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					                                            IRISH MEDICINES BOARD




                 40th EDITION                          NEWSLETTER
               Multaq (dronedarone) – Association with Severe Liver Injury


Dronedarone is indicated in clinically stable                  complications with the medicine. The Commit-
adult patients with a history of, or current non-              tee recommended the inclusion of warnings
permanent atrial fibrillation (AF) to prevent                  and precautions in the medicine’s prescribing
recurrence of AF or to lower ventricular rate.                 information, to ensure appropriate monitoring
                                                               of liver function before initiation of and during
Since dronedarone was licensed in 2009, there                  treatment with dronedarone, recommending
have been reports of liver function test abnor-                that treatment is stopped if there are signs of
malities and hepatocellular liver injury in                    potential liver damage.
patients taking dronedarone, including two
cases of acute liver failure requiring transplan-              Further evaluation of the data is continuing in
tation. Some of these cases occurred early after               the context of a formal EU wide referral proce-
the start of treatment, with the two cases                     dure, the outcome of which will be communi-
requiring liver transplantation occurring at 4.5               cated once the CHMP has reached its final
and 6 months after initiation of treatment in                  opinion.
patients with normal baseline liver function
tests. In one case the liver injury was not                    In the meantime, the new European regula-
reversible after discontinuation of drone-                     tory recommendations are as follows:
darone. Although both patients were taking
concomitant medications, a causal relation-                    Advice to Healthcare Professionals
ship with dronedarone could not be excluded.                   • For patients prescribed dronedarone, liver
                                                                   function tests should be performed:
Following receipt of these reports, the Commit-
tee for Medicinal Products for Human Use                           • prior to initiation of treatment,
(CHMP) of the European Medicines Agency                            • on a monthly basis for six months,
(EMA) has initiated a review of all available                      • at months 9 and 12, and periodically
data concerning the possible risks of liver                            thereafter.
injury associated with the use of dronedarone
and their impact on its benefit-risk balance.                  • Patients currently receiving dronedarone
                                                                   should be contacted within the next month
The Committee discussed dronedarone during                         so that liver function tests could be
its January 2011 meeting and concluded that                        performed and thereafter they should be
there was a need for urgent regulatory action to                   tested as listed above depending on when
help manage the possible risk of severe liver                      treatment was initiated

                 •   Multaq (dronedarone) – Association with Severe Liver Injury
                 •   Thelin (sitaxentan) – Marketing Authorisation withdrawal
     In
                 •   Fluoroquinolones and the risk of QT Prolongation
    this
                 •   View the Drug Safety Newsletter online or via email
   edition       •   Safe Use of Insulin Pens
                 •   Direct Healthcare Professional Communications




Drug Safety – February 2011 – Issue Number 40                                                                 1
• If alanine transaminase (ALT) levels are
                                                     Thelin (sitaxentan) – Marketing
     elevated to ≥3 × upper limit of normal (ULN),
                                                     Authorisation withdrawal
     levels should be re-measured within 48 to 72
     hours. If ALT levels are confirmed to be ≥3 ×
                                                     Sitaxentan (Thelin) is an endothelin receptor
     ULN after re-measurement, dronedarone
                                                     antagonist, indicated for the treatment of
     treatment should be withdrawn.
                                                     patients with pulmonary arterial hyperten-
                                                     sion classified as WHO functional class III, to
• Patients should be advised to contact
                                                     improve exercise capacity.
     healthcare professionals immediately in
     case of signs or symptoms of liver injury.      In December 2010 the marketing authorisation
     Patients should be advised to immediately       holder for Thelin announced its decision to
     report any symptoms of potential liver          withdraw the product from all markets world-
     injury (such as sustained new-onset             wide and to discontinue all ongoing clinical
     abdominal pain, anorexia, nausea, vomit-        trials. This decision was made after a review of
     ing, fever, malaise, fatigue, jaundice, dark    fatal cases associated with hepatic injury,
     urine or itching) to their physician.           including a reported case from the UK (in 2009)
                                                     and two cases from clinical trials in India and
The product information (Summary of                  the Ukraine, which occurred in 2010.
Product Characteristics [SmPC] and package
leaflet) will be revised to include this informa-    Hepatic reactions are known side effects of
tion. Updated educational materials will be          sitaxentan, and warnings have been included
distributed when available.                          in the product information and educational
                                                     materials since it was first licensed. These
                                                     warnings were updated to provide further
The current European public assessment
                                                     guidance regarding hepatic safety monitoring
report for Multaq can be found on the EMA
                                                     after the fatal case which occurred in 2009.
website:
                                                     The new data suggest that serious hepatotoxi-
http://www.ema.europa.eu/docs/en_GB/do
                                                     city in association with sitaxentan is idiosyn-
cument_library/EPAR_-_Public_assess-
                                                     cratic and cannot be prevented in all patients.
ment_report/human/001043/WC500044538
                                                     In some patients, development of liver injury
.pdf
                                                     was not related to identifiable risk factors, was
                                                     unlikely to be detected by monthly monitor-
                                                     ing, and did not resolve when sitaxentan was
                                                     discontinued. Based on the information
    Key Message:                                     available and the availability of alternative
    Cases of liver injury, including two cases       treatments, the marketing authorisation
    of liver failure requiring transplantation       holder concluded that the overall benefit of
    have been reported in patients receiving         Thelin no longer outweighed the risk in the
    dronedarone. Some of these cases                 general population of PAH patients and
    occurred early after the start of treatment.     voluntarily withdrew the product from all
                                                     markets worldwide.
    For patients prescribed dronedarone, liver
    function tests should be performed:              Alternative treatments for pulmonary arterial
                                                     hypertension are available in Ireland.
    • prior to treatment,
    • on a monthly basis for six months,             Advice was provided directly to prescribers
                                                     indicating that patients should be switched to
    • at months 9 and 12, and periodically
                                                     an alternative treatment as soon as is safely
      thereafter.
                                                     possible. The Dear Healthcare Professional
                                                     Communication is available on the IMB
                                                     website. www.imb.ie.




2                                                     Drug Safety – February 2011 – Issue Number 40
                                                   Europe in relation to the updated assessment
Fluoroquinolones and the risk of QT
                                                   of the risk of QT interval prolongation for the
Prolongation
                                                   individual substances. For further information
                                                   and the complete list of fluoroquinolones
Fluoroquinolones are broad spectrum
                                                   considered as part of the review please see the
antibiotics, authorised for a wide range of
                                                   following link:
indications. Those currently authorised in
Ireland include: moxifloxacin, levofloxacin,
                                                   http://www.ema.europa.eu/docs/en_GB/do
ofloxacin and ciprofloxacin*.
                                                   cument_library/Report/2011/01/WC500100
                                                   459.pdf)
The potential for fluoroquinolones to cause QT
prolongation is recognised and has been
previously considered on the basis of available      Key Message:
data for the individual substances, as reflected     • The risk of QT interval prolongation with
in the product specific information. A further         fluoroquinolone antibiotics varies across the
                                                       class
recent European review of study and post-
marketing data in relation to QT prolongation        • Due to an increased risk of QT prolongation
and fluoroquinolones concluded that the risk of        (in addition to the potential for other serious
QT prolongation does not appear to be similar          risks, i.e. serious hepatotoxicity), oral
across this class of antibiotics, but that             moxifloxacin should only be used when use
substances may be classified according to their        of other antibacterial agents is inappropri-
potential to prolong QT interval and precipitate       ate, or have failed.
cardiac events (i.e. ventricular arrhythmia).
                                                     • Consideration should be given to official
                                                       guidance on the appropriate use of antibac-
As moxifloxacin has been associated with an            terial agents.
established potential for increased risk of QT
prolongation, prescribers are reminded to use
moxifloxacin only when it is considered            * Brands include:
inappropriate to use antibacterial agents that     Moxifloxacin – Avelox          Levofloxacin – Tavanic, Tavager
                                                   Ofloxacin - Tarivid, Biravid   Ciprofloxacin – Truoxin, Ciproxin
are commonly recommended or when these
have failed for the treatment of: acute
bacterial sinusitis, acute exacerbations of
chronic bronchitis, community acquired             View the Drug Safety Newsletter online
pneumonia (except severe cases) and mild to        or via email
moderate pelvic inflammatory disease.
                                                   The IMB publishes an electronic version of the Drug
Following assessment of the available              Safety Newsletter on its website, www.imb.ie.
evidence, levofloxacin, ofloxacin and cipro-       Should you wish to receive an email alert notifying
floxacin are considered to have a lower            you that future editions of the newsletter are avail-
potential to induce QT interval prolongation.      able online, please submit your request to
                                                   imbpharmacovigilance@imb.ie. Alternatively the
It is important to note that in the context of     electronic version can be emailed directly to you.
conditions which favour the development of         Signing up to this service will ensure you no longer
QT prolongation e.g. hypokalaemia, hypo-           receive a print version. The online edition is in PDF
magnesaemia, bradycardia, patients with            format, thus allowing you to save the newsletter
congenital or acquired QT prolongation, some       and/or print specific pages. The online version will
fluoroquinolones have the potential to induce      also contain hyperlinks to the product information
life-threatening Torsades de Pointes (e.g.         and other documents on the IMB and EMA
moxifloxacin).                                     websites. By signing up to this environmentally
                                                   friendly online service, you will receive prompt
The product information for fluoroquinolones       notification of publications and will assist the IMB
will be updated and harmonised throughout          to reduce postage, production and related costs.




Drug Safety – February 2011 – Issue Number 40                                                                    3
                                                            of the supportive evidence, recipients, and
Safe Use of Insulin Pens
                                                            distribution timetable.
The Medical Device Vigilance group of the IMB               DHPCs are an important communication tool
recently issued an Advisory Notice (available               that can aid education and risk management
on www.imb.ie) outlining the potential risk of              for healthcare professionals. Situations where
bloodborne pathogen transmission if insulin                 a DHPC should be considered as part of the
pens are used on more than a single patient,                risk-management process include:
even if needles are changed between patients.
Healthcare professionals are reminded that                  • Suspension, withdrawal, revocation of a
these products should be used in accordance                     marketing authorisation with recall of the
with the recommendations in the device                          medicine from the market for safety reasons
labelling/Summaries of Product Characteristics              • Important changes to the Summary of
(SmPC) for the individual products.                             Product Characteristics (SmPC) e.g. new
                                                                warnings or contraindications, reduced
                                                                recommended dose, or restricted indications
Direct Healthcare Professional                                  or availability
Communications
                                                            • A change in the balance of benefits and
In the case of urgent and/or important safety                   risks for a medicine
issues about a medicinal product, a Direct
                                                            DHPCs are published on the IMB website
Healthcare Professional Communication
                                                            (www.imb.ie) under ‘Publications’ once they
(DHPC) is used to notify healthcare
                                                            have been distributed. Recent DHPCs published
professionals. A DHPC (also known as a ‘Dear
                                                            on the IMB website are outlined below and will
Doctor Letter’) aims to ensure safe and
                                                            be listed in future issues of the Drug Safety
effective use of a marketed medicine and is
                                                            Newsletter.
delivered directly to healthcare professionals
by marketing authorisation holders or by                    Further information can be found on the IMB
competent authorities such as the IMB.                      website and/or in Volume 9A of The Rules
                                                            Governing Medicinal Products in the European
The initiative for issuing a DHPC can come                  Union – Guidelines on pharmacovigilance for
from the European or National regulatory                    medicinal products for human use – which
authorities or the marketing authorisation                  outlines the obligations of marketing author-
holder. Agreement is needed between the                     isation holders and national competent
marketing     authorisation    holder   and                 authorities for pharmacovigilance of licensed
competent authorities on the content and                    medicines including guidance on risk
format of the information with consideration                communication and DHPCs.

Recent DHPCs published on the IMB website:

 P r o d u ct                                 S af e t y I s s u e
 Dianeal, Extraneal and Nutrineal solutions   Potential presence of endotoxins and risk of aseptic peritonitis
 for peritoneal dialysis
 Vistide (cidofovir)                          Risk of serious adverse reactions with off-label use
 Multaq (dronedarone)                         Information on severe liver injury associated with use of Multaq
 Cubicin (daptomycin)                         Association with eosinophilic pneumonia
 Gadolinium containing contrast agents        Information on the risk of Nephrogenic Systemic Fibrosis (NSF)



                                 Drug Safety – February 2011 – Issue Number 40
                                 Correspondence/Comments should be sent to the
                                 Pharmacovigilance Section, Irish Medicines Board,
                                 Kevin O’Malley House, Earlsfort Centre, Earlsfort Terrace, Dublin 2.

                                 Tel: 676 4971-7 Fax: 676 2517 Email: imbpharmacovigilance@imb.ie

				
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