Weekly drug presentation

Dr Navojit Chowdhury
MD part 3 student

Moderator : Dr Zillur Rahaman

Asst .Proffessor

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)

DOSAGE FORMS AND STRENGTHS

400 mg film-coated tablets

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

diameter 50 mm or left ventricular ejection fraction [LVEF] <40%),

who are in sinus rhythm or who will be cardioverted.

DOSAGE AND ADMINISTRATION One tablet of 400 mg twice a day with morning and evening meals

DOSAGE FORMS AND STRENGTHS 400 mg film-coated tablets

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

WARNINGS AND PRECAUTIONS

Heart failure: If heart failure develops or worsens, consider the suspension or discontinuation of Dronedarone Hypokalemia and hypomagnesemia: Maintain potassium and magnesium levels within the normal range QT prolongation: Stop Dronedarone if QTc Bazett 500ms Increase in creatinine: Within a week, Dronedarone causes a small increase in serum creatinine that does not reflect a change in underlying renal function Teratogen: Women of childbearing potential should use effective contraception while using Dronedarone

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

CYP 3A inducers: Avoid concomitant use

Grapefruit juice: Avoid concomitant use

Statins: concomitant use of certain statins with a CYP 3A and PgP inhibitor like dronedarone CYP 3A substrates with a narrow therapeutic index (e.g., sirolimus and tacrolimus): Monitor and adjust dosage of as needed

Clinical Studies
1.ATHENA(1) [ A Trial With Dronedarone to Prevent Hospitalization or Death in
Patients With Atrial Fibrillation]

2.EURIDIS and ADONIS(2) [EURopean trial In atrial fibrillation patients

receiving Dronedarone for the maintenance of Sinus rhythm ] [American- Australian-African trial with Dronedarone In atrial fibrillation patients for the maintenance of Sinus rhythm]

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 ]

Studies about dronadarone Dronadarone vs placebo (8)

Trial Year No. of Patients Inclusion Criteria Exclusion criteria blind Mean follow up (month s)
6

P value

DAFNEDrone darone Atrial FibrillatioN study after Electrical Cardioversion

2003

142

Persistent AF Ages 21-85 yrs

Permanent AF NYHA functional class III to IV QT 500 ms LVEF 35%

Double-blind

p=.001

EURIDIS

2007

612

AF episode within previous 3 months Age 21 yrs

Permanent AF HR 50 beats/min NYHA functional class III to IV Cr 1.7 mg/

Double-blind

12

p=.01

ADONIS

2007

625

AF episode within previous 3 months Age 21 yrs

Permanent AF HR 50 beats/min NYHA functional class III to IV Cr 1.7 mg/dl

Double-blin

12

p=.002

ATHENA

2009

4,628

Paroxysmal or persistent AF Age 70 or 70 yrs with additional risk factor for stroke

Permanent AF NYHA functional class IV HR 50 beats/min GFR 10 ml/min

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)

EURIDIS and ADONIS(2)

Dronedarone
delayed the time to first recurrence of AF/AFL (primary endpoint), lowering the risk of first AF/AFL recurrence during the 12-month study period by about 25%,with an absolute difference in recurrence rate of about 11% at 12 months.

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)

[ WARNING: HEART FAILURE FDA

.
Dronadarone is contraindicated in patients with NYHA Class IV heart failure, or NYHA Class II III heart failure with a recent Decompensation requiring hospitalization or referral to a specialized heart failure clinic .

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 on amiodarone/odds of event on dronedarone

[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) .

Amiodarone was superior to dronedarone at preventing AF (OR, 0.49) p<0.001,

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

RATE CONTROL vs RYTHM CONTROL in AF(7)(6)

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.