Dronedarone
Encyclopedia
Dronedarone is a drug
by Sanofi-Aventis
, mainly for the indication of cardiac arrhythmias. It was approved by the FDA on July 2, 2009. It is now available as 400 mg tablets in 20, 60 and 100 count packages. It is used as an alternative to amiodarone
for the treatment of atrial fibrillation
and atrial flutter
in patients whose hearts have either returned to normal rhythm or who undergo drug therapy or electric shock treatment
to maintain normal rhythm. However, the FDA did not approve dronedarone for reducing deaths. 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.
In order for dronedarone to be FDA approved the manufacturer had to add a Black box
warning, stating that Multaq 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 FDA alerted healthcare professionals to rare cases of severe liver damage associated with the use of dronedarone.
derivative related to amiodarone
, a popular antiarrhythmic
the use of which is limited by toxicity due its high iodine
content (pulmonary fibrosis
, thyroid
disease) as well as by liver
disease.
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.
Yet it displays amiodarone-like class III antiarrhythmic activity in vitro and in clinical trials. The drug also appears to exhibit activity in each of the 4 Vaughan-Williams antiarrhythmic classes.
potential of the SA node and return patients to a normal heart rhythm. 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).
. This treatment for AF is also known to reduce associated mortality
and hospitalizations compared to other similar antiarrhythmic agent
s.
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.
However, in the ANDROMEDA study (2007), dronedarone doubled the death rate compared to placebo, and the trial was halted early. 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. There was a significant reduction in the rate of cardiovascular death, but not in the rate of death from any cause. Later post-hoc analysis of the ATHENA-results showed a significant reduction in the rate of stroke.
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.
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."
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.
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
by Sanofi-Aventis
Sanofi-Aventis
Sanofi S.A. is a multinational pharmaceutical company headquartered in Paris, France, the world's fourth-largest by prescription sales. Sanofi engages in the research and development, manufacturing and marketing of pharmaceutical products for sale principally in the prescription market, but the...
, mainly for the indication of cardiac arrhythmias. It was approved by the FDA on July 2, 2009. It is now available as 400 mg tablets in 20, 60 and 100 count packages. It is used as an alternative to amiodarone
Amiodarone
Amiodarone is an antiarrhythmic agent used for various types of tachyarrhythmias , both ventricular and supraventricular arrhythmias. Discovered in 1961, it was not approved for use in the United States until 1985...
for the treatment of atrial fibrillation
Atrial fibrillation
Atrial fibrillation is the most common cardiac arrhythmia . It is a common cause of irregular heart beat, identified clinically by taking a pulse. Chaotic electrical activity in the two upper chambers of the heart result in the muscle fibrillating , instead of achieving coordinated contraction...
and atrial flutter
Atrial flutter
Atrial flutter is an abnormal heart rhythm that occurs in the atria of the heart. When it first occurs, it is usually associated with a fast heart rate or tachycardia , and falls into the category of supra-ventricular tachycardias. While this rhythm occurs most often in individuals with...
in patients whose hearts have either returned to normal rhythm or who undergo drug therapy or electric shock treatment
Defibrillation
Defibrillation is a common treatment for life-threatening cardiac arrhythmias, ventricular fibrillation and pulseless ventricular tachycardia. Defibrillation consists of delivering a therapeutic dose of electrical energy to the affected heart with a device called a defibrillator...
to maintain normal rhythm. However, the FDA did not approve dronedarone for reducing deaths. 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.
In order for dronedarone to be FDA approved the manufacturer had to add a Black box
Black box warning
In the United States, a black box warning is a type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects...
warning, stating that Multaq 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 FDA alerted healthcare professionals to rare cases of severe liver damage associated with the use of dronedarone.
Chemistry
Chemically, dronedarone is a benzofuranBenzofuran
Benzofuran is the heterocyclic compound consisting of fused benzene and furan rings. This colourless liquid is a component of coal tar. Benzofuran is the "parent" of many related compounds with more complex structures. For example, psoralen is a benzofuran derivative that occurs in several...
derivative related to amiodarone
Amiodarone
Amiodarone is an antiarrhythmic agent used for various types of tachyarrhythmias , both ventricular and supraventricular arrhythmias. Discovered in 1961, it was not approved for use in the United States until 1985...
, a popular antiarrhythmic
Antiarrhythmic agent
Antiarrhythmic agents are a group of pharmaceuticals that are used to suppress abnormal rhythms of the heart , such as atrial fibrillation, atrial flutter, ventricular tachycardia, and ventricular fibrillation....
the use of which is limited by toxicity due its high iodine
Iodine
Iodine is a chemical element with the symbol I and atomic number 53. The name is pronounced , , or . The name is from the , meaning violet or purple, due to the color of elemental iodine vapor....
content (pulmonary fibrosis
Pulmonary fibrosis
Pulmonary fibrosis is the formation or development of excess fibrous connective tissue in the lungs. It is also described as "scarring of the lung".-Symptoms:Symptoms of pulmonary fibrosis are mainly:...
, thyroid
Thyroid
The thyroid gland or simply, the thyroid , in vertebrate anatomy, is one of the largest endocrine glands. The thyroid gland is found in the neck, below the thyroid cartilage...
disease) as well as by liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
disease.
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.
Yet it displays amiodarone-like class III antiarrhythmic activity in vitro and in clinical trials. The drug also appears to exhibit activity in each of the 4 Vaughan-Williams antiarrhythmic classes.
Pharmacokinetics
Dronedarone is less lipophilic than amiodarone, has a much smaller volume of distribution, and has an elimination half-life of 24 hours—this stands in contrast to amiodarone's half-life of several weeks. As a result of these pharmacokinetic characteristics, dronedarone dosing may be less complicated than amiodarone.Mechanism of action
Dronedarone has been termed a “multichannel blocker” however it is unclear which channel(s) play a pivotal role in its success. Thus dronedarones actions at the cellular level are controversial with most studies suggesting an inhibition in multiple inward potassium currents including rapid delayed rectifier, slow delayed rectifier and Ach-activated inward rectifier. 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 K-Ach channel or associated GTP-binding proteins. Reduction of K+ current by 69% lead to increased AP duration and increased effective refractory periods, thus shown to suppress pacemakerPacemaker
An artificial pacemaker is a medical device that uses electrical impulses to regulate the beating of the heart.Pacemaker may also refer to:-Medicine:...
potential of the SA node and return patients to a normal heart rhythm. 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).
Cautions
- NYHA (New York Heart Association) Class IV heart failure or NYHA Class II or III heart failure with a recent decompensation requiring hospitalization or referral to a specialized heart failure clinic.
- Second or third degree atrioventricular (AV) block or sick sinus syndrome (exception in patients with a functional pacemaker)
- Bradycardia less than 50 beats per minute
- QT interval corrected for rate of 500 msec or greater
- PR interval exceeding 280 msec
- Use of cytochrome P-450 (CYP) 3a isoenzyme inhibitors (includes: clarithromycin, cyclosporine, itraconazole, ketoconazole, nefazodone, ritonavir, telithromycin, voriconazole)
- Use with drugs or herbal supplements that prolong QT interval or increase risk of torsades de points (Class I or III antiarrhythmic agents, phenothiazines, tricyclic antidepressants, certain oral macrolides, ephedra)
- Hepatic impairment. In Jan 2011 the FDA advised about cases of rare, but severe, liver injury, including two cases of acute liver failure leading to liver transplant in patients treated with dronedarone (Multaq). It is not known whether routine periodic monitoring of serum liver enzymes (ALT, AST, and alkaline phosphatase) and bilirubin in patients taking dronedarone will prevent the development of severe liver injury.
- Women who are or may become pregnant
- Nursing women
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. Dronedarone is a non-iodinated class III anti-arrhythmic drug which helps patients return to normal sinus rhythmSinus rhythm
In medicine, sinus rhythm is the normal beating of the heart, as measured by an electrocardiogram . It has certain generic features that serve as hallmarks for comparison with normal ECGs.- ECG structure :...
. This treatment for AF is also known to reduce associated mortality
Mortality rate
Mortality rate is a measure of the number of deaths in a population, scaled to the size of that population, per unit time...
and hospitalizations compared to other similar antiarrhythmic agent
Antiarrhythmic agent
Antiarrhythmic agents are a group of pharmaceuticals that are used to suppress abnormal rhythms of the heart , such as atrial fibrillation, atrial flutter, ventricular tachycardia, and ventricular fibrillation....
s.
In the EURIDIS and ADONIS trials in atrial fibrillation
Atrial fibrillation
Atrial fibrillation is the most common cardiac arrhythmia . It is a common cause of irregular heart beat, identified clinically by taking a pulse. Chaotic electrical activity in the two upper chambers of the heart result in the muscle fibrillating , instead of achieving coordinated contraction...
(2007), dronedarone was significantly more effective than placebo in maintaining sinus rhythm, with no difference in lung and thyroid function in the short term.
However, in the ANDROMEDA study (2007), dronedarone doubled the death rate compared to placebo, and the trial was halted early. ANDROMEDA enrolled patients with moderate to severe congestive heart failure, a relatively sicker patient population.
In a more recent atrial fibrillation
Atrial fibrillation
Atrial fibrillation is the most common cardiac arrhythmia . It is a common cause of irregular heart beat, identified clinically by taking a pulse. Chaotic electrical activity in the two upper chambers of the heart result in the muscle fibrillating , instead of achieving coordinated contraction...
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. There was a significant reduction in the rate of cardiovascular death, but not in the rate of death from any cause. Later post-hoc analysis of the ATHENA-results showed a significant reduction in the rate of stroke.
Patients randomized to dronedarone were more likely to develop bradycardia
Bradycardia
Bradycardia , in the context of adult medicine, is the resting heart rate of under 60 beats per minute, though it is seldom symptomatic until the rate drops below 50 beat/min. It may cause cardiac arrest in some patients, because those with bradycardia may not be pumping enough oxygen to their heart...
and QT-interval prolongation (but only 1 case of Torsades). Nausea, diarrhea, rash, and creatinine elevation also were more common in the dronedarone arm.
Electro-Cardio conversion results
Multaq has been used by the Veteran's Administration to prepare patients for electro-conversion to sinus rythmn. A patient who had failed conversion 5 times with electro-shock alone, returned to sinus mode after more than 6 years of continuous afibrillation. Doctors prepared for conversion with a ten month loading course of Multaq.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. The FDA approved dronedarone on July 2, 2009.Health Canada
Health Canada
Health Canada is the department of the government of Canada with responsibility for national public health.The current Minister of Health is Leona Aglukkaq, a Conservative Member of Parliament appointed to the position by Prime Minister Stephen Harper.-Branches, regions and agencies: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."
The European Medicines Agency
European Medicines Agency
The European Medicines Agency is a European agency for the evaluation of medicinal products. From 1995 to 2004, the European Medicines Agency was known as European Agency for the Evaluation of Medicinal Products.Roughly parallel to the U.S...
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.