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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
