Products
Dronedarone is commercially available in the form of film-coated tablets (Multaq). It was approved in 2009, first in the United States, then in Canada, in many countries, and in November throughout the European Union.
Structure and properties
Dronedarone (C31H44N2O5S, Mr = 556.76 g/mol) is a benzofuran derivative and an analog of the antiarrhythmic drug amiodarone (Cordarone, generics), itself derived from the coumarin khellin. Dronedarone was developed as a successor to amiodarone, which is well efficacious but can cause numerous adverse effects affecting the skin, lungs, thyroid (hyperthyroidism), eyes, liver, and nervous system, among others. Amiodarone is lipophilic, has a high volume of distribution, and is deposited in tissues, resulting in a very long half-life of 20 to 100 days. Dronedarone is less lipophilic due to the methylsulfonamide group, distributes more poorly, and has a much shorter half-life of approximately 25-30 hours. It does not contain iodine in the molecule, which is thought to be responsible for thyroid dysfunction.
Effects
Dronedarone (ATC C01BD07) is antiarrhythmic. It decreases the recurrence of atrial fibrillation or flutter, normalizes and maintains sinus rhythm, reduces and stabilizes heart rate, and results in a reduction in the rate of hospitalization for cardiovascular events. Its efficacy and superiority to placebo has been demonstrated in large clinical trials. Like amiodarone, it cannot be classified according to the classic Vaugham-Williams classification for antiarrhythmic drugs because it has properties from all four classes. It is a multichannel blocker and attacks different ion channels, with effects on potassium, sodium, and calcium current. It prolongs the action potential and is antiadrenergic.
Indications
As a 2nd-line agent to preserve sinus rhythm after successful cardioversion in clinically stable patients with nonpermanent atrial fibrillation and to induce a reduction in the rate of hospitalization for cardiovascular events in this patient population. Atrial fibrillation is the most common cardiac arrhythmia and affects up to 1% of the population. It occurs when the atria of the heart contract irregularly and rapidly and can lead to acute symptoms and severe complications such as heart failure, stroke and death. In 2011 and 2012, respectively, the indication was restricted based on new study results. One study investigated its use in patients with permanent atrial fibrillation and additional risk factors. It had to be stopped due to severe cardiovascular events in the dronedarone group. Since then, dronedarone has not been allowed to be used in permanent AF.
Dosage
The usual adult dosage is 400 mg each with breakfast and with dinner. Taking with food is recommended because it may increase bioavailability. Grapefruit juice should not be consumed during treatment because grapefruit juice inhibits CYP3A4, which may increase concentrations of dronedarone and increase adverse effects.
Contraindications
Refer to the SmPC for complete precautions. Concomitant use of strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, voriconazole, telithromycin, clarithromycin, ciclosporin, ritonavir) and drugs that can cause torsades de pointes, such as phenothiazines, cisapride, bepridil, tricyclic antidepressants, terfenadine, some macrolides, and some Class I and Class III antiarrhythmics, is not indicated.
Interactions
Dronedarone is well absorbed but has high first-pass metabolism and therefore only a profound bioavailability of about 15%. It is metabolized by CYP3A4 and eliminated via feces. It is itself a moderate inhibitor of CYP3A4, a weak inhibitor of CYP2D6, and a strong inhibitor of P-glycoprotein and consequently has a high interaction potential. The corresponding drug-drug interactions must be taken into account. It must not be taken concomitantly with strong inhibitors of CYP3A4 because this may increase plasma concentrations and potentiate effects and adverse reactions. CYP inducers may reduce efficacy.Drugs that cause Torsades de Pointes are contraindicated because of the risk of cardiac arrhythmia. Full details of interactions can be found in the Drug Information Leaflet.
Adverse Effects
The most commonly observed adverse effects include slow pulse (bradycardia), taste disturbances, diarrhea, vomiting, nausea, lower abdominal pain, indigestion, rash, pruritus, fatigue, and weakness. Erythema, eczema, and, possibly due to the coumarin or sulfonamide structure, photodermatosis occur occasionally. Rarely, taste perception may be completely absent. It may increase plasma creatinine levels. Dronedarone may prolong the QT interval. However, it appears to be only weakly proarrhythmic, does not increase mortality, and did not cause torsades de pointes in the studies performed. This is a significant point, as some antiarrhythmic drugs have been shown in the past to increase mortality rather than decrease it. However, in the Andromeda study, it was shown that when administered to patients with severe heart failure, mortality is increased (contraindication). In addition, there is a risk that dronedarone may cause cardiac arrhythmias if used inappropriately. Therefore, attention to contraindications, precautions, and drug-drug interactions is essential. On January 21, 2011, the EMA drew attention to the fact that very rare cases of liver injury had occurred in patients treated with dronedarone. A connection with the treatment could not be ruled out. Therefore, it was ordered that liver function tests be performed as a precautionary measure with immediate effect.