ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
MULTAQ 400 mg film-coated tablets
2.
Each tablet contains 400 mg of dronedarone (as hydrochloride).
Excipients:
Each tablet also contains 41.65 mg of lactose (as monohydrate).
For a full list of excipients, see section 6.1.
3.
Film-coated tablet (tablet).
White, oblong shaped tablets, engraved with a double wave marking on one side and “4142”code on
the other side.
4.
MULTAQ is indicated in adult clinically stable patients with a history of, or current non-permanent
atrial fibrillation (AF) to prevent recurrence of AF or to lower ventricular rate (see section 5.1).
Treatment with MULTAQ can be initiated in an outpatient setting.
The recommended dose is 400 mg twice daily in adults. It should be taken as
•
one tablet with the morning meal and
one tablet with the evening meal.
Grapefruit juice should not be taken together with MULTAQ (see section 4.5).
If a dose is missed, patients should take the next dose at the regular scheduled time and should not
double the dose.
Treatment with Class I or III antiarrhythmics (such as flecainide, propafenone, quinidine,
disopyramide, dofetilide, sotalol, amiodarone) must be stopped before starting MULTAQ (see sections
4.3 and 5.1).
Paediatric Population
There is no experience in children and adolescents below 18 years of age. Therefore, MULTAQ is not
recommended in this population.
Elderly
Efficacy and safety were comparable in both elderly and younger patients. Although plasma exposure
in elderly females was increased in a pharmacokinetic study conducted in healthy subjects, dose
adjustments are not considered necessary (see sections 5.1 and 5.2).
2
•
Hepatic impairment
MULTAQ is contraindicated in patients with severe hepatic impairment because of the absence of data
(see section 4.3). No dose adjustment is required in patients with mild or moderate hepatic impairment
(see section 5.2).
Renal impairment
MULTAQ is contraindicated in patients with severe renal impairment (creatinine clearance
(CrCl) <30 ml/min) (see section 4.3). No dose adjustment is required in other patients with renal
impairment (see sections 4.4 and 5.2).
•
Hypersensitivity to the active substance or to any of the excipients
•
Second- or third- degree Atrio-Ventricular block or sick sinus syndrome (except when used in
conjunction with a functioning pacemaker)
•
Bradycardia <50 beats per minute (bpm)
•
Patients in unstable hemodynamic conditions including patients with symptoms of heart failure
at rest or with minimal exertion (corresponding with NYHA class IV and unstable class III
patients).
•
Co-administration with potent cytochrome P 450 (CYP) 3A4 inhibitors, such as ketoconazole,
itraconazole, voriconazole, posaconazole, telithromycin, clarithromycin, nefazodone and
ritonavir (see section 4.5)
•
Medicinal products inducing torsades de pointes such as phenothiazines, cisapride, bepridil,
tricyclic antidepressants, terfenadine and certain oral macrolides, Class I and III antiarrhythmics
(see section 4.5)
•
QTc Bazett interval ≥500 milliseconds
•
Severe hepatic impairment
•
Severe renal impairment (CrCl <30ml/min)
Patients with stable NYHA class III heart failure or LVEF <35%
Because of the unexplained results of ANDROMEDA study, the use of dronedarone in unstable
patients with NYHA class III and IV heart failure is contraindicated (see sections 4.3 and 5.1).
Because of limited experience in stable patients with recent (1 to 3 months) NYHA class III heart
failure or with Left Ventricular Ejection Fraction (LVEF) <35%, the use of MULTAQ is not
recommended
.
Management of plasma creatinine increase
It is recommended to measure plasma creatinine values 7 days after initiation of dronedarone. An
increase in plasma creatinine has been observed with dronedarone 400 mg twice daily in healthy
subjects and in patients. This increase occurs early after treatment initiation and reaches a plateau after
7 days. If an increase in creatininemia is observed, this value should be used as the new reference
baseline taking into account that this may be expected with dronedarone.
An increase in creatininemia should not necessarily lead to the discontinuation of treatment with ACE-
inhibitors or Angiotensin II Receptors Antagonists (AIIRAs).
Patients with renal impairment
MULTAQ is contraindicated in patients with CrCl <30 ml/min (see section 4.3).
Electrolytes imbalance
Since antiarrhythmic medicinal products may be ineffective or may be arrhythmogenic in patients with
hypokalemia, any potassium or magnesium deficiency should be corrected before initiation and during
dronedarone therapy.
3
QT prolongation
The pharmacological action of dronedarone may induce a moderate QTc Bazett prolongation (about
10 msec), related to prolonged repolarisation. These changes are linked to the therapeutic effect of
dronedarone and do not reflect toxicity. Follow up, including ECG (electrocardiogram), is
recommended during treatment. If QTc Bazett interval is ≥500 milliseconds, dronedarone should be
stopped (see section 4.3).
Based on clinical experience, dronedarone has a low pro-arrhythmic effect and has shown a decrease
in arrhythmic death in the ATHENA study (see section 5.1).
However, proarrhythmic effects may occur in particular situations such as concomitant use with
medicinal products favouring arrhythmia and/or electrolytic disorders (see sections 4.4 and 4.5).
Patients with galactose intolerance
Due to the presence of lactose in this medicinal product, patients with rare hereditary problems of
galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption, should not take
this medicine.
Interactions (see section 4.5)
Potent CYP3A4 inducers such as rifampicin, phenobarbital, carbamazepine, phenytoin or St John’s
Wort are not recommended.
Administration of dronedarone to patients receiving digoxin will bring about an increase in the plasma
digoxin concentration and thus precipitate symptoms and signs associated with digoxin toxicity.
Clinical, ECG and biological monitoring is recommended, and digoxin dose should be halved. A
synergistic effect on heart rate and atrioventricular conduction is also possible. The co-administration
of beta-blockers or calcium antagonists with depressant effect on sinus and atrio-ventricular node
should be undertaken with caution. These medicinal products should be initiated at low dose and up-
titration should be done only after ECG assessment. In patients already on calcium antagonists or beta
blockers at time of dronedarone initiation, an ECG should be performed and the dose should be
adjusted if needed.
Statins should be used with caution. Lower starting dose and maintenance doses of statins should be
considered and patients monitored for clinical signs of muscular toxicity.
Patients should be warned to avoid grapefruit juice beverages while taking dronedarone.
Dronedarone is primarily metabolised by CYP 3A4 (see section 5.2). Therefore, inhibitors and
inducers of CYP 3A4 have the potential to interact on dronedarone. Dronedarone is a moderate
inhibitor of CYP 3A4, a mild inhibitor of CYP 2D6 and a potent inhibitor of P-glycoproteins (P-gp).
Dronedarone therefore, has the potential to interact on medicinal products substrates of P-
glycoproteins, CYP 3A4 or CYP 2D6. Dronedarone has no significant potential to inhibit CYP 1A2,
CYP 2C9, CYP 2C19, CYP 2C8 and CYP 2B6.
A potential pharmacodynamic interaction can also be expected with beta-blockers, calcium antagonists
and digitalis.
Medicinal products inducing torsades de pointes
Medicinal products inducing torsades de pointes such as phenothiazines, cisapride, bepridil, tricyclic
antidepressants, certain oral macrolides, terfenadine and Class I and III antiarrhythmics are
contraindicated because of the potential risk of proarrhythmia (see section 4.3). Caution should also be
taken with co-administration with beta-blockers or digoxin.
Effect of other medicinal products on MULTAQ
Potent CYP 3A4 inhibitors
Repeated doses of 200 mg ketoconazole daily resulted in a 17-fold increase in dronedarone exposure.
Therefore, concomitant use of ketoconazole as well as other potent CYP 3A4 inhibitors such as
itraconazole, voriconazole, pozaconazole, ritonavir, telithromycin, clarithromycin or nefazodone is
contraindicated (see section 4.3).
4
Moderate/weak CYP 3A4 inhibitors: calcium antagonists
Calcium antagonists, diltiazem and verapamil, are substrates and/or moderate inhibitors of CYP 3A4.
Moreover, due to their heart rate-lowering properties, verapamil and diltiazem have the potential to
interact with dronedarone from a pharmacodynamic point of view.
Repeated doses of diltiazem (240 mg twice daily), verapamil (240 mg once daily) and nifedipine
(20 mg twice daily) resulted in an increase in dronedarone exposure of 1.7-, 1.4- and 1.2- fold,
respectively. Calcium antagonists also have their exposure increased by dronedarone (400 mg twice
daily) (verapamil by 1.4- fold, and nisoldipine by 1.5- fold). In clinical trials, 13% of patients received
calcium antagonists concomitantly with dronedarone. There was no increased risk of hypotension,
bradycardia and heart failure.
Overall, due to the pharmacokinetic interaction and possible pharmacodynamic interaction, calcium
antagonists with depressant effects on sinus and atrio-ventricular node such as verapamil and diltiazem
should be used with caution when associated with dronedarone. These medicinal products should be
initiated at low dose and up-titration should be done only after ECG assessment. In patients already on
calcium antagonists at time of dronedarone initiation, an ECG should be performed and the calcium
antagonist dose should be adjusted if needed (see section 4.4).
Other moderate inhibitors of the CYP3A4 such as erythromycin are also likely to increase
dronedarone exposure.
CYP 3A4 inducers
Rifampicin (600 mg once daily) decreased dronedarone exposure by 80% with no major change on its
active metabolite exposure. Therefore, co-administration of rifampicin and other potent CYP 3A4
inducers such as phenobarbital, carbamazepine, phenytoin or St John’s Wort is not recommended as
they decrease dronedarone exposure.
Effect of MULTAQ on other medicinal products
Interaction on medicinal products metabolized by CYP 3A4
Statins:
Dronedarone can increase exposure of statins that are substrates of CYP 3A4 and/or P-gp substrates.
Dronedarone (400 mg twice daily) increased simvastatin and simvastatin acid exposure by 4- fold and
2- fold respectively. It is predicted that dronedarone could also increase the exposures of lovastatin
and atorvastatin within the same range as simvastatin acid. Interaction of dronedarone on statins
transported by OATP, such as fluvastatin and rosuvastatin
has not been studied. In clinical trials, there
was no evidence of safety concerns when dronedarone was co-administered with statins metabolized
by CYP 3A4.
As high doses of statins increase the risk of myopathy, concomitant use of statins should be
undertaken with caution. Lower starting dose and maintenance doses of statins should be considered
according to the statin label recommendations and patients monitored for clinical signs of muscular
toxicity (see section 4.4).
Calcium antagonists
The interaction of dronedarone on calcium antagonists is described above (see section 4.4).
Sirolimus, tacrolimus
Dronedarone could increase plasma concentrations of tacrolimus and sirolimus. Monitoring of their
plasma concentrations and appropriate dose adjustment is recommended in case of coadministration
with dronedarone.
•
Oral contraceptives
No decreases in ethinylestradiol and levonorgestrel were observed in healthy subjects receiving
dronedarone (800 mg twice daily) concomitantly with oral contraceptives.
5
•
•
•
Beta blockers
Beta blockers that are metabolized by CYP 2D6 can have their exposure increased by dronedarone.
Moreover, beta blockers have the potential to interact with dronedarone from a pharmacodynamic
point of view. Dronedarone 800 mg daily increased metoprolol exposure by 1.6- fold and propranolol
exposure by 1.3-fold (i.e. much below the 6- fold differences observed between poor and extensive
CYP 2D6 metabolisers). In clinical trials, bradycardia was more frequently observed when
dronedarone was given in combination with beta-blockers.
Due to the pharmacokinetic interaction and possible pharmacodynamic interaction, beta blockers
should be used with caution concomitantly with dronedarone. These medicinal products should be
initiated at low dose and up-titration should be done only after ECG assessment. In patients already
taking beta blockers at time of dronedarone initiation, an ECG should be performed and the beta
blocker dose should be adjusted if needed (see section 4.4).
Antidepressants
Since dronedarone is a weak inhibitor of CYP 2D6 in humans, it is predicted to have limited
interaction on antidepressant medicinal products metabolized by CYP 2D6.
Digoxin
Dronedarone (400 mg twice daily) increased digoxin exposure by 2.5- fold by inhibiting P-gp
transporter. Moreover, digitalis has the potential to interact with dronedarone from a
pharmacodynamic point of view. A synergistic effect on heart rate and atrio-ventricular conduction is
possible. In clinical trials, increased levels of digitalis and/or gastrointestinal disorders indicating
digitalis toxicity were observed when dronedarone was co-administered with digitalis.
The digoxin dose should be reduced by approximately 50%, serum levels of digoxin should be closely
monitored and clinical and ECG monitoring is recommended.
Interaction on warfarin and losartan (CYP 2C9 substrates)
Dronedarone (600 mg twice daily) increased by 1.2- fold S-warfarin with no change in R warfarin and
only a 1.07 increase in International Normalized Ratio (INR).
No interaction was observed between dronedarone and losartan and an interaction between
dronedarone and other AIIRAs(Angiotensin II Receptor Antagonists) is not expected.
Interaction on theophylline (CYP 1A2 substrates)
Dronedarone 400 mg twice daily does not increase the steady state theophylline exposure.
Other information
Pantoprazole (40 mg once daily), a medicinal product which increases gastric pH without any effect
on cytochrome P450, did not interact significantly on dronedarone pharmacokinetics.
Grapefruit juice (CYP 3A4 inhibitor)
Repeated doses of 300 ml of grapefruit juice three times daily resulted in a 3- fold increase in
dronedarone exposure. Therefore, patients should be warned to avoid grapefruit juice beverages while
taking dronedarone (see section 4.4).
Pregnancy
There are no adequate data from the use of dronedarone in pregnant women. Studies in animals have
shown reproductive toxicity (see section 5.3). Dronedarone is not recommended during pregnancy.
Women of childbearing potential should use effective methods of contraception during treatment with
MULTAQ.
6
Interaction on medicinal products metabolized by CYP 2D6: beta blockers, antidepressants
•
•
Interaction of P-gp substrate
•
Breast-feeding
It is not known whether dronedarone is excreted in human breast milk.
Animal studies have shown excretion of dronedarone and its metabolites in breast milk. A decision on
whether to continue/discontinue breast-feeding or to continue/discontinue therapy with MULTAQ
should be made taking into account the benefit of breast-feeding to the child and the benefit of
MULTAQ therapy to the woman.
Fertility
Dronedarone was not shown to alter fertility in animal studies.
No studies on the effects on the ability to drive and use machines have been performed.
The safety profile of dronedarone 400 mg twice daily in patients with atrial fibrillation (AF) or atrial
flutter (AFL) is based on 5 placebo controlled studies, in which a total of 6,285 patients were
randomised (3,282 patients received dronedarone 400 mg twice daily, and 2,875 received placebo).
The mean exposure across studies was 13 months. In ATHENA study, the maximum follow-up was
30 months.
Assessment of intrinsic factors such as gender or age on the incidence of any treatment emergent
adverse reactions showed
an interaction for gender (female patients) for the incidence of any adverse
reactions and for serious adverse reactions.
In clinical trials, premature discontinuation due to adverse reactions occurred in 11.8% of the
dronedarone-treated patients and in 7.7% in the placebo-treated group. The most common reasons for
discontinuation of therapy with MULTAQ were gastrointestinal disorders (3.2% of patients versus
1.8% in the placebo group).
The most frequent adverse reactions observed with dronedarone 400 mg twice daily in the 5 studies
were diarrhoea, nausea and vomiting, fatigue and asthenia.
Table 1 displays adverse reactions associated with dronedarone 400 mg twice daily in AF or AFL
patients, presented by system organ class and by decreasing order of frequency.
Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10); uncommon (≥1/1,000
to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
7
Table 1:
Adverse Reactions
System organ
class
Very
Common
(
Common
(
1/100 to <1/10)
Uncommon
(
1/10,000 to
<1/1,000)
≥
1/10)
Nervous system
disorders
Dysgeusia
Ageusia
Cardiac
disorders
Bradycardia
Gastrointestinal
disorders
Diarrhoea
Vomiting
Nausea
Abdominal pains
Dyspepsia
Skin and
subcutaneous
tissue disorders
Rashes (including
generalised,
macular, maculo-
papular)
Pruritus
Erythemas
(including
erythema and rash
erythematous)
Eczema
Photosensitivity
reaction
Dermatitis allergic
Dermatitis
General
disorders and
administration
site conditions
Fatigue
Asthenia
Investigations
Blood
creatinine
increased*
QTc Bazett
prolonged
#
* ≥10% five days after treatment initiation
# >450 msec in male >470 msec in female
It is not known whether dronedarone and/or its metabolites can be removed by dialysis (hemodialysis,
peritoneal dialysis, or hemofiltration).
There is no specific antidote available. In the event of overdose, treatment should be supportive and
directed toward alleviating symptoms.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: antiarrhythmic, ATC code:
not yet assigned
Mechanism of Action
In animals, dronedarone prevents atrial fibrillation or restores normal sinus rhythm depending on the
model used. It also prevents ventricular tachycardia and ventricular fibrillation in several animal
8
≥
1/1,000 to
<1/100)
≥
Rare
(
≥
models. These effects most likely result from its electrophysiological properties belonging to all four
Vaughan-Williams classes. Dronedarone is a multichannel blocker inhibiting the potassium currents
(including IK(Ach), IKur, IKr, IKs) and thus prolonging cardiac action potential and refractory periods
(Class III). It also inhibits the sodium currents (Class Ib) and the calcium currents (Class IV). It non-
competitively antagonises adrenergic activities (Class II).
Pharmacodynamic Properties
In animal models, dronedarone reduces the heart rate. It prolongs Wenckebach cycle length and AH-,
PQ-, QT- intervals; with no marked effect or weak increase on QTc-intervals, and with no change in
HV- and QRS- intervals. It increases effective refractory periods (ERP) of the atrium, atrio-ventricular
node, and ventricular ERP was slightly prolonged with a minimal degree of reverse-frequency-
dependency.
Dronedarone decreases arterial blood pressure and myocardial contractility (dP/dt max) with no
change in left ventricular ejection fraction and reduces myocardial oxygen consumption.
Dronedarone has vasodilatory properties, in coronary arteries (related to the activation of the nitric
oxide pathway) and in peripheral arteries.
Dronedarone displays indirect antiadrenergic effects and partial antagonism to adrenergic stimulation.
It reduces alpha-adrenergic blood pressure response to epinephrine and beta1 and beta2 responses to
isoproterenol.
Clinical data
Reduction of risk of AF-related hospitalisation
The efficacy of dronedarone in the reduction of risk of AF-related hospitalisation was demonstrated in
patients with AF or a history of AF and additional risk factors in the ATHENA multicenter,
multinational, double blind, and randomised placebo-controlled study.
Patients were to have at least one risk factor (including age, hypertension, diabetes, prior cerebro-
vascular accident, left atrium diameter ≥50 mm or LVEF < 0.40) together with AF/AFL and sinus
rhythm both documented within the last 6 months. Patients who received amiodarone within 4 weeks
prior to randomisation were not included. Patients could be in AF/AFL or in sinus rhythm after
spontaneous conversion or following any procedures.
Four thousand six hundred and twenty eight (4,628) patients were randomised and treated for up to 30
months maximum (median follow-up: 22 months) with either dronedarone 400 mg twice daily (2,301
patients) or placebo (2,327 patients), in addition to conventional therapy including beta blockers
(71%), ACE inhibitors or AIIRAs (69%) digitalis (14%), calcium antagonists (14%), statins (39%),
oral anticoagulants (60%), chronic antiplatelet therapy (6%) and/or diuretics (54%).
The primary endpoint of the study was the time to first hospitalisation for cardiovascular reasons or
death from any cause.
Patients ranged in age from 23 to 97 years and 42% were over 75 years old. Forty seven percent (47%)
of patients were female and a majority were Caucasian (89%).
The majority had hypertension (86%) and structural heart disease (60%) (including coronary artery
disease: 30%; congestive heart failure (CHF): 30% ; LVEF< 45%: 12%).
Twenty five percent (25%) had AF at baseline.
Dronedarone reduced the incidence of cardiovascular hospitalisation or death from any cause by
24.2% when compared to placebo (p<0.0001).
The reduction in cardiovascular hospitalisation or death from any cause was consistent in all
subgroups, irrespective of baseline characteristics or medications (ACE inhibitors or AIIRAs; beta-
blockers, digitalis, statins, calcium antagonists, diuretics) (see figure 1).
9
Figure 1
- Relative risk (dronedarone 400 mg twice daily versus placebo) estimates with 95%
confidence intervals according to selected baseline characteristics- first cardiovascular hospitalisation
or death from any cause.
Characteristic
N
RR [95% CI] (a) P-value (b)
Age (years)
<65
873 0.89 [0.71;1.11]
[65-75[
1830 0.71 [0.60;0.83]
>=75
1925 0.75 [0.65;0.87] 0.27
Gender
Male
2459 0.74 [0.64;0.85]
Female
2169 0.77 [0.67;0.89] 0.65
Presence of AF/AFL
Yes
1155 0.74 [0.61;0.91]
No
3473 0.76 [0.68;0.85] 0.85
Structural Heart Disease
Yes
2732 0.76 [0.67;0.85]
No
1853 0.77 [0.65;0.92] 0.85
LVEF<35% or NYHA>=class I
Yes
1417 0.74 [0.63;0.87]
No
3146 0.77 [0.68;0.87] 0.71
LVEF(%)
<35
179 0.68 [0.44;1.03]
>=35
4365 0.76 [0.69;0.84] 0.58
Beta blocking agents
Yes
3269 0.78 [0.69;0.87]
No
1359 0.71 [0.58;0.86] 0.41
ACE or All receptor antagonists
Yes
3216 0.74 [0.66;0.83]
No
1412 0.79 [0.66;0.95] 0.59
Digitalis
Yes
629 0.76 [0.59;0.98]
No
3999 0.76 [0.68;0.84] 0.96
Calcium antagonists (c)
Yes
638 0.63 [0.48;0.82]
No
3990 0.78 [0.70;0.87] 0.15
0.1
1.0
10.0
Dronedarone Better Placebo Better
a Determined from Cox regression model
b P-value of interaction between baseline characteristics and treatment based on Cox regression model
c Calcium antagonists with heart rate lowering effects restricted to diltiazem, verapamil and bepridil
Similar results were obtained on the incidence of cardiovascular hospitalisation with a risk reduction
of 25.5% (p<0.0001).
During the course of the study, the number of deaths from any cause was comparable between the
dronedarone (116/2,301) and placebo (139/2,327) groups.
Maintenance of sinus rhythm
In EURIDIS and ADONIS, a total of 1,237 patients with a prior episode of AF or AFL were
randomised in an outpatient setting and treated with either dronedarone 400 mg twice daily (n = 828)
or placebo (n = 409) on top of conventional therapies (including oral anticoagulants, beta blockers,
ACE inhibitors or AIIRAs, chronic antiplatelet agents, diuretics, statins, digitalis, and calcium
antagonists). Patients had at least one ECG-documented AF/AFL episode during the last 3 months and
were in sinus rhythm for at least one hour and were followed for 12 months. In patients who were
taking amiodarone, an ECG was to be performed about 4 hours after the first administration to verify
good tolerability. Other antiarrhythmic drugs had to be withdrawn for at least 5 plasma half-lives prior
to the first administration.
Patients ranged in age from 20 to 88 years, with the majority being Caucasian (97%), male (69%)
patients. The most common co-morbidities were hypertension (56.8%) and structural heart disease
(41.5%) including coronary heart disease (21.8%).
In the pooled data from EURIDIS and ADONIS as well as in the individual trials, dronedarone
consistently delayed the time to first recurrence of AF/AFL (primary endpoint). As compared to
10
placebo, dronedarone lowered the risk of first AF/AFL recurrence during the 12-month study period
by 25% (p = 0.00007). The median time from randomised to first AF/AFL recurrence in the
dronedarone group was 116 days, i.e. 2.2-fold longer than in the placebo group (53 days).
The DIONYSOS study compared the efficacy and safety of dronedarone (400 mg twice daily) versus
amiodarone (600 mg daily for 28 days, then 200 mg daily thereafter) over 6 months. A total of 504
patients with documented AF were randomised, 249 received dronedarone and 255 received
amiodarone. The incidence of the primary efficacy endpoint defined as first recurrence of AF or
premature study drug discontinuation for intolerance or lack of efficacy at 12 months was 75% in the
dronedarone group and 59% in the amiodarone group (hazard ratio=1.59, log-rank p-value <0.0001).
AF recurrence was 63.5% versus 42%, respectively. Recurrences of AF (including absence of
conversion) were more frequent in the dronedarone group, whereas premature study drug
discontinuations due to intolerance were more frequent in the amiodarone group. The incidence of the
main safety endpoint defined as the occurrence of thyroid, hepatic, pulmonary, neurological, skin, eye
or gastrointestinal specific events or premature study drug discontinuation following any adverse event
was reduced by 20% in the dronedarone group compared to the amiodarone group (p=0.129). This
reduction was driven by the occurrence of significantly fewer thyroid and neurological events and a
trend for less skin or ocular events, and fewer premature study drug discontinuations compared to the
amiodarone group.
More gastrointestinal adverse events, mainly diarrhoea, were observed in the dronedarone group
(12.9% versus 5.1%).
Control of Ventricular Rate
In the ERATO study, a double-blind, placebo-controlled 6-month clinical trial, 174 patients with
symptomatic permanent (lasting over 6 months) AF were randomised and treated with either
dronedarone 400 mg twice daily (85 patients) or placebo (89 patients), in addition to conventional
therapy. Patients ranged in age from 31 to 86 years, with the majority being Caucasian (99%), male
(70%) patients. The most common co-morbidities were hypertension (49%) and structural heart
disease (39%).
At day 14, dronedarone decreased mean ventricular rate as compared to placebo. This effect was
independent of background rate control therapies and maintained for 4 months after treatment
initiation with a mean decrease from baseline equal to 8.8 bpm (p < 0.0001). Under intake of beta-
blockers, digitalis, and calcium antagonists with heart rate lowering effects, the mean decrease of
ventricular rate and the 95% CI were 14.9 bpm [-20; -10], 11.5 bpm [-17; -6.4] and 5.05 bpm [-11;
0.92], respectively.
A decrease of ventricular rate was also observed during maximal exercise at day 14 (-24.5 bpm,
p < 0.0001).
In the pooled data from EURIDIS and ADONIS, patients treated with dronedarone 400 mg twice daily
had lower mean ventricular rates at the time of first recurrence (103.4 bpm) as compared to placebo
patients (117.1 bpm) (TTEM method, p <0.0001).
Patients with symptoms of heart failure at rest or with minimal exertion within the previous month
prior, or who were hospitalised for heart failure during the previous month.
The ANDROMEDA study was conducted in 627 patients with left ventricular dysfunction,
hospitalised with new or worsening heart failure and who had had at least one episode of shortness of
breath on minimal exertion or at rest (NYHA class III or IV) or paroxysmal nocturnal dyspnoea within
the month before admission.
The study was stopped prematurely due to an observed imbalance of deaths in the dronedarone group
[n = 25 versus 12 (placebo), p = 0.027] (see sections 4.3 and 4.4).
11
5.2 Pharmacokinetic properties
Absorption
Following oral administration in fed condition, dronedarone is well absorbed (at least 70%). However
due to presystemic first pass metabolism, the absolute bioavailability of dronedarone (given with food)
is 15%. Concomitant intake of food increases dronedarone bioavailability by on average 2- to 4- fold.
After oral administration in fed conditions, peak plasma concentrations of dronedarone and the main
circulating active metabolite (N-debutyl metabolite) are reached within 3 to 6 hours. After repeated
administration of 400 mg twice daily, steady state is reached within 4 to 8 days of treatment and the
mean accumulation ratio for dronedarone ranges from 2.6 to 4.5. The steady state mean dronedarone
Cmax is 84-147 ng/ml and the exposure of the main N-debutyl metabolite is similar to that of the
parent compound. The pharmacokinetics of dronedarone and its N-debutyl metabolite both deviate
moderately from dose proportionality: a 2-fold increase in dose results in an approximate 2.5- to
3.0-fold increase with respect to Cmax and AUC.
Distribution
The
in vitro
plasma protein binding of dronedarone and its N-debutyl metabolite is 99.7% and 98.5%
respectively and is not saturable. Both compounds bind mainly to albumin. After intravenous (IV)
administration the volume of distribution at steady state (Vss) ranges from 1,200 to 1,400 l.
Metabolism
Dronedarone is extensively metabolised, mainly by CYP 3A4 (see section 4.5). The major metabolic
pathway includes N-debutylation to form the main circulating active metabolite followed by
oxidation, oxidative deamination to form the inactive propanoic acid metabolite, followed by
oxidation, and direct oxidation. The N-debutyl metabolite exhibits pharmacodynamic activity but is 3
to 10-times less potent than dronedarone. This metabolite contributes to the pharmacological activity
of dronedarone in humans.
Elimination
After oral administration, approximately 6% of the labelled dose is excreted in urine mainly as
metabolites (no unchanged compound excreted in urine) and 84% are excreted in faeces mainly as
metabolites. After IV administration the plasma clearance of dronedarone ranges from 130 to 150 l/h.
The terminal elimination half-life of dronedarone is around 25-30 hours and that of its N-debutyl
metabolite around 20-25 hours. In patients, dronedarone and its metabolite are completely eliminated
from the plasma within 2 weeks after the end of a 400 mg twice daily- treatment.
Special populations
The pharmacokinetics of dronedarone in patients with AF is consistent with that in healthy subjects.
Gender, age and weight are factors that influence the pharmacokinetics of dronedarone. Each of these
factors has a limited influence on dronedarone.
Gender
In female patients, dronedarone exposures and its N-debutyl metabolite exposure are on average 1.3 to
1.9-fold higher as compared to male patients.
Elderly
Of the total number of subjects in clinical studies of dronedarone, 73% were 65 years of age and over
and 34% were 75 years of age and over. In patients aged 65 years of age and over, dronedarone
exposures are 23% higher in comparison with patients aged below 65 years of age.
Hepatic impairment
In subjects with moderate hepatic impairment, dronedarone unbound exposure is increased by 2-fold.
That of the active metabolite is decreased by 47% (see section 4.2).
The effect of severe hepatic impairment on the pharmacokinetics of dronedarone was not assessed
(see section 4.3).
12
Renal impairment
The effect of renal impairment on dronedarone pharmacokinetics has not been evaluated in a specific
study. Renal impairment is not expected to modify the pharmacokinetics of dronedarone because no
unchanged compound was excreted in urine and only approximately 6% of the dose was excreted in
urine as metabolites (see section 4.2).
5.3
Preclinical safety data
Dronedarone had no genotoxic effects, based on one in vivo micronucleus test in mice and four in
vitro tests.
In 2-year oral carcinogenicity studies, the highest dronedarone dose administered for 24 months was
70 mg/kg/day in rats and 300 mg/kg/day in mice.
Observations were increased incidence of mammary gland tumors in female mice, histiocytic
sarcomas in mice and hemangiomas at the mesenteric lymph node level in rats, all at the highest tested
dose only (corresponding to an exposure of 5 to 10 times that of the human therapeutic dose).
Hemangiomas are not precancerous changes and do not transform into malignant hemangiosarcomas
in either animals or man. None of these observations was considered relevant for humans.
In chronic toxicity studies, slight and reversible phospholipidosis (accumulation of foamy
macrophages) was observed in mesenteric lymph nodes mainly in the rat. This effect is considered
specific to this species and not relevant to humans.
Dronedarone caused marked effects on embryo-foetal development at high doses in rats, such as
increased post-implantation losses, reduced foetal and placental weights, and external, visceral and
skeletal malformations.
6.
6.1 List of excipients
Core of the tablets
:
Hypromellose (E464),
maize starch,
crospovidone (E1202),
poloxamer 407,
lactose monohydrate,
colloidal anhydrous silica,
magnesium stearate(E572).
Coating / Polishing of the tablets
:
hypromellose (E464),
macrogol 6000,
titanium dioxide (E171),
carnauba wax (E903).
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
13
6.5 Nature and contents of container
•
20, 50 and 60 film-coated tablets in opaque PVC/Aluminium blister packs
•
100x1 film-coated tablets in opaque PVC/Aluminium unit dose blister packs.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
sanofi-aventis
174, avenue de France
F-75013 Paris
France
8.
9.
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA)
http://www.emea.europa.eu
14
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
15
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Sanofi Winthrop Industrie
1 rue de la Vierge
Ambarès et Lagrave
F-33565 Carbon Blanc Cedex
France
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to medical prescription.
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
The Marketing Authorisation Holder shall ensure that Health care professionals who intend to
prescribe MULTAQ and pharmacists are provided with an SPC, drug interaction check-card and
educational information about the following risks associated with the use of the product. The messages
will be conveyed through educational material. The format of the educational material should be
discussed with the appropriate learned societies in each Member State and the material should be
agreed with the National Competent Authority prior to launch in each Member State.
Important information:
•
That MULTAQ must not be used in patients with unstable haemodynamic conditions
including patients with symptoms of heart failure at rest or with minimal exertion
(corresponding to NYHA class IV and unstable class III patients)
•
That use of MULTAQ is not recommended in patients with recent (1-3 months) stable NYHA
class III heart failure or with LVEF <35%.
•
That MULTAQ may interact with a number of other medications. Thus, MULTAQ SPC
should be referred to prior to prescribing MULTAQ and also prior to prescribing additional
drugs to a patient already taking MULTAQ.
•
In particular MULTAQ must not be used
in patients taking potent CYP3A inhibitors including ketoconazole, itraconazole,
voriconazole, posaconazole, telithromycin, clarithromycin, nefazodone and ritonavir.
in combination with drugs which have the potential to induce torsades de pointe including
phenothiazines, cisapride, bepridil, trycyclic antidepressants, terfenadine and certain oral
macrolides.
in combination with Class I or Class III antiarrhythmics.
•
That plasma creatinine levels may rise initially due to inhibition of the renal tubular excretion
of creatinine and are not indicative of a deterioration in renal function
•
That patients should be counselled that:
MULTAQ interacts with a number of medicines
if they consult other doctors they should inform them that they are taking MULTAQ
they should not take St John’s Wort with MULTAQ
16
they should avoid grapefruit juice
Drug interaction check-card:
The check-card should contain a list of drugs which interact with MULTAQ classified according to
the seriousness of the interaction (eg contraindication, not recommended, use with caution).
•
Contraindication:
o
CYP3A inhibitors including ketoconazole, itraconazole, voriconazole,
posaconazole, telithromycin, clarithromycin, nefazodone and ritonavir.
o
potential torsades de pointe inducers including phenothiazines, cisapride, bepridil,
trycyclic antidepressants, terfenadine and certain oral macrolides.
o
Class I or Class III antiarrhythmics
•
Not recommended/to be avoided:
o
grapefruit juice,
o
potent CYP3A4 inducers including rifampicin, phenobarbital, carbamazepine,
phenytoin, St John’s Wort
•
Use with caution: in association with digoxin, beta blockers, calcium antagonists and statins
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 2.4 (31 July
2009) presented in Module 1.8.1. of the Marketing Authorisation Application, is in place and
functioning before and whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 1.5 (23 September 2009) of the Risk Management
Plan (RMP) presented in Module 1.8.2. of the Marketing Authorisation Application and any
subsequent updates of the RMP agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
•
At the request of the EMEA
17
ANNEX III
LABELLING AND PACKAGE LEAFLET
18
A. LABELLING
19
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Outer cartons of 20, 50, 60 or 100x1 tablets
1.
MULTAQ 400 mg film-coated tablets
dronedarone
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 400 mg dronedarone (as hydrochloride).
3.
LIST OF EXCIPIENTS
Also contains: lactose (as monohydrate). See leaflet for further information.
4.
20 film-coated tablets
50 film-coated tablets
60 film-coated tablets
100x1 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
20
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
sanofi-aventis
174 avenue de France
F-75013 Paris
France
EU/0/00/000/000 20 film-coated tablets
EU/0/00/000/000 50 film-coated tablets
EU/0/00/000/000 60 film-coated tablets
EU/0/00/000/000 100x1 film-coated tablets
13. BATCH NUMBER
Batch :
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
MULTAQ 400 mg
21
MINIMUM PARTICULARS TO APPEAR ON BLISTERS
Blisters of 10 tablets
1.
MULTAQ 400 mg tablets
dronedarone
2.
sanofi-aventis
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Batch:
5.
OTHER
22
MINIMUM PARTICULARS TO APPEAR ON BLISTERS
Blisters of 100x1 tablets
1.
MULTAQ 400 mg tablets
dronedarone
2.
sanofi-aventis
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Batch:
5.
OTHER
23
B. PACKAGE LEAFLET
24
PACKAGE LEAFLET: INFORMATION FOR THE USER
MULTAQ 400 mg film-coated tablets
dronedarone
Read all of this leaflet carefully before you start taking this medicine.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1.
What MULTAQ is and what it is used for
2.
Before you take MULTAQ
4.
Possible side effects
5
How to store MULTAQ
6.
Further information
1.
WHAT MULTAQ IS AND WHAT IT IS USED FOR
MULTAQ contains an active substance named dronedarone. It belongs to a group of medicines called
anti-arrhythmics that help regulate your heart beat.
MULTAQ is used if you have had or are currently experiencing a problem with your heart beat (your
heart beats out of time - atrial fibrillation).
MULTAQ prevents repetition of your problem of irregular heart beat and slows down your heart rate.
2.
BEFORE YOU TAKE MULTAQ
Do not take MULTAQ if:
-
you are allergic (hypersensitive) to dronedarone or to any of the other ingredients of MULTAQ
(listed in section 6),
-
you have a problem with the nerves in your heart (heart block). Your heart might beat very
slowly or you may feel dizzy. If you have had a pacemaker fitted for this problem, you can use
MULTAQ,
-
you have a very slow heart beat (less than 50 beats a minute),
-
your ECG (electrocardiogram), shows a heart problem called “prolonged QT corrected interval”
(this interval is more than 500 milliseconds),
-
you have a problem where you heart cannot pump the blood round your body as well as it
should (severe heart failure) and your problem is not controlled. You may have swollen feet or
legs, trouble breathing when lying down or sleeping, or shortness of breath when moving
around,
-
you take medicines for infection (including fungal infection or AIDS), allergies, heart beat
problems, depression, after a transplant (see section below on “Taking other medicines”. This
will give you more details on exactly what medicines you cannot take with MULTAQ),
-
you have a severe kidney problem.
If any of the above apply to you, do not take MULTAQ.
25
-
Keep this leaflet. You may need to read it again.
3.
How to take MULTAQ
-
you have a severe liver problem,
Take special care with MULTAQ if:
•
you have a problem that gives you a low level of potassium or magnesium in your blood. This
problem should be corrected before starting treatment with MULTAQ
•
you have a problem where your heart does not adequately pump the blood round your body as
well as it should (heart failure). You may have swollen feet or legs, trouble breathing when lying
down or sleeping, shortness of breath when moving around, or weight increase but your problem
is controlled and your symptoms do not change.
If this applies to you (or you are not sure), please talk to your doctor or pharmacist before taking
MULTAQ.
MULTAQ is not recommended in children and adolescents below 18 years of age.
Heart and blood tests
While you are taking MULTAQ, your doctor may perform tests to check your medical condition and
how the medicine is working for you.
•
Your doctor may look at your heart’s electrical activity using an ECG (electrocardiogram)
machine.
•
Your doctor may also do blood tests. The results of one of the blood tests (blood creatinine levels)
may be changed by MULTAQ. Your doctor will take this into account when checking your blood
levels and will use another reference of the “normal” value of blood creatinine.
Please tell any other person who checks your blood that you are taking MULTAQ.
Taking other medicines
MULTAQ and some other medicines can affect each other and cause serious side effects. Your doctor
may change the dose of any other medicines you are taking.
You must not take any of the following with MULTAQ:
•
other medicines used to control an irregular or fast heart beat such as flecainide, propafenone,
quinidine, disopyramide, dofetilide, sotalol, amiodarone,
•
some medicines for fungal infections such as ketoconazole, voricanozole, itraconazole or
posaconazole,
•
some medicines for infections called macrolides,
•
some medicines for depression called tricyclic antidepressants,
•
some tranquilising medicines called phenothiazines,
•
bepridil for chest pain caused by heart disease,
•
telithromycin or clarithromycin (antibiotics for infections),
•
terfenadine - for allergies,
•
nefazodone - for depression,
•
cisapride - for food and acid reflux from your stomach to your mouth,
•
ritonavir - for AIDS infection,
You must tell your doctor or pharmacist if you are taking any of the following medicines:
•
other medicines for high blood pressure, for chest pain caused by heart disease, or other heart
problems, such as verapamil, diltiazem, nifedipine, metoprolol, propranolol or digoxin,
•
some medicines for reducing the cholesterol in your blood (such as simvastatin, lovastatin,
atorvastatin or pravastatin),
•
some medicines for epilepsy called phenobarbital, carbamazepine or phenytoin ,
•
sirolimus and tacrolimus (used after a transplant ),
•
St John’s Wort - a herbal medicine for depression,
•
rifampicin - for tuberculosis.
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines. This
includes medicines obtained without a prescription or herbal medicines.
26
Taking MULTAQ with food and drink
Take one tablet during your morning meal and one tablet during your evening meal.
Do not drink grapefruit juice while taking MULTAQ. It can interfere with the usual effect of your
medicine.
Pregnancy and breast-feeding
•
MULTAQ is not recommended if you are pregnant or you think you may be pregnant.
•
Do not take MULTAQ if you are a woman able to have children and you are not using a reliable
contraceptive method.
•
Stop taking your tablets and talk to your doctor straight away if you get pregnant while taking
MULTAQ.
•
If you are a mother breast feeding a baby, you should discuss with your doctor before taking
MULTAQ.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
No studies on the effects on the ability to drive and use machines have been performed.
Important information about some of the ingredients of MULTAQ
MULTAQ contains lactose, which is a type of sugar. If you have been told by your doctor that you
have intolerance to some sugars, contact your doctor before taking MULTAQ.
3.
HOW TO TAKE MULTAQ
Always take MULTAQ exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
How much to take
The usual dose is one 400 mg tablet twice a day. Take:
•
one tablet during your morning meal and
•
one tablet during your evening meal.
If you think that your medicine is too strong or too weak, talk to your doctor or pharmacist.
Taking this medicine
Swallow the tablets whole with a drink of water during a meal.
If you take more MULTAQ
than you should
Contact immediately your doctor or the nearest emergency department or hospital. Take the medicine
pack with you.
If you forget to take MULTAQ
Do not take a double dose to make up for a forgotten tablet. Take the next dose when you are normally
due to take it.
If you stop taking MULTAQ
Do not stop taking this medicine without first talking to your doctor or pharmacist.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
27
4.
POSSIBLE SIDE EFFECTS
Like all medicines, MULTAQ can cause side effects, although not everybody gets them.
The following side effects have been reported with this medicine:
The frequency of possible side effects listed below is defined using the following convention:
•
very common (affects more than 1 user in 10)
•
common (affects 1 to 10 users in 100)
•
uncommon (affects 1 to 10 users in 1,000)
•
rare (affects 1 to 10 users in 10,000)
•
very rare (affects less than 1 user in 10,000)
•
not known (frequency cannot be estimated from the available data).
Very Common
•
changes in the results of one blood test: your blood creatinine level,
•
changes in your ECG (electrocardiogram).
Common
•
problems with your digestion such as diarrhoea, nausea, vomiting and stomach pain
•
feeling tired,
•
slow heart beat ,
•
skin problems such as rash or itching.
Uncommon
•
other skin problems such as redness of the skin or eczema (redness, itching, burning or
blistering),
•
your skin being more sensitive to the sun,
•
change in how things taste.
Rare
•
losing your sense of taste.
If any of the side effects gets serious or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE MULTAQ
Keep out of the reach and sight of children.
Do not use MULTAQ after the expiry date, which is stated on the carton after “EXP.” The expiry date
refers to the last day of that month.
This medicinal product does not require any special storage conditions.
Do not use MULTAQ if you notice any visible sign of deterioration (see in section 6 “What MULTAQ
looks like and content of the pack”).
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
28
6.
FURTHER INFORMATION
What MULTAQ contains
-
The active substance is dronedarone.
Each film-coated tablet contains 400 mg of dronedarone (as hydrochloride).
-
The other ingredients in the film-coated tablet core are hypromellose, maize starch,
crospovidone, poloxamer 407, lactose monohydrate, colloidal anhydrous silica, magnesium
stearate.
-
The other ingredients in the coating of the film-coated tablets are hypromellose, macrogol 6000,
titanium dioxide (E171), carnauba wax.
What MULTAQ looks like and content of the pack
MULTAQ is a white, oval, film-coated tablet (tablet) with a double wave marking on one side and
“4142” on the other side.
MULTAQ film-coated tablets are supplied in packs of 20, 50, 60 tablets in opaque PVC and
aluminium blisters and 100x1 tablets in opaque PVC and aluminium perforated unit dose blisters.
Not all pack size may be marketed.
Marketing Authorisation Holder
sanofi-aventis
174, avenue de France
75013 Paris – France
Manufacturer
Sanofi Winthrop Industrie
1 rue de la Vierge, Ambarès & Lagrave,
F-33565 Carbon Blanc Cedex - France
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder.
België/Belgique/Belgien
sanofi-aventis Belgium
Tél/Tel: +32 (0)2 710 54 00
Luxembourg/Luxemburg
sanofi-aventis Belgium
Tél/Tel: +32 (0)2 710 54 00 (Belgique/Belgien)
България
sanofi-aventis Bulgaria EOOD
Тел.: +359 (0)2 970 53 00
Magyarország
sanofi-aventis zrt., Magyarország
Tel.: +36 1 505 0050
Česká republika
sanofi-aventis, s.r.o.
Tel: +420 233 086 111
Malta
sanofi-aventis Malta Ltd.
Tel: +356 21493022
Danmark
sanofi-aventis Denmark A/S
Tlf: +45 45 16 70 00
Nederland
sanofi-aventis Netherlands B.V.
Tel: +31 (0)182 557 755
Deutschland
Sanofi-Aventis Deutschland GmbH
Tel: +49 (0)180 2 222010
Norge
sanofi-aventis Norge AS
Tlf: +47 67 10 71 00
29
Eesti
sanofi-aventis Estonia OÜ
Tel: +372 627 34 88
Österreich
sanofi-aventis GmbH
Tel: +43 1 80 185 – 0
Ελλάδα
sanofi-aventis AEBE
Τηλ: +30 210 900 16 00
Polska
sanofi-aventis Sp. z o.o.
Tel.: +48 22 280 00 00
España
sanofi-aventis, S.A.
Tel: +34 93 485 94 00
Portugal
sanofi-aventis - Produtos Farmacêuticos, S.A.
Tel: +351 21 35 89 400
France
sanofi-aventis France
Tél: 0 800 222 555
Appel depuis l’étranger : +33 1 57 63 23 23
România
sanofi-aventis România S.R.L.
Tel: +40 (0) 21 317 31 36
Ireland
sanofi-aventis Ireland Ltd.
Tel: +353 (0) 1 403 56 00
Slovenija
sanofi-aventis d.o.o.
Tel: +386 1 560 48 00
Ísland
Vistor hf.
Sími: +354 535 7000
Slovenská republika
sanofi-aventis Pharma Slovakia s.r.o.
Tel: +421 2 57 103 777
Italia
sanofi-aventis S.p.A.
Tel: +39 02 393 91
Suomi/Finland
sanofi-aventis Oy
Puh/Tel: +358 (0) 201 200 300
Κύπρος
sanofi-aventis Cyprus Ltd.
Τηλ: +357 22 871600
Sverige
sanofi-aventis AB
Tel: +46 (0)8 634 50 00
Latvija
sanofi-aventis Latvia SIA
Tel: +371 67 33 24 51
United Kingdom
sanofi-aventis
Tel: +44 (0) 1483 505 515
Lietuva
UAB sanofi-aventis Lietuva
Tel: +370 5 2755224
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web
site: .
http://www.emea.europa.eu
30
Source: European Medicines Agency
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