4.1. Therapeutic indications

Dronedarone Aristo 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), Dronedarone Aristo should only be prescribed after alternative treatment options have been considered.

Dronedarone Aristo 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 Aristo 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 Aristo

There is limited information on the optimal timing to switch from amiodarone to Dronedarone Aristo. 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 Dronedarone Aristo (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.

Special populations

Elderly

Efficacy and safety were comparable in elderly patients who did not suffer from other cardiovascular diseases and younger patients. In patients ≥75 years 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 section 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 dronedarone in children and adolescents 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

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 Aristo should be discontinued.

Patients with history of, or current heart failure or left ventricular systolic dysfunction

Dronedarone Aristo 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 Aristo 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 Aristo 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).

Women of child bearing potential and pregnancy

Dronedarone is not recommended during pregnancy and in women of childbearing potential not using contraception. Women of childbearing potential should use effective methods of contraception during treatment with dronedarone and for 7 days after the final dose. Prior to initiating dronedarone, the prescriber should confirm that women of childbearing potential are not pregnant (see section 4.6).

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.

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 creatininemia is observed, serum creatinine should be re-measured after a further 7 days. If no further increase in creatinaemia 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 creatininemia 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 postmarketing 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 hypokalemia, 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 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 medicine.

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 therefore, has 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-blockers 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 Aristo

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, posaconazole, ritonavir, telithromycin, clarithromycin or nefazodone is contraindicated (see section 4.3).

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 Aristo on other medicinal products

Interaction with medicinal products metabolized 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).

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).

Immunosuppressants

Dronedarone could increase plasma concentrations of immunosuppressants (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 2D

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.

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 AIIRAs (Angiotensin II Receptor Antagonists)

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

Dronedarone is not recommended during pregnancy and in women of childbearing potential not using contraception. 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).

Women of childbearing potential should use effective methods of contraception treatment with dronedarone and for 7 days after the final dose.

Prior to initiating dronedarone, the prescriber should confirm that women of childbearing potential are not pregnant.

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.

Women should be advised not to breastfeed during treatment with dronedarone and for 7 days (about 5 half-lives) after the final dose.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from dronedarone 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

Dronedarone 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.

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 and4.4)

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)

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 Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.