Description of Dronedarone
Dronedarone is an antiarrhythmic agent developed to have similar efficacy to amiodarone with an improved safety and tolerability profile. However, dronedarone carries a boxed warning contraindicating its use in patients with NYHA Class IV heart failure, patients with symptomatic heart failure with recent decompensation, and in patients in atrial fibrillation who cannot be cardioverted into normal sinus rhythm; dronedarone use doubles mortality risk and/or serious adverse events in these populations. In an unpublished trial comparing dronedarone to amiodarone, amiodarone had greater control of cardiac rhythm than dronedarone. Data from this trial also indicate that dronedarone therapy results in a greater incidence of diarrhea while amiodarone therapy results in a higher incidence of thyroid dysfunction, significant bradycardia, and more pronounced QTc interval prolongation. Unlike other dronedarone trials , the ANDROMEDA trial enrolled high-risk patients with symptomatic heart failure and severe left ventricular systolic dysfunction. Interim safety analysis revealed an excess risk of death in the dronedarone group compared to placebo. The increased mortality was predominately due to worsening heart failure. Because of structural modifications made to dronedarone (removal of iodine moiety and addition of methane-sulfonamyl group), dronedarone has decreased lipophilicity, resulting in a shorter half-life (13—19 hours compared to 58 days for amiodarone), and lower tissue accumulation compared to amiodarone. These characteristics of the dronedarone molecule are postulated to account for the improved safety profile seen with dronedarone; however, trials lasting longer than 12 months have not been conducted. Dronedarone is indicated to reduce the risk of hospitalization for atrial fibrillation in patients in sinus rhythm with a history of paroxysmal or persistent atrial fibrillation. It should not be used in patients with permanent atrial fibrillation as this use is associated with an increased risk of death, stroke, and heart failure. Dronedarone (Multaq) was approved by the FDA in July 2009.
Mechanism of Action of Dronedarone
Dronedarone is a benzofuran derivative of amiodarone. The exact mechanism of action of dronedarone is unknown. Similar to amiodarone, dronedarone has a complex electrophysical profile and possesses antiarrhythmic properties belonging to all four Vaughan-Williams classes. Like Class III antiarrhythmics, dronedarone lengthens cardiac action potential and refractory periods by inhibiting the potassium currents IKr, IKl, IKACh, and Isus. Dronedarone also inhibits sodium channels, thereby decreasing the slope of the depolarization phase of the action potential, a Class Ib property, and also inhibits the slow L-type calcium channels, a class IV property. Furthermore, dronedarone also possesses antiadrenergic properties, which is a Class II property. In healthy subjects, dronedarone was found to significantly prolong the RR and QT interval in a dose-dependent manner.
Structural modifications made to the dronedarone molecule include the removal of the iodine moiety and the addition of a methane-sulfonamyl group. These modifications result in a molecule with decreased lipophilicity, resulting in a shorter half-life, and lower tissue accumulation. Specifically, removal of the iodine moiety allows for a reduced risk of thyroid function abnormalities known to occur with amiodarone therapy. Animal studies indicate dronedarone does not affect circulating plasma thyroid hormones.
Pharmacokinetics
Dronedarone is administered orally. Dronedarone and its metabolite are highly bound to plasma proteins (> 98%), mainly albumin. This protein binding is not saturable. Dronedarone is extensively metabolized, mainly involving the CYP3A isoenzyme. The main active metabolite is 1/10—1/3 as potent as dronedarone. Approximately 30 other uncharacterized metabolites also exist. About 6% of radiolabeled dronedarone is excreted in urine and 84% is excreted in feces, mainly as metabolites. The elimination half-life is 13—19 hours.
Dronedarone possesses electrophysiological properties of all four Vaughan-Williams classes. It was evaluated in healthy volunteers receiving repeated oral doses of up to 1600 mg once daily or 800 mg twice daily for 14 days and 1600 mg twice daily for 10 days. A dose-dependent increase in the PR interval of 5 milliseconds occurred in the 400 mg twice daily group and an increase of up to 50 milliseconds occurred in the 1600 mg twice daily group. A similar dose-related effect occurred in the QT interval with an increase of 10 milliseconds in the 400 mg twice daily group and an increase of up to 25 milliseconds in the 1600 mg twice daily group.
Affected cytochrome P450 isoenzymes and drug transporter: CYP3A, CYP2D6, P-gp
Dronedarone is a moderate inhibitor of CYP3A and CYP2D6 and an inhibitor of P-glycoprotein (P-gp) transport. It is also a substrate of CYP3A.
Route-Specific Pharmacokinetics
Oral Route
Due to first pass metabolism, the bioavailability of dronedarone is approximately 4%. When administered with a high fat meal, the bioavailability increases to 15%. The peak plasma concentration of dronedarone and its main active metabolite, N-debutyl metabolite, are reached within 3—6 hours. The steady state concentration is reached within 4—8 days of repeated oral administration of 400 mg twice daily. A 2-fold increase in dose results in an approximate 2.5- to 3-fold increase in Cmax and AUC. Similar pharmacokinetic properties are seen with the main active metabolite.
Special Populations
Hepatic Impairment
For patients with moderate hepatic impairment, the mean dronedarone exposure increased by 1.3 fold and the exposure of the active metabolite decreased by 50% compared to healthy subjects. Dronedarone was not studied in patients with severe hepatic impairment.
Renal Impairment
No differences in pharmacokinetic parameters were seen in patients with mild to severe renal impairment compared to those with normal renal function.
Geriatric
Patients >= 65 years of age have a dronedarone exposure approximately 23% higher than those < 65 years of age.
Gender Differences
The exposure of dronedarone is approximately 30% higher in females compared to males.
Generic Name
Dronedarone Hydrochloride
Brand Names
Multaq
Therapeutic Class
Antiarrhythmic
Benzofuran
FDA-Label Indications
Atrial fibrillation, In sinus rhythm with history of paroxysmal or persistent atrial fibrillation: Adult
Common Effects
Gastrointestinal: Abdominal pain (4% ), Diarrhea (9% ), Indigestion (2% ), Nausea (5% ), Vomiting (2% )
Neurologic: Asthenia (7% )
Renal: Serum creatinine raised (51% )
Serious Effects
Cardiovascular: Heart failure, Prolonged QT interval (28% )
Hepatic: Hepatotoxicity, Liver failure
Renal: Acute renal failure, Renal failure
Respiratory: Interstitial lung disease
Administration
NIOSH Group 3 Non-antineoplastics With Reproductive Risks
NIOSH: This drug presents a potential occupational hazard to men and women actively trying to conceive and women who are pregnant or may become pregnant, and are breast feeding, due to presence of the drug in breast milk .
NIOSH: Use of single gloves by anyone handling intact tablets or capsules or administering from a unit-dose package is recommended .
NIOSH: In the preparation of tablets or capsules, including cutting, crushing, or manipulating, or the handling of uncoated tablets, use double gloves and a protective gown. Prepare in a ventilated control device, if possible. Use respiratory protection if not prepared in a control device. During administration, wear single gloves, and wear eye/face protection if the formulation is hard to swallow or if the patient may resist, vomit, or spit up .
Oral: Take with morning and evening meals .
How Supplied – Trade
Multaq: Oral Tablet: 400 MG
Adult Dose
Important Note: Strong CYP3A4 inhibitors (eg, ketoconazole) and Class I or III antiarrhythmics (eg, amiodarone, flecainide, propafenone, quinidine, disopyramide, dofetilide, sotalol) must be discontinued prior to initiating dronedarone hydrochloride .
Important Note: Beers Criteria: Use dronedarone with caution in older adults with heart failure who are asymptomatic. Avoid use in older adults with permanent atrial fibrillation or heart failure that is symptomatic, severe, or recently decompensated, as dronedarone may worsen outcomes .
Atrial fibrillation, In sinus rhythm with history of paroxysmal or persistent atrial fibrillation: 400 mg orally twice daily with morning and evening meals
Pediatric Dose
Important Note: Strong CYP3A4 inhibitors (eg, ketoconazole) and Class I or III antiarrhythmics (eg, amiodarone, flecainide, propafenone, quinidine, disopyramide, dofetilide, sotalol) must be discontinued prior to initiating dronedarone hydrochloride .
Important Note: Beers Criteria: Use dronedarone with caution in older adults with heart failure who are asymptomatic. Avoid use in older adults with permanent atrial fibrillation or heart failure that is symptomatic, severe, or recently decompensated, as dronedarone may worsen outcomes .
General Dosage Information: Safety and efficacy not established in patients less than 18 years of age
Black Box Warning
Oral (Tablet): In patients with symptomatic heart failure and recent decompensation requiring hospitalization or NYHA Class IV heart failure, dronedarone hydrochloride doubles the risk of death. Dronedarone hydrochloride is contraindicated in patients with symptomatic heart failure with recent decompensation requiring hospitalization or NYHA Class IV heart failure. In patients with permanent atrial fibrillation, dronedarone hydrochloride doubles the risk of death, stroke, and hospitalization for heart failure. Dronedarone hydrochloride is contraindicated in patients in atrial fibrillation (AF) who will not or cannot be cardioverted into normal sinus rhythm .
Pharmacokinetics
Tmax, Oral: 3 to 6 hours .
Bioavailability, Oral: About 4% (without food)
Effect of Food: 15% bioavailability when administered with a high-fat meal