Class: Antiarrhythmic agent
- Tablets, oral 400 mg
Exact mechanism is not known; has antiarrhythmic properties belonging to all 4 Vaughan-Williams classes.
Bioavailability is 4% without food; it increases to 15% when administered with a high-fat meal. T max is 3 to 6 h and steady-state concentrations are reached in 4 to 8 days.
More than 98% protein bound, mostly to albumin. Vd after IV administration is approximately 1,400 L.
Extensively metabolized by CYP3A to the N-debutyl metabolite (active), which is 1/10 to 1/3 as potent as dronedarone, and the propanoic acid metabolite (inactive).
Elimination half-life is 13 to 19 h. Excreted primarily in the feces (84%), with 6% excreted in the urine. Cl after IV administration is 130 to 150 L/h.
Special PopulationsRenal Function Impairment
No pharmacokinetic difference was observed.Hepatic Function Impairment
Patients with moderate hepatic impairment had an increase in mean exposure of 1.3-fold and a decrease in mean exposure of the N-debutyl metabolite by 50% compared with patients with healthy hepatic function. The effect of severe hepatic impairment on pharmacokinetics was not assessed and dronedarone is contraindicated in these patients.Elderly
Dronedarone exposure is 23% higher in patients 65 y and older compared with those younger than 65 y.Gender
Dronedarone exposure is 30% higher in females than in males.Race
After single-dose administration, Asian (Japanese) males had a 2-fold higher exposure than white males.
Indications and Usage
To reduce the risk of hospitalization for atrial fibrillation (AF) in patients in sinus rhythm with a history of paroxysmal or persistent AF.
Permanent AF (patients in whom normal sinus rhythm will not or cannot be restored); symptomatic heart failure with recent decompensation requiring hospitalization or New York Heart Association (NYHA) class IV symptoms; liver toxicity related to the previous use of amiodarone; second or third-degree AV block or sick sinus syndrome (except when used in conjunction with a functioning pacemaker); bradycardia less than 50 bpm; concomitant use of strong CYP3A inhibitors (eg, ketoconazole, itraconazole, voriconazole, cyclosporine, telithromycin, clarithromycin, nefazodone, ritonavir); concomitant use of drugs or herbal products that prolong the QT interval and might increase the risk of torsades de pointes (eg, phenothiazine antipsychotics, tricyclic antidepressants, certain oral macrolide antibiotics, class I and III antiarrhythmics); QTc Bazett interval 500 ms or more or PR interval more than 280 ms; severe hepatic impairment; pregnancy; breast-feeding women.
Dosage and AdministrationAdults
PO 400 mg twice daily.
- Administer 1 tablet with the morning meal and 1 tablet with the evening meal.
- Treatment with class I or III antiarrhythmics must be stopped before initiating dronedarone.
Store between 59° and 86°F.
Drug InteractionsBeta-blockers (eg, metoprolol, propranolol), calcium channel blockers (eg, diltiazem, nifedipine, verapamil)
Increased plasma levels of beta-blockers and calcium channel blockers may occur. Give lower doses of beta-blockers and calcium channel blockers and increase only after ECG verification of good tolerability. Verapamil and diltiazem increase dronedarone exposure. Bradycardia occurs more frequently when dronedarone is coadministered with beta-blockers.CYP2D6 (eg, SSRIs [eg, fluoxetine]) and CYP3A (eg, midazolam, pimozide, sirolimus, tacrolimus) substrates
Plasma concentrations of drugs metabolized by these CYP enzymes may be elevated, increasing the risk of adverse reactions. Monitor the clinical response. Dose adjustment may be needed.CYP3A inducers (eg, carbamazepine, phenobarbital, phenytoin, rifampin, St. John's wort)
Dronedarone plasma levels may be reduced. Avoid coadministration.CYP3A inhibitors (eg, clarithromycin, cyclosporine, itraconazole, ketoconazole, nefazodone, ritonavir, telithromycin, voriconazole)
Concomitant use of strong CYP3A inhibitors is contraindicated.Dabigatran
Dabigatran exposure may be increased. Lower dabigatran doses may be needed when given with dronedarone.Drugs known to increase the QT interval (eg, arsenic trioxide, chloroquine, cisapride, citalopram, class I [eg, procainamide] and III [eg, dofetilide] antiarrhythmics, clozapine, crizotinib, dolasetron, droperidol, fingolimod, fluconazole, haloperidol, iloperidone, macrolide antibiotics [eg, clarithromycin], maprotiline, mefloquine, methadone, nilotinib, ondansetron, paliperidone, pentamidine, phenothiazines [eg, thioridazine], phosphodiesterase type 5 inhibitors [eg, vardenafil], pimozide, propafenone, quetiapine, tacrolimus, tetrabenazine, toremifene, tricyclic antidepressants [eg, amitriptyline], tyrosine kinase receptor inhibitors [eg, dasatinib, lapatinib, pazopanib], vandetanib, ziprasidone)
Risk of life-threatening arrhythmias, including torsades de pointes, may be increased. Caution is advised when 2 drugs that are suspected to prolong the QT interval are given concurrently. If coadministration is not contraindicated in the respective product information, monitor patients for QT prolongation, especially when a new drug is added to a stable regimen of another QT-prolonging agent.Food
Because of presystemic first-pass metabolism, the absolute bioavailability of dronedarone without food is low, approximately 4% compared with approximately 15% when administered with a high-fat meal. Dronedarone should be taken with a meal.Grapefruit juice
Dronedarone exposure increased with coadministration. Avoid concomitant use.HMG-CoA reductase inhibitors (eg, simvastatin)
Simvastatin plasma levels may be elevated, increasing the risk of adverse reactions. Advise patients to report any unexplained muscle pain, tenderness, or weakness.P-glycoprotein substrates (eg, digoxin)
P-glycoprotein substrate levels are increased and may result in toxicity. If coadministration cannot be avoided, reduce digoxin dose by approximately 50%, monitor serum levels closely, and observe patient for toxicity.Potassium-depleting diuretics (eg, furosemide, hydrochlorothiazide)
Hypokalemia or hypomagnesemia may occur with coadministration. Ensure that potassium levels are within the normal range.Warfarin
S-warfarin levels may be increased. Monitor INR.
Bradycardia (3%); new or worsening heart failure (postmarketing).
Asthenic conditions (7%).
Skin conditions, including allergic dermatitis, dermatitis, eczema, pruritus, rash (generalized, macular, maculopapular, erythematous) (5%).
Diarrhea (9%); nausea (5%); abdominal pain (4%); dyspeptic signs and symptoms, vomiting (2%).
Liver injury (postmarketing).
Serum creatinine increased more than 10% (51%); QTc prolonged (28%).
Interstitial lung disease, including pneumonitis and pulmonary fibrosis (postmarketing).
Dronedarone is contraindicated in patients with symptomatic heart failure with recent decompensation requiring hospitalization or NYHA class IV heart failure. Dronedarone doubles the risk of death in these patients.
Dronedarone is contraindicated in patients with AF who will not or cannot be cardioverted into normal sinus rhythm. In patients with permanent AF, dronedarone doubles the risk of death, stroke, and hospitalization for heart failure.
Obtain periodic hepatic serum enzymes, especially during the first 6 mo of treatment. Monitor renal function and potassium levels periodically and cardiac rhythm no less than every 3 mo.
Category X . Contraindicated women who are or may be pregnant.
Undetermined. Contraindicated in breast-feeding women.
Safety and efficacy not established.
Contraindicated in patients with severe hepatic impairment.
Hypokalemia or hypomagnesemia may occur with coadministration of potassium-depleting diuretics. Potassium levels should be within the normal range prior to administration of dronedarone and maintained in the normal range during administration.
New or worsening heart failure may develop during treatment with dronedarone. If heart failure develops or worsens, consider suspending or discontinuing dronedarone.
Hepatocellular liver injury, including acute liver failure requiring transplant, has been reported.
Dronedarone induces a moderate QTc prolongation. If the QTc Bazett interval is 500 ms or greater, discontinue dronedarone.
Serum creatinine levels increase approximately 0.1 mg/dL after initiation of dronedarone. The elevation onset is rapid, reaches a plateau after 7 days, and is reversible upon discontinuation.
Changes in cardiac rhythm and BP.
- Advise patients or caregivers to read the Medication Guide carefully before starting therapy and to read and check for new information each time the medication is refilled.
- Advise patients to take each dose with food.
- Instruct patients to avoid drinking grapefruit juice while taking dronedarone.
- Advise patients to inform their health care provider of any history of heart failure, rhythm disturbance other than AF or flutter, or predisposing conditions, such as uncorrected hypokalemia.
- Instruct patients to contact their health care provider if they develop symptoms of heart failure, such as acute weight gain, dependent edema, or increasing shortness of breath.
- Caution women of childbearing potential to avoid becoming pregnant during treatment with dronedarone; counsel patients regarding appropriate contraception choices.
- Advise women not to breast-feed.
- Advise patients to immediately report any symptoms of potential liver injury (such as anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant abdominal discomfort, jaundice, dark urine, itching) to their health care provider.
Copyright © 2009 Wolters Kluwer Health.