Multaq心韻定

Multaq

dronedarone

Manufacturer:

Sanofi

Distributor:

DCH Auriga - Healthcare
/
Four Star
Full Prescribing Info
Contents
Dronedarone HCl.
Description
Multaq also contains the following excipients: Tablet Core: Hypromellose (E464), maize starch, crospovidone (E1202), poloxamer 407, lactose monohydrate 41.65 mg, anhydrous colloidal silica, magnesium stearate (E572). Film-Coating/Polishing: Hypromellose (E464), macrogol 6000, titanium dioxide (E171), carnauba wax (E903).
Action
Pharmacotherapeutic Group: Antiarrhythmic. ATC Code: C01BD07.
Pharmacology:
 Pharmacodynamics: 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 4 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 noncompetitively antagonizes adrenergic activities (class II).
Pharmacodynamic Effects: In animal models, dronedarone reduces 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, atrioventricular node and ventricular ERP was slightly prolonged with a minimal degree of reverse-frequency-dependency.
Dronedarone decreases arterial blood pressure and myocardial contractility (dP/dtmax) with no change in left ventricular ejection fraction (LVEF) 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 α-adrenergic blood pressure response to epinephrine, and β1 and β2 responses to isoproterenol.
Clinical Safety Data: Reduction of Risk of Atrial Fibrillation (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 1 risk factor (including age, hypertension, diabetes, prior cerebrovascular accident, left atrium diameter ≥50 mm or LVEF <0.4) 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 (4628) patients were randomised and treated for up to 30 months maximum (median follow-up: 22 months) with either dronedarone 400 mg twice daily (2301 patients) or placebo (2327 patients), in addition to conventional therapy including β-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 1st hospitalisation for cardiovascular reasons or death from any cause.
Patients ranged in age from 23-97 years and 42% were >75 years. Forty seven percent (47%) of patients were female and a majority were Caucasian (89%).
The majority had hypertension (86%) and structural heart disease (60%) (including coronary artery disease: 30%; congestive heart failure (CHF): 30% ; LVEF<45%: 12%).
Twenty five percent (25%) had AF at baseline.
Dronedarone reduced the incidence of cardiovascular hospitalisation or death from any cause by 24.2% when compared to placebo (p<0.0001).
The reduction in cardiovascular hospitalisation or death from any cause was consistent in all subgroups, irrespective of baseline characteristics or medications (ACE inhibitors or AIIRAs; β-blockers, digitalis, statins, calcium antagonists, diuretics) (see figure).

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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 (116/2301) and placebo (139/2327) groups.
Maintenance of Sinus Rhythm: In EURIDIS and ADONIS, a total of 1237 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, β-blockers, ACE inhibitors or AIIRAs, chronic antiplatelet agents, diuretics, statins, digitalis and calcium antagonists). Patients had at least 1 ECG-documented AF/AFL episode during the last 3 months and were in sinus rhythm for at least 1 hr and were followed for 12 months. In patients who were taking amiodarone, an ECG was to be performed about 4 hrs after the 1st administration to verify good tolerability. Other antiarrhythmic drugs had to be withdrawn for at least 5 plasma half-lives prior to the 1st administration.
Patients ranged in age from 20-88 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 by 25% (p=0.00007). The median time from randomised to first AF/AFL recurrence in the dronedarone group was 116 days ie, 2.2-fold longer than in the placebo group (53 days).
The Dionysos study compared the efficacy and safety of dronedarone (400 mg twice daily) versus amiodarone (600 mg daily for 28 days, then 200 mg daily thereafter) over 6 months. A total of 504 patients with documented AF were randomised, 249 received dronedarone and 255 received amiodarone. The incidence of the primary efficacy endpoint defined as first recurrence of AF or premature study drug discontinuation for intolerance or lack of efficacy at 12 months was 75% in the dronedarone group and 59% in the amiodarone group (hazard ratio=1.59, log-rank p-value <0.0001). AF recurrence was 63.5% vs 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% vs 5.1%).
Patients with Symptoms of Heart Failure at Rest or with Minimal Exertion within the Previous Month Prior, or who were Hospitalised for Heart Failure During the Previous Month: The Andromeda study was conducted in 627 patients with left ventricular dysfunction, hospitalised with new or worsening heart failure and who had had at least 1 episode of shortness of breath on minimal exertion or at rest (NYHA class III or IV) or paroxysmal nocturnal dyspnoea within the month before admission.
The study was stopped prematurely due to an observed imbalance of deaths in the dronedarone group [n=25 vs 12 (placebo), p=0.027] (see Contraindications and Precautions).
Patients with Permanent Atrial Fibrillation: The Pallas study was a randomized placebo-controlled study investigating the clinical benefit of dronedarone 400 mg twice daily on top of standard therapy in patients with permanent AF 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 3149 patients (placebo=1577; dronedarone=1572) 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 Contraindications and Precautions).
Pharmacokinetics: Absorption: Following oral administration in fed conditions, 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 average of 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 3-6 hrs. After repeated administration of 400 mg twice daily, steady-state is reached within 4-8 days of treatment and the mean accumulation ratio for dronedarone ranges from 2.6-4.5. 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: 2-fold increase in dose results in an approximate 2.5- to 3-fold increase with respect to Cmax and AUC.
Distribution: The in vitro plasma protein-binding of dronedarone and its N-debutyl metabolite is 99.7 and 98.5%, respectively, and is not saturable. Both compounds bind mainly to albumin. After IV administration, the volume of distribution at steady state (Vss) ranges from 1200-1400 L.
Biotransformation: Dronedarone is extensively metabolized, mainly by CYP3A4 (see Interactions). 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 Interactions).
The N-debutyl metabolite exhibits pharmacodynamic activity but is 3-10 times less potent than dronedarone. This metabolite contributes to the pharmacological activity of dronedarone in humans.
Elimination: After oral administration, approximately 6% of the labelled dose is excreted in urine mainly as metabolites (no unchanged compound excreted in urine) and 84% are excreted in faeces mainly as metabolites. After IV administration, the plasma clearance of dronedarone ranges from 130-150 L/hr. The terminal elimination half-life of dronedarone is around 25-30 hrs and that of its N-debutyl metabolite around 20-25 hrs. 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 and 34% were ≥75 years. In patients ≥65 years, dronedarone exposures are 23% higher in comparison with patients <65 years.
Hepatic Impairment: In subjects with moderate hepatic impairment, dronedarone unbound exposure is increased by 2-fold. That of the active metabolite is decreased by 47% (see Dosage & Administration).
The effect of severe hepatic impairment on the pharmacokinetics of dronedarone was not assessed (see Contraindications).
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 Dosage & Administration).
Toxicology: Preclinical Safety Data: Dronedarone had no genotoxic effects, based on 1 in vivo micronucleus test in mice and 4 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 5-10 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 embryofoetal development at high doses in rats eg, increased post-implantation losses, reduced foetal and placental weights, and external, visceral and skeletal malformations.
Indications/Uses
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 Contraindications and Precautions), Multaq should only be prescribed after alternative treatment options have been considered.
Multaq should not be given to patients with left ventricular systolic dysfunction or to patients with current or previous episodes of heart failure.
Dosage/Direction for Use
Treatment should be initiated and monitored only under specialist supervision (see Precautions).
Treatment with Multaq can be initiated in an outpatient setting.
Treatment with class I or III antiarrhythmics (eg, flecainide, propafenone, quinidine, disopyramide, dofetilide, sotalol, amiodarone) must be stopped before starting Multaq.
There is limited information on the optimal timing to switch from amiodarone to Multaq. 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 Pharmacology: Pharmacodynamics under Actions and Contraindications).
Adults: Recommended Dose: 400 mg twice daily.
If a dose is missed, patients should take the next dose at the regular scheduled time and should not double the dose.
Children: The safety and efficacy of Multaq in children <18 years have not yet been established. No data are available.
Elderly: Efficacy and safety were comparable in elderly patients who did not suffer from other cardiovascular diseases and younger patients. Caution is needed in patients ≥75 years when co-morbidities are present (see Pharmacology: Pharmacodynamics under Actions, Contraindications and Precautions). Although plasma exposure in elderly females was increased in a pharmacokinetic study conducted in healthy subjects, dose adjustments are not considered necessary (see Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions).
Hepatic Impairment: Multaq is contraindicated in patients with severe hepatic impairment because of the absence of data (see Contraindications). No dose adjustment is required in patients with mild or moderate hepatic impairment (see Pharmacology: Pharmacokinetics under Actions).
Renal Impairment: Multaq is contraindicated in patients with severe renal impairment [creatinine clearance (CrCl) <30 mL/min] (see Contraindications). No dose adjustment is required in other patients with renal impairment (see Pharmacokinetics under Actions and Precautions).
Administration: It should be taken as 1 tablet with the morning meal and 1 tablet with the evening meal.
Grapefruit juice should not be taken together with Multaq (see Interactions).
Overdosage
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.
Contraindications
Hypersensitivity to dronedarone HCl or to any of the excipients of Multaq. Second- or 3rd-degree atrioventricular 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 min (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 eg, ketoconazole, itraconazole, voriconazole, posaconazole, telithromycin, clarithromycin, nefazodone and ritonavir (see Interactions); medicinal products inducing Torsades de pointes eg, phenothiazines, cisapride, bepridil, tricyclic antidepressants, terfenadine and certain oral macrolides (eg, erythromycin), class I and III antiarrhythmics (see Interactions); QTc Bazett interval ≥500 millisec; severe hepatic impairment; severe renal impairment (CrCl <30mL/min).
Special Precautions
Careful monitoring during dronedarone administration is recommended by regular assessment of cardiac, hepatic and pulmonary function (as follows). If AF re-occurs 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 (see Contraindications). Monitoring of co-administered drugs like digoxin and anticoagulants 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 Multaq (see Pharmacodynamics under Pharmacology under Actions). 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.
Patients with History of, or Current Heart Failure or Left Ventricular Systolic Dysfunction: Multaq is contraindicated in patients in unstable hemodynamic conditions, with history of, or current heart failure or left ventricular systolic dysfunction (see Contraindications).
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 eg, 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.
Patients with Coronary Artery Disease: Caution is needed in patients with coronary artery disease.
Liver Injury: 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 1 week and after 1 month following initiation of treatment and then repeated monthly for 6 months, at months 9 and 12, and periodically, thereafter.
If alanine aminotransferase (ALT) levels are elevated ≥3x upper limit of normal (ULN), ALT levels should be remeasured within 48-72 hrs. If ALT levels are confirmed to be ≥3x ULN, treatment with dronedarone should be withdrawn. Appropriate investigation and close observation of patients should continue until normalization of ALT.
Patient should immediately report any symptoms of potential liver injury (eg, 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 mcmol/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 remeasured 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 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 Contraindications and Precautions). It is recommended to monitor renal function periodically and to consider further investigations as needed.
Patients with Renal Impairment: Multaq is contraindicated in patients with CrCl <30 mL/min (see Contraindications).
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 millisec), related to prolonged repolarisation. These changes are linked to the therapeutic effect of dronedarone and do not reflect toxicity. Follow up, including ECG, is recommended during treatment. If QTc Bazett interval is ≥500 millisec, dronedarone should be stopped (see Contraindications).
Based on clinical experience, dronedarone has a low proarrhythmic effect and has shown a decrease in arrhythmic death in the Athena study (see Pharmacology: Pharmacodynamics under Actions). However, proarrhythmic effects may occur in particular situations eg, concomitant use with medicinal products favouring arrhythmia and/or electrolytic disorders (see Interactions).
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 nonproductive 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 Interactions): 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 β-blockers or calcium antagonists with depressant effect on sinus and atrioventricular 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 β-blockers at time of dronedarone initiation, an ECG should be performed and the dose should be adjusted if needed.
Anticoagulation: Patients should be appropriately anticoagulated as per clinical AF guidelines. International normalized ratio (INR) should be closely monitored after initiating dronedarone in patients taking vitamin K antagonists as per their label.
Dabigatran: Dronedarone increases the exposure of dabigatran (see Interactions). No clinical data are available regarding the co-administration of these drugs in AF patients. Their co-administration is not recommended.
Potent CYP3A4 inducers eg, 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.
Patients with Galactose Intolerance: Due to the presence of lactose in Multaq, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption, should not take Multaq.
Effects on the Ability to Drive or Operate Machinery: No studies on the effects on the ability to drive and use machines have been performed.
Fertility: Dronedarone was not shown to alter fertility in animal studies.
Use in 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 Pharmacology: Toxicology under Actions). Dronedarone is not recommended during pregnancy and in women of childbearing potential not using contraception.
Use in lactation: It is not known 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 breastfeeding or to discontinue/abstain from Multaq therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
Use in the elderly: Caution is needed in elderly patients ≥75 years with multiple co-morbidities (see Pharmacology under Actions and Dosage & Administration).
Use In Pregnancy & Lactation
Use in 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 Pharmacology: Toxicology under Actions). Dronedarone is not recommended during pregnancy and in women of childbearing potential not using contraception.
Use in lactation: It is not known 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 breastfeeding or to discontinue/abstain from Multaq therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
Adverse Reactions
Summary of the Safety Profile: 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 6285 patients were randomized (3282 patients received dronedarone 400 mg twice daily and 2875 received placebo).
The mean exposure across studies was 13 months. In Athena study, the maximum follow-up was 30 months.
Assessment of intrinsic factors eg, gender or age on the incidence of any treatment emergent adverse reactions showed an interaction for gender (female patients) for the incidence of any adverse reactions and for serious adverse reactions.
In clinical trials, premature discontinuation due to adverse reactions occurred in 11.8% of the dronedarone-treated patients and in 7.7% in the placebo-treated group. The most common reasons for discontinuation of therapy with Multaq were gastrointestinal disorders (3.2 vs 1.8% patients in the placebo group).
The most frequent adverse reactions observed with dronedarone 400 mg twice daily in the 5 studies were diarrhea, nausea and vomiting, fatigue and asthenia. Listed as follows are adverse reactions associated with dronedarone 400 mg twice daily in AF or AFL patients, presented by system organ class and by decreasing order of frequency. Frequencies are defined as: Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Immune System Disorders: Rare: Anaphylactic reactions eg, angioedema.
Nervous System Disorders: Uncommon: Dysgeusia. Rare: Ageusia.
Cardiac Disorders: Very common: Congestive heart failure. Common: Bradycardia.
Vascular Disorders: Rare: Vasculitis, eg, leukocytoclastic vasculitis.
Respiratory, Thoracic and Mediastinal Disorders: Uncommon: Interstitial lung disease eg, pneumonitis and pulmonary fibrosis.
Gastrointestinal Disorders: Common: Diarrhoea, vomiting, nausea, abdominal pain, dyspepsia.
Hepatobiliary Disorders: Common: Abnormal liver function test.  Rare: Hepatocellular liver injury, eg, life-threatening acute liver failure (see Precautions).
Skin and Subcutaneous Tissue Disorders: Common: Rashes (eg, generalised, macular, maculopapular), pruritus. Uncommon: Erythemas (eg, erythema and rash erythematous), eczema photosensitivity reaction, dermatitis, allergic dermatitis.
General Disorders and Administration Site Conditions: Common: Fatigue, asthenia.
Investigations: Very common: Increased blood creatinine (≥10% 5 days after treatment initiation), prolonged QTc Bazett  (>450 msec in male >470 msec in female).
Post-marketing Experience: The following adverse reactions have been identified during post-approval use of dronedarone. The adverse reactions are derived from spontaneous reports and therefore, the frequency is not known (cannot be estimated from the available data).
Cardiac disorders: A few cases of atrial flutter with 1:1 atrioventricular conduction have been reported.
Description of Selected Adverse Reactions: In the 5 placebo-controlled studies, CHF occurred in the dronedarone group with rates comparable with placebo (very commonly, 11.2% vs 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 unknown) (see Precautions).
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 unknown). A number of patients had been previously exposed to amiodarone (see Precautions).
Drug Interactions
Dronedarone is primarily metabolized by CYP3A4 (see Pharmacology: Pharmacokinetics under Actions). Therefore, inhibitors and inducers of CYP3A4 have the potential to interact with dronedarone. Dronedarone is a moderate inhibitor of CYP3A4, a mild inhibitor of CYP2D6 and a potent inhibitor of P-glycoproteins (P-gp). Dronedarone therefore, has the potential to interact with medicinal products that are substrates of P-gp, CYP3A4 or CYP2D6. 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 CYP1A2, CYP2C9, CYP2C19, CYP2C8 and CYP2B6.
A potential pharmacodynamic interaction can also be expected with β-blockers, calcium antagonists and digitalis.
Medicinal Products Inducing Torsades de Pointes: Medicinal products inducing Torsades de pointes eg, phenothiazines, cisapride, bepridil, tricyclic antidepressants, certain oral macrolides (eg, erythromycin), terfenadine and class I and III antiarrhythmics are contraindicated because of the potential risk of proarrhythmia (see Contraindications). Caution should also be taken with co-administration with β-blockers or digoxin.
Effect of Other Medicinal Products on Multaq: Potent CYP3A4 Inhibitors: Repeated doses of ketoconazole 200 mg daily resulted in a 17-fold increase in dronedarone exposure. Therefore, concomitant use of ketoconazole as well as other potent CYP3A4 inhibitors eg, itraconazole, voriconazole, pozaconazole, ritonavir, telithromycin, clarithromycin or nefazodone is contraindicated (see Contraindications).
Moderate/Weak CYP3A4 Inhibitors: Erythromycin: Erythromycin, an oral macrolide, may induce Torsades de pointes and, as such, is contraindicated (see Contraindications). Repeated doses of erythromycin (500 mg 3 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 CYP3A4. Moreover, due to their heart rate-lowering properties, verapamil and diltiazem have the potential to interact with dronedarone from a pharmacodynamic point of view.
Repeated doses of diltiazem (240 mg twice daily), verapamil (240 mg once daily) and nifedipine (20 mg twice daily) resulted in an increase in dronedarone exposure of 1.7-, 1.4- and 1.2-fold, respectively. Calcium antagonists also have their exposure increased by dronedarone (400 mg twice daily) (verapamil by 1.4-fold, and nisoldipine by 1.5-fold). In clinical trials, 13% of patients received calcium antagonists concomitantly with dronedarone. There was no increased risk of hypotension, bradycardia and heart failure.
Overall, due to the pharmacokinetic interaction and possible pharmacodynamic interaction, calcium antagonists with depressant effects on sinus and atrioventricular node eg, 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 Precautions).
Other Moderate/Weak CYP3A4 Inhibitors: Other moderate inhibitors of CYP3A4 are also likely to increase dronedarone exposure.
CYP3A4 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 CYP3A4 inducers eg, 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 Pharmacology: Pharmacokinetics under Actions and Precautions).
Effect of Multaq on Other Medicinal Products: Interaction on medicinal products metabolized by CYP3A4.
Statins: Dronedarone can increase exposure of statins that are substrates of CYP3A4 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, eg, 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 metabolized by CYP3A4.
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 Precautions).
Calcium Antagonists: The interaction of dronedarone on calcium antagonists is described previously (see Precautions).
Immunosuppresants: Dronedarone could increase plasma concentrations of immunosuppresants (tacorlimus, sirolimus, everolimus and cyclosporine). Monitoring of their plasma concentrations and appropriate dose adjustment is recommended in case of co-administration 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 on Medicinal Products Metabolized by CYP2D6: Beta-Blockers: β-blockers that are metabolized by CYP2D6 can have their exposure increased by dronedarone. Moreover, β-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 (ie, much below the 6-fold differences observed between poor and extensive CYP2D6 metabolisers). In clinical trials, bradycardia was more frequently observed when dronedarone was given in combination with β-blockers.
Due to the pharmacokinetic interaction and possible pharmacodynamic interaction, β-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 β-blockers at time of dronedarone initiation, an ECG should be performed and the β-blocker dose should be adjusted if needed (see Precautions).
Antidepressants: Since dronedarone is a weak inhibitor of CYP2D6 in humans, it is predicted to have limited interaction on antidepressant medicinal products metabolized by CYP2D6.
Interaction of P-gp Substrates: Digoxin: Dronedarone (400 mg twice daily) increased digoxin exposure by 2.5-fold by inhibiting the 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 atrioventricular conduction is possible. In clinical trials, increased levels of digitalis and/or gastrointestinal disorders indicating digitalis toxicity were observed when dronedarone was co-administered with digitalis.
The digoxin dose should be reduced by approximately 50%, serum levels of digoxin should be closely monitored and clinical and ECG monitoring is recommended.
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 drugs in AF patients. Their co-administration is not recommended (see Precautions).
Interaction on Warfarin and Losartan (CYP2C9 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 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 on Theophylline (CYP1A2 Substrate): Dronedarone 400 mg twice daily does not increase the steady-state theophylline exposure.
Interaction on Metformin (OCT1 and OCT2 Substrate): No interaction was observed between dronedarone and metformin, an OCT1 and OCT2 substrate.
Interaction on Omeprazole (CYP2C19 Substrate): Dronedarone does not affect the pharmacokinetics of omeprazole, a CYP2C19 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 (CYP), did not interact significantly on dronedarone pharmacokinetics.
Grapefruit Juice (CYP3A4 Inhibitor): Repeated doses of grapefruit juice 300 mL 3 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 Precautions).
MIMS Class
ATC Classification
C01BD07 - dronedarone ; Belongs to class III antiarrhythmics.
Presentation/Packing
FC tab 400 mg (white, oblong-shaped, engraved with a double-wave marking on one side and “4142” code on the other side) x 60's.
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