Multaq

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ANNEX I 

 
SUMMARY OF PRODUCT CHARACTERISTICS 

 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
MULTAQ 400 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each tablet contains 400 mg of dronedarone (as hydrochloride). 
 
Excipient with known effect: 
 
Each tablet also contains 41.65 mg of lactose (as monohydrate). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
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. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
MULTAQ is indicated for the maintenance of sinus rhythm after successful cardioversion in adult 
clinically stable patients with paroxysmal or persistent atrial fibrillation (AF). Due to its safety profile 
(see sections 4.3 and 4.4), MULTAQ should only be prescribed after alternative treatment options 
have been considered. 
MULTAQ must not be given to patients with left ventricular systolic dysfunction or to patients with 
current or previous episodes of heart failure. 
 
4.2 Posology and method of administration 
 
Treatment should be initiated and monitored only under specialist supervision (see section 4.4). 
Treatment with dronedarone can be initiated in an outpatient setting. 
 
Treatment with Class I or III antiarrhythmics (such as flecainide, propafenone, quinidine, 
disopyramide, dofetilide, sotalol, amiodarone) must be stopped before starting dronedarone.  
There is limited information on the optimal timing to switch from amiodarone to dronedarone. It 
should be considered that amiodarone may have a long duration of action after discontinuation due to 
its long half-life. If a switch is envisaged, this should be done under the supervision of a specialist (see 
sections 4.3 and 5.1). 
 
Posology 
 
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 to dronedarone (see section 4.5). 
 



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If a dose is missed, patients should take the next dose at the regular scheduled time and should not 
double the dose. 
 
Special populations 
 
Elderly 
Efficacy and safety were comparable in elderly patients who did not suffer from other cardiovascular 
diseases and younger patients. In patients ≥75years old, clinical signs of heart failure and ECG should 
be monitored on a regular basis when co-morbidities are present (see sections 4.3, 4.4 and 5.1). 
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). 
 
Hepatic impairment 
Dronedarone is contraindicated in patients with severe hepatic impairment because of the absence of 
data (see sections 4.3 and 4.4). No dose adjustment is required in patients with mild or moderate 
hepatic impairment (see section 5.2).  
 
Renal impairment  
Dronedarone 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). 
 
Paediatric population 
The safety and efficacy of MULTAQ in children aged below 18 years of age have not yet been 
established. No data are available. 
 
Method of administration 
 
Oral use. 
It is recommended to swallow the tablet whole with a drink of water during a meal. The tablet cannot 
be divided into equal doses. 
 
4.3 Contraindications 
 
 Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 
 Second- or third- degree atrio-ventricular block, complete bundle branch block, distal block, 

sinus node dysfunction, atrial conduction defects, or sick sinus syndrome (except when used in 
conjunction with a functioning pacemaker) 

 Bradycardia <50 beats per minute (bpm) 
 Permanent AF with an AF duration ≥6 months (or duration unknown) and attempts to restore 

sinus rhythm no longer considered by the physician 
 Patients in unstable hemodynamic conditions 
 History of, or current heart failure or left ventricular systolic dysfunction  
 Patients with liver and lung toxicity related to the previous use of amiodarone 
 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 (such as erythromycin), Class I 
and III antiarrhythmics (see section 4.5) 

 QTc Bazett interval ≥500 milliseconds 
 Severe hepatic impairment 
 Severe renal impairment (CrCl <30 ml/min) 
 Co-administration with dabigatran 
 



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4.4 Special warnings and precautions for use 
 
Careful monitoring during dronedarone administration is recommended by regular assessment of 
cardiac, hepatic and pulmonary function (see below). If AF reoccurs, discontinuation of dronedarone 
should be considered.  
Treatment with dronedarone should be stopped during the course of treatment, in case the patient 
develops any of the conditions which would lead to a contraindication as mentioned in section 4.3.  
Monitoring of co-administered medicinal products like digoxin and anti-coagulants is necessary.  
 
Patients developing permanent AF during treatment  
 
A clinical study in patients with permanent AF (AF duration for at least 6 months) and cardiovascular 
risk factors was stopped early due to an excess of cardiovascular death, stroke and heart failure in 
patients receiving dronedarone (see section 5.1). It is recommended to perform ECGs serially, at least 
every 6 months. If patients treated with dronedarone develop permanent AF, treatment with 
dronedarone should be discontinued. 
 
Patients with history of, or current heart failure or left ventricular systolic dysfunction 
 
Dronedarone is contraindicated in patients in unstable hemodynamic conditions, with history of, or 
current heart failure or left ventricular systolic dysfunction (see section 4.3).  
Patients should be carefully evaluated for symptoms of Congestive Heart Failure. There have been 
spontaneously reported events of new or worsening heart failure during treatment with dronedarone. 
Patients should be advised to consult a physician if they develop or experience signs or symptoms of 
heart failure, such as weight gain, dependent oedema, or increased dyspnoea. If heart failure develops, 
treatment with dronedarone should be discontinued. 
Patients should be followed for the development of left ventricular systolic dysfunction during 
treatment. If left ventricular systolic dysfunction develops, treatment with dronedarone should be 
discontinued. 
 
Patients with coronary artery disease  
 
In patients with coronary artery disease, clinical signs of heart failure and ECG should be regularly 
monitored to detect early signs of heart failure. In ESC and ACC/AHA/HRS guidelines dronedarone 
has a class IA recommendation in patients with paroxysmal/persistent AF and coronary artery disease. 
 
Elderly 
 
In elderly patients ≥75 years with multiple co-morbidities, clinical signs of heart failure and ECG 
should be monitored on a regular basis (see sections 4.2 and 5.1). 
 
Liver injury 
 
Hepatocellular liver injury, including life-threatening acute liver failure, has been reported in patients 
treated with dronedarone in the post-marketing setting. Liver function tests should be performed prior 
to initiation of treatment with dronedarone, after one week and after one month following initiation of 
treatment and then repeated monthly for six months, at months 9 and 12, and periodically thereafter.  
If alanine aminotransferase (ALT) levels are elevated ≥3 × upper limit of normal (ULN), ALT levels 
should be re-measured within 48 to 72 hours. If ALT levels are confirmed to be ≥3 × ULN, treatment 
with dronedarone should be withdrawn. Appropriate investigation and close observation of patients 
should continue until normalisation of ALT.  
Patients should immediately report any symptoms of potential liver injury (such as sustained 
new-onset abdominal pain, anorexia, nausea, vomiting, fever, malaise, fatigue, jaundice, dark urine or 
itching) to their physician.  
 



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Management of plasma creatinine increase 
 
An increase in plasma creatinine (mean increase 10 μmol/L) has been observed with dronedarone 
400 mg twice daily in healthy subjects and in patients. In most patients this increase occurs early after 
treatment initiation and reaches a plateau after 7 days. It is recommended to measure plasma creatinine 
values prior to and 7 days after initiation of dronedarone. If an increase in creatininaemia is observed, 
serum creatinine should be re-measured after a further 7 days. If no further increase in creatininaemia 
is observed, this value should be used as the new reference baseline taking into account that this may 
be expected with dronedarone. If serum creatinine continues to rise then consideration should be given 
to further investigation and discontinuing treatment.  
An increase in creatininaemia should not necessarily lead to the discontinuation of treatment with 
ACE inhibitors or Angiotensin II Receptors Antagonists (AIIRAs). 
Larger increases in creatinine after dronedarone initiation have been reported in the post-marketing 
setting. Some cases also reported increases in blood urea nitrogen possibly due to hypoperfusion 
secondary to developing CHF (pre-renal azotaemia). In such cases dronedarone should be stopped (see 
sections 4.3 and 4.4). It is recommended to monitor renal function periodically and to consider further 
investigations as needed. 
 
Electrolytes imbalance  
 
Since antiarrhythmic medicinal products may be ineffective or may be arrhythmogenic in patients with 
hypokalaemia, any potassium or magnesium deficiency should be corrected before initiation and 
during dronedarone therapy. 
 
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). 
 
Respiratory, thoracic and mediastinal disorders  
 
Cases of interstitial lung disease including pneumonitis and pulmonary fibrosis have been reported in 
post-marketing experience. Onset of dyspnoea or non-productive cough may be related to pulmonary 
toxicity and patients should be carefully evaluated clinically. If pulmonary toxicity is confirmed, 
treatment should be discontinued.  
 
Interactions (see section 4.5) 
 
Digoxin  
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. 
 
Beta-blockers and calcium antagonists 
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 



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antagonists or beta blockers at time of dronedarone initiation, an ECG should be performed and the 
dose should be adjusted if needed. 
 
Vitamin K antagonists 
Patients should be appropriately anti-coagulated as per clinical AF guidelines. International 
Normalised Ratio (INR) should be closely monitored after initiating dronedarone in patients taking 
vitamin K antagonists as per their label. 
 
Potent CYP3A4 inducers  
Potent CYP3A4 inducers such as rifampicin, phenobarbital, carbamazepine, phenytoin or St John’s 
Wort are not recommended. 
 
Statins  
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.  
 
Grapefruit juice 
Patients should be warned to avoid grapefruit juice beverages while taking dronedarone.  
 
Lactose 
 
This medicinal product contains lactose. Patients with rare hereditary problems of galactose 
intolerance, total lactase deficiency or glucose-galactose malabsorption, should not take this medicinal 
product. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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 has, therefore, the potential to interact on medicinal products 
substrates of P-glycoproteins, CYP 3A4 or CYP 2D6. Dronedarone and/or its metabolites also have 
been shown to inhibit transport proteins of the Organic Anion Transporter (OAT), Organic Anion 
Transporting Polypeptide (OATP) and Organic Cation Transporter (OCT) families in vitro. 
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 (such as erythromycin), terfenadine and Class I and III 
antiarrhythmics are contraindicated because of the potential risk of proarrhythmia (see section 4.3).  
In patients already taking beta-blockers at time of dronedarone initiation, an ECG should be performed 
and the dose of beta-blocker should be adjusted if needed (see section 4.4). 
Clinical, ECG and biological monitoring is recommended, and digoxin dose should be halved (see 
section 4.4). 
  
Effect of other medicinal products on dronedarone  
 
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). 



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Moderate/weak CYP 3A4 inhibitors 
 
Erythromycin 
Erythromycin, an oral macrolide, may induce torsades de pointes and, as such, is contraindicated (see 
section 4.3). Repeated doses of erythromycin (500 mg three times a day for 10 days) resulted in an 
increase in steady state dronedarone exposure of 3.8-fold. 
 
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 studies, 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/weak CYP 3A4 Inhibitors 
Other moderate inhibitors of CYP3A4 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. 
 
MAO inhibitors 
In an in vitro study MAO contributed to the metabolism of the active metabolite of dronedarone. The 
clinical relevance of this observation is not known (see sections 4.4 and 5.2). 
 
Effect of dronedarone on other medicinal products 
 
Interaction with medicinal products metabolised by CYP 3A4 
 
Dabigatran 
When dabigatran etexilate 150 mg once daily was co-administered with dronedarone 400 mg twice 
daily, the dabigatran AUC0-24, and Cmax were increased by 100% and 70%, respectively. No clinical 
data are available regarding the co-administration of these medicinal products in AF patients. Their 
co-administration is contraindicated (see section 4.3).  
 
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 exposure of lovastatin 
within the same range as simvastatin acid. There was a weak interaction between dronedarone and 
atorvastatin (which resulted in a mean 1.7-fold increase in atorvastatin exposure). There was a weak 
interaction between dronedarone and statins transported by OATP, such as rosuvastatin (which 
resulted in a mean 1.4-fold increase in rosuvastatin exposure). 



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In clinical trials, there was no evidence of safety concerns when dronedarone was co-administered 
with statins metabolised by CYP 3A4. However, spontaneously reported cases of rhabdomyolysis 
when dronedarone was given in combination with a statin (simvastatin in particular) have been 
reported, and, therefore, 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). 
 
Immunosupressants 
Dronedarone could increase plasma concentrations of immunosupressants (tacrolimus, sirolimus, 
everolimus and cyclosporine). 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. 
 
Interaction with medicinal products metabolised by CYP 2D6 
 
Beta-blockers  
Sotalol must be stopped before starting dronedarone (see sections 4.2 and 4.3). Beta-blockers that are 
metabolised 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 studies, 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 metabolised by CYP 2D6. 
 
Interaction with P-gp substrates 
 
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 studies, 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 with medicinal products metabolised by CYP 3A4 and P-gp  

Rivaroxaban 
Dronedarone is likely to increase the exposure of rivaroxaban (a CYP3A4 and P-gp substrate) and 
consequently concomitant use may increase the risk of bleedings. Concomitant use of rivaroxaban and 
dronedarone is not recommended. 



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Apixaban 
Dronedarone may increase the exposure of apixaban (a CYP3A4 and P-gp substrate). However, no 
dose adjustment for apixaban is required when co-administered with agents that are not strong 
inhibitors of both CYP3A4 and P-gp, such as dronedarone. 
 
Edoxaban  
In in vivo studies edoxaban (a CYP3A4 and P-gp substrate) exposure was increased when 
administered with dronedarone. The edoxaban dose should be reduced according to the edoxaban label 
recommendations. 
 
Interaction with warfarin and losartan (CYP 2C9 substrates) 
 
Warfarin and other vitamin K antagonists 
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 Normalised Ratio (INR).  
However, clinically significant INR elevations (≥5) usually within 1 week after starting dronedarone 
were reported in patients taking oral anticoagulants. Consequently, INR should be closely monitored 
after initiating dronedarone in patients taking vitamin K antagonists as per their label. 
 
Losartan and other Angiotensin II Receptor Antagonists (AIIRAs) 
No interaction was observed between dronedarone and losartan and an interaction between 
dronedarone and other AIIRAs is not expected. 
 
Interaction with theophylline (CYP 1A2 substrate) 
Dronedarone 400 mg twice daily does not increase the steady state theophylline exposure. 
 
Interaction with metformin (OCT1 and OCT2 substrate) 
No interaction was observed between dronedarone and metformin, an OCT1 and OCT2 substrate. 
 
Interaction with omeprazole (CYP 2C19 substrate) 
Dronedarone does not affect the pharmacokinetics of omeprazole, a CYP 2C19 substrate.  
 
Interaction with clopidogrel  
Dronedarone does not affect the pharmacokinetics of clopidogrel and its active metabolite.  
 
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). 
 
4.6 Fertility, pregnancy and lactation 
 
Women of child bearing potential and pregnancy  
 
There are no or limited amount of data from the use of dronedarone in pregnant women. Studies in 
animals have shown reproductive toxicity (see section 5.3).  
MULTAQ is not recommended during pregnancy and in women of childbearing potential not using 
contraception. 
 



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Breast-feeding 
 
It is unknown whether dronedarone and its metabolites are excreted in human milk. Available 
pharmacodynamic/toxicological data in animals have shown excretion of dronedarone and its 
metabolites in milk. A risk to the newborns/infants cannot be excluded.  
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from 
MULTAQ therapy taking into account the benefit of breast-feeding for the child and the benefit of 
therapy for the woman. 
 
Fertility 
 
Dronedarone was not shown to alter fertility in animal studies. 
 
4.7 Effects on ability to drive and use machines 
 
MULTAQ has no or negligible influence on the ability to drive and use machines. However, ability to 
drive and use machines may be affected by adverse reactions such as fatigue. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
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 studies, 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 dronedarone 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 (9%), nausea (5%) and vomiting (2%), fatigue and asthenia (7%).  
 
Tabulated list of adverse reactions 
 
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. Some adverse reactions were also identified during post-marketing surveillance. 
Adverse reactions are presented by system organ class. 
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); not known (cannot be estimated from 
the available data). Within each frequency grouping, adverse reactions are presented in order of 
decreasing seriousness. 
  



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Table 1: Adverse reactions 
 
System organ 
class 

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) 

Immune system 
disorders 

   Anaphylactic 
reactions 
including 
angioedema 

Nervous system 
disorders 

  Dysgeusia Ageusia 

Cardiac disorders Congestive heart 
failure 
(see below) 

Bradycardia (see 
sections 4.3 and 
4.4) 
 

  

Vascular 
disorders 

   Vasculitis, 
including 
leukocytoclastic 
vasculitis 

Respiratory, 
thoracic and 
mediastinal 
disorders 

  Interstitial lung 
disease including 
pneumonitis and 
pulmonary fibrosis 
(see below) 

 

Gastrointestinal 
disorders 

 Diarrhoea  
Vomiting  
Nausea 
Abdominal pain 
Dyspepsia 

  

Hepatobiliary 
disorders 

 Liver function 
test 
abnormalities 

 Hepatocellular 
liver injury, 
including 
life-threatening 
acute liver failure 
(see section 4.4) 

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 (see section 4.4) 
# >450 msec in male >470 msec in female (see section 4.4) 



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Description of selected adverse reactions 
 
Congestive heart failure 
In the 5 placebo controlled studies, CHF occurred in the dronedarone group with rates comparable 
with placebo (very commonly, 11.2% versus 10.9%). This rate should be considered in the context of 
the underlying elevated incidence of CHF in AF patients. Cases of CHF have also been reported in 
post-marketing experience (frequency not known) (see section 4.4). 
 
Interstitial lung disease including pneumonitis and pulmonary fibrosis 
In the 5 placebo controlled studies, 0.6% of patients in the dronedarone group had pulmonary events 
versus 0.8% of patients receiving placebo. Cases of interstitial lung disease including pneumonitis and 
pulmonary fibrosis have been reported in post-marketing experience (frequency not known). A 
number of patients had been previously exposed to amiodarone (see section 4.4). 
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
In the event of overdose, monitor the patient’s cardiac rhythm and blood pressure. Treatment should 
be supportive and based on symptoms. 
 
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. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: cardiac therapy, antiarrhythmics class III, ATC code: C01BD07 
 
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 
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 



13 

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 efficacy and safety 
 
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 
cerebrovascular 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 was 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 medicinal products (ACE inhibitors or AIIRAs; 
beta-blockers, digitalis, statins, calcium antagonists, diuretics) (see figure 1). 
 



14 

Figure 1 - Relative risk (dronedarone 400 mg twice daily versus placebo) - first cardiovascular 
hospitalisation or death from any cause.  
 

 
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 medicinal products 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 
placebo, dronedarone lowered the risk of first AF/AFL recurrence during the 12-month study period 



15 

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. Patients ranged in age from 28 to 90 years, 49% were more than 65 years old. 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%). 
 
Patients with symptoms of heart failure at rest or with minimal exertion within the previous month 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. Patients ranged in age from 27 to 96 years, 68% were more than 65 years 
old. 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).  
 
Patients with permanent atrial fibrillation 
The PALLAS study was a randomised placebo-controlled study investigating the clinical benefit of 
dronedarone 400 mg BID on top of standard therapy in patients with permanent atrial fibrillation and 
additional risk factors (patients with congestive heart failure ~ 69%, coronary heart disease ~ 41%, 
prior stroke or TIA ~ 27%; LVEF ≤40% ~ 20.7% and patients ≥75 years with hypertension and 
diabetes ~ 18%). The study was prematurely stopped after randomization of 3,149 patients 
(placebo = 1,577; dronedarone = 1,572) due to the significant increase in heart failure (placebo = 33; 
dronedarone = 80; HR = 2.49 (1.66-3.74)]; stroke [placebo = 8; dronedarone = 17; HR = 2.14 
(0.92-4.96)] and cardiovascular death [placebo = 6; dronedarone = 15; HR = 2.53 (0.98-6.53)] (see 
sections 4.3 and 4.4). 
 
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. 



16 

 
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 
administration the volume of distribution at steady state (Vss) ranges from 1,200 to 1,400 L. 
 
Biotransformation 
 
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. Monoamine Oxidases contribute partially to the metabolism of the 
active metabolite of dronedarone (see section 4.5).  
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 intravenous 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. 
The mean exposure of the N-debutyl 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). 
 
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). 
 



17 

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. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core  
 
Hypromellose (E464) 
Maize starch 
Crospovidone (E1202) 
Poloxamer 407 
Lactose monohydrate 
Colloidal anhydrous silica 
Magnesium stearate (E572) 
 
Tablet coat  
 
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. 
 



18 

6.5 Nature and contents of container 
 
 Opaque PVC/Aluminium blister in packs of 20, 50 and 60 film-coated tablets 
 Opaque PVC/Aluminium perforated unit dose blister in packs of 100x1 film-coated tablets. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements.  
 
 
7. MARKETING AUTHORISATION HOLDER 
 
sanofi-aventis groupe 
54, rue La Boétie 
F-75008 Paris  
France 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/09/591/001 - cartons of 20 film-coated tablets  
EU/1/09/591/002 - cartons of 50 film-coated tablets  
EU/1/09/591/003 - cartons of 60 film-coated tablets  
EU/1/09/591/004 - cartons of 100 x 1 film-coated tablets 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 26 November 2009  
Date of latest renewal: 19 September 2019 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 
 

  



19 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURERS RESPONSIBLE FOR BATCH 
RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE  
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 
 



20 

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturers responsible for batch release  
 
Sanofi Winthrop Industrie 
1 rue de la Vierge 
Ambarès et Lagrave 
F-33565 Carbon Blanc Cedex  
France 
 
Chinoin Pharmaceutical and Chemical Works Private Co.Ltd  
2112 Veresegyhaz Lévai u.5 
Hungary 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE  
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  
 
 Periodic safety update reports (PSURs)  
 
The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
 Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2. of the marketing 
authorisation and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted 

 At the request of the European Medicines Agency;  
 Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 
 Additional risk minimisation measures 
 
The marketing authorisation holder shall ensure that Health care professionals who intend to prescribe 
or dispense MULTAQ are provided or have access to the most recent version of SmPC and MULTAQ 
Prescriber guide.  



21 

The content and format of the MULTAQ Prescriber guide, together with the communication and 
distribution plan should be agreed with the National Competent Authority in each Member State prior 
to distribution. 
 
The following risks: 
• Heart Failure (including use in patients with unstable hemodynamic conditions with history of, 

or current heart failure or left ventricular systolic dysfunction, and pre-renal azotemia) 
• Use in Permanent atrial fibrillation defined as an AF duration ≥6 months (or duration 

unknown) and attempts to restore sinus rhythm no longer considered by the physician 
• Pulmonary-interstitial lung disease (ILD) 
• Hepatotoxicity 
are concerned by the additional minimization measures. 
 
The educational material is a Prescriber Guide to: 
• Screen patients before treatment initiation 

- Contra indication of Permanent Atrial fibrillation 
- Contra indication of history, or current heart failure or left ventricular systolic 

dysfunction (LVSD) 
- Prevention of drug-drug interaction 
- Liver, lung and renal safety of use. 

• Monitor patients during treatment and discontinue dronedarone when required 
- ECG 
- Cardiac clinical symptoms 
- Drug interaction 
- Liver, pulmonary, coagulation and renal function tests 

• Counsel patients about its use 
- Educate patients on symptoms 
- Encourage reporting to Pharmacovigilance 

 
The Prescriber Guide should display information to help physician assess whether the patient is 
eligible for MULTAQ prescription and whether the patient remains within the prescribing information. 
 
  



22 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



23 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



24 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
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. See leaflet for further information.  
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
20 film-coated tablets 
50 film-coated tablets 
60 film-coated tablets 
100x1 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use.  
Oral use.  
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children.  
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP  
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



25 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
sanofi-aventis groupe 
54, rue La Boétie 
F-75008 Paris 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/09/591/001 20 film-coated tablets  
EU/1/09/591/002 50 film-coated tablets 
EU/1/09/591/003 60 film-coated tablets 
EU/1/09/591/004 100x1 film-coated tablets 
 
 
13. BATCH NUMBER 
 
Batch  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
MULTAQ 400 mg  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  
 
  



26 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTERS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
MULTAQ 400 mg tablets  
dronedarone 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
sanofi-aventis groupe 
 
 
3. EXPIRY DATE 
 
EXP  
 
 
4. BATCH NUMBER 
 
Batch 
 
 
5. OTHER 
 
  



27 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 
  



28 

Package leaflet: Information for the patient 
 

MULTAQ 400 mg film-coated tablets 
dronedarone 

 
 

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4.  
 
What is in this leaflet  
1. What MULTAQ is and what it is used for 
2. What you need to know before you take MULTAQ 
3. How to take MULTAQ 
4. Possible side effects 
5 How to store MULTAQ 
6. Contents of the pack and other 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 a problem with your heart rhythm (your heart beats out of time - atrial 
fibrillation) and spontaneously, or through a treatment called cardioversion has changed your heartbeat 
back to normal rhythm.  
MULTAQ prevents repetition of your problem of irregular heart rhythm. MULTAQ is used only in 
adults. 
 
Your doctor will consider all available treatment options before prescribing MULTAQ to you. 
 
 
2. What you need to know before you take MULTAQ 
 
Do not take MULTAQ: 
 
- if you are allergic to dronedarone or to any of the other ingredients of this medicine (listed in 

section 6), 
- if 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,  

- if you have a very slow heart beat (less than 50 beats a minute), 
- if your ECG (electrocardiogram) shows a heart problem called “prolonged QT corrected 

interval” (this interval is more than 500 milliseconds), 
- if you have a type of atrial fibrillation called permanent atrial fibrillation (AF). In permanent 

AF, the AF has been present for a long time (at least during 6 months) and a decision has been 
made not to change back your heart rhythm to atrial normal rhythm with a treatment called 
cardioversion, 

- if you have instability (drops) in your blood pressure which can lead to inadequate arterial blood 
flow to your organs, 



29 

- if you have or had a problem where your heart cannot pump the blood round your body as well 
as it should (condition called heart failure). You may have swollen feet or legs, trouble 
breathing when lying down or sleeping, or shortness of breath when moving around,  

- if the percentage of blood leaving your heart each time it contracts is too low (condition called 
left ventricular dysfunction), 

- if you took amiodarone (another antiarrhythmic medicine) previously and experienced lung or 
liver problems, 

- if you take medicines for infection (including fungal infection or AIDS), allergies, heart beat 
problems, depression, after a transplant (see section below on “Other medicines and 
MULTAQ”. This will give you more details on exactly what medicines you cannot take with 
MULTAQ), 

- if you have a severe liver problem, 
- if you have a severe kidney problem, 
- if you take dabigatran (see section below on “Other medicines and MULTAQ”). 
 
If any of the above apply to you, do not take MULTAQ.  
 
Warnings and precautions  
Talk to your doctor or pharmacist before taking 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 are more than 75 years old, 
 you have a condition when the vessel that supplies blood to heart muscle becomes hardened and 

narrowed (coronary artery disease). 
 
While taking MULTAQ, tell your doctor if  
 your atrial fibrillation becomes permanent while you are taking MULTAQ. You should stop 

taking MULTAQ, 
 you have swollen feet or legs, trouble breathing when lying down or sleeping, shortness of 

breath when moving around, or weight increase (which are signs and symptoms of heart 
failure), 

 tell your doctor immediately if you develop any of these signs and symptoms of liver problems: 
stomach (abdominal) area pain or discomfort, loss of appetite, nausea, vomiting, yellowing of 
the skin or the whites of the eyes (jaundice), unusual darkening of the urine, fatigue (especially 
in association with other symptoms listed above), itching, 

 you have breathlessness or non-productive cough. Tell your doctor, he/she will check your lung. 
 
If this applies to you (or you are not sure), please talk to your doctor or pharmacist before taking 
MULTAQ.  
 
Heart, lung 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 will order blood tests to check your liver function before you start taking 

MULTAQ and during treatment.  
 If you are taking some medicines against blood clot formation such as warfarin, your doctor will 

order a blood test called INR to check how well your medicine is working.  
 Your doctor may also do other blood tests. The results of one of the blood tests to check kidney 

function (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.  

 Your doctor may check your lungs. 
In some cases, MULTAQ treatment may need to be stopped. 



30 

Please tell any other person who checks your blood that you are taking MULTAQ. 
 
Children and adolescents 
MULTAQ is not recommended in children and adolescents below 18 years of age.  
 
Other medicines and MULTAQ 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. 
Your doctor may recommend that you use a medicine against blood clot formation according to your 
condition.  
 
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, voriconazole, itraconazole or 

posaconazole, 
 some medicines for depression called tricyclic antidepressants,  
 some tranquilising medicines called phenothiazines, 
 bepridil for chest pain caused by heart disease, 
 telithromycin, erythromycin, or clarithromycin (antibiotics for infections), 
 terfenadine (a medicine for allergies), 
 nefazodone (a medicine for depression),  
 cisapride (a medicine for food and acid reflux from your stomach to your mouth), 
 ritonavir (a medicine for AIDS infection), 
 dabigatran (a medicine for prevention of blood clot formation). 
 
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 rosuvastatin),  
 some medicines against blood clot formation such as warfarin, rivaroxaban, edoxaban and 

apixaban. 
 some medicines for epilepsy called phenobarbital, carbamazepine or phenytoin, 
 sirolimus, tacrolimus, everolimus and cyclosporine (used after a transplant), 
 St John’s Wort - a herbal medicine for depression, 
 rifampicin - for tuberculosis. 
 
MULTAQ with food and drink 
Do not drink grapefruit juice while taking MULTAQ. It can increase the blood levels of dronedarone 
and may increase your chance of getting side effects. 
 
Pregnancy and breast-feeding  
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor for advice before taking this medicine. 
 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. 
 It is not known if MULTAQ passes into your breast milk. You and your doctor should decide if 

you will take MULTAQ or breastfeed. You should not do both. 
 



31 

Driving and using machines 
MULTAQ does not usually affect your ability to drive or use machine. However, your ability to drive 
and use machines may be affected by side effects such as tiredness. 
 
MULTAQ contains lactose 
Lactose 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 this medicine. 
 
 
3. How to take MULTAQ 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 
Treatment with MULTAQ will be overseen by a doctor who is experienced in the treatment of heart 
disease. 
 
If you need to change from amiodarone (another medicine for irregular heart beat) to MULTAQ, your 
doctor can provide special recommendations, for example pausing amiodarone before switching. Tell 
your doctor about all the medicines you take. 
 
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 tablet whole with a drink of water during a meal. The tablet cannot be divided into equal 
doses. 
 
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 medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
The following side effects have been reported with this medicine:  
 
Talk to your doctor straight away, if you notice any of the following serious side effects – you 
may need urgent medical assistance 
Very common (may affect more than 1 in 10 people) 
 Problem where your heart does not adequately pump the blood round your body as well as it 

should (congestive heart failure) In clinical studies, this side effect was observed at a similar rate 
in patients receiving MULTAQ and in patients receiving placebo. Signs include swollen feet or 



32 

legs, trouble breathing when lying down or sleeping, shortness of breath when moving around, 
or weight increase. 

 
Common (may affect up to 1 in 10 people) 
 Diarrhoea, vomiting when excessive as it can lead to kidney problems. 
 Slow heart beat. 
 
Uncommon (may affect up to 1 in 100 people) 
 Inflammation of the lungs (including scarring and thickening of the lungs). Signs include 

breathlessness or non-productive cough.  
 
Rare (may affect up to 1 in 1,000 people) 
 Liver problems including life threatening liver failure. Signs include stomach (abdominal) area 

pain or discomfort, loss of appetite, nausea, vomiting, yellowing of the skin or the whites of the 
eyes (jaundice), unusual darkening of the urine, fatigue (especially in association with other 
symptoms listed above), itching. 

 Allergic reactions, including swelling of the face, lips, mouth, tongue or throat. 
 
Other side effects include: 
Very Common  
 changes in the results of one blood test: your blood creatinine level, 
 changes in your ECG (electrocardiogram) called QTc Bazett prolonged. 
 
Common 
 problems with your digestive system such as indigestion, diarrhoea, nausea, vomiting and 

stomach pain, 
 feeling tired,  
 skin problems such as rash or itching, 
 change in the results of blood tests used to check your liver function. 
 
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, 
 inflammation of blood vessels (vasculitis including leukocytoclastic vasculitis). 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store MULTAQ 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date, which is stated on the blister and carton after “EXP.” 
The expiry date refers to the last day of that month. 
 
This medicinal product does not require any special storage conditions. 



33 

 
Do not use this medicine if you notice any visible sign of deterioration (see section 6). 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment.  
 
 
6. Contents of the pack and other 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 tablet core are hypromellose (E464), maize starch, crospovidone 

(E1202), poloxamer 407, lactose monohydrate (see section 2 under ‘MULTAQ contains 
lactose’), colloidal anhydrous silica, magnesium stearate (E572). 

- The other ingredients in the tablet coat are hypromellose (E464), macrogol 6000, titanium 
dioxide (E171), carnauba wax (E903). 

 
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 groupe 
54, rue La Boétie 
F-75008 Paris – France 
 
Manufacturer 
Sanofi Winthrop Industrie 
1 rue de la Vierge, Ambarès & Lagrave, 
F-33565 Carbon Blanc Cedex - France 
 
Chinoin Pharmaceutical and Chemical Works Private Co.Ltd  
2112 Veresegyhaz Lévai u.5 
Hungary 
 
For any information about this medicinal product, please contact the local representative of the 
Marketing Authorisation Holder. 
 
België/Belgique/Belgien 
Sanofi Belgium 
Tél/Tel: +32 (0)2 710 54 00 
 

Lietuva 
UAB "SANOFI-AVENTIS LIETUVA" 
Tel: +370 5 2755224 
 

България 
SANOFI BULGARIA EOOD 
Тел.: +359 (0)2 970 53 00 
 

Luxembourg/Luxemburg 
Sanofi Belgium  
Tél/Tel: +32 (0)2 710 54 00 (Belgique/Belgien) 
 

Česká republika 
sanofi-aventis, s.r.o. 
Tel: +420 233 086 111 
 

Magyarország 
SANOFI-AVENTIS Zrt. 
Tel.: +36 1 505 0050 
 



34 

Danmark 
Sanofi A/S 
Tlf: +45 45 16 70 00 
 

Malta 
Sanofi S.p.A 
Tel: +39 02 39394275  

Deutschland 
Sanofi-Aventis Deutschland GmbH 
Tel.: 0800 52 52 010 
Tel. aus dem Ausland: +49 69 305 21 131 
 

Nederland 
sanofi-aventis Netherlands B.V. 
Tel: +31 20 245 4000 
 

Eesti 
sanofi-aventis Estonia OÜ 
Tel: +372 627 34 88 
 

Norge 
sanofi-aventis Norge AS 
Tlf: +47 67 10 71 00 
 

Ελλάδα 
sanofi-aventis AEBE 
Τηλ: +30 210 900 16 00 
 

Österreich 
sanofi-aventis GmbH 
Tel: +43 1 80 185 – 0 
 

España 
sanofi-aventis, S.A. 
Tel: +34 93 485 94 00 
 

Polska 
sanofi-aventis Sp. z o.o. 
Tel.: +48 22 280 00 00 
 

France 
sanofi-aventis France 
Tél: 0 800 222 555 
Appel depuis l’étranger : +33 1 57 63 23 23 

Portugal 
Sanofi - Produtos Farmacêuticos, Lda. 
Tel: +351 21 35 89 400 
 

Hrvatska 
sanofi-aventis Croatia d.o.o. 
Tel: +385 1 600 34 00 

România 
Sanofi Romania SRL 
Tel: +40 (0) 21 317 31 36 
 

Ireland 
sanofi-aventis Ireland Ltd. T/A SANOFI 
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 33 100 100 
 

Italia 
Sanofi S.p.A. 
Tel: 800.536389 
 

Suomi/Finland 
Sanofi Oy 
Puh/Tel: +358 (0) 201 200 300 
 

Κύπρος 
sanofi-aventis Cyprus Ltd. 
Τηλ: +357 22 871600 
 

Sverige 
Sanofi AB 
Tel: +46 (0)8 634 50 00 
 

Latvija 
sanofi-aventis Latvia SIA 
Tel: +371 67 33 24 51 
 

United Kingdom 
Sanofi 
Tel: +44 (0) 845 372 7101 
 

 
This leaflet was last revised in  
 
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.  



35 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX IV 

SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS 
OF THE MARKETING AUTHORISATION(S) 

 
 

 



36 

Scientific conclusions 

Taking into account the PRAC Assessment Report on the PSUR(s) for dronedarone, the scientific 
conclusions of CHMP are as follows:  

The potential drug-drug PK interaction between rivaroxaban and dronedarone and the risk of 
bleeding was assessed based on the review of the Sanofi global safety database (GSD), worldwide 
scientific literature and PK plausibility.  

This review identified four cases with a positive de-challenge without identified co-medication or 
comorbidity that might provide alternative explanations. The increased bleeding risk resolved after 
discontinuation of dronedarone while rivaroxaban use continued. 

The non-interventional retrospective cohort study (DRONEC09460) evaluating the “Concomitant 
Use of Dronedarone and Direct Oral Anticoagulants and the Risk of Major Bleeding in Patients 
with Nonvalvular Atrial Fibrillation” reported an increased risk of major bleeding, driven by GI 
bleeding with concomitant use of rivaroxaban with dronedarone compared to those taking 
rivaroxaban alone. For both dabigatran and rivaroxaban, major bleeding was higher among those 
taking dronedarone and dabigatran/rivaroxaban concomitantly compared to those taking 
dabigatran/rivaroxaban alone. This increased bleeding risk was not seen with concomitant use of 
apixaban and dronedarone, but this could be explained by the different non-metabolic clearance of 
apixaban that reduces the potential for drug-drug interaction. 

Literature shows that in vitro there might be an 31% increase in rivaroxaban exposure due to 
inhibition of metabolism by dronedarone. A physiological based pharmacokinetic model showed a 
weak to moderate increase of the AUC of rivaroxaban in combination with dronedarone. 

In relation to non-vit K antagonist regarding concomitant use with dronedarone the European Heart 
Rhythm Association guide 2018 states: "There are no interaction pharmacokinetic data available for 
rivaroxaban and apixaban but effects on their plasma levels can be anticipated based on P-gp and 
CYP3A4 interactions, calling for caution (i.e. ‘yellow’) or avoidance (for rivaroxaban)."  

Furthermore, the SmPC of rivaroxaban mentions that active substances strongly inhibiting only one 
of the rivaroxaban elimination pathways, either CYP3A4 or P-gp, are expected to increase 
rivaroxaban plasma concentrations to a lesser extent. Dronedarone is a moderate CYP3A4 inhibitor 
and a moderate -strong Pgp inhibitor.  

In view of available data, concomitant use of dronedarone and rivaroxaban is expected to increase 
the plasma concentrations of rivaroxaban. The interaction may not be clinically relevant in most 
patients but could be significant in high-risk patients. Based on similar mechanism of action, the 
same can be expected for apixaban and edoxaban. As the level of evidence for drug-drug 
interactions between dronedarone and the different DOACs leading to increased exposure of the 
DOAC varies, slightly different recommendations on concomitant use with the different DOACs in 
section 4.5 of SmPC are recommended. A warning is also included in the corresponding part of the 
Package leaflet. 

The CHMP agrees with the scientific conclusions made by the PRAC. 

 

Grounds for the variation to the terms of the marketing authorisation(s) 

On the basis of the scientific conclusions for dronedarone the CHMP is of the opinion that the 
benefit-risk balance of the medicinal product(s) containing dronedarone is unchanged subject to the 
proposed changes to the product information 



37 

The CHMP recommends that the terms of the marketing authorisation(s) should be varied. 

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETINGAUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE ANDEFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
	SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMSOF THE MARKETING AUTHORISATION(S)