Dronedaron

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Structural formula
Structural formula of dronedarone
General
Non-proprietary name Dronedaron
other names
  • N - (2-Butyl-3- {4- [3- (dibutylamino) propoxy] -benzoyl} -1-benzofuran-5-yl) methanesulfonamide ( IUPAC )
  • SR 33589
Molecular formula C 31 H 44 N 2 O 5 S
External identifiers / databases
CAS number
EC number 604-240-2
ECHA InfoCard 100.109.411
PubChem 208898
ChemSpider 180996
DrugBank DB04855
Wikidata Q408637
Drug information
ATC code

C01 BD

Drug class

Class III antiarrhythmics

Mechanism of action
  • Blockage of sodium, potassium and calcium channels
  • has an anti-adrenergic effect
properties
Molar mass 556.76 g · mol -1
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
09 - Dangerous for the environment

Caution

H and P phrases H: 410
P: ?
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Dronedarone (trade name Multaq ) is the generic name of a drug , which as antiarrhythmic agent for the treatment of cardiac arrhythmias is used. The drug is produced and marketed by Sanofi as 400 mg tablets . The recommended dosage is 400 mg twice a day.

chemistry

As a benzofuran derivative, dronedarone is similar in chemical structure and effect to amiodarone . Amiodarone is the most widely used drug for restoring and maintaining sinus rhythm in cardiac arrhythmias, but it has significant systemic side effects. Dronedarone is a further development of amiodarone and was developed to reduce these side effects. In contrast to amiodarone, dronedarone has no iodine components and is less lipophilic. 70–94% of it is absorbed after oral ingestion, which can be increased by administration with food.

pharmacology

Mechanism of action and indications

In the conduction system of the heart, the drug blocks the sodium, potassium and calcium channels ( "multi channel blocker") and acts antiadrenerg. It has been approved by the American FDA for the treatment of patients with paroxysmal or persistent atrial fibrillation who are in sinus rhythm or who are cardioverted after an episode of atrial fibrillation or flutter with associated other cardiovascular risk factors such as old age, high blood pressure, diabetes, etc. According to the EMEA approval, dronedarone is "indicated in adult, clinically stable patients with non-permanent atrial fibrillation (AF) (current or history) to prevent recurrence of atrial fibrillation or to lower the ventricular heart rate". In a Rote Hand Brief from September 2011, the indication was reduced to “adult, clinically stable patients with paroxysmal or persistent atrial fibrillation (AF) to maintain sinus rhythm after successful cardioversion”.

Metabolism

Dronedarone is metabolized in the liver via the cytochrome P450 3A (CYP3A) pathway and is a moderate inhibitor of CYP3A and CYP2D6. It has no significant effects against the other cytochrome components CYP1A2, CYP2C9 , CYP2C19, CYP2C8 and CYP2B6. The elimination half-life in the body is 13–19 hours.

Drug interactions

Dronedarone has potentially important pharmadynamic interactions with other antiarrhythmics, digoxin, calcium channel blockers, beta blockers , CYP3A inducing drugs, grapefruit juice, statins , CYP3A substrates with a narrow therapeutic index (e.g. sirolimus, tacrolimus).

Side effects

Since dronedarone no iodine containing component, typical of amiodarone and associated with iodine side effects (are over- and sub-functions of the thyroid gland ) can not be expected. In the approval studies, adverse drug reactions did not occur more frequently than with placebo. The medication insert indicates the following side effects: decreased heartbeat ( bradycardia ), stomach problems (diarrhea, nausea , vomiting , abdominal pain, digestive problems), tiredness and weakness, skin irritation (redness, rash, itching). In January 2011, the US Food and Drug Administration issued a warning regarding the occurrence of severe liver damage with dronedarone treatment. This side effect rarely occurs, but can lead to life-threatening liver damage. The FDA therefore recommends regular monitoring of liver values , especially in the first six months of therapy.

Admission

history

Dronedarone was approved by the Food and Drug Administration (FDA) in July 2009 based on the results of the ATHENA study following an accelerated approval process ; This was followed by approval in Canada, Switzerland and in November 2009 in the countries of the EU.

Studies

Dronedarone was examined in an extensive clinical study program, the results of which have mostly been published, for its effect on rhythm control, but also on frequency control.

DAFNE

The clinical phase II study ("Dronedarone Atrial Fibrillation study after Electrical Cardioversion", DAFNE) was carried out to determine the optimal dose of dronedarone. Patients (n = 199) with persistent atrial fibrillation were treated with 800, 1200, or 1600 mg dronedarone or placebo after cardioversion and were observed for the following 6 months. The time to recurrence of atrial fibrillation was significantly longer in the dronedarone-treated group (60 days) than in the placebo group (5.3 days). An increased dose of dronedarone showed no significant differences. After 6 months, 10% of the placebo-treated patients and 35% of the dronedarone-treated patients were still in sinus rhythm. No proarrhythmic effects were observed.

EURIDIS and ADONIS

In two studies ("European Trial in Atrial Fibrillation or Flutter Patients Receiving Dronedarone for the Maintenance of Sinus Rhythm", EURIDIS and "American-Australian Trial with Dronedarone in Atrial Fibrillation or Flutter Patients for the Maintenance of Sinus Rhythm", ADONIS) with a total of 1237 study participants, a beneficial effect could be demonstrated in patients with atrial fibrillation or cardiac arrhythmias (n = 828) when administered twice 400 mg dronedarone per day. Both studies started in November 2001, EURIDIS ended in August and ADONIS in September 2003. The patients were observed over a period of 12 months. Patients in both study arms were also treated with various standard medication for atrial fibrillation. When compared with placebo (n = 409), dronedarone treatment had fewer episodes of atrial fibrillation and the pulse rate was lower during the episodes . Furthermore, the recurrence of cardiac arrhythmias in dronedarone-treated patients was delayed by 25%. The incidence of pulmonary toxic side effects as well as thyroid or liver dysfunction was not significantly increased under dronedarone. Both studies were published together.

ANDROMEDA

In the ANDROMEDA study, around 1000 patients at high risk of premature cardiac death were to be investigated whether dronedarone had a positive effect in heart failure patients (atrial fibrillation did not have to be present in these patients). The study started in June 2002, but was terminated prematurely after the inclusion of 627 patients in August 2003, as the therapy led to increased mortality in severely heart failure patients. Most deaths were due to worsening heart failure rather than arrhythmia. In order to rule out this risk, the FDA approved, among other things, the treatment of heart failure patients of the New York Heart Association (NYHA) Class IV.

ERATO

The study “European Study of Dronedarone in Atrial Fibrillation” (ERATO) began in August 2002 and ended in June 2004. A total of 174 patients with permanent atrial fibrillation were additionally treated with either Dronedarone (400 mg twice daily) (n = 85) or with Placebo (n = 89) treated over a period of six months. The study showed that dronedarone reduced the average heart rate by 11.7 beats per minute compared to the placebo-treated group. It was thus shown that, in addition to its antiarrhythmic effects, dronedarone also leads to the desired reduction in heart rate in patients with permanent atrial fibrillation. Dronedarone was well tolerated as the frequency of the various side effects did not differ from that in the placebo group.

DIONYSOS

The study on "Efficacy & Safety of Dronedarone Versus Amiodarone for the Maintenance of Sinus Rhythm in Patients With Atrial Fibrillation" (DIONYSOS) was the first direct comparative study between dronedarone and amiodarone. It started in June 2007 and ended in October 2008. In this study, 505 patients were treated with either dronedarone (400 mg BID) or amiodarone (600 mg daily for 28 days, then 200 mg daily) and compared the maintenance of sinus rhythm in patients with persistent atrial fibrillation> 72 hours after primary successful cardioversion . Preliminary results show that in the dronedarone-treated arm, recurrent atrial fibrillation occurred in 36.5% of patients compared to 24.3% in the amiodarone-treated group. Although amiodarone was more effective in this regard, dronedarone was significantly less toxic and produced fewer side effects.

ATHENA

The “Prevention of Cardiovascular Hospitalization or Death From Any Cause in Patients with Atrial Fibrillation / Atrial Flutter” (ATHENA) study was carried out from June 2005 to January 2008. It was investigated in 4628 elderly patients (dronedarone arm n = 2301, placebo arm n = 2327) whether dronedarone had a positive influence on the mortality and morbidity of high-risk patients with atrial fibrillation. The patients had at least one risk factor such as diabetes mellitus , high blood pressure , or decreased cardiac output. The placebo-controlled international study found that during the investigation period of an average of 21 months, the primary endpoint “death or hospitalization due to cardiovascular events” occurred less frequently with dronedarone (31.9%) than with placebo (39.4%). Arrhythmia-related deaths were also less common with dronedarone. In ATHENA, both study arms were also treated with various standard drugs against atrial fibrillation. Furthermore, the ATHENA study showed in analyzes that were not planned in advance (post-hoc) that the risk of a stroke in the study arm treated with dronedarone was 1.2% per year, lower than the risk in the control arm (1.8% per year) % per year).

PALLAS

The manufacturer and the European Medicines Agency (EMA) announced in July 2011 that the PALLAS study had been discontinued due to serious cardiovascular events in patients who had taken dronedarone. The aim of the study was to examine the influence of dronedarone as an add-on to standard therapy on the rate of cardiovascular events or deaths in patients over 65 years of age with permanent atrial fibrillation versus placebo. The Committee for Medicinal Products for Human Use (CHMP) at the EMA wants to decide in July 2011 on the need for further measures. In December 2011, the US health authority (FDA) published a corresponding safety announcement (“increased risk of death and serious cardiovascular side effects”).

Individual evidence

  1. ↑ a b c Accelerated approval for dronedarone . In: Pharmaceutical newspaper . No. 34 , 2008, p. 26 ( online ).
  2. ↑ Template: CL Inventory / not harmonized There is not yet a harmonized classification for this substance . A labeling of N- (2-butyl-3- {p- [3- (dibutylamino) propoxy] benzoyl} -5-benzofuranyl) methane sulfonamide Template: Linktext-Check / Escaped in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA ) is shown, which is derived from a self-classification by the distributor ), accessed March 2, 2016.
  3. ↑ Wolfram Domschke: Therapy Manual for Internal Medicine . Elsevier, Urban & Fischer Verlag, 2011, ISBN 978-3-437-22702-8 , pp. 58 ( limited preview in Google Book search).
  4. ^ Richard L. Page, Bashar Hamad, Peter Kirkpatrick: Dronedarone . In: Nature Reviews Drug Discovery . tape 8 , no. 10 , 2009, p. 769-770 , doi : 10.1038 / nrd2998 .
  5. ^ A. Manning et al .: SR 33589, a new amiodarone-like antiarrhythmic agent: electrophysiological effects in anesthetized dogs . In: J Cardiovasc Pharmacol . 25, pp. 252-261, 1995, PMID 8583788 .
  6. ^ O. Finance et al .: Effects of a new amiodarone-like agent, SR 33589, in comparison to amiodarone, D, L-sotalol, and lignocaine, on ischemia-induced ventricular arrhythmias in anesthetized pigs . In: J Cardiovasc Pharmacol . 26, pp. 570-576, 1995, PMID 8569217 .
  7. ↑ a b c d e US Prescribing Information Multaq ( Memento of April 27, 2011 in the Internet Archive ) (PDF; 271 kB).
  8. ↑ JC Laughlin, PR Kowey: Dronedarone: a new treatment for atrial fibrillation . In: J. Cardiovasc. Electrophysiol. . 19, No. 11, November 2008, pp. 1220-6. doi : 10.1111 / j.1540-8167.2008.01251.x . PMID 18702618 .
  9. ↑ Information about a restriction on the use of Multaq (dronedarone) (PDF) Sanofi-Aventis
  10. ↑ Drug Safety Notice. FDA January 14, 2010; Retrieved January 18, 2010.
  11. ↑ FDA Approves Multaq to Treat Heart Rhythm Disorder . FDA July 2, 2009.
  12. ↑ Brigitte M. Gensthaler, Kerstin A. Graefe, Sven Siebenand: New on the market: Dronedaron, Indacaterol and Prucaloprid . In: Pharmaceutical newspaper . No. 5 , 2010 ( online ).
  13. ↑ Sanofi receives Multaq approval . pharmacy ad-hoc, November 30, 2009.
  14. ↑ Paul Touboul, Josep Brugada, Alessandro Capucci, Harry JGM Crijns, Nils Edvardsson, Stefan H. Hohnloser: Dronedarone for prevention of atrial fibrillation: A dose-ranging study . In: European Heart Journal . tape 24 , no. 16 , 2003, p. 1481–1487 , doi : 10.1016 / S0195-668X (03) 00321-X (free full text).
  15. ↑ Bramah N. Singh, Stuart J. Connolly, Harry JGM Crijns, Denis Roy, Peter R. Kowey, Alessandro Capucci, David Radzik, Etienne M. Aliot, Stefan H. Hohnloser: Dronedarone for Maintenance of Sinus Rhythm in Atrial Fibrillation or Flutter . In: New England Journal of Medicine . tape 357 , no. 10 , 2007, p. 987-999 , doi : 10.1056 / NEJMoa054686 , PMID 17804843 (free full text).
  16. ↑ Lars Kober, Christian Torp-Pedersen, John JV McMurray, Ole Gøtzsche, Samuel Levy, Harry Crijns, Jan Amélie, Jan Carlsen: Increased Mortality after Dronedarone Therapy for Severe Heart Failure . In: New England Journal of Medicine . tape 358 , no. 25 , 2008, p. 2678–2687 , doi : 10.1056 / NEJMoa0800456 , PMID 18565860 (free full text).
  17. ↑ JM Davy et al .: Dronedarone for the control of ventricular rate in permanent atrial fibrillation: the Efficacy and safety of dRonedArone for the control of ventricular rate during atrial fibrillation (ERATO) study . In: Am Heart J . , 2008 Sep, 156 (3), PMID 18760136 .
  18. ↑ a b DIONYSOS Study Results Showed the Respective Profiles of Dronedarone and Amiodarone . ( Memento of March 4, 2014 in the Internet Archive ) (PDF).
  19. ↑ Stefan H. Hohnloser, Harry JGM Crijns, Martin van Eickels, Christophe Gaudin, Richard L. Page, Christian Torp-Pedersen, Stuart J. Connolly: Effect of Dronedarone on Cardiovascular Events in Atrial Fibrillation . In: New England Journal of Medicine . tape 360 , no. 7 , 2009, p. 668-678 , doi : 10.1056 / NEJMoa0803778 , PMID 19213680 (free full text).
  20. ↑ Stuart J. Connolly, Harry JGM Crijns, Christian Torp-Pedersen, Martin van Eickels, Christophe Gaudin, Richard L. Page, Stefan H. Hohnloser: 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 . In: Circulation . tape 120 , no. 13 , 2009, p. 1174–1180 , doi : 10.1161 / CIRCULATIONAHA.109.875252 , PMID 19752319 (free full text).
  21. ↑ PALLAS study on Multaq® (dronedarone) discontinued in patients with permanent atrial fibrillation ; Drugs Commission of the German Medical Association (AkdÄ) of July 18, 2011.
  22. ↑ Review update of Multaq (dronedarone) and increased risk of death and serious cardiovascular adverse events . FDA Drug Safety Communication dated December 19, 2011.