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Dronedarone

Classification: A

Drug products: MULTAQ

ATC code: C01BD07

Substances: dronedarone, dronedarone hydrochloride

Summary

The effect of dronedaron in atrial fibrillation is similar in men and women.

There are data implying that the same dose results in a higher plasma concentration in women. Since there is only one dose used, it has been discussed whether women risk a higher amount of dose dependent side effects. An association between female sex and adverse events has been reported. At present, this is unclear.

Additional information

Pharmacokinetics and dosing

It is reported that women compared to men have 30-90% higher plasma concentration of dronedarone and the metabolite N-debutyl [1]. In a double-blind, randomized and placebo-controlled study, it was found that dronedarone pharmacokinetics were affected by age. After 800 mg dronedarone, elderly men had an approximately 30% higher exposure than young men. Elderly women had 23% higher dronedarone exposure and 40% lower apparent clearance (CL/F) than elderly men. The apparent clearance of elderly men was approximately 20% lower than that of young men. Potentially, elderly women may have dronedarone exposure that is about 50% of that of young men[k1] . No young women were included in the study [2].

The observed sex differences in dronedarone pharmacokinetics do not appear to warrant dosing adjustments, as the difference in exposure is relatively small (~25%) and becomes statistically insignificant when correcting for body weight [2].

In the large placebo-controlled clinical trial of dronedarone ATHENA [3], no dosage alterations were made and the benefit of dronedarone over placebo was not significantly related to age or patient’s sex.

Effects

The large ATHENA clinical trial (2459 men, 2169 women) evaluated the use of dronedarone 400 mg twice a day in patients with atrial fibrillation. The effect of dronedarone on the primary outcome (first hospitalization due to cardiovascular events or death) was similar in men and women [3].

Adverse effects

Side effects reported in eight randomized clinical trials (DAFNE, EURIDIS, ADONIS, ERATO, ANDROMEDA, ATHENA, DIONYSOS, PALLAS; totally 6487 men and 4118 women) were discussed in a review. Acute hepatic failure was reported in two participants, both women. Hepatocellular injury with an onset within 30 days of dronedarone initiation was reported in 17 women and 13 men [4-11].

Evaluation of patient specific factors on the frequency of adverse events showed an association between female sex and all adverse events and also for serious adverse events [1].

Reproductive health issues

Regarding teratogenic aspects, please consult the Drugs and Birth Defects Database (in Swedish, Janusmed fosterpåverkan).

Updated: 2019-05-27

Date of litterature search: 2019-02-27

References

  1. Multaq (dronedaron). European Medicines Agency (EMA) [www]. [updated 2017-02-01, cited 2019-02-27]. länk
  2. Food and Drug Administration (FDA). Clinical Pharmacology and Biopharmaceutics Review - dronedarone hydrochloride.
  3. Hohnloser SH, Crijns HJ, van Eickels M, Gaudin C, Page RL, Torp-Pedersen C et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med. 2009;360:668-78. PubMed
  4. De Ferrari GM, Dusi V. Drug safety evaluation of dronedarone in atrial fibrillation. Expert Opin Drug Saf. 2012;11:1023-45. PubMed
  5. Touboul P, Brugada J, Capucci A, Crijns HJ, Edvardsson N, Hohnloser SH. Dronedarone for prevention of atrial fibrillation: a dose-ranging study. Eur Heart J. 2003;24:1481-7. PubMed
  6. Singh BN, Connolly SJ, Crijns HJ, Roy D, Kowey PR, Capucci A et al. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med. 2007;357:987-99. PubMed
  7. Davy JM, Herold M, Hoglund C, Timmermans A, Alings A, Radzik D 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. Am Heart J. 2008;156:527e1-9. PubMed
  8. Køber L, Torp-Pedersen C, McMurray JJ, Gøtzsche O, Lévy S, Crijns H et al. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med. 2008;358:2678-87. PubMed
  9. Hohnloser SH, Connolly SJ, Crijns HJ, Page RL, Seiz W, Torp-Petersen C. Rationale and design of 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. J Cardiovasc Electrophysiol. 2008;19:69-73. PubMed
  10. Le Heuzey JY, De Ferrari GM, Radzik D, Santini M, Zhu J, Davy JM. A short-term, randomized, double-blind, parallel-group study to evaluate the efficacy and safety of dronedarone versus amiodarone in patients with persistent atrial fibrillation: the DIONYSOS study. J Cardiovasc Electrophysiol. 2010;21:597-605. PubMed
  11. Connolly SJ, Camm AJ, Halperin JL, Joyner C, Alings M, Amerena J et al. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med. 2011;365:2268-76. PubMed
  12. Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2018 [cited 2019-03-08.] länk

Authors: Linnéa Karlsson Lind

Reviewed by: Mia von Euler

Approved by: Karin Schenck-Gustafsson