Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: sanofi-aventis groupe, 54, rue La Boétie, F-75008, Paris, France
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.
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 MULTAQ (see section 5.1). It is recommended to perform ECGs serially, at least every 6 months. If patients treated with MULTAQ develop permanent AF, treatment with MULTAQ should be discontinued.
MULTAQ 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 MULTAQ.
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 MULTAQ 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 MULTAQ should be discontinued.
Caution is needed in patients with coronary artery disease.
Caution is needed in elderly patients ≥75 years with multiple co-morbidities (see sections 4.2 and 5.1).
Hepatocellular liver injury, including life-threatening acute liver failure, has been reported in patients treated with MULTAQ 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.
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.
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.
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).
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.
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.
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.
Anticoagulation:
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 such as rifampicin, phenobarbital, carbamazepine, phenytoin or St John’s Wort are not recommended.
MAO inhibitors might decrease the clearance of the active metabolite of dronedarone and should therefore be used with caution.
Statins should be used with caution. Lower starting dose and maintenance doses of statins should be considered and patients monitored for clinical signs of muscular toxicity.
Patients should be warned to avoid grapefruit juice beverages while taking dronedarone.
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption, should not take this medicine.
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 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). Caution should also be taken with co-administration with beta-blockers or digoxin.
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).
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.
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.
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).
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).
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.
Beta blockers:
Sotalol must be stopped before starting MULTAQ (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.
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.
Dabigatran:
When dabigatran etexilate 150 mg once daily was co-administered with dronedarone 400 mg twice daily, the dabigatran AUC0-24, and C max 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).
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.
Dronedarone 400 mg twice daily does not increase the steady state theophylline exposure.
No interaction was observed between dronedarone and metformin, an OCT1 and OCT2 substrate.
Dronedarone does not affect the pharmacokinetics of omeprazole, a CYP 2C19 substrate.
Dronedarone does not affect the pharmacokinetics of clopidogrel and its active metabolite.
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.
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).
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.
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.
Dronedarone was not shown to alter fertility in animal studies.
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.
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 MULTAQ were gastrointestinal disorders (3.2% of patients versus 1.8% in the placebo group).
The most frequent adverse reactions observed with dronedarone 400 mg twice daily in the 5 studies were diarrhoea, nausea and vomiting, fatigue and asthenia.
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:
Rare: Anaphylactic reactions including angioedema
Uncommon: Dysgeusia
Rare: Ageusia
Very Common: Congestive heart failure (see below)
Common: Bradycardia (see sections 4.3 and 4.4)
Rare: Vasculitis, including leukocytoclastic vasculitis
Uncommon: Interstitial lung disease including pneumonitis and pulmonary fibrosis (see below)
Common: Diarrhoea, Vomiting, Nausea, Abdominal pain, Dyspepsia
Common: Liver function test abnormalities
Rare: Hepatocellular liver injury, including life-threatening acute liver failure (see section 4.4)
Common: Rashes (including generalised, macular, maculo-papular), Pruritus
Uncommon: Erythemas (including erythema and rash erythematous), Eczema, Photosensitivity reaction, Dermatitis allergic, Dermatitis
Common: Fatigue, Asthenia
Very Common: 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)
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).
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 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.
Not applicable.
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