name to the Health Products alternatively submit your email address Regulatory Authority (HPRA) at the to [email protected] to allow an The HPRA website, beginning of July 2014, to more clearly electronic version to be emailed www.hpra.ie reflect the wider scope of our work, directly to you. functions and responsibilities across the health product sector. The DSN will continue to be published by the HPRA approximately 6 times per annum in electronic format, to highlight important regulatory updates to support the safe and appropriate use of medicines.
Kevin O’Malley House, Earlsfort Centre, Earlsfort Terrace, Dublin 2, Ireland T: +353 1 676 4971 E: [email protected] www.hpra.ie Transdermal fentanyl: Reminder about the potential for life-threatening harm from accidental exposure to transdermal fentanyl
The European Medicines Agency’s Advice to Healthcare Pharmacovigilance Risk Assessment Committee (PRAC) recently completed Professionals Key a review of global reports of accidental • Accidental exposure by patch exposure to transdermal fentanyl transfer - Caution is needed to Message patches. Accidental exposure to prevent accidental transfer of the transdermal fentanyl can occur if a fentanyl patch to a non-patch user, Cases of accidental patch is swallowed or transferred to e.g., while being in close contact. exposure to transdermal another individual. A recent EU-wide Patients and carers should be fentanyl in non-patch review emphasised the need for safe advised that if a patch is accidentally wearers, especially in handling of patches. In addition, transferred to another person, children, continue to be children are at risk as they may touch, the transferred patch should be reported. To prevent suck, chew, or swallow a patch that removed immediately and medical potential life threatening has not been disposed of properly. advice sought. harm from accidental In addition, children have a lower • Accidental ingestion - Patients and threshold for fentanyl overdose than exposure to fentanyl, carers should be advised to choose adults. healthcare professionals the patch application site carefully are reminded of the Healthcare professionals are therefore and to monitor the adhesion of importance of providing reminded to provide clear information the patch closely, especially at the clear information to patients to patients and carers regarding the edges. and carers regarding the risk of accidental exposure by patch • Used patches - Used patches may transfer, risk of accidental ingestion of risk of accidental exposure still contain some active substance patches and the need for appropriate by patch transfer, risk of which could be potentially harmful disposal of patches. Patients and accidental ingestion and to children and others. Patients and caregivers should be advised to follow the need for appropriate carers should be advised that used the instructions on the patch carton disposal of patches. patches should be folded as soon as and in the accompanying leaflet. they are removed from the patient so that the adhesive side of the Children are at risk as patch sticks firmly to itself before Further details on transdermal fentanyl they may touch, suck, being disposed of safely. products are available at www.hpra.ie chew, or swallow a • Please report any suspected cases and www.ema.europa.eu/ema. of adverse reactions associated patch that has not been with accidental exposure to disposed of properly. fentanyl patches to the HPRA via the on-line, downloadable or post- paid reporting options www.hpra.ie (www.hpra.ie).
2 HPRA Drug Safety Newsletter – September 2014 – Edition 63 Denosumab (Prolia): Updated information to minimise the risk of osteonecrosis of the jaw and hypocalcaemia
Following a Prolia contains the active substance Prolia inhibits osteoclast bone densoumab and is authorised for resportion, thereby decreasing European-wide review the treatment of osteoporosis in the release of calcium from bone postmenopausal women and in men, into the blood stream. In the post- of the latest safety at increased risk of fractures. marketing setting, rare cases of severe symptomatic hypocalcaemia have data for Prolia, the ONJ is a condition in which the been reported. The majority of cases jawbone becomes necrotic, exposed product information occurred in the few weeks following and does not heal within eight initiation of treatment with Prolia and for Prolia has been weeks. It has been reported rarely in renal insufficiency was also described clinical studies and also in the post- updated to include in the majority of cases. marketing setting in patients treated updated information with Prolia 60mg every six months for Severe symptomatic hypocalcaemia osteoporosis. ONJ has been reported can manifest as QT interval and revised commonly however in patients prolongation, tetany, seizures and recommendations with advanced cancer treated with altered mental status. Additional denosumab (Xgeva) at a dose symptoms of hypocalcaemia include to minimise the risk of 120mg monthly. muscle stiffness, twitching, spasms and muscle cramps. To minimise the of osteonecrosis of Known risk factors for ONJ risk of ONJ and hypocalcaemia during include previous treatment with treatment with Prolia, healthcare the jaw (ONJ) and bisphosphonates, older age, poor oral professionals are reminded of the hygiene, invasive dental procedures hypocalcaemia during following recommendations: (tooth extractions, dental implants treatment etc), co-morbid disorders (e.g. pre- existing dental disease, anaemia, etc), smoking and concomitant therapies (e.g. chemotherapy, corticosteroids, radiotherapy to head and neck).
3 HPRA Drug Safety Newsletter – September 2014 – Edition 63 Advice for Healthcare Professionals to minimise the risk of ONJ Key • Prescribing doctors should evaluate • If a patient experiences ONJ while Message all patients for ONJ risk factors on Prolia therapy, a management prior to treatment with Prolia. plan for the individual patient Prior to commencing should be developed in close • A dental examination with treatment with Prolia, collaboration with a dentist and/or appropriate preventive dentistry all patients should be oral surgeon with expertise in the is recommended in patients with evaluated for ONJ risk area. concomitant risk factors. factors which include • Temporary interruption of treatment age, poor oral hygiene, • Patients should be advised to with Prolia should be considered maintain good oral hygiene co-morbid disorders until the condition resolves and practices, attend routine dental and smoking. During contributing risk factors are check-ups and immediately report treatment, patients should mitigated, where possible. any oral symptoms (such as pain be encouraged to maintain or swelling) during treatment with • Please report any suspected cases good oral hygiene practices Prolia. of ONJ with Prolia to the HPRA and report any oral via the online downloadable or symptoms experienced. post paid reporting options. If ONJ occurs, temporary (www.hpra.ie) interruption of treatment should be considered until the condition resolves
Patients should be informed of the signs and The risk of developing hypocalcaemia while being symptoms of ONJ and hypocalcaemia and advised treated with Prolia increases to report if any of these effects are experienced. with increasing degree of renal impairment. Any pre-existing hypocalcaemia must be corrected prior Advice for Healthcare Professionals to initiating Prolia therapy to minimise the risk of hypocalcaemia and calcium levels should be monitored before • Hypocalcaemia is a known risk in - Prior to each dose of Prolia. each dose and for those patients treated with Prolia, which - Within two weeks after the initial patients predisposed to increases with the degree of renal dose in patients predisposed to hypocalcaemia, within impairment. hypocalcaemia (e.g. patients with two weeks after the initial • Pre-existing hypocalcaemia must severe renal impairment, creatinine dose. Patients should be be corrected prior to initiating clearance <30ml/min). informed of the signs and therapy with Prolia. - If suspected symptoms of symptoms of hypocalcaemia • All patients taking Prolia should hypocalcaemia occur, or if and advised to report any be encouraged to maintain an otherwise indicated based on the experienced. adequate intake of calcium and clinical condition of the patient. vitamin D. This is especially • Patients should be informed important in patients with severe of the signs and symptoms of Further details of the product renal impairment. hypocalcaemia and advised to information for Prolia available • Monitoring of calcium levels should report any experienced. at www.hpra.ie and be conducted: www.ema.europa.eu/ema. • This information was highlighted in a Direct Healthcare Professional Communication (DHPC) circulated to relevant healthcare professionals in September 2014.
4 HPRA Drug Safety Newsletter – September 2014 – Edition 63
Ferumoxytol (Rienso): New important advice to mitigate the risk of serious hypersensitivity reactions.
Rienso (containing the active sub- During post marketing use of Rienso, stance ferumoxytol) was authorised serious hypersensitivity reactions for the intravenous treatment of iron including anaphylactic reactions, some Key deficiency anaemia in adult patients of which have been life-threatening or with chronic kidney disease (CKD) in fatal, have been reported in patients Message June 2012. receiving Rienso. The benefits and risks of Rienso have been evaluated Rienso is now contraindicated Parenterally administered iron prepara- in the context of a regular procedure in patients with any known tions are known to cause hypersensi- known as Periodic Safety Update history of drug allergy, tivity reactions including serious and Report (PSUR), which has resulted potentially fatal anaphylactic reac- including hypersensitivity in new recommendations for use. In tions. Hypersensitivity reactions have to other parenteral iron order to mitigate the risk of hyper- also been reported after previously products. Rienso should sensitivity reactions following use uneventful doses of parenteral iron only be administered as with Rienso, healthcare professionals complexes. an intravenous infusion should be aware of these new recom- (50-250 ml of sterile 0.9% mendations, as follows: sodium chloride or sterile 5% dextrose), over a minimum period of 15 minutes and Advice to Healthcare Professionals must not be administered • Rienso is contraindicated • Patients should be carefully by injection. Rienso should in patients with any known monitored for signs and symptoms only be administered by history of drug allergy including of hypersensitivity reactions, staff trained to evaluate hypersensitivity to other including monitoring of blood and manage anaphylactic parenteral iron products. pressure and pulse, during and reactions and in a setting for at least 30 minutes after each where resuscitation facilities • Rienso should only be administered administration of Rienso. as an intravenous infusion (50-250 are immediately available. ml of sterile 0.9% sodium chloride • Before each administration, or sterile 5% dextrose), over a patients should be informed minimum period of 15 minutes of the risk of hypersensitivity. This information was highlighted and must not be administered by Patients should also be informed via a Direct Healthcare Professional injection. of the relevant symptoms and Communication (DHPC) asked to seek urgent medical circulated to relevant healthcare • Rienso should only be administered attention if a reaction occurs. professionals in August 2014. when staff trained to evaluate and manage anaphylactic reactions as • Any suspected adverse reactions Further details of the product well as resuscitation facilities are associated with use of Rienso information for Rienso are available immediately available. should be reported to the HPRA at www.hpra.ie. via the on-line, downloadable or • Patients should be placed in a post-paid reporting options reclined or semi-reclined position (www.hpra.ie). during the Rienso infusion and for at least 30 minutes thereafter.
5 HPRA Drug Safety Newsletter – September 2014 – Edition 63 Beta interferons: Risk of thrombotic microangiopathy and nephrotic syndrome
A recent Europe-wide review has The cases of TMA mostly presented recommended updates to the as thrombotic thrombocytopenic product information for interferon- purpura or haemolytic uraemic beta products*. This review was syndrome, some of which resulted in a Key triggered after reports of thrombotic fatal outcome. The cases of nephrotic microangiopathy (TMA) and nephrotic syndrome reported in association with Message syndrome were received in association interferon-beta products had different with the use of these products for the underlying nephropathies. Since TMA Reports of thrombotic treatment of multiple sclerosis. The and nephrotic syndrome can develop microangiopathy (TMA) review could not out-rule a causal several weeks to several years after and nephrotic syndrome association between interferon-beta starting treatment with these products, have been received in products and nephrotic syndrome healthcare professionals should be alert association with interferon- or TMA. to the potential for these conditions beta products for the and manage them promptly in line with treatment of multiple the following advice: sclerosis. Since TMA and nephrotic syndrome can develop several weeks Advice to Healthcare Professionals to several years after • Clinical features of TMA include • If nephrotic syndrome occurs, starting treatment with thrombocytopenia, new onset patients should be treated promptly, these products, healthcare hypertension, fever, central nervous with consideration given to stopping professionals should be system symptoms (such as confusion treatment with beta interferon. alert to these conditions and paresis) and impaired renal and manage them promptly • The product information (Summary function. if diagnosed. of Product Characteristics (SmPC) • If clinical features of TMA are and Package Leaflet (PL)) has been observed, blood platelet levels, updated to include information serum lactate dehydrogenase levels, on TMA and nephrotic syndrome * Interferon-beta products authorised renal function and red blood cell for interferon beta products, as in Ireland for the treatment of fragments on a blood film should all appropriate. multiple sclerosis include the be tested. following, (please note not all • A Direct Healthcare Professional products may be marketed): • If TMA diagnosis is confirmed, Communication (DHPC) was • Avonex (interferon beta-1a) then prompt treatment (consider circulated to relevant healthcare • Rebif (interferon beta-1a) plasma exchange) is required and professionals in September 2014. immediate discontinuation of • Betaferon (interferon beta-1b) • Any suspected adverse reactions interferon-beta is recommended. • Extavia (interferon beta-1b) associated with use of interferon- • Plegridy (peginterferon beta-1a) • Patients’ renal function should be beta products should be reported monitored periodically to ensure to the HPRA via the on-line, Further details of the product early signs or symptoms of nephrotic downloadable or post-paid information for individual beta syndrome (oedema, proteinuria, reporting options (www.hpra.ie). interferon products available impaired renal function) are at www.hpra.ie and identified. www.ema.europa.eu/ema.
6 HPRA Drug Safety Newsletter – September 2014 – Edition 63 Adverse Reaction Reporting during 2013
The HPRA continues to place great emphasis on encouraging and promoting the submission of adverse reaction reports associated with the use of medicines from its stakeholders. These reports are important to signal potential During 2013, a total of 2,835 suspected safety issues from adverse reaction reports were received Figure 2. from healthcare professionals, members Reporting adverse medicines in use and of the public and pharmaceutical reactions on companies, indicating a small increase www.hpra.ie ultimately assist the in reporting figures for 2012. A HPRA in monitoring breakdown of the reports by source is outlined below and it is important the safety of medicines to note that reports submitted by on the Irish market. pharmaceutical companies, will have Source of Suspected first been brought to their attention by Adverse healthcare professionals, patients and consumers, prior to onward reporting Reaction Reports % to HPRA. In keeping with experience Pharmaceutical Company 64 in other European countries, reporting rates were highest for newly authorised Community Care Doctor 9 medicines. Reporting rates are General Practitioner 5 influenced by their ease of recognition Hospital Doctor 4 and may be stimulated by publicity about a particular medicine or reaction. Hospital Pharmacist 4 Reporting rates are also influenced Community Pharmacist 4 by proactive and repeated requests Nurse 5 to healthcare professionals to submit reports on certain medicines as part of Patient/Consumer 1 ongoing post marketing surveillance, Other 4 as well as other promotional and data collection activities.
7 HPRA Drug Safety Newsletter – September 2014 – Edition 63 The HPRA greatly appreciates the contribution of busy healthcare professionals in reporting suspected adverse reactions, facilitating the continued surveillance of the safety of medicines.
Individual case reports are followed The HPRA greatly appreciates the There are several options in place for up by the HPRA, with feedback contribution of busy healthcare reporting suspected adverse reactions information provided to reporters, as professionals in reporting suspected to the HPRA. These are as follows: appropriate. Relevant, anonymised adverse reactions, facilitating the • By following the links to the online reports (i.e. serious, suspected cases) continued surveillance of the safety of reporting options accessible for the notified directly to the HPRA by medicines. While the time-consuming HPRA homepage (www.hpra.ie); healthcare professionals or members nature of form-filling and the provision of the public are forwarded to the of follow-up information to the HPRA • Using the downloadable report appropriate marketing authorisation is recognised and acknowledged; form also accessible from the HPRA holders (MAHs) and the European the collection and evaluation of website, which may be completed Medicines Agency (EMA) within the comprehensive reports is essential manually and submitted to the HPRA agreed timeframes and formats. The to ensure that appropriately detailed via ‘freepost’; HPRA also continues to provide details case information is available for the • Using the traditional ‘yellow card’ of reports received to the World Health continuous surveillance of the safety of report, which also utilises a freepost Organisation (WHO) for inclusion on its medicines. Such reports are essential system; international database. for the HPRA to ensure that regulatory action/proposals take account of all • By telephone to the HPRA available data. Pharmacovigilance section (01-6764971).
Direct Healthcare Professional Communications published on the HPRA website since the last Drug Safety Newsletter
PRODUCT SAFETY ISSUE
Simulect (basiliximab) Warning against off-label use in cardiac transplantation
Beta interferons Risk of thrombotic microangiopathy and nephrotic syndrome.
Rienso (ferumoxytol) New important advice to mitigate risk of serious hypersensitivity.
Ikorel (nicorandil) Advice on the risk of serious ulcerations or related events.
Arzerra (ofatumumab) Reminder of risk of serious and fatal infusion reactions
Vibativ (telavancin) Recommendations for use and important risks (nephrotoxicity, QTc prolongation, reproductive toxicity and off-label use).
Transdermal Fentanyl Reminder about the potential for life-threatening harm from accidental exposure to transdermal fentanyl.
Correspondence/Comments should be sent to the Pharmacovigilance Section, Health Products Regulatory Authority, Kevin O’Malley House, Earlsfort Centre, Earlsfort Terrace, Dublin 2. Tel: 676 4971-7 Fax: 676 2517
8 Kevin O’Malley House, Earlsfort Centre, Earlsfort Terrace, Dublin 2, Ireland T: +353 1 676 4971 E: [email protected] www.hpra.ie