Drug Description
Each tablet contains 400 mg of dronedarone (as hydrochloride).Excipients:Each tablet also contains 41.65 mg of lactose (as monohydrate).

Presentation
Film-coated tablet (tablet).White, oblong shaped tablets, engraved with a double wave marking on one side and “4142”code on the other side.

Indications
MULTAQ is indicated in adult clinically stable patients with a history of, or current non-permanent atrial fibrillation (AF) to prevent recurrence of AF or to lower ventricular rate.

Adult Dosage
Treatment with MULTAQ can be initiated in an outpatient setting.The recommended dose is 400 mg twice daily in adults. It should be taken asone tablet with the morning meal andone tablet with the evening meal.Grapefruit juice should not be taken together with MULTAQ.If a dose is missed, patients should take the next dose at the regular scheduled time and should not double the dose.Treatment with Class I or III antiarrhythmics (such as flecainide, propafenone, quinidine, disopyramide, dofetilide, sotalol, amiodarone) must be stopped before starting MULTAQ.Paediatric PopulationThere is no experience in children and adolescents below 18 years of age. Therefore, MULTAQ is not recommended in this population.ElderlyEfficacy and safety were comparable in both elderly and younger patients. Although plasma exposure in elderly females was increased in a pharmacokinetic study conducted in healthy subjects, dose adjustments are not considered necessary.Hepatic impairmentMULTAQ is contraindicated in patients with severe hepatic impairment because of the absence of data. No dose adjustment is required in patients with mild or moderate hepatic impairment.Renal impairment MULTAQ is contraindicated in patients with severe renal impairment (creatinine clearance (CrCl) <30 ml/min). No dose adjustment is required in other patients with renal impairment.

Contra Indications
Hypersensitivity to the active substance or to any of the excipients Second- or third- degree Atrio-Ventricular block or sick sinus syndrome (except when used in conjunction with a functioning pacemaker) Bradycardia <50 beats per minute (bpm) Patients in unstable hemodynamic conditions including patients with symptoms of heart failure at rest or with minimal exertion (corresponding with NYHA class IV and unstable class III patients). Co-administration with potent cytochrome P 450 (CYP) 3A4 inhibitors, such as ketoconazole, itraconazole, voriconazole, posaconazole, telithromycin, clarithromycin, nefazodone and ritonavir Medicinal products inducing torsades de pointes such as phenothiazines, cisapride, bepridil, tricyclic antidepressants, terfenadine and certain oral macrolides, Class I and III antiarrhythmics QTc Bazett interval 500 milliseconds Severe hepatic impairment Severe renal impairment (CrCl <30ml/min)

Special Precautions
Patients with stable NYHA class III heart failure or LVEF <35% Because of the unexplained results of ANDROMEDA study, the use of dronedarone in unstable patients with NYHA class III and IV heart failure is contraindicated.Because of limited experience in stable patients with recent (1 to 3 months) NYHA class III heart failure or with Left Ventricular Ejection Fraction (LVEF) <35%, the use of MULTAQ is not recommended.Management of plasma creatinine increaseIt is recommended to measure plasma creatinine values 7 days after initiation of dronedarone. An increase in plasma creatinine has been observed with dronedarone 400 mg twice daily in healthy subjects and in patients. This increase occurs early after treatment initiation and reaches a plateau after 7 days. If an increase in creatininemia is observed, this value should be used as the new reference baseline taking into account that this may be expected with dronedarone.An increase in creatininemia should not necessarily lead to the discontinuation of treatment with ACE-inhibitors or Angiotensin II Receptors Antagonists (AIIRAs).Patients with renal impairmentMULTAQ is contraindicated in patients with CrCl <30 ml/min.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 prolongationThe 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.Based on clinical experience, dronedarone has a low pro-arrhythmic effect and has shown a decrease in arrhythmic death in the ATHENA study.However, proarrhythmic effects may occur in particular situations such as concomitant use with medicinal products favouring arrhythmia and/or electrolytic disorders.Patients with galactose intolerance Due to the presence of lactose in this medicinal product, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption, should not take this medicine.Interactions Potent CYP3A4 inducers such as rifampicin, phenobarbital, carbamazepine, phenytoin or St John's Wort are not recommended.Administration of dronedarone to patients receiving digoxin will bring about an increase in the plasma digoxin concentration and thus precipitate symptoms and signs associated with digoxin toxicity. Clinical, ECG and biological monitoring is recommended, and digoxin dose should be halved. A synergistic effect on heart rate and atrioventricular conduction is also possible. The co-administration of beta-blockers or calcium antagonists with depressant effect on sinus and atrio-ventricular node should be undertaken with caution. These medicinal products should be initiated at low dose and up-titration should be done only after ECG assessment. In patients already on calcium antagonists or beta blockers at time of dronedarone initiation, an ECG should be performed and the dose should be adjusted if needed.Statins should be used with caution. Lower starting dose and maintenance doses of statins should be considered and patients monitored for clinical signs of muscular toxicity.Patients should be warned to avoid grapefruit juice beverages while taking dronedarone.

Interactions
Dronedarone is primarily metabolised by CYP 3A4 (see section 5.2). Therefore, inhibitors and inducers of CYP 3A4 have the potential to interact on dronedarone. Dronedarone is a moderate inhibitor of CYP 3A4, a mild inhibitor of CYP 2D6 and a potent inhibitor of P-glycoproteins (P-gp). Dronedarone therefore, has the potential to interact on medicinal products substrates of P-glycoproteins, CYP 3A4 or CYP 2D6. Dronedarone has no significant potential to inhibit CYP 1A2, CYP 2C9, CYP 2C19, CYP 2C8 and CYP 2B6.A potential pharmacodynamic interaction can also be expected with beta-blockers, calcium antagonists and digitalis.Medicinal products inducing torsades de pointesMedicinal products inducing torsades de pointes such as phenothiazines, cisapride, bepridil, tricyclic antidepressants, certain oral macrolides, terfenadine and Class I and III antiarrhythmics are contraindicated because of the potential risk of proarrhythmia. Caution should also be taken with co-administration with beta-blockers or digoxin.Effect of other medicinal products on MULTAQPotent CYP 3A4 inhibitorsRepeated 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.Moderate/weak CYP 3A4 inhibitors: calcium antagonistsCalcium antagonists, diltiazem and verapamil, are substrates and/or moderate inhibitors of CYP 3A4. Moreover, due to their heart rate-lowering properties, verapamil and diltiazem have the potential to interact with dronedarone from a pharmacodynamic point of view.Repeated doses of diltiazem (240 mg twice daily), verapamil (240 mg once daily) and nifedipine (20 mg twice daily) resulted in an increase in dronedarone exposure of 1.7-, 1.4- and 1.2- fold, respectively. Calcium antagonists also have their exposure increased by dronedarone (400 mg twice daily) (verapamil by 1.4- fold, and nisoldipine by 1.5- fold). In clinical trials, 13% of patients received calcium antagonists concomitantly with dronedarone. There was no increased risk of hypotension, bradycardia and heart failure.Overall, due to the pharmacokinetic interaction and possible pharmacodynamic interaction, calcium antagonists with depressant effects on sinus and atrio-ventricular node such as verapamil and diltiazem should be used with caution when associated with dronedarone. These medicinal products should be initiated at low dose and up-titration should be done only after ECG assessment. In patients already on calcium antagonists at time of dronedarone initiation, an ECG should be performed and the calcium antagonist dose should be adjusted if needed.Other moderate inhibitors of the CYP3A4 such as erythromycin are also likely to increase dronedarone exposure.CYP 3A4 inducersRifampicin (600 mg once daily) decreased dronedarone exposure by 80% with no major change on its active metabolite exposure. Therefore, co-administration of rifampicin and other potent CYP 3A4 inducers such as phenobarbital, carbamazepine, phenytoin or St John's Wort is not recommended as they decrease dronedarone exposure.Effect of MULTAQ on other medicinal productsInteraction on medicinal products metabolized by CYP 3A4Statins: Dronedarone can increase exposure of statins that are substrates of CYP 3A4 and/or P-gp substrates. Dronedarone (400 mg twice daily) increased simvastatin and simvastatin acid exposure by 4- fold and 2- fold respectively. It is predicted that dronedarone could also increase the exposures of lovastatin and atorvastatin within the same range as simvastatin acid. Interaction of dronedarone on statins transported by OATP, such as fluvastatin and rosuvastatin has not been studied. In clinical trials, there was no evidence of safety concerns when dronedarone was co-administered with statins metabolized by CYP 3A4.As high doses of statins increase the risk of myopathy, concomitant use of statins should be undertaken with caution. Lower starting dose and maintenance doses of statins should be considered according to the statin label recommendations and patients monitored for clinical signs of muscular toxicity.Calcium antagonists The interaction of dronedarone on calcium antagonists is described above.Sirolimus, tacrolimus Dronedarone could increase plasma concentrations of tacrolimus and sirolimus. Monitoring of their plasma concentrations and appropriate dose adjustment is recommended in case of coadministration with dronedarone.Oral contraceptives No decreases in ethinylestradiol and levonorgestrel were observed in healthy subjects receiving dronedarone (800 mg twice daily) concomitantly with oral contraceptives.Interaction on medicinal products metabolized by CYP 2D6: beta blockers, antidepressantsBeta blockers Beta blockers that are metabolized by CYP 2D6 can have their exposure increased by dronedarone. Moreover, beta blockers have the potential to interact with dronedarone from a pharmacodynamic point of view. Dronedarone 800 mg daily increased metoprolol exposure by 1.6- fold and propranolol exposure by 1.3-fold (i.e. much below the 6- fold differences observed between poor and extensive CYP 2D6 metabolisers). In clinical trials, bradycardia was more frequently observed when dronedarone was given in combination with beta-blockers.Due to the pharmacokinetic interaction and possible pharmacodynamic interaction, beta blockers should be used with caution concomitantly with dronedarone. These medicinal products should be initiated at low dose and up-titration should be done only after ECG assessment. In patients already taking beta blockers at time of dronedarone initiation, an ECG should be performed and the beta blocker dose should be adjusted if needed.Antidepressants Since dronedarone is a weak inhibitor of CYP 2D6 in humans, it is predicted to have limited interaction on antidepressant medicinal products metabolized by CYP 2D6.Interaction of P-gp substrateDigoxin Dronedarone (400 mg twice daily) increased digoxin exposure by 2.5- fold by inhibiting P-gp transporter. Moreover, digitalis has the potential to interact with dronedarone from a pharmacodynamic point of view. A synergistic effect on heart rate and atrio-ventricular conduction is possible. In clinical trials, increased levels of digitalis and/or gastrointestinal disorders indicating digitalis toxicity were observed when dronedarone was co-administered with digitalis.The digoxin dose should be reduced by approximately 50%, serum levels of digoxin should be closely monitored and clinical and ECG monitoring is recommended.Interaction on warfarin and losartan (CYP 2C9 substrates)Dronedarone (600 mg twice daily) increased by 1.2- fold S-warfarin with no change in R warfarin and only a 1.07 increase in International Normalized Ratio (INR).No interaction was observed between dronedarone and losartan and an interaction between dronedarone and other AIIRAs(Angiotensin II Receptor Antagonists) is not expected.Interaction on theophylline (CYP 1A2 substrates)Dronedarone 400 mg twice daily does not increase the steady state theophylline exposure.Other informationPantoprazole (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.

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.Assessment of intrinsic factors such as gender or age on the incidence of any treatment emergent adverse reactions showed an interaction for gender (female patients) for the incidence of any adverse reactions and for serious adverse reactions.In clinical trials, premature discontinuation due to adverse reactions occurred in 11.8% of the dronedarone-treated patients and in 7.7% in the placebo-treated group. The most common reasons for discontinuation of therapy with MULTAQ were gastrointestinal disorders (3.2% of patients versus 1.8% in the placebo group).The most frequent adverse reactions observed with dronedarone 400 mg twice daily in the 5 studies were diarrhoea, nausea and vomiting, fatigue and asthenia.Table 1 displays adverse reactions associated with dronedarone 400 mg twice daily in AF or AFL patients, presented by system organ class and by decreasing order of frequency.Frequencies are defined as: very common (1/10), common (1/100 to <1/10); uncommon (1/1,000 to <1/100); rare (1/10,000 to <1/1,000); very rare (<1/10,000).Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.Table 1: Adverse ReactionsSystem organ classVery Common(1/10)Common(1/100 to <1/10)Uncommon(1/1,000 to <1/100)Rare(1/10,000 to <1/1,000)Nervous system disordersDysgeusiaAgeusiaCardiac disordersBradycardiaGastrointestinal disordersDiarrhoeaVomitingNauseaAbdominal painsDyspepsiaSkin and subcutaneous tissue disordersRashes (including generalised, macular, maculo-papular)PruritusErythemas (including erythema and rash erythematous)EczemaPhotosensitivity reactionDermatitis allergicDermatitisGeneral disorders and administration site conditionsFatigueAstheniaInvestigationsBlood creatinine increased*QTc Bazett prolonged #* 10% five days after treatment initiation# 450 msec in male>470 msec in female

Manufacturer
Sanofi-aventis

Drug Availability
POM – Prescription Only Medicine

Updated
06 September 2010