Dronedarone

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Dronedarone
Clinical data
Trade namesMultaq
Other namesSR33589
AHFS/Drugs.comMonograph
MedlinePlusa609034
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
Bioavailability15% (with a high-fat meal)[2]
Protein binding>98%
MetabolismLiver (mainly by CYP3A)
Elimination half-life13–19 hours
ExcretionFeces (84%), urine (~6%)
Identifiers
  • N-(2-Butyl-3-(p-(3-(dibutylamino)propoxy)benzoyl)-5-benzofuranyl)methanesulfonamide
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 checkY
  • Key:ZQTNQVWKHCQYLQ-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Dronedarone, sold under the brand name Multaq, is a class III antiarrhythmic

class III antiarrhythmic drug.[3] 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.[4] 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.[5]

The FDA label for dronedarone includes a

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.[6]

It is approved as a

generic medication.[7]

Mechanism of action

Dronedarone has been termed a "multichannel blocker".[

pacemaker potential of the SA node and return patients to a normal heart rhythm.[9] 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).[10]

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.[4]

Dronedarone displays amiodarone-like

class III antiarrhythmic activity in vitro[11] and in clinical trials.[5] The drug also appears to exhibit activity in each of the 4 Vaughan-Williams antiarrhythmic classes.[12]

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

Contraindications

  • Permanent AF (patients in whom normal sinus rhythm will not or cannot be restored)[2]
  • Recently decompensated heart failure requiring hospitalization or Class IV heart failure.[2]
  • Second-or third-degree AV block or sick sinus syndrome (except when used in conjunction with a functioning pacemaker)[2]
  • Bradycardia[2]
  • Concomitant use of a strong CYP3A inhibitor[2]
  • Concomitant use of drugs or herbal products that prolong the QT interval and may induce Torsade de Pointes[2]
  • Liver or lung toxicity related to the previous use of amiodarone[2]
  • Severe hepatic impairment[2]
  • QTc Bazett interval ≥500 ms,[2] or 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).[citation needed]
  • Pregnancy and nursing mothers[2]
  • Hypersensitivity to dronedarone[2]
  • Hepatic impairment. In January 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.[6]
  • PR interval exceeding 280 ms [citation needed]
  • Use of cytochrome P-450 (CYP) 3a isoenzyme inhibitors (includes: clarithromycin, cyclosporine, itraconazole, ketoconazole, nefazodone, ritonavir, telithromycin, voriconazole)

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.

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.[14]

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.[15]

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.[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.[16] 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.[14]

Patients

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".[17] 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.[16] The results of a recently concluded randomized study (ELECTRA) may clarify the safety and ideal modalities of dronedarone use at the time of cardioversion.[18]

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).[19] 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."[20]

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.[21]

Research

In July 2019, a new drug called

ventricular arrhythmia.[23][24]

References

  1. FDA
    . Retrieved October 22, 2023.
  2. ^ a b c d e f g h i j k l m n o "Multaq- dronedarone tablet, film coated". DailyMed. October 15, 2020. Retrieved November 18, 2020.
  3. ^ "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.
  4. ^
    PMID 19403901
    .
  5. ^
    PMID 18565860
    .
  6. ^ a b "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.
  7. ^ "First-Time Generic Drug Approvals 2024". U.S. Food and Drug Administration (FDA). March 8, 2024. Retrieved March 9, 2024.
  8. ^
    PMID 11117382
    .
  9. ^
    PMID 10604978
    .
  10. PMID 17804843
    .
  11. PMID 10578003
    .
  12. ^ "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".
  13. S2CID 22339555
    .
  14. ^
    PMID 19752319
    .
  15. PMID 17804843
    .
  16. ^
    PMID 19213680
    .
  17. PMID 22082198
    .
  18. ^ 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
  19. ^ "FDA briefing document on dronedarone" (PDF). Food and Drug Administration. Archived from the original (PDF) on March 3, 2017. Retrieved December 16, 2019.
  20. ^ "Multaq® (Dronedarone) for Atrial Fibrillation Now Approved in Canada - insciences". Archived from the original on July 18, 2011. Retrieved August 13, 2009.
  21. ^ "Summary of Positive Opinion for Multaq" (PDF). European Medicines Agency. September 24, 2009. Retrieved December 1, 2009.
  22. ^ US20220267288A1, Chan, Chun Yong Eric; Karkhanis, Aneesh Vidyadhar & Venkatesan, Gopalakrishnan, "Poyendarone, a cardiac therapeutic", issued 2022-08-25 
  23. PMID 36213535
    .
  24. ^ "New drug molecule for treatment of atrial fibrillation". Medicalxpress. July 18, 2022.
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