Dronedarone

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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
Pharmacokinetic data
Bioavailability 15% (with a high-fat meal) [2]
Protein binding >98%
Metabolism 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 class III antiarrhythmic medication developed by Sanofi-Aventis.[ citation needed ] It was approved by the US Food and Drug Administration (FDA) in July 2009.[ citation needed ] Besides being indicated in arrhythmias, 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.[ medical citation needed ] It is a class III antiarrhythmic drug. [4] The FDA 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. [5] A trial of the drug in heart failure was stopped as an interim analysis showed a possible increase in heart failure deaths, in people with moderate to severe congestive heart failure. [6]

Contents

The FDA label for dronedarone includes a boxed warning, stating that dronedarone is contraindicated in patients with NYHA Class IV heart failure, NYHA Class II and 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. [7]

It is approved as a generic medication. [8]

Mechanism of action

Dronedarone has been termed a "multichannel blocker".[ citation needed ] However, it is unclear which channel(s) play a pivotal role in its success. [9] 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. [10] It is also believed to reduce inward rapid Na current and L-type Ca channels.[ medical citation needed ] 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. [9] 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. [10] 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). [11]

Chemistry

Chemically, dronedarone is a benzofuran derivative related to amiodarone, a popular antiarrhythmic.[ medical citation needed ] The use of amiodarone is limited by toxicity due its high iodine content (pulmonary fibrosis, thyroid disease) as well as by liver disease.[ medical citation needed ] In dronedarone, the iodine moieties are not present, reducing toxic effects on the thyroid and other organs.[ medical citation needed ] A methylsulfonamide group is added to reduce solubility in fats (lipophobicity) and thus reduce neurotoxic effects. [5]

Dronedarone displays amiodarone-like class III antiarrhythmic activity in vitro [12] and in clinical trials. [6] The drug also appears to exhibit activity in each of the 4 Vaughan-Williams antiarrhythmic classes. [13]

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] [14] As a result of these pharmacokinetic characteristics, dronedarone dosing may be less complicated than amiodarone.[ medical citation needed ]

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. [5] [9] Dronedarone is a non-iodinated class III anti-arrhythmic drug which helps patients return to normal sinus rhythm.[ medical citation needed ] This treatment for AF is also known to reduce associated mortality and hospitalizations compared to other similar antiarrhythmic agents. [15]

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. [16]

However, in the ANDROMEDA study (2007), dronedarone doubled the death rate compared to placebo, and the trial was halted early. [6] ANDROMEDA enrolled patients with moderate to severe congestive heart failure, a relatively sicker patient population.[ medical citation needed ]

In a later 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. [17] There was a significant reduction in the rate of cardiovascular death, but not in the rate of death from any cause. [5] Later post-hoc analysis of the ATHENA-results showed a significant reduction in the rate of stroke. [15]

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

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". [18] 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.[ medical citation needed ]

Direct current cardioversion results

Dronedarone has been tested in some trials as a way to improve the success rate of electrical cardioversion.[ medical citation needed ] In one such trial by the Veteran's Administration it was used prepare patients for electrical conversion to sinus rhythm.[ medical citation needed ] In the ATHENA study, 25% of patients were started on dronedarone before cardioversion. [17] The results of a recently concluded randomized study (ELECTRA) may clarify the safety and ideal modalities of dronedarone use at the time of cardioversion. [19]

Regulatory review

Originally submitted as a New Drug Application in 2005, dronedarone was reviewed and recommended for approval in March 2009, by an Advisory Committee of the United States Food and Drug Administration (FDA). [20] The FDA approved dronedarone in July 2009.[ citation needed ]

Health Canada was the second major regulatory body to approve the drug, giving its approval in August 2009.[ citation needed ] 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." [21]

The European Medicines Agency issued a Summary of Positive Opinion regarding dronedarone in September 2009, recommending to the European Commission to grant a marketing authorization within the European Union. [22]

Research

In July 2019, a new drug called poyendarone was patented by the department of pharmacy of National University of Singapore (NUS). [23] It was developed by modifying the dronedarone molecule to remove its tendency to cause ventricular arrhythmia. [24] [25]

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.

<span class="mw-page-title-main">Tachycardia</span> Heart rate exceeding normal resting rate

Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal or abnormal.

<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.

<span class="mw-page-title-main">Antiarrhythmic agent</span> Heart rhythm medication

Antiarrhythmic agents, also known as cardiac dysrhythmia medications, are a class of drugs 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> Abnormal heart rhythm beginning in the atria

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, ventricular fibrillation, and wide complex tachycardia, 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">Ventricular tachycardia</span> Abnormally fast rhythm of the hearts ventricles

Ventricular tachycardia is a cardiovascular disorder in which fast heart rate occurs in the ventricles of the heart. Although a few seconds of VT may not result in permanent problems, longer periods are dangerous; and multiple episodes over a short period of time are referred to as an electrical storm. Short periods may occur without symptoms, or present with lightheadedness, palpitations, shortness of breath, chest pain, and decreased level of consciousness. Ventricular tachycardia may lead to coma and persistent vegetative state due to lack of blood and oxygen to the brain. Ventricular tachycardia may result in ventricular fibrillation (VF) and turn into cardiac arrest. This conversion of the VT into VF is called the degeneration of the VT. It is found initially in about 7% of people in cardiac arrest.

<span class="mw-page-title-main">Metoprolol</span> Medication of the selective β1 receptor blocker type

Metoprolol, sold under the brand name Lopressor among others, is a medication used to treat angina and a number of conditions involving an abnormally fast heart rate. It is also used to prevent further heart problems after myocardial infarction and to prevent headaches in those with migraines. It is a selectiveβ1 receptor blocker medication. It is taken by mouth or is given intravenously.

<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">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. Therapeutic benefits appear smaller in females than males. It is taken by mouth.

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

Vernakalant, sold under the brand name Brinavess, is a class III antiarrhythmic 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 United Kingdom since 2010. The US Food and Drug Administration denied approval in 2008 and 2019.

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

Pilsicainide (INN) is an antiarrhythmic agent. It is marketed in Japan as サンリズム (Sunrythm). It was developed by Suntory Holdings Limited and first released in 1991. The JAN applies to the hydrochloride salt, pilsicainide hydrochloride.

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

Landiolol, sold under the brand name Onoact among others, is a medication used for the treatment of tachycardia, atrial fibrillation, and atrial flutter. It is a beta-adrenergic blocker; 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. It is used as landiolol hydrochloride.

<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.

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

Arrhythmias, also known as cardiac arrhythmias, 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.

References

  1. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved October 22, 2023.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 "Multaq- dronedarone tablet, film coated". DailyMed. October 15, 2020. Retrieved November 18, 2020.
  3. ↑ "Multaq EPAR". European Medicines Agency (EMA). November 26, 2009. Retrieved September 6, 2024.
  4. ↑ "FDA Approves Multaq to Treat Heart Rhythm Disorder" (Press release). U.S. Food and Drug Administration (FDA). July 2, 2009. Archived from the original on July 4, 2009. Retrieved July 2, 2009.
  5. 1 2 3 4 Zimetbaum PJ (April 2009). "Dronedarone for atrial fibrillation--an odyssey". The New England Journal of Medicine. 360 (18): 1811–1813. doi:10.1056/NEJMp0902248. PMID   19403901.
  6. 1 2 3 Køber L, Torp-Pedersen C, McMurray JJ, Gøtzsche O, Lévy S, Crijns H, et al. (June 2008). "Increased mortality after dronedarone therapy for severe heart failure". The New England Journal of Medicine. 358 (25): 2678–2687. doi: 10.1056/NEJMoa0800456 . PMID   18565860.
  7. 1 2 "FDA Drug Safety Communication: Severe liver injury associated with the use of dronedarone (marketed as Multaq). Safety Announcement". U.S. Food and Drug Administration (FDA). January 14, 2011.
  8. ↑ "First-Time Generic Drug Approvals 2024". U.S. Food and Drug Administration (FDA). March 8, 2024. Retrieved March 9, 2024.
  9. 1 2 3 Guillemare E, Marion A, Nisato D, Gautier P (December 2000). "Inhibitory effects of dronedarone on muscarinic K+ current in guinea pig atrial cells". Journal of Cardiovascular Pharmacology. 36 (6): 802–5. doi: 10.1097/00005344-200012000-00017 . PMID   11117382.
  10. 1 2 Aimond F, Beck L, Gautier P, Chérif OK, Davy JM, Lorente P, et al. (January 2000). "Cellular and in vivo electrophysiological effects of dronedarone in normal and postmyocardial infarcted rats". The Journal of Pharmacology and Experimental Therapeutics. 292 (1): 415–424. PMID   10604978.
  11. ↑ Singh BN, Connolly SJ, Crijns HJ, Roy D, Kowey PR, Capucci A, et al. (EURIDIS and ADONIS Investigators) (September 2007). "Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter". The New England Journal of Medicine. 357 (10): 987–999. doi: 10.1056/NEJMoa054686 . PMID   17804843.
  12. ↑ Sun W, Sarma JS, Singh BN (November 1999). "Electrophysiological effects of dronedarone (SR33589), a noniodinated benzofuran derivative, in the rabbit heart : comparison with amiodarone". Circulation. 100 (22): 2276–2281. doi: 10.1161/01.CIR.100.22.2276 . PMID   10578003.
  13. ↑ "Medscape Drugs & Diseases - Comprehensive peer-reviewed medical condition, surgery, and clinical procedure articles with symptoms, diagnosis, staging, treatment, drugs and medications, prognosis, follow-up, and pictures".
  14. ↑ Dale KM, White CM (April 2007). "Dronedarone: an amiodarone analog for the treatment of atrial fibrillation and atrial flutter". The Annals of Pharmacotherapy. 41 (4): 599–605. doi:10.1345/aph.1H524. PMID   17389667. S2CID   22339555.
  15. 1 2 Connolly SJ, Crijns HJ, Torp-Pedersen C, van Eickels M, Gaudin C, Page RL, et al. (September 2009). "Analysis of stroke in ATHENA: a placebo-controlled, double-blind, parallel-arm trial to assess the efficacy of dronedarone 400 mg BID for the prevention of cardiovascular hospitalization or death from any cause in patients with atrial fibrillation/atrial flutter". Circulation. 120 (13): 1174–1180. doi: 10.1161/CIRCULATIONAHA.109.875252 . PMID   19752319.
  16. ↑ Singh BN, Connolly SJ, Crijns HJ, Roy D, Kowey PR, Capucci A, et al. (September 2007). "Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter". The New England Journal of Medicine. 357 (10): 987–999. doi:10.1056/NEJMoa054686. hdl: 11566/54713 . PMID   17804843.
  17. 1 2 Hohnloser SH, Crijns HJ, van Eickels M, Gaudin C, Page RL, Torp-Pedersen C, et al. (February 2009). "Effect of dronedarone on cardiovascular events in atrial fibrillation". The New England Journal of Medicine. 360 (7): 668–678. doi: 10.1056/NEJMoa0803778 . PMID   19213680.
  18. ↑ Connolly SJ, Camm AJ, Halperin JL, Joyner C, Alings M, Amerena J, et al. (December 2011). "Dronedarone in high-risk permanent atrial fibrillation". The New England Journal of Medicine. 365 (24): 2268–2276. doi:10.1056/NEJMoa1109867. PMC   3860949 . PMID   22082198.
  19. ↑ Clinical trial number NCT01026090 for "A Phase IV, Double-blind, Placebo-controlled, Canadian Multicentre Study Comparing Two Treatment Strategies of Dronedarone Administration Following ELECTive caRdioversion for Prevention of Symptomatic Atrial Fibrillation (AF) Recurrence" at ClinicalTrials.gov
  20. ↑ "FDA briefing document on dronedarone" (PDF). Food and Drug Administration . Archived from the original (PDF) on March 3, 2017. Retrieved December 16, 2019.
  21. ↑ "Multaq® (Dronedarone) for Atrial Fibrillation Now Approved in Canada - insciences". Archived from the original on July 18, 2011. Retrieved August 13, 2009.
  22. ↑ "Summary of Positive Opinion for Multaq" (PDF). European Medicines Agency. September 24, 2009. Retrieved December 1, 2009.
  23. ↑ US20220267288A1,Chan, Chun Yong Eric; Karkhanis, Aneesh Vidyadhar& Venkatesan, Gopalakrishnan,"Poyendarone, a cardiac therapeutic",issued 2022-08-25
  24. ↑ Karkhanis AV, Venkatesan G, Kambayashi R, Leow JW, Han MQ, Izumi-Nakaseko H, et al. (October 2022). "Site-directed deuteration of dronedarone preserves cytochrome P4502J2 activity and mitigates its cardiac adverse effects in canine arrhythmic hearts". Acta Pharmaceutica Sinica. B. 12 (10): 3905–3923. doi:10.1016/j.apsb.2022.03.008. PMC   9532722 . PMID   36213535.
  25. ↑ "New drug molecule for treatment of atrial fibrillation". Medicalxpress. July 18, 2022.
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