TABLE 23.

Specific Drug Therapy for Maintenance of Sinus Rhythm in Patients With AF

Drug	Loading Dose	Maintenance Dose	Primary Route(s) of Elimination	Elimination Half-Life	Mechanism of Action	Major Adverse Effects	Important Pharmacokinetic Drug Interactions
Amiodarone	Total loading dose 6-10 g, given 400-800 mg daily in 2-4 divided doses for 1-4 wk	200 mg once daily	Liver metabolism Biliary excretion	14-59 d	Inhibits IKr, IKs, INa, IKur, Ito, ICa-L, IKAch Noncompetitive beta blocker	AV block Bradycardia Corneal microdeposits Elevation in transaminases Hepatotoxicity Hyperthyroidism Hypothyroidism Nausea QT prolongation Peripheral neuropathy Photosensitivity Pulmonary fibrosis Skin pigmentation (blue-gray) TdP	Moderate* inhibitor of CYP2C9, weak† inhibitor of CYP2D6 Some inhibition of CYP3A Increases plasma concentrations of warfarin, lovastatin,‡ simvastatin,§ cyclosporine Inhibits p-gp Increases plasma concentrations of digoxin
Dofetilide	N/A	CrCl >60 mL/min: 500 μg twice daily CrCl 40-60 mL/min: 250 μg twice daily CrCl 20-40 mL/min: 125 μg twice daily CrCl <20 mL/min: Contraindicated	Kidney	10 h	Inhibits IKr and augments late INa	QT prolongation TdP	Dofetilide is renally excreted via the renal cation transport system. These drugs inhibit renal cation transport, increase plasma dofetilide concentrations, and are contraindicated in patients taking dofetilide: Cimetidine Dolutegravir Ketoconazole Megestrol Prochlorperazine Trimethoprim (alone or in combination with sulfamethoxazole) Verapamil In addition, hydrochlorothiazide (alone or in combination with triamterene) increases plasma dofetilide concentrations and should not be coadministered with dofetilide
Dronedarone	N/A	400 mg twice daily	Liver metabolism	13-19 h	Inhibits IKr IKs, INa, IKur, Ito, ICa-L, IKAch Noncompetitive beta blocker	Abdominal pain Asthenia Bradycardia Diarrhea Nausea and vomiting QT prolongation Rash TdP	Dronedarone is a substrate for CYP3A and is a moderate inhibitor of CYP3A and CYP2D6 Dronedarone is also a substrate for, and inhibitor of, p-gp Dronedarone may increase plasma concentrations of: Dabigatran Digoxin Simvastatin∥ Sirolimus Tacrolimus Warfarin These drugs may increase plasma dronedarone concentrations: Grapefruit juice These drugs may decrease plasma dronedarone concentrations: CYP3A inducers including St. John’s wort, rifampin, and phenytoin
Flecainide	N/A	50-300 mg/d PO divided q 8-12 h	Liver (70%) Kidney (30%)¶	12-27 h	Inhibits INa	Atrial flutter AV block Dizziness Dyspnea Exacerbation of HFrEF Headache Nausea QT prolongation VT Visual disturbances	Flecainide is a substrate for CYP2D6 These drugs may increase plasma flecainide concentrations: Amiodarone Duloxetine Fluoxetine Paroxetine
Propafenone	N/A	150-300 mg PO q 8 h, ER 225-425 POq 12 h	Liver	9 h	Inhibits INa	Atrial flutter Bradycardia AV block Dizziness Dyspnea Exacerbation of HFrEF Nausea Taste disturbances VT Visual disturbances	Propafenone is a substrate for CYP2D6 These drugs may increase plasma propafenone concentrations: Fluoxetine Paroxetine Propafenone may increase plasma digoxin concentrations Propafenone may increase plasma warfarin concentrations
Sotalol	CrCl >60 mL/min: 40-80 mg twice daily for 3 d CrCl: 40-60 mL/min: 80 mg once daily for 3 d CrCl <40 mL/min: Contraindicated	CrCl >60 mL/min: 80-160 mg twice daily CrCl: 40-60 mL/min: 80-160 mg once daily CrCl <40 mL/min: Contraindicated	Kidney	12 h	Inhibits IKr Beta blocker d-Sotalol augments late INa	AV block Bradycardia Bronchospasm Diarrhea Exacerbation of HFrEF Fatigue Nausea and vomiting QT prolongation TdP	None

^*Moderate inhibitor: Causes a 2-fold to <5-fold increase in AUC or a 50% to 80% decrease in clearance.

^†Mild inhibitor: Causes a ≥1.25-fold but <2-fold increase in AUC or a 20% to 50% decrease in clearance.

^‡Lovastatin doses should not exceed 40 mg daily in patients taking amiodarone.

^§Simvastatin doses should not exceed 20 mg daily in patients taking amiodarone.

^∥Simvastatin doses should not exceed 10 mg daily in patients taking dronedarone.

^¶Percentage of a dose excreted unchanged in urine.

AF indicates atrial fibrillation; AUC, area under the plasma concentration versus time curve; AV, atrioventricular; CrCl, creatinine clearance; CYP, cytochrome P-450; ER, extended release; HFrEF, heart failure with reduced ejection fraction; IV, intravenous; N/A, not applicable; NAPA, N-acetylprocainamide; p-gp, p-glycoprotein; PO, orally; TdP, torsades de pointes; and VT, ventricular tachycardia.