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Dr Navojit Chowdhury
MD part 3 student
Dronedarone
chemistry
Dronedarone is a novel antiarrhythmic drug with electrophysiological properties that are similar to those of amiodarone, but it does not contain iodine.
In dronedarone, the iodine moieties were removed, to reduce toxic effects on the thyroid and other organs; and a methylsulfonamide group was added, to reduce solubility in fats (lipophilicity) and thus reduce neurotoxic effects.
approved for atrial fibrillation by FDA :july 7 ,2009 DOSAGE AND ADMINISTRATION One tablet of 400 mg twice a day with morning and evening meals (2)
Pharmacokinetics
Absorption: Poor bioavailability (4%) due to extensive first pass hepatic metabolism 4%) food increases bioavailability (15%) Distribution: Unknown Protein Binding: >98%
Metabolism and Excretion: Undergoes extensive first pass hepatic metabolism; mostly by the CYP3A enzyme system. 6% excreted in urine as metabolites,
84% was excreted in feces as metabolites. Minimal elimination as unchanged drug Half-life: 1319 hr
INDICATION Dronedarone is an antiarrhythmic drug indicated to reduce the risk of cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL),with a recent episode of AF/AFL and associated cardiovascular risk factors (i.e., age >70, hypertension, diabetes, prior cerebrovascular accident, left atrial
DOSAGE AND ADMINISTRATION One tablet of 400 mg twice a day with morning and evening meals
CONTRAINDICATIONS
Class IV heart failure or symptomatic heart failure with a recent decompensation Second- or third- degree atrioventicular (AV) block or sick sinus syndrome (except when used in conjunction with a functioning pacemaker) Bradycardia <50 bpm Concomitant use of a strong CYP3A inhibitor Concomitant use of drugs or herbal products that prolong the QT interval and may induce Torsade de Pointes QTc interval 500 ms Severe hepatic impairment Pregnancy Nursing mothers
ADVERSE REACTIONS Most common adverse reactions (2%) are diarrhea, nausea, abdominal pain, vomiting, and asthenia
DRUG INTERACTIONS a moderate inhibitor of CYP 3A and has potentially important pharmacodynamic interactions Antiarrhythmics: Avoid concomitant use Digoxin: discontinuation or halve dose of digoxin before treatment and monitor Calcium channel blockers (CCB): Initiate CCB with low dose and increase after ECG verification of tolerability Beta-blockers: May provoke excessive bradycardia, Initiate with low dose and increase after ECG verification of tolerability
Clinical Studies
1.ATHENA(1) [ A Trial With Dronedarone to Prevent Hospitalization or Death in
Patients With Atrial Fibrillation]
3.ANDROMEDA(3) (Antiarrhythmic Trial with Dronedarone in Moderate-to-Severe Congestive Heart Failure EvaluatingMorbidity Decrease)
4.ERATO(4) The Efficacy and safety of
during atrial fibrillation dRonedArone for The cOntrol of ventricular rate
5.DIONYSOS(5) [Efficacy & Safety of Dronedarone Versus Amiodarone for the Maintenance of Sinus Rhythm in Patients With Atrial Fibrillation ]
P value
2003
142
Double-blind
p=.001
EURIDIS
2007
612
Double-blind
12
p=.01
ADONIS
2007
625
Double-blin
12
p=.002
ATHENA
2009
4,628
Paroxysmal or persistent AF Age 70 or 70 yrs with additional risk factor for stroke
Double-blind
21
<.0001
ATHENA(1)
inclusion criteria : 75 years old, or 70 years old with at least one risk factor (including hypertension, diabetes, prior cerebrovascular accident, left atrial diameter 50 mm or LVEF<0.40). Patients had both AF/AFL and sinus rhythm documented within the previous 6 months.Patients in AF were converted to sinus.
dronadarone 400 mg twice daily vs placebo (2327 patients), in addition to conventional therapy for cardiovascular diseases.
The primary endpoint of the study was the time to first hospitalization for cardiovascular reasons or death from any cause. For primary end point Dronadarone showed 24% RRR vs placebo(p<0.0001),
ATHENA
Study Selected Adverse Events and Laboratory Abnormalities in Patients Who Received the drug.(1)
Study Selected Adverse Events and Laboratory Abnormalities in Patients Who Received the drug(Continued)(1)
In the European trial, the median times to the recurrence of arrhythmia were 41days in the placebo group and 96 days in the dronedarone group (P = 0.01). The corresponding durations in the non-European trial were 59 and 158 days (P = 0.002).
Rates of pulmonary toxic effects and of thyroid and liver dysfunction were not significantly increased in the dronedarone group.
ANDROMEDA Study (Increased Mortality in Patients with Severe Heart Failure) (3)
Patients recently hospitalized with symptomatic heart failure and severe left ventricular systolic dysfunction (wall motion index 1.2) were randomized to either MULTAQ 400 mg twice daily or matching placebo, with a primary composite end point of all-cause mortality or hospitalization for heart failure. After enrollment of 627 of 1000 planned patients (310 and 317 in the dronedarone and placebo groups, respectively), and a median follow-up of 63 days, the trial was terminated because of excess mortality in the dronedarone group. Twenty-five (25) patients in the dronedarone group (8.1%) versus 12 patients in the placebo group (3.8%) had died, hazard ratio 2.13; 95% CI: 1.07 to 4.25; p=0.027. The main reason for death was worsening heart failure. There were also excess hospitalizations for cardiovascular reasons in the dronedarone group (71 versus 51 for placebo)
the ANDROMEDA Study, patients given dronedarone had a greater than two-fold increase in mortality. Such patients should not be given dronedarone
DYNOSOS STUDY(4)
Comparing dronadarone and amiodarone in maintaining sinus rythm in persistent atrial fibrilation in 504 patients The primary endpoint was defined as ECG-documented atrial fibrillation recurrence or premature study drug discontinuation for intolerance or lack of efficacy. there were 184 patients (73.9%) who reached the primary endpoint in the dronedarone arm as compared to 141 (55.3%) in the amiodarone arm (p<0.001). In the primary endpoint, atrial fibrillation after electrical cardioversion occurred in 36.5% of patients in the dronedarone arm vs. 24.3 % of patients in the amiodarone arm. Patients on amiodarone tended to experience more premature drug discontinuation (34 vs. 26) than patients on dronedarone Less bradycardia (8 vs. 22) and less pronounced QTc prolongation (27 vs. 52) was seen in the dronedarone arm than the amiodarone arm and no torsades de pointes were reported in the study
Comparative Efficacy of Dronedarone and Amiodarone for the Maintenance of Sinus Rhythm in Atrial Fibrillation(8)
4 placebo-controlled trials of dronedarone, 4 placebo-controlled trials of amiodarone, and 1 trial of dronedarone versus amiodarone(DYNOSOS).
To estimate a comparison between amiodarone and dronedarone from these data, following product was calculated
[Odds of event amiodarone/Odds of event on placebo] / [ Odds of event on dronedarone/Odds of event on placebo]
AF was significantly less common in patients who received amiodarone than in those who received placebo (odds ratio, 0.12).
The odds ratio for AF also was lower with dronedarone than with placebo (OR, 0.79) .
but also was associated with significantly more adverse events that required drug discontinuation (OR, 1.81) and with somewhat higher mortality (OR, 1.6; P=0.07).
The Efficacy and safety of dRonedArone for The cOntrol of ventricular rate during atrial fibrillation ERATO study (5)
In this randomized, double-blind, multinational trial, dronedarone, 400 mg twice a day (n = 85), or matching placebo (n = 89) was administered for 6 months to adult patients with permanent AF, in addition to standard therapy primary end point was the change in mean ventricular rate between baseline and day 14 effect at day 14 was a reduction of 11.7 beats per minute (p<.0001). Comparable reductions were sustained throughout the 6-month trial. During maximal exercise and compared to placebo, there was a mean reduction of 24.5 beat/min (p< .0001), without any reduction in exercise tolerance as measured by maximal exercise duration. The effects of dronedarone were additive to those of other rate-control agents, including -blockers, calcium antagonists, and digoxin. Dronedarone was well tolerated, with no organ toxicities or proarrhythmia
conclusion
The results from ERATO in permanent AF and EURIDIS and ADONIS studies in paroxysmal and persistent AF and flutter shows, dronedarone significantly reduced the risk of AFrecurrence but, in addition, proved effective in controlling ventricular rate , in which no proarrhythmic episodes or signs of extracardiac organ toxicity.(5) Indirect meta-analysis and direct randomized data also suggest that dronedarone has substantially less efficacy for the maintenance of sinus rhythm. (8) More long-term data are needed to refine these estimates and to define the optimum balance of efficacy and toxicity for patients with AF.(8)
REFERENCES
1.Singh BN, Connolly SJ, Crijns HJ,Dronedarone for maintenance of sinusrhythm in atrial fibrillation or flutter.N Engl J Med 2007;357:987-99. 2007;356:935 41. 2. Hohnloser SH, Crijns HJ, van Eickels M, et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med 2009;360:66878. 3 Kber L, Torp-Pedersen C, McMurray JJV, et al. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med 2008;358:2678-2687. 4. Barquet P. DIONYSOS Study Results Showed the Respective Profilesof Dronedarone and Amiodarone [cited 23 December 2008]. Press release. Available at: http://en.sanofiaventis.com/binaries/20081223_dionysos_fe_en_en_tcm28-23624.pdf. Accessed July 13, 2009. 5. American Heart Journal. 2008;156(3):527.e1-527.e9. 2008 Mosby, Inc 6. AFFIRM First Antiarrhythmic Drug Substudy Investigators. Maintenanceof sinus rhythm in patients with atrial fibrillation: an AFFIRM substudy of the first antiarrhythmic drug. J Am Coll Cardiol2003;42:20 9. 7. ESC Congress 2008 ESC Congress 2008 Clinical Trial Summary Slides 8. Piccini, Hasselblad,et al, Comparative Efficacy of Dronedarone and Amiodarone for the Maintenance of Sinus Rhythm in Patients With Atrial Fibrillation, J. Am. Coll. Cardiol. 2009;54;1089-1095
Dronedarone in AMI
Comparative antiarrhythmic efficacy of amiodarone and dronedarone during acute myocardial infarction in rats
(European Journal of Pharmacology Volume 564, Issues 1-3, 14 June 2007, Pages 150-157 )
total mortality did not differ between groups (38.8% in controls, 30.0% in the amiodarone group and 58.8% in the dronedarone group),because of excess bradyarrhythmic mortality in both drug groups that reached significance in the dronedarone group.
Dronedarone and amiodarone display similar antiarrhythmic efficacy postmyocardial infarction,how ever dronedarone increases bradyarrhythmic mortality possibly secondary to its negative inotropic effects.