Dronedarone : anti arrhythmic drug

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Weekly drug presentation

Dr Navojit Chowdhury

MD part 3 student

Moderator : Dr Zillur Rahaman

Asst .Proffessor


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Dronedarone


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chemistry

Dronedarone is a novel antiarrhythmic drug withelectrophysiological properties that are similar to those ofamiodarone, but it does not contain iodine.

In dronedarone, the iodine moieties were removed, toreduce toxic effects on the thyroid and other organs; anda methylsulfonamide group was added, to reducesolubility in fats (lipophilicity) and thus reduce neurotoxiceffects.


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approved for atrial fibrillation by FDA :july 7 ,2009

DOSAGE AND ADMINISTRATION

One tablet of 400 mg twice a day with morning and eveningmeals (2)

DOSAGE FORMS AND STRENGTHS

400 mg film-coated tablets
http://www.news-medical.net/news/20090707/Multaq-approved-for-atrial-fibrillation-by-FDA.aspxhttp://www.news-medical.net/news/20090707/Multaq-approved-for-atrial-fibrillation-by-FDA.aspxhttp://www.news-medical.net/news/20090707/Multaq-approved-for-atrial-fibrillation-by-FDA.aspxhttp://www.news-medical.net/news/20090707/Multaq-approved-for-atrial-fibrillation-by-FDA.aspxhttp://www.news-medical.net/news/20090707/Multaq-approved-for-atrial-fibrillation-by-FDA.aspx


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Pharmacokinetics

Absorption: Poor bioavailability (4%) due to extensive first pass hepaticmetabolism 4%) food increases bioavailability (15%)

Distribution: Unknown Protein Binding: >98%

Metabolism and Excretion: Undergoes extensive first pass hepaticmetabolism; mostly by the CYP3A enzyme system.

6% excreted in urine as metabolites,

84% was excreted in feces as metabolites. Minimal elimination asunchanged drug

Half-life: 1319 hr


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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]


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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


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CONTRAINDICATIONS

Class IV heart failure or symptomatic heart failure with arecent decompensation

Second- or third- degree atrioventicular (AV) block or sicksinus syndrome (except when used in conjunction with afunctioning pacemaker) Bradycardia


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WARNINGS AND PRECAUTIONS

Heart failure: If heart failure develops or worsens, consider the suspensionor discontinuation of Dronedarone

Hypokalemia and hypomagnesemia: Maintain potassium and magnesiumlevels within the normal range

QT prolongation: Stop Dronedarone if QTc Bazett 500ms

Increase in creatinine: Within a week, Dronedarone causes a smallincrease in serum creatinine that does not reflect a change in underlying renalfunctionTeratogen: Women of childbearing potential should use effectivecontraception while using Dronedarone


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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 pharmacodynamicinteractionsAntiarrhythmics: Avoid concomitant useDigoxin: discontinuation or halve dose of digoxin before treatment and monitor

Calcium channel blockers (CCB): Initiate CCB with low dose and increase afterECG verification of tolerabilityBeta-blockers: May provoke excessive bradycardia, Initiate with low dose andincrease after ECG verification of tolerability


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CYP 3A inducers: Avoid concomitant use

Grapefruit juice: Avoid concomitant use

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


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Clinical Studies

1.ATHENA(1) [A Trial With Dronedarone to Prevent Hospitalization or Death inPatients With Atrial Fibrillation]

2.EURIDIS and ADONIS(2) [EURopean trial In atrial fibrillation patientsreceiving Dronedarone for the maintenance of Sinus rhythm ] [American- Australian-African trialwith Dronedarone In atrial fibrillation patients for the maintenance of Sinus rhythm]

3.ANDROMEDA(3) (Antiarrhythmic Trial with Dronedarone in Moderate-to-SevereCongestive Heart Failure EvaluatingMorbidity Decrease)

4.ERATO(4)The Efficacy and safety of dRonedArone for The cOntrol of ventricular rateduring atrial fibrillation

5.DIONYSOS(5) [Efficacy & Safety of DronedaroneVersus Amiodarone forthe Maintenance of Sinus Rhythm in PatientsWith Atrial Fibrillation ]


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Studies about dronadarone Dronadarone vs placebo (8)Trial Year No. of

PatientsInclusionCriteria

Exclusioncriteria

blind Meanfollowup(months)

P value

DAFNEDronedaroneAtrialFibrillatioNstudy afterElectricalCardioversion

2003 142 Persistent AFAges 21-85yrs

Permanent AFNYHA functionalclass III to IVQT 500 msLVEF 35%

Double-blind 6 p=.001

EURIDIS 2007 612 AF episodewithin

previous3 monthsAge 21 yrs

Permanent AFHR 50 beats/min

NYHA functionalclass III to IVCr 1.7 mg/

Double-blind 12 p=.01

ADONIS 2007 625 AF episodewithinprevious3 monthsAge 21 yrs

Permanent AFHR 50 beats/minNYHA functionalclass III to IVCr 1.7 mg/dl

Double-blin 12 p=.002

ATHENA 2009 4,628 Paroxysmal orpersistent AFAge 70 or 70yrs withadditionalrisk factor forstroke

Permanent AFNYHA functionalclass IVHR 50 beats/minGFR 10 ml/min

Double-blind 21


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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


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ATHENA


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Study Selected Adverse Events and LaboratoryAbnormalities in Patients Who Received thedrug.(1)


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Study Selected Adverse Events and LaboratoryAbnormalities in Patients Who Received thedrug(Continued)(1)


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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.


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ANDROMEDA Study (Increased Mortality in Patients with SevereHeart Failure) (3)

Patients recently hospitalized with symptomatic heart failure and severe

left ventricular systolic dysfunction (wall motion index 1.2) wererandomized 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)


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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


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DYNOSOS STUDY(4)

Comparing dronadarone and amiodarone in maintaining sinus rythm inpersistent atrial fibrilation in 504 patients

The primary endpoint was defined as ECG-documented atrial fibrillationrecurrence or premature study drug discontinuation for intolerance or lack ofefficacy.

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


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Comparative Efficacy of Dronedarone and Amiodaronefor the Maintenance of Sinus Rhythm in Atrial

Fibrillation(8)

4 placebo-controlled trials of dronedarone, 4 placebo-controlled trials ofamiodarone, and 1 trial of dronedarone versus amiodarone(DYNOSOS).

To estimate a comparison between amiodarone and dronedarone fromthese data, following product was calculated

odds of event on amiodarone/odds of eventon dronedarone

[Odds of event amiodarone/Odds of event on placebo] / [ Odds of event

on dronedarone/Odds of event on placebo]


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AF was significantly less common in patients who received amiodaronethan 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


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The Efficacy and safety ofdRonedArone 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 adultpatients with permanent AF, in addition to standard therapy

primary end point was the change in mean ventricular rate between baseline and day14

effect at day 14 was a reduction of 11.7 beats per minute (p


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


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conclusion

The results from ERATO in permanent AF and EURIDIS andADONIS 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 noproarrhythmic episodes or signs of extracardiac organ toxicity.(5)

Indirect meta-analysis and direct randomized data also suggest thatdronedarone has substantially less efficacy for the maintenance of

sinus rhythm. (8)

More long-term data are needed to refine these estimates and todefine the optimum balance of efficacy and toxicity for patients withAF.(8)


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REFERENCES

1.Singh BN, Connolly SJ, Crijns HJ,Dronedarone for maintenance of sinusrhythm in atrial fibrillation or flutter.NEngl 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 atrialfibrillation. N Engl J Med 2009;360:66878.

3 Kber L, Torp-Pedersen C, McMurray JJV, et al. Increased mortality after dronedarone therapy for severe heartfailure. N Engl J Med 2008;358:2678-2687.

4. Barquet P. DIONYSOS Study Results Showed the Respective Profilesof Dronedarone and Amiodarone [cited23 December 2008]. Press release. Available at: http://en.sanofi-aventis.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 atrialfibrillation: an AFFIRM

substudy of the first antiarrhythmic drug. J Am Coll Cardiol2003;42:209.

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 ofSinus Rhythm in Patients With Atrial Fibrillation, J. Am. Coll. Cardiol. 2009;54;1089-1095


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Dronedarone in AMI

Comparative antiarrhythmic efficacy of amiodarone anddronedarone during acute myocardial infarction in rats(European Journal of PharmacologyVolume 564, Issues 1-3, 14 June 2007,Pages 150-157 )

total mortality did not differ between groups (38.8% in controls, 30.0% inthe amiodarone group and 58.8% in the dronedarone group),because ofexcess bradyarrhythmic mortality in both drug groups that reachedsignificance in the dronedarone group.

Dronedarone and amiodarone display similar antiarrhythmic efficacy post-myocardial infarction,how ever dronedarone increases bradyarrhythmicmortality possibly secondary to its negative inotropic effects.
http://www.sciencedirect.com/science/journal/00142999http://www.sciencedirect.com/science?_ob=PublicationURL&_tockey=%23TOC%234892%232007%23994359998%23652149%23FLA%23&_cdi=4892&_pubType=J&view=c&_auth=y&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=9016b7e606fbf305c1df3f507d4c4f6dhttp://www.sciencedirect.com/science?_ob=PublicationURL&_tockey=%23TOC%234892%232007%23994359998%23652149%23FLA%23&_cdi=4892&_pubType=J&view=c&_auth=y&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=9016b7e606fbf305c1df3f507d4c4f6dhttp://www.sciencedirect.com/science?_ob=PublicationURL&_tockey=%23TOC%234892%232007%23994359998%23652149%23FLA%23&_cdi=4892&_pubType=J&view=c&_auth=y&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=9016b7e606fbf305c1df3f507d4c4f6dhttp://www.sciencedirect.com/science?_ob=PublicationURL&_tockey=%23TOC%234892%232007%23994359998%23652149%23FLA%23&_cdi=4892&_pubType=J&view=c&_auth=y&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=9016b7e606fbf305c1df3f507d4c4f6dhttp://www.sciencedirect.com/science/journal/00142999

Dronedarone : anti arrhythmic drug

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