Dronedarone

Last updated
Dronedarone
Dronedarone structure.svg
Clinical data
Trade names Multaq
Other namesSR33589
AHFS/Drugs.com Monograph
MedlinePlus a609034
License data
Pregnancy
category
  • AU:D
Routes of
administration
By mouth
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: WARNING [1] Rx-only [2]
  • EU:Rx-only
Pharmacokinetic data
Bioavailability 15% (with a high-fat meal) [2]
Protein binding >98%
Metabolism Extensive Liver (mainly by CYP3A)
Elimination half-life 13–19 hours
Excretion Feces (84%), urine (~6%)
Identifiers
  • N-(2-Butyl-3-(p-(3-(dibutylamino)propoxy)benzoyl)-5-benzofuranyl)methanesulfonamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.109.411 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C31H44N2O5S
Molar mass 556.76 g·mol−1
3D model (JSmol)
  • O=S(=O)(Nc3cc1c(oc(c1C(=O)c2ccc(OCCCN(CCCC)CCCC)cc2)CCCC)cc3)C
  • InChI=1S/C31H44N2O5S/c1-5-8-12-29-30(27-23-25(32-39(4,35)36)15-18-28(27)38-29)31(34)24-13-16-26(17-14-24)37-22-11-21-33(19-9-6-2)20-10-7-3/h13-18,23,32H,5-12,19-22H2,1-4H3 Yes check.svgY
  • Key:ZQTNQVWKHCQYLQ-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Dronedarone, sold under the brand name Multaq, is a medication by Sanofi-Aventis, mainly for the indication of cardiac arrhythmias. It was approved by the FDA on July 2, 2009. It was recommended as an alternative to amiodarone for the treatment of atrial fibrillation and atrial flutter in people whose hearts have either returned to normal rhythm or who undergo drug therapy or electric shock treatment i.e. direct current cardioversion (DCCV) to maintain normal rhythm. It is a class III antiarrhythmic drug. [3] In the United States, the FDA approved label includes a claim for reducing hospitalization, but not for reducing mortality, as a reduction in mortality was not demonstrated in the clinical development program. [4] A trial of the drug in heart failure was stopped as an interim analysis showed a possible increase in heart failure deaths, in patients with moderate to severe CHF. [5]

Contents

The U.S. label for dronedarone includes a boxed warning, stating that dronedarone is contraindicated in patients with NYHA Class IV heart failure, with NYHA Class II–III heart failure with a recent decompensation requiring hospitalization or referral to a specialized heart failure clinic, or with permanent atrial fibrillation." [2] Dronedarone is also associated with rare cases of severe liver damage, including liver failure. [6]

Mechanism of action

Dronedarone has been termed a "multichannel blocker". However, it is unclear which channel(s) play a pivotal role in its success. [7] Thus, dronedarone's actions at the cellular level are controversial, with most studies suggesting an inhibition in multiple outward potassium currents including rapid delayed rectifier, slow delayed rectifier and ACh-activated inward rectifier. [8] It is also believed to reduce inward rapid Na current and L-type Ca channels. The reduction in K current in some studies was shown to be due to the inhibition of the K-ACh channel or associated GTP-binding proteins. [7] Reduction of K+ current by 69% led to increased AP duration and increased effective refractory periods, thus shown to suppress pacemaker potential of the SA node and return patients to a normal heart rhythm. [8] In a European trial, the average time to recurrence of an arrhythmia was 41 days in the placebo group vs. 96 days in the dronedarone group (similar results obtained in the non-European trial, 59 and 158 days respectively). [9]

Chemistry

Chemically, dronedarone is a benzofuran derivative related to amiodarone, a popular antiarrhythmic. The use of amiodarone is limited by toxicity due its high iodine content (pulmonary fibrosis, thyroid disease) as well as by liver disease. In dronedarone, the iodine moieties are not present, reducing toxic effects on the thyroid and other organs. A methylsulfonamide group is added to reduce solubility in fats (lipophobicity) and thus reduce neurotoxic effects. [4]

Dronedarone displays amiodarone-like class III antiarrhythmic activity in vitro [10] and in clinical trials. [5] The drug also appears to exhibit activity in each of the 4 Vaughan-Williams antiarrhythmic classes. [11]

Pharmacokinetics

Dronedarone is less lipophilic than amiodarone, has a much smaller volume of distribution, and has an elimination half-life of 13–19 hours—this stands in contrast to amiodarone's half-life of several weeks. [2] [12] As a result of these pharmacokinetic characteristics, dronedarone dosing may be less complicated than amiodarone.

Contraindications

Clinical trials

Clinical trials have compared dronedarone to placebo and to amiodarone, for its ability to reduce atrial fibrillation, to reduce mortality overall and from cardiac causes, and for its adverse effects, including excess mortality. [4] [7] Dronedarone is a non-iodinated class III anti-arrhythmic drug which helps patients return to normal sinus rhythm. This treatment for AF is also known to reduce associated mortality and hospitalizations compared to other similar antiarrhythmic agents. [13]

In the EURIDIS and ADONIS trials in atrial fibrillation (2007), dronedarone was significantly more effective than placebo in maintaining sinus rhythm, with no difference in lung and thyroid function in the short term. [14]

However, in the ANDROMEDA study (2007), dronedarone doubled the death rate compared to placebo, and the trial was halted early. [5] ANDROMEDA enrolled patients with moderate to severe congestive heart failure, a relatively sicker patient population.

In a more recent atrial fibrillation trial, ATHENA, with 4628 subjects, dronedarone was significantly more effective than placebo in reducing the composite endpoint of first hospitalization due to cardiovascular events or death. [15] There was a significant reduction in the rate of cardiovascular death, but not in the rate of death from any cause. [4] Later post-hoc analysis of the ATHENA-results showed a significant reduction in the rate of stroke. [13]

Patients randomized to dronedarone were more likely to develop bradycardia and QT-interval prolongation (but only 1 case of Torsades). Nausea, diarrhea, rash, and creatinine elevation also were more common in the dronedarone arm.

The PALLAS trial (2011) was stopped for safety concerns due to the finding that "dronedarone increased rates of heart failure, stroke, and death from cardiovascular causes in patients with permanent atrial fibrillation who were at risk for major vascular events". [16] A Black Box warning was subsequently added by the FDA stating that the risk of death, stroke, and hospitalization for congestive heart failure doubled in patients with permanent atrial fibrillation.

Direct current cardioversion results

Dronedarone has been tested in some trials as a way to improve the success rate of electrical cardioversion. In one such trial by the Veteran's Administration it was used prepare patients for electrical conversion to sinus rhythm. In the ATHENA study, 25% of patients were started on dronedarone before cardioversion. [15] The results of a recently concluded randomized study (ELECTRA) may clarify the safety and ideal modalities of dronedarone use at the time of cardioversion. [17]

Regulatory review

Originally submitted as a New Drug Application in 2005, dronedarone was reviewed and recommended for approval on March 18, 2009, by an Advisory Committee of the United States Food and Drug Administration (FDA). The FDA is not bound by the committee's recommendation, but it takes its advice into consideration when reviewing new drug applications. [18] The FDA approved dronedarone on July 2, 2009.

Health Canada was the second major regulatory body to approve the drug, giving its approval on August 12, 2009. The approval is for "treatment of patients with a history of, or current atrial fibrillation to reduce their risk of cardiovascular hospitalization due to this condition." [19]

The European Medicines Agency issued a Summary of Positive Opinion regarding dronedarone on 24 September 2009 recommending to the European Commission to grant a marketing authorization within the European Union. [20]

Research

A follow on drug, poyendarone, has been developed by modifying the Dronedarone molecule to remove its tendency to cause ventricular arrhythmia. The new drug was developed by the National University of Singapore (NUS) Department of Pharmacy and patents have been applied for. [21] [22]

Related Research Articles

<span class="mw-page-title-main">Cardioversion</span> Conversion of a cardiac arrhythmia to a normal rhythm using an electrical shock or medications

Cardioversion is a medical procedure by which an abnormally fast heart rate (tachycardia) or other cardiac arrhythmia is converted to a normal rhythm using electricity or drugs. Synchronized electrical cardioversion uses a therapeutic dose of electric current to the heart at a specific moment in the cardiac cycle, restoring the activity of the electrical conduction system of the heart. Pharmacologic cardioversion, also called chemical cardioversion, uses antiarrhythmia medication instead of an electrical shock.

<span class="mw-page-title-main">Digoxin</span> Plant-derived medication

Digoxin, sold under the brand name Lanoxin among others, is a medication used to treat various heart conditions. Most frequently it is used for atrial fibrillation, atrial flutter, and heart failure. Digoxin is one of the oldest medications used in the field of cardiology. It works by increasing myocardial contractility, increasing stroke volume and blood pressure, reducing heart rate, and somewhat extending the time frame of the contraction. Digoxin is taken by mouth or by injection into a vein. Digoxin has a half life of approximately 36 hours given at average doses in patients with normal renal function. It is excreted mostly unchanged in the urine.


Antiarrhythmic agents, also known as cardiac dysrhythmia medications, are a group of pharmaceuticals that are used to suppress abnormally fast rhythms (tachycardias), such as atrial fibrillation, supraventricular tachycardia and ventricular tachycardia.

<span class="mw-page-title-main">Atrial flutter</span> Medical condition

Atrial flutter (AFL) is a common abnormal heart rhythm that starts in the atrial chambers of the heart. When it first occurs, it is usually associated with a fast heart rate and is classified as a type of supraventricular tachycardia. Atrial flutter is characterized by a sudden-onset (usually) regular abnormal heart rhythm on an electrocardiogram (ECG) in which the heart rate is fast. Symptoms may include a feeling of the heart beating too fast, too hard, or skipping beats, chest discomfort, difficulty breathing, a feeling as if one's stomach has dropped, a feeling of being light-headed, or loss of consciousness.

<span class="mw-page-title-main">Dofetilide</span> Antiarrhythmic medication

Dofetilide is a class III antiarrhythmic agent. It is marketed under the trade name Tikosyn by Pfizer, and is available in the United States in capsules containing 125, 250, and 500 µg of dofetilide. It is not available in Europe or Australia.

<span class="mw-page-title-main">Quinidine</span> Antiarrythmic medication

Quinidine is a class IA antiarrhythmic agent used to treat heart rhythm disturbances. It is a diastereomer of antimalarial agent quinine, originally derived from the bark of the cinchona tree. The drug causes increased action potential duration, as well as a prolonged QT interval. As of 2019, its IV formulation is no longer being manufactured for use in the United States.

<span class="mw-page-title-main">Amiodarone</span> Antiarrhythmic medication used for various types of irregular heartbeats

Amiodarone is an antiarrhythmic medication used to treat and prevent a number of types of cardiac dysrhythmias. This includes ventricular tachycardia (VT), ventricular fibrillation (VF), and wide complex tachycardia, as well as atrial fibrillation and paroxysmal supraventricular tachycardia. Evidence in cardiac arrest, however, is poor. It can be given by mouth, intravenously, or intraosseously. When used by mouth, it can take a few weeks for effects to begin.

<span class="mw-page-title-main">Sotalol</span> Medication

Sotalol, sold under the brand name Betapace among others, is a medication used to treat and prevent abnormal heart rhythms. Evidence does not support a decreased risk of death with long term use. It is taken by mouth or given by injection into a vein.

<span class="mw-page-title-main">Ivabradine</span> Heart medication

Ivabradine, sold under the brand name Procoralan among others, is a medication, which is a pacemaker current (If) inhibitor, used for the symptomatic management of heart-related chest pain and heart failure. Patients who qualify for use of Ivabradine for coronary heart failure are patients who have symptomatic heart failure, with reduced ejection volume, and heart rate at least 70 bpm, and the condition not able to be fully managed by beta blockers.

<span class="mw-page-title-main">Ibutilide</span> Chemical compound

Ibutilide is a Class III antiarrhythmic agent that is indicated for acute cardioconversion of atrial fibrillation and atrial flutter of a recent onset to sinus rhythm. It exerts its antiarrhythmic effect by induction of slow inward sodium current, which prolongs action potential and refractory period of myocardial cells. Because of its Class III antiarrhythmic activity, there should not be concomitant administration of Class Ia and Class III agents.

<span class="mw-page-title-main">Ranolazine</span> Drug used to treat angina

Ranolazine, sold under the brand name Ranexa among others, is a medication used to treat heart related chest pain. Typically it is used together with other medications when those are insufficient. Benefits appear smaller in women than men. It is taken by mouth.

<span class="mw-page-title-main">Vernakalant</span> Medication for the acute treatment of atrial fibrillation

Vernakalant is a pharmaceutical drug for the acute conversion of atrial fibrillation, a kind of irregular heartbeat, in form of an intravenous infusion. It has been approved for use in the European Union and the UK since 2010. The US Food and Drug Administration denied approval in 2008 and 2019.

<span class="mw-page-title-main">Landiolol</span> Chemical compound

Landiolol (INN) is an ultra short-acting, β1-superselective intravenous adrenergic antagonist, which decreases the heart rate effectively with less negative effect on blood pressure or myocardial contractility. In comparison to other beta blockers, landiolol has the shortest elimination half-life, ultra-rapid onset of effect, and predictable effectiveness with inactive metabolites. The pure S-enantiomer structure of landiolol is believed to develop less hypotensive side effects in comparison to other β-blockers. This has a positive impact on the treatment of patients when reduction of heart rate without decrease in arterial blood pressure is desired. Landiolol was developed by modifying the chemical structure of esmolol to produce a compound with a higher rate of cardioselectivity and a greater potency without increasing its duration of action. It is sold as landiolol hydrochloride. Based on its positive benefit risk profile, landiolol has been granted the marketing authorization and introduced to the European markets under the brand names Rapibloc, Raploc, Runrapiq, Landibloc mid 2016. Landiolol is available in Japan under the brand names Onoact (50 mg) and Corbeta.

<span class="mw-page-title-main">Atrial fibrillation</span> Irregular beating of the atria of the heart

Atrial fibrillation is an abnormal heart rhythm (arrhythmia) characterized by rapid and irregular beating of the atrial chambers of the heart. It often begins as short periods of abnormal beating, which become longer or continuous over time. It may also start as other forms of arrhythmia such as atrial flutter that then transform into AF.

The management of atrial fibrillation (AF) is focused on preventing temporary circulatory instability, stroke and other ischemic events. Control of heart rate and rhythm are principally used to achieve the former, while anticoagulation may be employed to decrease the risk of stroke. Within the context of stroke, the discipline may be referred to as stroke prevention in atrial fibrillation (SPAF). In emergencies, when circulatory collapse is imminent due to uncontrolled rapid heart rate, immediate cardioversion may be indicated.

<span class="mw-page-title-main">Arrhythmia</span> Group of medical conditions characterized by irregular heartbeat

Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults – is called tachycardia, and a resting heart rate that is too slow – below 60 beats per minute – is called bradycardia. Some types of arrhythmias have no symptoms. Symptoms, when present, may include palpitations or feeling a pause between heartbeats. In more serious cases, there may be lightheadedness, passing out, shortness of breath, chest pain, or decreased level of consciousness. While most cases of arrhythmia are not serious, some predispose a person to complications such as stroke or heart failure. Others may result in sudden death.

<span class="mw-page-title-main">Celivarone</span> Experimental drug being tested for use in pharmacological antiarrhythmic therapy

Celivarone is an experimental drug being tested for use in pharmacological antiarrhythmic therapy. Cardiac arrhythmia is any abnormality in the electrical activity of the heart. Arrhythmias range from mild to severe, sometimes causing symptoms like palpitations, dizziness, fainting, and even death. They can manifest as slow (bradycardia) or fast (tachycardia) heart rate, and may have a regular or irregular rhythm.

<span class="mw-page-title-main">Budiodarone</span> Chemical compound

Budiodarone (ATI-2042) is an antiarrhythmic agent and chemical analog of amiodarone that is currently being studied in clinical trials. Amiodarone is considered the most effective antiarrhythmic drug available, but its adverse side effects, including hepatic, pulmonary and thyroid toxicity as well as multiple drug interactions, are discouraging its use. Budiodarone only differs in structure from amiodarone through the presence of a sec-butyl acetate side chain at position 2 of the benzofuran moiety. This side chain allows for budiodarone to have a shorter half-life in the body than amiodarone which allows it to have a faster onset of action and metabolism while still maintaining similar electrophysiological activity. The faster metabolism of budiodarone allows for fewer adverse side effects than amiodarone principally due to decreased levels of toxicity in the body.

<span class="mw-page-title-main">Peter R. Kowey</span> American cardiologist and medical researcher

Peter R. Kowey is an American cardiologist and medical researcher. He is Professor of Medicine and Clinical Pharmacology at Jefferson Medical College of Thomas Jefferson University and holds the William Wikoff Smith Chair in Cardiovascular Research at Lankenau Institute for Medical Research.

<span class="mw-page-title-main">Yaariv Khaykin</span> Canadian cardiologist

Yaariv Khaykin is a Canadian cardiologist and a clinical researcher in the area of electrophysiology. He is the director of the Newmarket Electrophysiology Research Group at the Southlake Regional Health Centre. He has published research into complex ablation and pioneered cardiac ablation methods.

References

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