Intravenous dofetilide and its uses

Abstract

The present invention relates to a safe dosing regimen comprising intravenous administration followed by oral administration of dofetilide. In a first aspect, the present invention includes a method for reducing the risk of developing atrial fibrillation (AF) and / or atrial flutter (AFL) after coronary artery bypass surgery (CABS) by administering a loading and maintenance dose of dofetilide intravenously followed by oral administration. In a second aspect, the present invention includes a method for terminating an arrhythmia storm in a patient with an implantable cardioverter-defibrillator by administering a loading and maintenance dose of dofetilide intravenously followed by oral administration. In a third aspect, the present invention includes a method for converting atrial fibrillation (AF) or atrial flutter (AFL) in a patient with severe AF or AFL by administering at least a loading dose of dofetilide intravenously, or, if that fails, by chronic oral administration after cardioversion and maintenance infusion.

Description

[Technical Field]

[0001] The present invention relates to a novel method for reducing the risk of developing atrial fibrillation (AF) and / or atrial flutter (AFL) after coronary artery bypass surgery (CABS) by intravenously administering dofetilide to patients who have undergone CABS.

[0002] The present invention further relates to a novel method of administering dofetilide intravenously to terminate an arrhythmic storm in a patient after implantation of a cardiac defibrillator.

[0003] The present invention further relates to a novel method of intravenously administering dofetilide to convert atrial fibrillation (AF) or atrial flutter (AFL) in patients with severe, symptomatic AF or AFL. [Background technology]

[0004] Dofetilide is a Vaughn Williams Class III antiarrhythmic drug. Its action is specifically to prolong repolarization time, thereby increasing action potential duration. Dofetilide achieves this by blocking the outward potassium channel IKr (rapid potassium rectifier current). This action has both antiarrhythmic and proarrhythmic effects. Excessive prolongation of repolarization time can lead to life-threatening arrhythmias, particularly torsade de pointe ventricular tachycardia (Tpd). The repolarization time of cardiac cells is expressed as a prolongation of the QT interval on a surface electrocardiogram (ECG). Because this QT interval varies with heart rate, the QT interval is often measured as heart rate corrected QT (QTc). QTc interval prolongation by medications can potentially lead to arrhythmias. Therefore, monitoring the QTc interval is crucial during the initial loading phase or dose-titration procedure to prevent excessive QTc prolongation and, consequently, the development of life-threatening ventricular tachycardia, particularly Tdp-type tachycardia. For these reasons, the FDA mandates QTc monitoring during initial dofetilide loading or dose escalation during hospitalization. However, for patients requiring chronic dofetilide therapy (e.g., patients with intermittent atrial fibrillation who are currently in sinus rhythm), it takes at least 3 days for oral dofetilide to reach steady-state concentrations and for these concentrations to be fully reflected in QTc prolongation. Therefore, patients typically require a 3-day hospital stay to avoid the risk of developing arrhythmias outside of the hospital, where help is often unavailable.

[0005] The relationship between dofetilide blood concentration and QTc can be expressed as QTc = baseline QTc + (slope relationship × blood dofetilide concentration). The relationship between dofetilide plasma concentration and QTc has been established. As reported by Sedgwick et al., Br J. Clin Pharmacol 1991:31:515-519, QTc varies between 15 and 25 msec / ng / mL (mean = 20 msec). Therefore, if a patient with an initial QTc of 405 msec / QT receives 2.4 μg / kg IV (equivalent to chronic administration of 500 μg bid), the mean QTc is expected to be 459 msec, a 13% increase from baseline. This is within the acceptable range. QTc = 405 ms + (20 ms / ng / mL × 2.7 ng / mL) = 459 ms

[0006] When administering dofetilide, physicians first assess the QTc interval. If the QTc is greater than 440 milliseconds (500 milliseconds in patients with ventricular conduction abnormalities), dofetilide is not indicated. Clinicians then calculate the patient's creatinine clearance (CrCl, a useful approximation of glomerular filtration rate (GFR)) using the following formula: Creatinine clearance (men) = ((140 - age) x weight (kg)) / (72 x serum creatinine (mg / dL)) Creatinine clearance (women) = Creatine clearance (men) x 0.85

[0007] After CrCl calculation, the starting dose of dofetilide is determined as follows: Creatinine clearance (CrCl) Starting dose of dofetilide 60mL / min or more 500 μg bid 40-<60mL / min 250 μg bid 20-<40mL / min 125 μg bid <20mL / min Dofetilide not indicated

[0008] Physicians then need to monitor the QTc until steady state is achieved, which requires 5–6 administrations or a 3-day hospital stay with ECG monitoring—an expensive and time-consuming procedure that is impractical if the goal is to rapidly administer dofetilide to prevent immediate postoperative AF / AFL.

[0009] [Patent Document 1] (U.S. Patent No. 11,364,213) (US'213) relates to a method for shortening the 3-day administration period in patients requiring chronic oral dofetilide. Typically, these patients who present with intermittent atrial fibrillation but are currently in sinus rhythm are first administered intravenous dofetilide, followed by oral dofetilide twice daily (BID). US'213 states that the claimed method can assess the risk of dofetilide in patients within one day, thereby reducing the costs (e.g., hospitalization costs) associated with initiating chronic oral dofetilide therapy.

[0010] Approximately 400,000 open-chest coronary artery bypass surgeries and an additional 100,000 heart valve surgeries are performed annually in the United States. The incidence of postoperative AF / AFL is 30–50% within 3–5 days of surgery, which involves pericardial opening, cardiac manipulation, and placement of a temporary atrial pacing lead. AF / AFL can progress very rapidly, causing symptoms and hemodynamic deterioration in patients. Postoperative AF / AFL can lead to serious complications and significantly prolong patients' hospital stays.

[0011] Although dofetilide is an effective drug for preventing AF / AFL, its only currently approved method of administration, oral administration, is time-consuming, limiting its effectiveness in preventing early onset of AF / AFL. Although effective concentrations can be achieved rapidly with an intravenous loading dose, dofetilide can cause QT prolongation, and overdose can lead to life-threatening ventricular arrhythmias.

[0012] Therefore, it would be beneficial to develop a method for preventing AF and / or AFL using dofetilide in patients undergoing open-chest coronary artery bypass surgery. The above situation applies to patients who require chronic dofetilide therapy, especially those who present with arrhythmia storms. Currently, it takes at least 3 days for oral dofetilide to reach steady-state concentrations, which is unsatisfactory. Physicians must then monitor the QTc until a steady-state concentration is reached, which would require 5–6 doses or a 3-day hospital stay with ECG monitoring—which is not realistic if the goal is to rapidly terminate the arrhythmia storm and prevent recurrence.

[0013] The availability of implantable cardioverter-defibrillators for patients who have experienced "sudden death" or who are at high risk for life-threatening ventricular arrhythmias has been a major benefit to patients. Implantable cardioverter-defibrillators (IDs) have significantly reduced the incidence of arrhythmia-related deaths in patients at high risk for cardiac arrest. Patients with severe heart failure, patients who have survived cardiac arrest, and patients with recent onset of ventricular tachycardia have all benefited from the availability of IDs.

[0014] However, ID procedures and tests can lead to recurrent and sustained ventricular tachycardia (VT) and ventricular fibrillation (VF). These sustained arrhythmias are ineffective at terminating them with many currently available medications and can be extremely difficult to treat. The persistent and recurrent aspects of arrhythmia storms are particularly prevalent in patients with reduced left ventricular function. These patients are also prone to arrhythmias (proarrhythmic) in response to many antiarrhythmic drugs. Dofetilide, a Vaughan-Williams type III antiarrhythmic drug that prolongs cardiac repolarization, has been shown to be safe in patients with reduced cardiac function (Diamond Study (Torp-Pedersen et al NEJM 1999;341:857-65)). However, despite the fact that arrhythmia storms require immediate treatment, the need for oral dofetilide, which requires a 3-day inpatient stay, makes its use impractical.

[0015] Therefore, it would be beneficial to develop a method for intravenously administering dofetilide in a rapid-dose paradigm for the treatment of arrhythmia storm, with patient safety being an important consideration. Atrial fibrillation (AF) or atrial flutter (AFL) can be highly symptomatic and can lead to cardiac decompensation and death in patients with compromised myocardial function. Symptomatic AF / AFL can be terminated by medical therapy or electrical cardioversion to restore normal sinus rhythm. Dofetilide is known to be effective in suppressing AF / AFL and preventing recurrence of arrhythmias. It is approved by the U.S. Food and Drug Administration (FDA) for the treatment of symptomatic AF / AFL. However, the currently approved method of oral administration over several days poses a significant obstacle to suppression, especially when urgent suppression is required given the patient's condition. Although rapid infusion of intravenous dofetilide appears to be effective in converting atrial fibrillation, dofetilide can cause excessive QT prolongation and potentially lead to the development of serious, life-threatening torsades de pointes-type ventricular arrhythmias.

[0016] Therefore, it would be beneficial to develop an effective administration method for intravenous dofetilide that can be administered in a controlled manner with careful patient evaluation to avoid the induction of life-threatening drug-induced arrhythmias. This is particularly necessary in patients with impaired cardiac function, as many drugs in this setting are prone to inducing life-threatening arrhythmias. Although atrial fibrillation / atrial fibrillation (AF / AFL) frequently occurs in patients with impaired cardiac function, clinical trials have shown that dofetilide does not increase the incidence of life-threatening arrhythmias in this population of heart failure patients. [Prior art documents] [Patent documents]

[0017] [Patent Document 1] U.S. Patent No. 11,364,213 [Non-patent literature]

[0018] [Non-Patent Document 1] Sedgwick et al(Br J. Clin Pharmacol 1991:31:515-519) [Non-patent document 2] Diamond Study (Torp-Pedersen et al NEJM 1999;341:857-65) Summary of the Invention [Problem to be solved by the invention]

[0019] Thus, the present invention provides a novel and safe method for administering dofetilide intravenously, maintaining it, and then safely switching to oral administration. [Means for solving the problem]

[0020] The present invention particularly provides a pharmaceutical dofetilide IV composition for use in treating a patient in need thereof, comprising the steps of: I. The patient is given a loading dose of dofetilide intravenously, the loading dose being administered over 30 to 60 minutes; II. 0-4 hours after the completion of the IV loading dose, administer a maintenance infusion of dofetilide intravenously over 12 hours. III. Once the patient is able to take oral dofetilide, discontinue the above IV maintenance infusion; IV. 2 to 6 hours after discontinuing the IV maintenance infusion, administer dofetilide orally every 12 hours. V. The above maintenance infusion doses will be determined based on the patient's creatinine clearance (CrCl) as shown in the table below: CrCl IV maintenance infusion oral dose (Over 12 hours) (Every 12 hours) ≧60mL / min 450~500μg 500μg 40-<60mL / min 225~250μg 250μg 20-<40mL / min 100~125μg 125μg <20mL / min Dofetilide not indicated Dofetilide not indicated VI. Measure the patient's QTc before the intravenous loading dose of dofetilide to establish a baseline QTc, then measure QTc every 15-30 minutes for 60 minutes, before the intravenous maintenance infusion, and before each oral dose; VII. However, if the patient's QTc increases by 15% from baseline, or if a QTc of >500 msec is measured, or if the patient has ventricular conduction abnormalities and a QTc of >550 msec is measured, reduce the oral dose from 500 mcg to 250 mcg, from 250 mcg to 125 mcg, or discontinue administration if initially at 125 mcg.

[0021] In a preferred embodiment, the present invention comprises a novel method for administering and maintaining intravenous dofetilide to patients after coronary artery bypass surgery, with the goal of reducing the risk of developing postoperative AF / AFL.

[0022] In another preferred embodiment, the present invention comprises a novel method of intravenously administering dofetilide to patients who experience an arrhythmic storm after placement of an implantable cardioverter-defibrillator.

[0023] In another alternative embodiment, the method of the present invention involves administering an intravenous loading dose to a patient experiencing an arrhythmic storm after implantation of an implantable cardioverter-defibrillator, followed by an intravenous maintenance infusion of dofetilide, and then switching to oral administration for maintenance.

[0024] These and other objects, which will become apparent from the detailed description below, have been achieved by the inventors' discovery that intravenous dofetilide can be safely administered until a patient is able to take dofetilide orally, and then can be safely switched to oral administration.

[0025] Preferably, the pharmaceutical dofetilide IV composition according to one embodiment of the present invention is for use in treating a patient in need thereof to reduce the risk of developing atrial fibrillation (AF) and / or atrial flutter (AFL) in patients who have undergone coronary artery bypass surgery (CABS).

[0026] Preferably, the pharmaceutical dofetilide IV composition according to one embodiment of the present invention is for use in treating a patient in need thereof to terminate an arrhythmic storm in the patient after implantation of an implantable cardioverter-defibrillator.

[0027] Preferably, the pharmaceutical dofetilide IV composition according to one embodiment of the present invention is for use in treating a patient in need thereof to improve atrial fibrillation (AF) or atrial flutter (AFL) in patients presenting with severe symptomatic AF or AFL.

[0028] Preferably, the pharmaceutical dofetilide IV composition according to one embodiment of the present invention is for use in treating a patient in need thereof, wherein the patient is administered a loading dose of 450-500 μg of dofetilide intravenously.

[0029] Preferably, a pharmaceutical dofetilide IV composition according to one embodiment of the present invention is for use in treating a patient in need thereof, wherein the patient receives a maintenance infusion of 100-500 μg of dofetilide intravenously over 12 hours.

[0030] Preferably, the pharmaceutical dofetilide IV composition according to any one of claims 1 to 6 is for use in treating a patient in need thereof, and has a duration between the Cmax dofetilide concentration obtained after a loading dose of dofetilide IV and the Cmax dofetilide concentration obtained after the first oral administration of dofetilide of 14 to 18 hours. These and other objects have been achieved by the inventors' discovery that intravenous dofetilide can be used to treat arrhythmia storms in patients after implantation of an implantable cardioverter-defibrillator, as will become apparent from the detailed description that follows. DETAILED DESCRIPTION OF THE INVENTION

[0031] A. Intravenous dofetilide for reducing the risk of developing AF / AFL after coronary artery bypass surgery

[0032] All references cited herein are incorporated by reference in their entirety.

[0033] definition

[0034] "About" is defined as ±10% of the numerical value.

[0035] BID or bid or bid means twice a day or once every 12 hours.

[0036] BP is blood pressure.

[0037] HR is the heart rate.

[0038] IV means intravenous or intravenous administration.

[0039] Dofetilide

[0040] Previous studies have reported that a single dose of 1.5 μg / kg of dofetilide, administered over a 10-minute infusion, resulted in a peak plasma concentration of 1.74 ng / mL (Sedgwick et al., Br. J. Clin Pharmacol 1991:31:515-519 and Rasmussen et al., J. Cardiovascular Pharmacology 20:1992, S96-101). A 3.0 μg / mL infusion resulted in a plasma concentration of 5.35 ng / mL (Sedgwick et al. and Rasmussen et al.). Coz and associates (Clin. Pharmacology & Therapeutics, Therapeutics, 1995;57(5) 533-54) reported that oral administration of 500 μg of dofetilide resulted in a plasma Cmax of 1.9 ng / mL. Therefore, if a single dose achieves 70% of the predicted steady-state concentration, then at steady state, a 500 μg / mL dose administered twice daily for at least five doses can be estimated to result in a Cmax of 2.7 ng / mL. If we know that a 1.5 μg / kg IV dose results in a peak concentration of 1.7 ng / mL, assuming linear kinetics, a 2.4 μg / kg dose would achieve a peak concentration of 2.7 ng / mL, exposing the patient to the highest predicted steady-state serum concentration and thus the greatest QTc prolongation. This fully exposes the patient to potentially the greatest arrhythmia risk in the short term during hospitalization and monitoring.

[0041] Intravenous dofetilide kinetics are linear, resulting in a direct relationship between the administered intravenous dose and the resulting serum concentration. Intravenous administration avoids serum concentration "overshoot," avoiding excessive dofetilide blood concentrations and, therefore, the development of arrhythmias. The relationship between serum concentration and QTc interval is well known and highly correlated.

[0042] CABS: Coronary Artery Bypass Surgery

[0043] It is generally recommended that the heart undergoing surgery not be exposed to antiarrhythmic medications that may lead to adverse outcomes, and it is known that CABS patients have a 30-50% chance of developing atrial fibrillation (AF) and / or atrial flutter (AFL) within 3-5 days after surgery.

[0044] In light of the above, the present invention provides a novel loading dose method for dofetilide to maximize patient safety by carefully achieving the minimum necessary effective drug blood concentration so as to avoid excessive QT prolongation, which can cause cardiac repolarization abnormalities and lead to life-threatening ventricular arrhythmias.

[0045] Thus, in one aspect, the present invention provides a novel method for reducing the risk of developing AF and / or AFL after CABS by intravenously administering dofetilide to a patient who has experienced CABS. In another aspect, the method comprises intravenously administering a loading dose of dofetilide and intravenously administering a maintenance dose of dofetilide. In another aspect, the method comprises orally administering dofetilide BID. In another aspect, the method comprises intravenously administering a loading dose and at least one maintenance dose of dofetilide, followed by switching to an oral maintenance dose.

[0046] Risk reduction refers to a 30-50% reduction in the risk of developing AF / AFL 3-5 days after CABS surgery. Examples include reducing the risk of developing AF and / or AFL to approximately 25%, 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, or 0%.

[0047] In another aspect, the present invention provides a novel method for reducing the risk of developing atrial fibrillation (AF) and / or atrial flutter (AFL) in a patient who has undergone coronary artery bypass surgery (CABS), comprising the steps of: a Measure the patient's QTc to establish a baseline QTc, then measure the QTc approximately every 15 to 30 minutes. b A loading dose of dofetilide was administered intravenously to patients undergoing CABS, where: (A) The loading dose is approximately 450–500 μg of dofetilide. (B) The loading dose is administered over approximately 30 to 60 minutes. c Approximately 0-4 hours after completion of the IV loading dose, administer a maintenance dose of dofetilide intravenously over approximately 12 hours, with the maintenance dose administered based on the creatinine clearance of the patient with CABS, as shown in the table below: Creatinine clearance (CrCl) IV dofetilide maintenance dose (12 hours) 60mL / min or more 450~500μg 40―<60mL / min 225~250μg 20―<40mL / min 100~125μg <20mL / min Dofetilide not indicated d Once the patient has recovered from CABS and is able to receive oral dofetilide, discontinue IV maintenance therapy.

[0048] In another embodiment, the method further comprises: Approximately 2-6 hours after discontinuing the maintenance dose, administer dofetilide orally every 12 hours, with the oral dose administered based on the creatinine clearance of the patient with CABS, as shown in the table below: Creatinine clearance (CrCl) Oral dofetilide dose 60mL / min or more 500μg bid 40―<60mL / min 250μg bid 20―<40mL / min 125μg bid <20mL / min Dofetilide not indicated However, if the patient's QTc increases by 15% from baseline, or if the QTc is measured to be >500 msec or >550 msec in patients with ventricular conduction abnormalities, reduce the oral dose of dofetilide from 500 μg to 250 μg, from 250 μg to 125 μg, or discontinue if initially at 125 μg.

[0049] Typically, a QTc measurement is performed before dofetilide administration to establish a baseline QTc, followed by additional QTc measurements for comparison with this QTc measurement. These QTc measurements are usually performed approximately every 15, 20, 25, or 30 minutes. These measurements can be discontinued once medical staff are confident that the patient is stable on dofetilide. For example, QTc measurements can be discontinued after the maintenance dose of dofetilide is discontinued. Alternatively, QTc measurements can be discontinued after a sufficient oral dose has been administered. The healthcare provider can determine when to discontinue QTc monitoring. Examples of sufficient oral doses include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 doses.

[0050] In another embodiment, the patient's QTc is measured by monitoring the patient with electrocardiography.

[0051] The loading dose for intravenous administration is typically about 450-500 μg of dofetilide, including, for example, about 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, and 500 μg of dofetilide. Typically, the loading dose selected is the amount that achieves the predicted maximum serum concentration following oral administration of 500 μg of dofetilide.

[0052] The intravenous loading dose is typically administered over about 30-60 minutes, for example, about 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 30, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 30, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 minutes.

[0053] In another embodiment, the intravenous maintenance dose is initiated at the completion of the loading dose. In another embodiment, the IV maintenance dose is initiated about 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5 to 6 hours after the loading dose is completed.

[0054] The IV maintenance dose is typically administered for about 12 hours, but can be discontinued at any time. In another embodiment, the maintenance dose is administered for about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours. Additional examples include about 1.5, 2, 2.5, 3, 3.5, or 4 days (or possibly longer).

[0055] The IV maintenance dose can be discontinued if necessary (e.g., if an elevation in QTc is measured). This is an advantage of intravenous administration compared to oral administration. If a patient experiences adverse effects from dofetilide, intravenous administration can be discontinued immediately.

[0056] The intravenous maintenance dose depends on the patient's CrCl, as shown in the table below. Creatinine clearance (CrCl) IV maintenance dofetilide dose (12 hours) 60mL / min or more 450~500μg 40―<60mL / min 225~250μg 20―<40mL / min 100~125μg <20 mL / min Dofetilide is not indicated

[0057] For patients with CrCl ≥ 60 mL / min, the IV maintenance dose is typically about 450-500 μg of dofetilide, typically administered over about 12 hours (although this can vary as noted above). Examples include about 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, or 500 μg of dofetilide, which corresponds to about 0.625-0.694 μg / min (450 / 720-500 / 720) of dofetilide. In another embodiment, the IV maintenance dose is about 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, or 0.7 μg / min.

[0058] For patients with CrCl between 40 and <60 mL / min, the IV maintenance dose is typically about 225-250 μg of dofetilide, typically administered over about 12 hours (although this can vary as noted above). Examples include about 225, 230, 235, 240, 245, or 250 μg of dofetilide, which corresponds to about 0.313-0.347 μg / min of dofetilide (225 / 720-250 / 720). In other embodiments, the IV maintenance dose is about 0.3, 0.31, 0.32, 0.33, 0.34, or 0.35 μg / min.

[0059] For patients with CrCl between 20 and <40 mL / min, the IV maintenance dose is typically about 100-125 μg of dofetilide, typically administered over about 12 hours (although this can vary as noted above). Examples include about 100, 105, 110, 115, 120, or 125 μg of dofetilide. This corresponds to about 0.139-0.174 μg / min of dofetilide (100 / 720-125 / 720). In other embodiments, the IV maintenance dose is about 0.13, 0.14, 0.15, 0.16, 0.17, or 0.18 μg / min.

[0060] During and immediately after CABS, patients are not awake and oral dofetilide cannot be administered. Therefore, one advantage of the present invention is that dofetilide can be administered before patients who have undergone CABS are typically able to take oral dofetilide. Once a patient is deemed sufficiently recovered from CABS to be able to take oral dofetilide, the IV dofetilide maintenance dose can be discontinued and a switch to oral dofetilide can be achieved. The patient's medical staff (e.g., surgeon, doctor, nurse, etc.) determines when a patient can take oral dofetilide. Oral medications are typically administered when the patient is alert. In some embodiments, this occurs when the patient awakens after surgery. In other embodiments, it may take a longer time for a patient to awaken and be sufficiently alert to swallow a pill.

[0061] In another embodiment, oral administration is initiated about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 hours after the maintenance dose has stopped. In another embodiment, oral administration is initiated about 3-6 hours after the maintenance dose has stopped.

[0062] Oral dofetilide is available in three capsule sizes: 125 μg, 250 μg, and 500 μg. In another embodiment, patients receive oral dofetilide BID (once every 12 hours). Examples of these doses include 125, 250, 375 (e.g., 125 capsules x 3 or 125 + 250 capsules), and 500 μg.

[0063] The standard dose for patients with a creatinine clearance (CrCl) (or calculated GFR (glomerular filtration rate)) of ≥ 60 mL / min is 500 μg, except that this dose is reduced if the patient's CrCl is < 60 mL / min, as shown in the table below. Creatinine clearance (CrCl) Initial oral dofetilide dose 60mL / min or more 500μgbid 40―<60mL / min 250μgbid 20-<40 mL / min 125 μg bid <20 mL / min Dofetilide is not indicated

[0064] The oral dofetilide dose should also be reduced if the patient's QTc indicates otherwise. For example, if the patient's QTc increases by 15% from baseline or if the QTc is measured to be >500 msec or >550 msec in patients with ventricular conduction abnormalities, the oral dofetilide dose should be reduced from 500 μg to 250 μg, or from 250 μg to 125 μg, or discontinued if the initial dose was 125 μg.

[0065] For patients with a CrCl ≥ 60 mL / min, the oral dose of dofetilide is 500 μg twice daily. In this embodiment, the oral dose is reduced to 250 μg if the patient's QTc increases by 15% over baseline QTc or if a QTc > 500 msec or > 550 msec is measured if the patient has ventricular conduction abnormalities.

[0066] For patients with a CrCl of 40-<60 mL / min, the oral dose of dofetilide is 250 μg twice daily. In this embodiment, the oral dose is reduced to 125 μg if the patient's QTc increases by 15% from baseline QTc or if a QTc of >500 msec or >550 msec is measured if the patient has ventricular conduction abnormalities.

[0067] For patients with a CrCl of 20-<40 mL / min, the oral dose of dofetilide is 125 μg twice daily. In this embodiment, treatment is discontinued if the patient's QTc increases by 15% from baseline QTc or if the QTc measures >500 msec or >550 msec if the patient has ventricular conduction abnormalities.

[0068] In another embodiment, patients with a CrCl of 20-<40 mL / min are administered dofetilide 125 μg orally once daily. This once-daily dosing regimen is selected based on the judgment of the patient's healthcare provider (e.g., internist, surgeon, physician, etc.). In this embodiment, treatment is discontinued if the patient's QTc increases by 15% from baseline or if a QTc of >500 ms is measured, or >550 ms if the patient has ventricular conduction abnormalities.

[0069] In another embodiment, the patient's CrCl is ≥ 60 mL / min, the IV maintenance dose is about 450-500 μg of dofetilide administered over about 12 hours, and the oral dose is 500 μg of dofetilide twice daily. In this embodiment, the oral dose is reduced to 250 μg if the patient's QTc increases by 15% from baseline QTc or if a QTc > 500 milliseconds or > 550 milliseconds is measured if the patient has ventricular conduction abnormalities.

[0070] In another embodiment, the patient has a CrCl of 40-<60 mL / min, the IV maintenance dose is about 225-250 μg of dofetilide administered over about 12 hours, and the oral dose is 250 μg of dofetilide twice daily. In this embodiment, the oral dose is reduced to 125 μg if the patient's QTc increases by 15% from baseline QTc or if a QTc >500 msec or >550 msec is measured if the patient has ventricular conduction abnormalities.

[0071] In another embodiment, the patient has a CrCl of 20-<40 mL / min and the IV maintenance dose is about 100-125 μg of dofetilide administered over about 12 hours, with the dose of dofetilide being 125 μg orally twice daily. In this embodiment, treatment is discontinued if the patient's QTc increases by 15% over baseline QTc or if a QTc of >500 milliseconds is measured, or >550 milliseconds if the patient has ventricular conduction abnormalities.

[0072] In another embodiment, the patient has a CrCl of 20-<40 mL / min and is receiving an intravenous maintenance dose of about 100-125 μg of dofetilide administered over about 12 hours, with the dose of dofetilide administered orally once daily at 125 μg. In this embodiment, treatment is discontinued if the patient's QTc increases by 15% over baseline QTc or if a QTc of >500 milliseconds is measured, or >550 milliseconds if the patient has ventricular conduction abnormalities.

[0073] A suitable intravenous formulation is described in US Pat. No. 11,364,213.

[0074] Examples of useful concentrations of dofetilide intravenous solution include about 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95-100 μg / mL.

[0075] The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The present invention encompasses any and all combinations of the aspects of the present invention described herein. It is understood that any embodiment of the present invention can be combined with any and all other embodiments to describe additional embodiments. It is also understood that each individual element of an embodiment is intended to be construed separately as its own independent embodiment. Furthermore, any element of an embodiment is intended to be combined with any and all other elements of any embodiment to describe additional embodiments.

[0076] Other features of the present invention will become apparent from the following description of exemplary embodiments which are given by way of illustration and are not intended to limit the invention to these embodiments. [Brief explanation of the drawings]

[0077] [Figure 1] The estimated blood dofetilide concentrations obtained with the dosing regimen are shown. [Example]

[0078] Example 1 A 70 kg patient with a CrCl >90 mL / min presents after coronary artery bypass surgery. To reduce the possibility of postoperative atrial fibrillation (AF), the patient receives a loading dose of dofetilide after the procedure is completed. The patient's electrocardiogram is continuously monitored. The patient then undergoes the following treatment with dofetilide: (A) Time 0: Intravenous (IV) loading dose: 450 μg infused over 1 hour. QTc, HR, and BP were measured every 15 minutes. (B) 1 hour later: IV maintenance dose: 450 μg infused over 12 hours, starting at the end of the loading dose. (C) 16 hours later: Oral administration: 500 μg orally every 12 hours (BID). Initiation of administration 3 hours after completion of IV maintenance fluids.

[0079] Figure 1 shows the estimated dofetilide blood concentrations obtained with the above dosing regimen. This graph was obtained by modeling the above dosing regimen. Bayesian PK modeling was performed using the software packages NONMEM® version 7.4 (ICON, Hanover, MD, USA) and MWpharm (Mediware, Prague, CZ). PsN7 (Uppsala University, School of Pharmacy, Uppsala, Sweden) was used for automated procedures. R (version 3.5.1, The R Foundation for Statistical Computing) was used for data preparation, graphical analysis, linear regression analysis, and statistical summarization. The R package "mrgsolve" was used for simulations.

[0080] Step (A): The loading dose (in this example, 450 μg of dofetilide administered IV over 1 hour) achieves the maximum serum concentration expected after oral administration of 500 μg of dofetilide, which peaks after six twice-daily doses of oral dofetilide. This peak concentration is typically achieved at the end of the infusion.

[0081] QTc is measured every 15 minutes.

[0082] Step (B): At the end of the 1-hour loading IV infusion, begin an IV maintenance dose of 450 μg of dofetilide (0.625 μg / min) infused IV over 12 hours. This dose can be maintained until the patient is awake and able to administer dofetilide orally.

[0083] Once the patient is able to tolerate oral dofetilide, the maintenance intravenous dofetilide is discontinued. Starting approximately 3 hours after discontinuing the maintenance intravenous dose, administer 500 μg of dofetilide orally (BID) every 12 hours.

[0084] If the QTc is prolonged by 15% above baseline or if a QTc of >500 msec (550 msec in patients with ventricular conduction abnormalities) is observed, the subsequent oral dose should be reduced to 250 mcg BID (or lower if the initial oral dose is lower; see below).

[0085] If the patient's CrCl is below the normal range, the initial target concentration will remain the same and the administered oral (maintenance) dose will be reduced to 250 μg or 125 μg BID (based on the table below). Creatinine clearance (CrCl) Oral dofetilide dose 60mL / min or more 500μg bid 40-<60 mL 250 μg bid 20-<40 mL 125 μg bid <20mL / min Dofetilide not indicated

[0086] Furthermore, in patients who demonstrate excessive QTc prolongation (>500 msec or >550 msec in patients with ventricular conduction abnormalities) after the initial dose, the initial oral dose should be reduced to 250 μg (or 125 μg if the starting oral dose is 250 μg based on the table above) and the expected peak concentration should be reassessed after 4 hours of QTc monitoring. In this way, the predicted blood concentration from chronic oral administration of 250 μg of dofetilide can be easily evaluated while monitoring QTc.

[0087] Example 2

[0088] A patient weighing 75 kg and with a CrCl of 45 mL / min undergoes CABGS after coronary artery bypass surgery. To reduce the possibility of postoperative atrial fibrillation (AF), the patient receives a loading dose of dofetilide after the procedure. The patient's electrocardiogram is continuously monitored. The patient then undergoes the following treatment with dofetilide: (A) Time 0: IV loading dose: 450 μg administered over 1 hour. QTc, HR, and BP were measured every 15 minutes. (B) 4 hours later: Maintenance infusion: 3 hours after the loading dose, intravenous administration of 225 μg was started over 12 hours. (C) 21 hours later: Oral administration begins. 250 μg orally every 12 hours. 5 hours after IV maintenance fluid infusion ends.

[0089] Numerous modifications and variations of the present invention are possible in light of the above teachings, and it is therefore understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein. Implementation - A. Prevention of AF(L) after CABS 1. A method for reducing the risk of developing atrial fibrillation (AF) and / or atrial flutter (AFL) in a patient who has undergone coronary artery bypass surgery (CABS), comprising the steps of: a. Measure the patient's QTc to establish a baseline QTc, followed by QTc measurements approximately every 15-30 minutes; b. A loading dose of dofetilide is administered intravenously to patients undergoing CABS, wherein: (A) The loading dose is approximately 450–500 μg of dofetilide; (B) The loading dose is administered over approximately 30 to 60 minutes; Approximately 0-4 hours after the completion of the intravenous loading dose, a maintenance dose of dofetilide is administered intravenously over approximately 12 hours. The maintenance dose is based on the creatinine clearance (CrCl) of the CABS patient, as shown in the table below. CrCl Intravenous maintenance dose Oral dose 60mL / min or more 450~500μg 500μg 40―<60mL / min 225~250μg 250μg 20―<40mL / min 100~125μg 125μg <20mL / min Dofetilide is not indicated Dofetilide is not indicated d When the patient has recovered from CABS sufficiently to administer oral dofetilide, discontinue the intravenous maintenance dose. e Approximately 2–6 hours after discontinuing the IV maintenance dose, oral dofetilide is administered every 12 hours, with the oral dose determined based on the CrCl of the CABS patient as shown in the table above. However, if the patient's QTc increases by 15% from baseline, or if the QTc is measured to be >500 msec or >550 msec if the patient has ventricular conduction abnormalities, reduce the oral dose from 500 mcg to 250 mcg, from 250 mcg to 125 mcg, or discontinue if initially at 125 mcg. 2. The method of embodiment 1, wherein the loading dose is about 450 μg. 3. The method of embodiment 1, wherein the loading dose is about 460 μg. 4. The method of embodiment 1, wherein the loading dose is about 470 μg. 5. The method of embodiment 1, wherein the loading dose is about 480 μg. 6. The method of embodiment 1, wherein the loading dose is about 490 μg. 7. The method of embodiment 1, wherein the loading dose is about 500 μg. 8. The method of embodiment 1, wherein the loading dose is administered over about 30 minutes. 9. The method of embodiment 1, wherein the loading dose is administered over about 40 minutes. 10. The method of embodiment 1, wherein the loading dose is administered over about 50 minutes. 11. The method of embodiment 1, wherein the loading dose is administered over about 60 minutes. 12. The method of embodiment 1, wherein the maintenance dose begins at about 0 hours after completion of the loading dose. 13. The method of embodiment 1, wherein the maintenance dose is initiated about 1 hour after completion of the loading dose. 14. The method of embodiment 1, wherein the maintenance dose is initiated about 2 hours after completion of the loading dose. 15. The method of embodiment 1, wherein the maintenance dose is initiated about 3 hours after completion of the loading dose. 16. The method of embodiment 1, wherein the maintenance dose is initiated about 4 hours after completion of the loading dose. 17. The method of embodiment 1, wherein the patient's CrCl is >60 mL / min and the IV maintenance dose is about 450-500 μg administered over about 12 hours and the oral dose is 500 μg. 18. The method of embodiment 17, wherein the oral dose is reduced to 250 μg if the QTc increases by 15% over the baseline QTc or if a QTc of >500 msec is measured, or >550 msec if the patient has a ventricular conduction abnormality. 19. The method of embodiment 1, wherein the patient's CrCl is 40-<60 mL / min, the IV maintenance dose is about 225-250 μg administered over about 12 hours, and the oral dose is 250 μg. 20. The method of embodiment 19, wherein the oral dose is reduced to 125 μg if the QTc increases by 15% over the baseline QTc, or if a QTc of >500 ms or >550 ms is measured if the patient has a ventricular conduction abnormality. 21. The method of embodiment 1, wherein the patient's CrCl is 20-<40 mL / min, the IV maintenance dose is about 100-125 μg administered over about 12 hours, and the oral dose is 125 μg. 22. The method of embodiment 21, wherein the oral dose is discontinued if the QTc increases by 15% over the baseline QTc, or if the QTc is measured to be >500 ms, or >550 ms if the patient has ventricular conduction abnormalities. 23. A method for reducing the risk of developing atrial fibrillation (AF) and / or atrial flutter (AFL) in patients undergoing coronary artery bypass surgery (CABS) and having a creatinine clearance (CrCl) of 20-<40 mL / min, comprising the steps of: a. Measure the patient's QTc to establish a baseline QTc, followed by QTc measurements approximately every 15-30 minutes; b. A loading dose of dofetilide is administered intravenously to a patient undergoing CABS, wherein: (A) The loading dose is approximately 450–500 μg of dofetilide. (B) The loading dose is administered over approximately 30 to 60 minutes. Approximately 0–4 hours after completion of the IV loading dose, a maintenance dose of 100–125 μg of dofetilide is administered intravenously over approximately 12 hours. This maintenance dose is based on the CrCl of the patient with CABS. d Once the patient has recovered from CABS sufficiently to administer oral dofetilide, discontinue the IV maintenance dose and e Approximately 2 to 6 hours after discontinuing the IV maintenance dose, administer dofetilide 125 μg orally every 24 hours. However, oral administration should be discontinued if the patient's QTc increases by 15% from baseline, or if the QTc is measured to be >500 msec or >550 msec if the patient has ventricular conduction abnormalities. Further Embodiments - A. Prevention of AF(L) after CABS 1. A method of treating a patient who has undergone coronary artery bypass surgery (CABS), comprising the steps of: a. A loading dose of approximately 450-500 μg of dofetilide is administered intravenously over approximately 30-60 minutes to patients in need thereof. b. Approximately 0-4 hours after completion of the loading dose, administer a maintenance dose of approximately 450-500 μg of dofetilide intravenously (the "IV maintenance dose") to patients with a creatine clearance of 60 mL / min or greater; c. The IV maintenance dose is administered over approximately 12 hours, d. Discontinue the above IV maintenance dose in patients who have fully recovered from CABS; e. Approximately 2 to 6 hours after discontinuing the above IV maintenance dose, administer dofetilide 500 μg orally every 12 hours to patients with a creatine clearance of 60 mL / min or greater. Here, for patients with a QTc prolongation of 15% from baseline, patients with a QTc >500 msec, or patients with a QTc >550 msec with ventricular conduction abnormalities, the oral dofetilide dose should be reduced to 250 μg, and the loading dose is expected to reach maximum serum concentrations at the end of the infusion. Patients are monitored to ensure that excessive QT prolongation does not lead to cardiac repolarization abnormalities that could result in life-threatening ventricular arrhythmias. 2. The method of embodiment 1 for reducing the risk of developing atrial fibrillation (AF) and / or atrial flutter (AFL) in patients who have undergone coronary artery bypass surgery (CABS), wherein risk reduction refers to a 30-50% reduction in the risk of developing AF / AFL within 3-5 days immediately following CABS surgery. 3. The method of embodiment 1, further comprising measuring the patient's QTc prior to intravenous administration of the loading dose of dofetilide, and then every 15 to 30 minutes thereafter until administration of the IV maintenance dose of dofetilide is discontinued or after a sufficient number of oral doses have been administered. 4. The method of embodiment 3, wherein the patient's medical staff determines when a sufficient number of oral doses have been administered. 5. The method of embodiment 4, wherein the patient's medical staff is the patient's surgeons, doctors and / or nurses. 6. The method of embodiment 1, wherein the loading dose is about 450-500 μg of dofetilide. 7. The method of embodiment 1, wherein a maintenance dose ("IV maintenance dose") of 450-500 μg of dofetilide is administered to patients with a creatine clearance of 60 mL / min or greater 1-3 hours after completion of the loading dose. 8. The method of embodiment 1, wherein the IV maintenance dose is about 450-500 μg of dofetilide. 9. The method of embodiment 1, wherein the creatine clearance is 60 mL / min or greater. 10. The method of embodiment 1, wherein the IV maintenance dose is discontinued after 2 to 6 hours. 11. The method of embodiment 1, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) prior to administering the IV maintenance dose to determine the amount of dofetilide appropriate for the IV maintenance dose. 12. The method of embodiment 1, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) prior to oral administration of dofetilide to determine the amount of dofetilide appropriate for oral dosing. 13. The method of embodiment 1, wherein dofetilide is orally administered when the patient has sufficiently recovered from CABS and is awake and conscious after surgery (as determined by the patient's medical staff). 14. The method of embodiment 13, wherein the patient's medical staff is the patient's surgeons, doctors and / or nurses. 15. The method of embodiment 1, wherein the intravenous loading dose is administered over about 40 to 50 minutes. 16. The method of embodiment 1, wherein the IV maintenance dose is administered over 12 hours. 17. The method of embodiment 1, wherein dofetilide is fully loaded within 3 days. 18. The method of embodiment 17, wherein dofetilide is fully loaded once a steady-state blood concentration is reached. 19. The method of embodiment 1, wherein intravenous dofetilide is administered in an initial loading dose and an ongoing IV maintenance dose. 20. The method of embodiment 1, wherein intravenous dofetilide administration prevents arrhythmias that can occur by avoiding excessive blood dofetilide concentrations. 21. The method of embodiment 1, wherein the patient can receive a loading dose of dofetilide by intravenous administration after surgery before the patient is conscious, alert, and able to take oral dofetilide. 22. A method of treating a patient who has undergone coronary artery bypass surgery (CABS), comprising the steps of: a. A loading dose of approximately 450 mg / kg is administered intravenously to a patient in need thereof; b. Patients with a creatine clearance of 60 mL / min or greater receive a maintenance dose of approximately 450-500 μg of dofetilide intravenously (hereinafter referred to as the "IV maintenance dose") approximately 0-4 hours after completion of the loading dose; c. The IV maintenance dose is administered over approximately 12 hours. d. For patients who have fully recovered from CABS, discontinue the IV maintenance dose. e. Approximately 2-6 hours after discontinuing the IV maintenance dose, administer dofetilide 250 μg orally every 12 hours to patients with creatine clearance of 40-<60 mL / min. The oral dofetilide dose was reduced to 125 μg for patients with a QTc interval 15% above baseline, a QTc interval >500 msec, or a ventricular conduction abnormality with a QTc interval >550 msec. Here, the loading dose is assumed to reach maximum serum concentration at the end of the infusion, Here, patients are monitored to ensure that excessive QT prolongation does not result in cardiac repolarization abnormalities that could lead to life-threatening ventricular arrhythmias. 23. The method of embodiment 22 for reducing the risk of developing atrial fibrillation (AF) and / or atrial flutter (AFL) in patients who have undergone coronary artery bypass surgery (CABS), wherein risk reduction refers to a 30-50% reduction in the risk of developing AF / AFL in the 3-5 days immediately following CABS surgery. 24. The method of embodiment 22, further comprising measuring the patient's QTc before administering the loading dose of dofetilide intravenously, and then every 15 to 30 minutes thereafter until administration of the IV maintenance dose of dofetilide is discontinued or after a sufficient number of oral doses have been administered. 25. The method of embodiment 24, wherein the patient's medical staff determines when a sufficient number of oral doses have been administered. 26. The method of embodiment 25, wherein the patient's medical staff is the patient's surgeons, doctors and / or nurses. 27. The method of embodiment 22, wherein the loading dose is 450-500 μg of dofetilide. 28. The method of embodiment 22, wherein a maintenance dose of 450-500 μg of dofetilide ("IV maintenance dose") is administered to patients with a creatine clearance of 60 mL / min or greater 1-3 hours after completion of the loading dose. 29. The method of embodiment 22, wherein the IV maintenance dose is 450-500 μg of dofetilide. 30. The method of embodiment 22, wherein creatine clearance is 60 mL / min or greater. 31. The method of embodiment 22, wherein the IV maintenance dose is discontinued after 3 to 5 hours. 32. The method of embodiment 22, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) prior to administering the IV maintenance dose to determine the amount of dofetilide appropriate for the IV maintenance dose. 33. The method of embodiment 22, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) before orally administering dofetilide, and determining the amount of dofetilide appropriate for the oral dose. 34. The method of embodiment 22, wherein dofetilide is administered orally once the patient has sufficiently recovered from CABS and the patient is awake and alert after surgery (as determined by the patient's medical staff). 35. The method of embodiment 34, wherein the patient's medical staff is the patient's surgeons, doctors and / or nurses. 36. The method of embodiment 22, wherein the intravenous loading dose is administered over about 30 to 60 minutes. 37. The method of embodiment 22, wherein the intravenous maintenance dose is administered over about 12 hours. 38. The method of embodiment 22, wherein dofetilide is fully loaded within 3 days. 39. The method of embodiment 38, wherein dofetilide is fully loaded when a steady-state blood concentration is reached. 40. The method of embodiment 22, wherein intravenous dofetilide is administered in an initial loading dose and a continuous IV maintenance dose. 41. The method of embodiment 22, wherein intravenous dofetilide administration prevents possible arrhythmias by avoiding excessive blood dofetilide concentrations. 42. The method of embodiment 22, wherein the patient can be given a loading dose of dofetilide by intravenous administration before the patient is conscious and alert after surgery and able to take oral dofetilide. 43. A method of treating a patient who has undergone coronary artery bypass surgery (CABS), comprising the steps of: a. A loading dose of approximately 450-500 μg of dofetilide is administered intravenously over approximately 30-60 minutes to patients in need thereof; b. Approximately 0-4 hours after completion of the loading dose, administer a maintenance dose of approximately 450-500 μg of dofetilide intravenously (hereinafter the "IV maintenance dose") to patients with a creatine clearance of 60 mL / min or greater; c. The IV maintenance dose is administered over approximately 12 hours. d. For patients who have fully recovered from CABS, discontinue the IV maintenance dose. e. Approximately 2-6 hours after discontinuing the IV maintenance dose, administer dofetilide 125 mcg orally every 12 hours to patients with creatine clearance of 20-<40 mL / min. In patients with a 15% increase in QTc from baseline, a QTc of >500 milliseconds, or a ventricular conduction abnormality with a QTc of >550 milliseconds, oral dofetilide administration was discontinued. Here, the loading dose assumes that the maximum serum concentration is reached at the end of the infusion. Here, patients are monitored to ensure that excessive QT prolongation does not lead to cardiac repolarization abnormalities that could result in life-threatening ventricular arrhythmias. 44. The method of embodiment 43 for reducing the risk of developing atrial fibrillation (AF) and / or atrial flutter (AFL) in patients who have undergone coronary artery bypass surgery (CABS), wherein the risk reduction refers to a 30-50% reduction in the risk of developing AF / AFL within 3-5 days immediately following CABS surgery. 45. The method of embodiment 43, further comprising measuring the patient's QTc before administering the loading dose of dofetilide intravenously, and every 15 to 30 minutes thereafter until administration of the intravenous maintenance dose of dofetilide is discontinued or after a sufficient number of oral doses have been administered. 46. ​​The method of embodiment 45, wherein the patient's medical staff determines when a sufficient number of oral doses have been administered. 47. The method of embodiment 46, wherein the patient's medical staff is the patient's surgeon, doctor, and / or nurse. 48. The method of embodiment 43, wherein the loading dose is about 450-500 μg of dofetilide. 49. The method of embodiment 43, wherein a maintenance dose of 450-500 μg of dofetilide ("IV maintenance dose") is administered to patients with a creatine clearance of 60 mL / min or greater 1-3 hours after completion of the loading dose. 50. The method of embodiment 43, wherein the IV maintenance dose is about 450-500 μg of dofetilide. 51. The method of embodiment 43, wherein creatine clearance is 60 mL / min or greater. 52. The method of embodiment 43, wherein a maintenance dose of 450-500 μg of dofetilide ("IV maintenance dose") is administered to patients with a creatine clearance of 60 mL / min or greater 1-3 hours after completion of the loading dose. 53. The method of embodiment 43, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) prior to administering the IV maintenance dose to determine the amount of dofetilide appropriate for the IV maintenance dose. 54. The method of embodiment 43, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) before orally administering dofetilide, and determining the amount of dofetilide appropriate for oral administration. 55. The method of embodiment 43, wherein dofetilide is administered orally once the patient has sufficiently recovered from CABS and the patient is awake and alert after surgery (as determined by the patient's medical staff). 56. The method of embodiment 55, wherein the patient's medical staff is the patient's surgeons, doctors and / or nurses. 57. The method of embodiment 43, wherein the intravenous loading dose is administered over approximately 30 to 60 minutes. 58. The method of embodiment 43, wherein the intravenous maintenance dose is administered over about 12 hours. 59. The method of embodiment 43, wherein dofetilide is fully loaded within 3 days. 60. The method of embodiment 59, wherein dofetilide is fully loaded when a steady-state concentration in the blood is reached. 61. The method of embodiment 43, wherein intravenous dofetilide is administered in an initial loading dose and a continuous IV maintenance dose. 62. The method of embodiment 43, wherein intravenous dofetilide administration prevents possible arrhythmias by avoiding excessive blood dofetilide concentrations. 63. The method of embodiment 43, wherein the patient can be given a loading dose of dofetilide by intravenous administration before the patient is conscious and alert after surgery and able to take oral dofetilide. 64. A method of treating a patient who has undergone coronary artery bypass surgery (CABS), comprising the steps of: a. A loading dose of approximately 450-500 μg of dofetilide is administered intravenously over approximately 30-60 minutes to patients in need thereof; b. Approximately 0-4 hours after completion of the loading dose, administer a maintenance dose of approximately 225-250 μg of dofetilide intravenously (the "IV maintenance dose") to patients with a creatine clearance of 40-<60 mL / min; c. The IV maintenance dose is administered over approximately 12 hours. d. For patients who have fully recovered from CABS, discontinue the above IV maintenance doses and e. Approximately 2 to 6 hours after discontinuing the IV maintenance dose, administer dofetilide 500 μg orally every 12 hours to patients with a creatine clearance of 60 mL / min or greater. The oral dofetilide dose was reduced to 250 μg for patients with a 15% increase in QTc from baseline, patients with a QTc of >500 msec, or patients with ventricular conduction abnormalities with a QTc of >550 msec. Here, the loading dose assumes that the maximum serum concentration is reached at the end of the infusion. Here, patients are monitored to ensure that excessive QT prolongation does not result in cardiac repolarization abnormalities that could lead to life-threatening ventricular arrhythmias. 65. The method of embodiment 64 for reducing the risk of developing atrial fibrillation (AF) and / or atrial flutter (AFL) in patients who have undergone coronary artery bypass surgery (CABS), wherein the risk reduction refers to a 30-50% reduction in the risk of developing AF / AFL within the first 3-5 days after CABS surgery. 66. The method of embodiment 64, further comprising measuring the patient's QTc before administering the loading dose of dofetilide intravenously, and then every 15 to 30 minutes thereafter until administration of the intravenous maintenance dose of dofetilide is discontinued or after a sufficient number of oral doses have been administered. 67. The method of embodiment 66, wherein the patient's medical staff determines when a sufficient number of oral doses have been administered. 68. The method of embodiment 67, wherein the patient's medical staff is the patient's surgeon, doctor, and / or nurse. 69. The method of embodiment 66, wherein the loading dose is 450 to 500 μg of dofetilide. 70. The method of embodiment 66, wherein a maintenance dose of 450-500 μg of dofetilide ("IV maintenance dose") is administered to patients with a creatine clearance of 60 mL / min or greater 1-3 hours after completion of the loading dose. 71. The method of embodiment 66, wherein the IV maintenance dose is 225 to 250 μg of dofetilide. 72. The method of embodiment 66, wherein creatine clearance is 60 mL / min or greater. 73. The method of embodiment 66, wherein a maintenance dose of 450-500 μg of dofetilide ("IV maintenance dose") is administered to patients with a creatine clearance of 60 mL / min or greater 1-3 hours after completion of the loading dose. 74. The method of embodiment 66, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) prior to administering the IV maintenance dose to determine the amount of dofetilide appropriate for the IV maintenance dose. 75. The method of embodiment 66, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) before orally administering dofetilide, and determining the amount of dofetilide appropriate for the oral dose. 76. The method of embodiment 66, wherein dofetilide is orally administered when the patient has sufficiently recovered from CABS and is awake and conscious after surgery (as determined by the patient's medical staff). 77. The method of embodiment 76, wherein the patient's medical staff is the patient's surgeons, doctors and / or nurses. 78. The method of embodiment 66, wherein the intravenous loading dose is administered over about 30 to 60 minutes. 79. The method of embodiment 66, wherein the IV maintenance dose is administered over about 12 hours. 80. The method of embodiment 66, wherein dofetilide is fully loaded within 3 days. 81. The method of embodiment 80, wherein dofetilide is fully loaded when a steady-state concentration in the blood is reached. 82. The method of embodiment 66, wherein intravenous dofetilide is administered in an initial loading dose and a continuous IV maintenance dose. 83. The method of embodiment 66, wherein intravenous dofetilide administration prevents possible arrhythmias by avoiding excessive blood dofetilide concentrations. 84. The method of embodiment 66, wherein the patient can be given a loading dose of dofetilide by intravenous administration before the patient is conscious and alert after surgery and able to take oral dofetilide. 85. A method of treating a patient who has undergone coronary artery bypass surgery (CABS), comprising the steps of: a. Administer a loading dose of approximately 450-500 μg of dofetilide intravenously over approximately 30-60 minutes to a patient in need thereof. b. Approximately 0-4 hours after completion of the loading dose, administer a maintenance dose of approximately 225-250 μg of dofetilide intravenously (the "IV maintenance dose") to patients with a creatine clearance of 40-<60 mL / min; c. The IV maintenance dose is administered over approximately 12 hours. d. For patients who have fully recovered from CABS, discontinue the above IV maintenance doses and e. Approximately 2 to 6 hours after discontinuing the IV maintenance dose, administer dofetilide 250 μg orally every 12 hours to patients with creatine clearance of 40 to less than 60 mL / min. The oral dofetilide dose was reduced to 125 μg for patients with a 15% increase in QTc from baseline, patients with a QTc of >500 msec, or patients with ventricular conduction abnormalities with a QTc of >550 msec. Here, the loading dose assumes that the maximum serum concentration is reached at the end of the infusion. Here, patients are monitored to ensure that excessive QT prolongation does not result in cardiac repolarization abnormalities that could lead to life-threatening ventricular arrhythmias. 86. The method of embodiment 85 for reducing the risk of developing atrial fibrillation (AF) and / or atrial flutter (AFL) in patients who have undergone coronary artery bypass surgery (CABS), wherein risk reduction refers to a 30-50% reduction in the risk of developing AF / AFL in the 3-5 days immediately following CABS surgery. 87. The method of embodiment 85, further comprising measuring the patient's QTc before administering the loading dose of dofetilide intravenously, and then every 15-30 minutes until administration of the IV maintenance dose of dofetilide is discontinued or until a sufficient number of oral doses have been administered. 88. The method of embodiment 87, in which the patient's medical staff determines whether a sufficient number of oral doses have been administered. 89. The method of embodiment 88, wherein the patient's medical staff is the patient's surgeon, doctor and / or nurse. 90. The method of embodiment 85, wherein the loading dose is 450 to 500 μg of dofetilide. 91. The method of embodiment 85, wherein a maintenance dose of 450-500 μg of dofetilide ("IV maintenance dose") is administered to patients with a creatine clearance of 60 mL / min or greater 1-3 hours after completion of the loading dose. 92. The method of embodiment 85, wherein the IV maintenance dose is 225-250 μg of dofetilide. 93. The method of embodiment 85, wherein a maintenance dose of 450-500 μg of dofetilide ("IV maintenance dose") is administered to patients with a creatine clearance of 60 mL / min or greater 1-3 hours after completion of the loading dose. 94. The method of embodiment 85, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) prior to administering the IV maintenance dose to determine the amount of dofetilide appropriate for the IV maintenance dose. 95. The method of embodiment 85, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) before orally administering dofetilide, and determining the amount of dofetilide appropriate for oral administration. 96. The method of embodiment 85, wherein dofetilide is administered orally once the patient has sufficiently recovered from CABS and the patient is awake and alert after surgery (as determined by the patient's medical staff). 97. The method of embodiment 96, wherein the patient's medical staff is the patient's surgeons, doctors and / or nurses. 98. The method of embodiment 85, wherein the intravenous loading dose is administered over approximately 30 to 60 minutes. 99. The method of embodiment 85, wherein the intravenous maintenance dose is administered over about 12 hours. 100. The method of embodiment 85, wherein dofetilide is fully loaded within 3 days. 101. The method of embodiment 100, wherein dofetilide is fully loaded when a steady-state concentration in the blood is reached. 102. The method of embodiment 85, wherein intravenous dofetilide is administered in an initial loading dose and a continuous IV maintenance dose. 103. The method of embodiment 85, wherein intravenous dofetilide administration prevents possible arrhythmias by avoiding excessive blood dofetilide concentrations. 104. The method of embodiment 85, wherein the patient can be given a loading dose of dofetilide by intravenous administration before the patient is conscious and alert after surgery and able to take oral dofetilide. 105. A method of treating a patient who has undergone coronary artery bypass surgery (CABS), comprising the steps of: a. Administer a loading dose of approximately 450-500 μg of dofetilide intravenously over approximately 30-60 minutes to a patient in need thereof. b. Approximately 0-4 hours after completion of the loading dose, administer a maintenance dose of approximately 225-250 μg of dofetilide intravenously (the "IV maintenance dose") to patients with a creatine clearance of 40-<60 mL / min; c. administer the above IV maintenance dose over approximately 12 hours; d. For patients who have fully recovered from CABS, discontinue the above IV maintenance doses and e. Approximately 2-6 hours after discontinuing the IV maintenance dose, administer oral dofetilide 125 mcg every 12 hours to patients with a creatine clearance of 20-<40 mL / min. Discontinue oral dofetilide in patients with a 15% increase in QTc from baseline, a QTc >500 msec, or a ventricular conduction abnormality with a QTc >550 msec. Here, the loading dose is assumed to reach maximum serum concentration at the end of the infusion, Here, patients are monitored to ensure that excessive QT prolongation does not result in cardiac repolarization abnormalities that could lead to life-threatening ventricular arrhythmias. 106. The method of embodiment 105 for reducing the risk of developing atrial fibrillation (AF) and / or atrial flutter (AFL) in patients who have undergone coronary artery bypass surgery (CABS), wherein risk reduction refers to a 30-50% reduction in the risk of developing AF / AFL in the 3-5 days immediately following CABS surgery. 107. The method of embodiment 105, further comprising measuring the patient's QTc before administering the loading dose of dofetilide intravenously, and then every 15 to 30 minutes thereafter until administration of the IV maintenance dose of dofetilide is discontinued or after a sufficient number of oral doses have been administered. 108. The method of embodiment 107, in which the patient's medical staff determines when a sufficient number of oral doses have been administered. 109. The method of embodiment 108, wherein the patient's medical staff is the patient's surgeons, doctors and / or nurses. 110. The method of embodiment 105, wherein the loading dose is 450 to 500 μg of dofetilide. 111. The method of embodiment 105, wherein a maintenance dose of 450-500 μg of dofetilide ("IV maintenance dose") is administered to patients with a creatine clearance of 60 mL / min or greater 1-3 hours after completion of the loading dose. 112. The method of embodiment 105, wherein the IV maintenance dose is 225-250 μg of dofetilide. 113. The method of embodiment 105, wherein a maintenance dose of 450-500 μg of dofetilide ("IV maintenance dose") is administered to patients with a creatine clearance of 60 mL / min or greater 1-3 hours after completion of the loading dose. 114. The method of embodiment 105, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) prior to administering the IV maintenance dose to determine the amount of dofetilide prescribed as the IV maintenance dose. 115. The method of embodiment 105, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) before orally administering dofetilide, and determining the amount of dofetilide appropriate for oral administration. 116. The method of embodiment 105, wherein dofetilide is orally administered once the patient has sufficiently recovered from CABS and is awake and conscious after surgery (as determined by the patient's medical staff). 117. The method of embodiment 116, wherein the patient's medical staff is the patient's surgeons, doctors and / or nurses. 118. The method of embodiment 105, wherein the intravenous loading dose is administered over about 30 to 60 minutes. 119. The method of embodiment 105, wherein the IV maintenance dose is administered over approximately 12 hours. 120. The method of embodiment 105, wherein dofetilide is fully loaded within 3 days. 121. The method of embodiment 120, wherein dofetilide is fully loaded once a steady state blood concentration is reached. 122. The method of embodiment 105, wherein intravenous dofetilide is administered in an initial loading dose and a continuous IV maintenance dose. 123. The method of embodiment 105, wherein intravenous dofetilide administration prevents the possibility of arrhythmias by avoiding excessive blood dofetilide concentrations. 124. The method of embodiment 105, wherein the patient can be loaded with dofetilide by intravenous administration before the patient is conscious and awake after surgery and able to take oral dofetilide. 125. A method of treating a patient who has undergone coronary artery bypass surgery (CABS), comprising the steps of: a. A loading dose of approximately 450-500 μg of dofetilide is administered intravenously over approximately 30-60 minutes to a patient in need thereof; b. Approximately 0-4 hours after completion of the loading dose, administer a maintenance dose of approximately 100-125 μg of dofetilide intravenously (the "IV maintenance dose") to patients with a creatine clearance of less than 20-40 mL / min; c. Administer an IV maintenance dose over approximately 12 hours; d. For patients who have fully recovered from CABS, discontinue IV maintenance doses and e. Approximately 2 to 6 hours after discontinuation of the IV maintenance dose, administer dofetilide 500 μg orally every 12 hours to patients with a creatine clearance of 60 mL / min or greater. The oral dofetilide dose was reduced to 250 μg for patients with a 15% increase in QTc from baseline, patients with a QTc of >500 msec, or patients with ventricular conduction abnormalities with a QTc of >550 msec. Here, the loading dose is used to expect maximum serum concentrations to be reached at the end of the infusion. Here, patients are monitored to ensure that excessive QT prolongation does not result in cardiac repolarization abnormalities that could lead to life-threatening ventricular arrhythmias. 126. The method of embodiment 125 for reducing the risk of developing atrial fibrillation (AF) and / or atrial flutter (AFL) in patients who have undergone coronary artery bypass surgery (CABS), wherein risk reduction refers to a 30-50% reduction in the risk of developing AF / AFL in the 3-5 days immediately following CABS surgery. 127. The method of embodiment 125, further comprising measuring the patient's QTc before administering the loading dose of dofetilide intravenously, and then every 15 to 30 minutes until administration of the intravenous maintenance dose of dofetilide is discontinued or after a sufficient number of oral doses have been administered. 128. The method of embodiment 127, in which the patient's medical staff determines when a sufficient number of oral doses have been administered. 129. The method of embodiment 128, wherein the patient's medical staff is the patient's surgeon, doctor and / or nurse. 130. The method of embodiment 125, wherein the loading dose is 450 to 500 μg of dofetilide. 131. The method of embodiment 125, wherein a maintenance dose of 450-500 μg of dofetilide ("IV maintenance dose") is administered to patients with a creatine clearance of 60 mL / min or greater 1-3 hours after completion of the loading dose. 132. The method of embodiment 125, wherein the IV maintenance dose is 100 to 125 μg of dofetilide. 133. The method of embodiment 125, wherein creatine clearance is 60 mL / min or greater. 134. The method of embodiment 125, in which dofetilide 500 μg is administered orally every 12 hours to patients with a creatine clearance of 60 mL / min or greater, 3 to 5 hours after discontinuing administration of the IV maintenance dose. 135. The method of embodiment 125, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) prior to administering the IV maintenance dose to determine the amount of dofetilide appropriate for the IV maintenance dose. 136. The method of embodiment 125, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) before orally administering dofetilide, and determining the amount of dofetilide appropriate for oral administration. 137. The method of embodiment 125, wherein dofetilide is orally administered once the patient has sufficiently recovered from CABS and is awake and conscious after surgery (as determined by the patient's medical staff). 138. The method of embodiment 137, wherein the patient's medical staff is the patient's surgeons, doctors and / or nurses. 139. The method of embodiment 125, wherein the intravenous loading dose is administered over about 30 to 60 minutes. 140. The method of embodiment 125, wherein the IV maintenance dose is administered over about 12 hours. 141. The method of embodiment 125, wherein dofetilide is fully loaded within 3 days. 142. The method of embodiment 141, wherein dofetilide is fully loaded once a steady state blood concentration is reached. 143. The method of embodiment 125, wherein intravenous dofetilide is administered in an initial loading dose and a continuous IV maintenance dose. 144. The method of embodiment 125, wherein intravenous dofetilide administration prevents the possibility of arrhythmias by avoiding excessive blood dofetilide concentrations. 145. The method of embodiment 125, wherein the patient can be loaded with dofetilide by intravenous administration before the patient is conscious and awake after surgery and able to take oral dofetilide. 146. A method of treating a patient who has undergone coronary artery bypass surgery (CABS), comprising the steps of: a. A loading dose of approximately 450-500 μg of dofetilide is administered intravenously over approximately 30-60 minutes to a patient in need thereof; b. Approximately 0-4 hours after completion of the loading dose, administer a maintenance dose of approximately 100-125 μg of dofetilide intravenously ("IV maintenance dose") to patients with a creatine clearance of 20-<40 mL / min; c. Administer an IV maintenance dose over approximately 12 hours; d. For patients who have fully recovered from CABS, discontinue IV maintenance doses and e. Approximately 2 to 6 hours after discontinuation of the IV maintenance dose, administer dofetilide 250 μg orally every 12 hours to patients with creatine clearance of 40 to <60 mL / min. The oral dofetilide dose was reduced to 125 μg for patients with a 15% increase in QTc from baseline, patients with a QTc of >500 msec, or patients with ventricular conduction abnormalities with a QTc of >550 msec. where the loading dose anticipates reaching maximum serum concentration at the end of the infusion, Here, patients are monitored to ensure that excessive QT prolongation does not result in cardiac repolarization abnormalities that could lead to life-threatening ventricular arrhythmias. 147. The method of embodiment 146 for reducing the risk of developing atrial fibrillation (AF) and / or atrial flutter (AFL) in patients who have undergone coronary artery bypass surgery (CABS), wherein risk reduction refers to a 30-50% reduction in the risk of developing AF / AFL in the 3-5 days immediately following CABS surgery. 148. The method of embodiment 146, further comprising measuring the patient's QTc before administering the loading dose of dofetilide intravenously, and then every 15 to 30 minutes until administration of the intravenous maintenance dose of dofetilide is discontinued or after a sufficient number of oral doses have been administered. 149. The method of embodiment 148, in which the patient's medical staff determines when a sufficient number of oral doses have been administered. 150. The method of embodiment 149, wherein the patient's medical staff is the patient's surgeon, doctor and / or nurse. 151. The method of embodiment 146, wherein the loading dose is 450 to 500 μg of dofetilide. 152. The method of embodiment 146, wherein a maintenance dose of 450-500 μg of dofetilide ("IV maintenance dose") is administered to patients with a creatine clearance of 60 mL / min or greater 1-3 hours after completion of the loading dose. 153. The method of embodiment 146, wherein the IV maintenance dose is 100 to 125 μg of dofetilide. 154. The method of embodiment 146, wherein the IV maintenance dose is discontinued 3 to 5 hours after the IV maintenance dose. 155. The method of embodiment 146, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) prior to administering the IV maintenance dose to determine the amount of dofetilide appropriate for the IV maintenance dose. 156. The method of embodiment 146, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) before orally administering dofetilide to determine an amount of dofetilide appropriate for oral administration. 157. The method of embodiment 146, wherein dofetilide is orally administered once the patient has sufficiently recovered from CABS and is awake and conscious (as determined by the patient's medical staff) after surgery. 158. The method of embodiment 157, wherein the patient's medical staff is the patient's surgeons, doctors, and / or nurses. 159. The method of embodiment 146, wherein the intravenous loading dose is administered over about 30 to 60 minutes. 160. The method of embodiment 146, wherein the IV maintenance dose is administered over about 12 hours. 161. The method of embodiment 146, wherein dofetilide is fully loaded within 3 days. 162. The method of embodiment 161, wherein dofetilide is fully loaded once a steady state blood concentration is reached. 163. The method of embodiment 146, wherein intravenous dofetilide is administered in an initial loading dose and a continuous IV maintenance dose. 164. The method of embodiment 146, wherein intravenous dofetilide administration prevents the possibility of arrhythmias by avoiding excessive blood dofetilide concentrations. 165. The method of embodiment 146, wherein the patient can be loaded with dofetilide by intravenous administration before the patient is conscious and awake after surgery and able to take oral dofetilide. 166. A method of treating a patient who has undergone coronary artery bypass surgery (CABS), comprising the steps of: a. A loading dose of approximately 450-500 μg of dofetilide is administered intravenously over approximately 30-60 minutes to a patient in need thereof; b. Approximately 0-4 hours after completion of the loading dose, administer a maintenance dose of approximately 100-125 μg of dofetilide intravenously ("IV maintenance dose") to patients with a creatine clearance of 20-<40 mL / min; c. administering the above IV maintenance dose over approximately 12 hours; d. For patients who have fully recovered from CABS, discontinue the IV maintenance dose and e. Approximately 2 to 6 hours after discontinuation of the IV maintenance dose, administer dofetilide 125 μg orally every 12 or 24 hours to patients with creatine clearance of 20 to <40 mL / min. In patients with a 15% increase in QTc from baseline, a QTc of >500 milliseconds, or a ventricular conduction abnormality with a QTc of >550 milliseconds, oral dofetilide administration was discontinued. Here, the loading dose is expected to reach maximum serum concentration at the end of the infusion, Here, patients are monitored to ensure that excessive QT prolongation does not lead to cardiac repolarization abnormalities that could result in life-threatening ventricular arrhythmias. 167. The method of embodiment 166 for reducing the risk of developing atrial fibrillation (AF) and / or atrial flutter (AFL) in patients who have undergone coronary artery bypass surgery (CABS), wherein risk reduction refers to a 30-50% reduction in the risk of developing AF / AFL within 3-5 days immediately following CABS surgery. 168. The method of embodiment 166, further comprising measuring the patient's QTc before intravenously administering the loading dose of dofetilide, and then every 15 to 30 minutes thereafter until administration of the IV maintenance dose is discontinued. 169. The method of embodiment 168, in which the patient's medical staff determines when a sufficient number of oral doses have been administered. 170. The method of embodiment 169, wherein the patient's medical staff is the patient's surgeon, doctor and / or nurse. 171. The method of embodiment 166, wherein the loading dose is 450 to 500 μg of dofetilide. 172. The method of embodiment 166, in which a maintenance dose of 450-500 μg of dofetilide ("IV maintenance dose") is administered to patients with a creatine clearance of 60 mL / min or greater 1-3 hours after completion of the loading dose. 173. The method of embodiment 166, wherein the IV maintenance dose is about 100 to 125 μg of dofetilide. 174. The method of embodiment 166, wherein the IV maintenance dose is discontinued 3 to 5 hours after initiation of administration of the IV maintenance dose. 175. The method of embodiment 166, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) prior to administering the IV maintenance dose to determine the amount of dofetilide appropriate for the IV maintenance dose. 176. The method of embodiment 166, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) before orally administering dofetilide, and determining the amount of dofetilide appropriate for the oral dose. 177. The method of embodiment 166, wherein dofetilide is orally administered once the patient has sufficiently recovered from CABS and is awake and conscious (as determined by the patient's medical staff) after surgery. 178. The method of embodiment 177, wherein the patient's medical staff is the patient's surgeon, doctor, and / or nurse. 179. The method of embodiment 166, wherein the intravenous loading dose is administered over about 30 to 60 minutes. 180. The method of embodiment 166, wherein the IV maintenance dose is administered over about 12 hours. 181. The method of embodiment 166, in which dofetilide is fully loaded within 3 days. 182. The method of embodiment 181, wherein dofetilide is fully loaded when a steady-state concentration in the blood is reached. 183. The method of embodiment 166, wherein intravenous dofetilide is administered in an initial loading dose and a continuous IV maintenance dose. 184. The method according to embodiment 166, in which intravenous dofetilide administration prevents the occurrence of arrhythmia by avoiding excessive dofetilide concentrations in the blood. 185. The method of embodiment 166, in which dofetilide can be administered to the patient by intravenous administration before the patient is conscious and alert after surgery and able to take oral dofetilide. B. Intravenous dofetilide to terminate arrhythmia storm after cardioverter-defibrillator implantation

[0090] All references cited herein are incorporated by reference in their entirety.

[0091] definition

[0092] "About" is defined as ±10% of the numerical value.

[0093] Arrhythmia storm (AS) is defined as the occurrence of three or more episodes of sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) within a 24-hour period.

[0094] BID (bid) or bid refers to twice a day or once every 12 hours.

[0095] BP is blood pressure.

[0096] HR is the heart rate.

[0097] IV means intravenous or intravenous administration.

[0098] Dofetilide

[0099] Previous studies have reported that a 10-minute infusion of 1.5 μg / kg of dofetilide resulted in a peak plasma concentration of 1.74 ng / mL (Sedgwick et al., Br. J. Clin Pharmacol 1991:31:515-519 and Rasmussen et al., J. Cardiovascular Pharmacology 20:1992, S96-101). A 3.0 μg / mL infusion resulted in a plasma concentration of 5.35 ng / mL (Sedgwick et al. and Rasmussen et al.). Coz and associates (Clin. Pharmacology & Therapeutics, Therapeutics, 1995;57(5) 533-54) reported that oral administration of 500 μg of dofetilide resulted in a plasma Cmax of 1.9 ng / mL. Therefore, if a single dose achieves 70% of the predicted steady-state concentration, then at steady state, we can estimate that a 500 μg / mL dose administered twice daily for at least five doses will result in a Cmax of 2.7 ng / mL. If we know that a 1.5 μg / kg IV dose will result in a peak concentration of 1.7 ng / mL, assuming linear kinetics, a 2.4 μg / kg dose would reach a peak concentration of 2.7 ng / mL, exposing the patient to the highest predicted steady-state serum concentration, i.e., maximum QTc prolongation. This exposes the patient to potentially maximum arrhythmia risk for the short term while they are monitored in the hospital.

[0100] Intravenous dofetilide kinetics are linear, resulting in a direct relationship between the intravenous dose administered and the resulting serum concentration. Intravenous administration avoids serum concentration "overshoot," avoiding excessive dofetilide blood concentrations and, therefore, the development of arrhythmias. The relationship between serum concentration and QTc interval is well-known and highly correlated.

[0101] Arrhythmic Storm )

[0102] In light of the above, the present invention provides a novel loading dose method for dofetilide that maximizes patient safety by carefully determining the required effective drug blood concentration and confirming that the concentration of dofetilide does not cause excessive QT prolongation, which can lead to cardiac repolarization abnormalities and potentially life-threatening ventricular arrhythmias.

[0103] Thus, in one embodiment, the invention comprises a novel method for terminating an arrhythmia storm in a patient after implantation of an implantable cardioverter-defibrillator. In another embodiment, the method comprises administering a loading dose and a maintenance infusion of dofetilide intravenously. In another embodiment, the method comprises administering dofetilide orally twice daily. In another embodiment, the method comprises administering a loading dose and at least one maintenance infusion of dofetilide intravenously, followed by switching to oral administration.

[0104] In another aspect, the present invention includes a novel method for terminating an arrhythmia storm in a patient after implantation of an implantable cardioverter-defibrillator, comprising the steps of: f Patients presenting with an arrhythmic storm after implantation of an implantable cardioverter-defibrillator were given a loading dose of dofetilide intravenously, where: (A) The loading dose is approximately 450-500 μg of dofetilide. (B) The loading dose is administered over approximately 30 to 60 minutes, Approximately 0-4 hours after the IV loading dose is completed, administer a maintenance infusion of dofetilide intravenously over approximately 12 hours, based on the patient's creatinine clearance (CrCl) as shown in the following table: CrCl IV maintenance fluid oral dose (12 hours or more) (Every 12 hours) ≧60mL / min 450~500μg 500μg 40―<60mL / min 225~250μg 250μg 20―<40mL / min 100~125μg 125μg <20 mL / min Dofetilide is not indicated Dofetilide is not indicated h After the arrhythmia episode has ended and the patient has recovered enough to administer oral dofetilide, IV maintenance fluids should be discontinued. However, if the patient's QTc increases by 15% from baseline or if the QTc is measured as >500 msec or >550 msec and the patient has ventricular conduction abnormalities, reduce the oral dose from 500 mcg to 250 mcg, from 250 mcg to 125 mcg, or discontinue if originally at 125 mcg.

[0105] In another aspect, the method further comprises: Approximately 2-6 hours after discontinuing the maintenance infusion, dofetilide is administered orally every 12 hours, with the oral dose administered determined based on the creatinine clearance of the patient with arrhythmic storm, as shown in the table below: Creatinine clearance (CrCl) Oral dose of dofetilide ≧60mL / min 500μg bid 40―<60mL / min 250μg bid 20―<40mL / min 125μg bid <20mL / min Dofetilide indication However, if the patient's QTc increases by 15% from baseline or if the QTc is measured to be >500 msec or >550 msec in patients with ventricular conduction abnormalities, reduce the oral dose of dofetilide from 500 μg to 250 μg, from 250 μg to 125 μg, or discontinue administration if initially administered at 125 μg.

[0106] In some embodiments, QTc is measured before dofetilide administration to establish a baseline QTc for comparison with subsequent QTc measurements. In some embodiments, QTc is measured during the initial infusion, approximately every 15-30 minutes thereafter for 60 minutes, before the IV maintenance infusion, and before each oral dose. These measurements can be discontinued once the physician confirms that the patient is receiving stable dofetilide. For example, QTc measurements can be discontinued once the loading infusion of dofetilide is completed. Alternatively, QTc measurements can be discontinued after the first oral dose is administered. The physician determines when to discontinue QTc measurements. Examples of sufficient oral doses include one, two, three, four, five, or six oral doses. Typically, steady state is achieved after six oral doses, and no further changes in maximum serum dofetilide concentrations or QT prolongation are expected.

[0107] In another embodiment, the patient has poor left ventricular function.

[0108] In another embodiment, the patient is monitored by electrocardiography to determine the patient's QTc.

[0109] The loading dose for IV administration is typically about 450-500 μg of dofetilide. Examples include about 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, and up to 500 μg of dofetilide. Typically, the loading dose is selected to achieve the maximum serum concentration predicted by oral administration of 500 μg of dofetilide.

[0110] An IV loading dose is typically administered over about 30-60 minutes, for example, about 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 30, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 30, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 minutes.

[0111] In another embodiment, the IV maintenance infusion is initiated at the completion of the loading dose. In another embodiment, the IV maintenance infusion is initiated about 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5 to 6 hours after the loading dose is completed.

[0112] IV maintenance infusions are typically administered for about 12 hours, but can be discontinued at any time. In other embodiments, maintenance infusions are administered for about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours. Additional examples include about 1.5, 2, 2.5, 3, 3.5, or 4 days (or possibly longer).

[0113] IV maintenance infusions can be discontinued as needed (e.g., if the QTc becomes excessively prolonged). This is an advantage of intravenous administration over oral administration: if the patient experiences adverse effects from dofetilide, intravenous administration can be discontinued quickly.

[0114] The dose of IV maintenance fluid depends on the patient's CrCl, as shown in the table below. Creatinine clearance (CrCl) Dofetilide IV maintenance infusion (Over 12 hours) ≧60mL / min 450~500μg 40―<60mL / min 225~250μg 20―<40mL / min 100~125μg <20mL / min Dofetilide not indicated

[0115] For patients with CrCl >60 mL / min, IV maintenance infusions are typically about 450-500 μg of dofetilide, usually administered over about 12 hours (although this may vary as noted above). Examples include about 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, and 500 μg of dofetilide. This corresponds to about 0.625-0.694 μg / min of dofetilide (450 / 720-500 / 720). Alternatively, IV maintenance infusions are about 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, and 0.7 μg / min.

[0116] For patients with a CrCl of 40-<60 mL / min, the IV maintenance infusion is typically about 225-250 μg of dofetilide, typically administered over about 12 hours (although this can vary as noted above). Examples include about 225, 230, 235, 240, and 245-250 μg of dofetilide, which corresponds to about 0.313-0.347 μg / min of dofetilide (225 / 720-250 / 720). In other embodiments, the IV maintenance infusion is about 0.3, 0.31, 0.32, 0.33, 0.34, or 0.35 μg / min.

[0117] For patients with CrCl between 20 and <40 mL / min, the IV maintenance infusion is typically about 100-125 μg of dofetilide, typically administered over about 12 hours (although this can vary as noted above). Examples include about 100, 105, 110, 115, and 120-125 μg of dofetilide. This corresponds to about 0.139-0.174 μg / min of dofetilide (100 / 720-125 / 720). In other embodiments, the IV maintenance infusion is about 0.13, 0.14, 0.15, 0.16, or 0.17-0.18 μg / min.

[0118] Patients typically cannot take oral medications after the termination of an arrhythmia storm (after implantation of an implantable cardioverter-defibrillator). Therefore, one advantage of the present invention is that it allows patients who have undergone arrhythmia storm termination to receive dofetilide before they would normally be able to take oral dofetilide. Once the patient is determined to have recovered sufficiently from the termination of the arrhythmia storm (and implantation of an implantable cardioverter-defibrillator) to be able to take oral dofetilide, the IV maintenance infusion of dofetilide can be discontinued and the patient can be switched to oral dofetilide. The patient's physician will determine when the patient can take oral dofetilide. Typically, patients can take oral medications when they are awake with a normal gag reflex. In some embodiments, this occurs when the patient wakes up after surgery. In other embodiments, the patient may require a longer time after awakening before they can swallow a tablet without aspiration.

[0119] In another embodiment, oral administration is initiated about 1, 2, 3, 4, 5, or 6 hours after the maintenance infusion is discontinued. In another embodiment, oral administration is initiated about 3-6 hours after the maintenance infusion is discontinued.

[0120] Oral dofetilide is available in three capsule sizes: 125, 250, and 500 μg. In another embodiment, patients receive oral dofetilide BID (every 12 hours). Examples of these doses include 125, 250, 375 (e.g., three 125 capsules or 125 + 250 capsules), and 500 μg.

[0121] The standard dose for patients with a creatinine clearance (CrCl) (or calculated GFR (glomerular filtration rate)) greater than 60 mL / min is 500 μg. However, this dose is reduced if the patient's CrCl is <60 mL / min, as shown in the table below: Creatinine clearance (CrCl) Dofetilide oral starting dose ≧60mL / min 500μg, bid 40―<60mL / min 250μg, bid 20―<40mL / min 125μg, bid <20mL / min Dofetilide indication

[0122] Reduce the oral dofetilide dose as needed based on the patient's QTc. For example, if the patient's QTc increases by 15% from baseline or if a QTc of >500 msec or >550 msec is measured in a patient with ventricular conduction abnormalities, reduce the oral dofetilide dose from 500 μg to 250 μg, or from 250 μg to 125 μg, or discontinue if the original dose was 125 μg.

[0123] For patients with a CrCl ≥ 60 mL / min, the oral dose of dofetilide is 500 μg twice daily. In this embodiment, if the patient's QTc increases by 15% over baseline QTc or if a QTc > 500 ms or > 550 ms is measured in the patient with ventricular conduction abnormalities, the oral dose is reduced to 250 μg.

[0124] For patients with a CrCl of 40 to <60 mL / min, the oral dose of dofetilide is 250 μg twice daily, reduced to 125 μg if the patient's QTc increases by 15% from baseline or if a QTc of >500 msec or >550 msec is measured and the patient has ventricular conduction abnormalities.

[0125] For patients with a CrCl of 20-<40 mL / min, the oral dose of dofetilide is 125 μg twice daily. In this embodiment, treatment is discontinued if the patient's QTc increases by 15% over baseline QTc or if the QTc measures >500 msec or >550 msec if the patient has ventricular conduction abnormalities.

[0126] In another embodiment, patients with a CrCl of 20 to <40 mL / min are administered dofetilide 125 μg orally once daily. This once-daily dosing regimen is selected at the discretion of the patient's physician. In this embodiment, treatment is discontinued if the patient's QTc increases by 15% from baseline or measures >550 ms, or >500 ms if the patient has ventricular conduction abnormalities.

[0127] In another embodiment, for patients with a CrCl ≥ 60 mL / min m, the IV maintenance infusion is about 450-500 μg of dofetilide administered over about 12 hours, with an oral dose of 500 μg twice daily. In this embodiment, if the patient's QTc increases by 15% over baseline QTc or if the QTc is > 500 μg, the oral dose is reduced to 250 μg.

[0128] In another embodiment, the patient's CrCl is 40-<60 mL / min, the IV maintenance infusion is about 225-250 μg of dofetilide administered over about 12 hours, and the oral dose is 250 μg of dofetilide twice daily. In this embodiment, the oral dose is reduced to 125 μg if the patient's QTc increases by 15% from baseline QTc or if the QTc is measured to be >500 msec or >550 msec if the patient has ventricular conduction abnormalities.

[0129] In another embodiment, the patient's CrCl is 20-<40 mL / min, the IV maintenance infusion is about 100-125 μg of dofetilide administered over about 12 hours, and the oral dose of dofetilide is 125 μg twice daily. In this embodiment, treatment is discontinued if the patient's QTc increases by 15% from baseline QTc or if a QTc of >500 msec or >550 msec is measured if the patient has ventricular conduction abnormalities.

[0130] In another embodiment, the patient's CrCl is 20-<40 mL / min, the IV maintenance infusion is about 100-125 μg of dofetilide administered over about 12 hours, and the oral dose of dofetilide is 125 μg once daily. In this embodiment, treatment is discontinued if the patient's QTc increases by 15% from baseline QTc or if the QTc measures >500 ms or >550 ms if the patient has ventricular conduction abnormalities.

[0131] A suitable intravenous formulation is described in US Pat. No. 11,364,213.

[0132] Examples of useful dofetilide intravenous solution concentrations include about 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95-100 μg / mL.

[0133] The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The present invention encompasses all combinations of the aspects of the present invention described herein. It is understood that any embodiment of the present invention may be taken in combination with other embodiments to describe additional embodiments. It is also understood that each individual element of an embodiment is intended to be taken separately as an independent embodiment. Furthermore, any element of an embodiment is intended to be combined with any other element of any embodiment to describe additional embodiments.

[0134] Other features of the present invention will become apparent through the following description of exemplary embodiments, which are provided to illustrate the invention and not to limit it. Example

[0135] Example 3

[0136] A patient weighing 70 kg and with a CrCl > 60 mL / min presented with an arrhythmic storm after implantation of an implantable cardioverter-defibrillator. The patient's physician decided to terminate the arrhythmic storm with an injection of dofetilide. The patient's electrocardiogram was continuously monitored. The patient then received the following treatment with dofetilide: (D) Time 0: Intravenous (IV) loading dose: 450 μg, infused over 1 hour, with QTc, HR, and BP measured every 15 minutes. (E) 1 hour later: IV maintenance infusion: 450 μg, 12-hour infusion, started at the end of the loading dose infusion. (F) 16 hours later: Oral administration: 500 μg every 12 hours (BID), starting 3 hours after the end of IV maintenance infusion.

[0137] Figure 1 shows the estimated blood dofetilide concentrations obtained with the above dosing regimen. This graph was obtained by modeling the above dosing regimen. Bayesian PK modeling was performed using the software packages NONMEM® version 7.4 (ICON, Hanover, MD, USA) and MWpharm (Mediware, Prague, CZ). PsN7 (Uppsala University, School of Pharmacy, Uppsala, Sweden) was used for automated procedures. R (version 3.5.1, The R Foundation for Statistical Computing) was used for data preparation, graphical analysis, linear regression analysis, and statistical summaries. The R package "mrgsolve" was used for simulations.

[0138] Step (A): The loading dose (in this example, 450 μg of dofetilide administered IV over 1 hour) is predicted to achieve the maximum serum concentration expected from chronic oral administration of 500 μg of dofetilide. When administered orally, peak serum concentrations are achieved after six twice-daily doses of dofetilide. Peak serum concentrations are typically achieved at the end of the infusion.

[0139] QTc is measured every 15 minutes during the infusion.

[0140] Step (B): At the end of the 1-hour loading IV infusion, begin an IV maintenance infusion of 450 μg of dofetilide over 12 hours (0.625 μg / min). This dose can be maintained until the patient is awake and able to administer dofetilide orally.

[0141] Once the patient is able to tolerate oral dofetilide, the IV dofetilide maintenance is discontinued. Administer dofetilide 500 μg orally BID approximately 3 hours after discontinuation of the IV maintenance infusion.

[0142] If the QTc is prolonged by 15% above baseline or if a QTc of >500 msec (>550 msec in patients with ventricular conduction abnormalities) is observed, reduce the subsequent oral dose to 250 mcg BID (or lower if the initial oral dose is lower; see below).

[0143] If the patient's CrCl is below the normal range, the initial target concentration remains the same, but the oral (maintenance) dose administered is reduced to 250 μg or 125 μg BID (based on the table below). Creatinine clearance (CrCl) Oral dofetilide dose ≧60mL / min 500μg bid 40―<60mL / min 250μg bid 20―<40mL / min 125μg bid <20mL / min Dofetilide not indicated

[0144] Furthermore, in patients who demonstrate excessive QTc prolongation (>500 msec or >550 msec in patients with ventricular conduction abnormalities) after the initial dose, the initial oral dose should be reduced to 250 μg (or 125 μg if the starting oral dose is 250 μg based on the table above), and the predicted peak concentration should be reassessed 4 hours after the onset of QTc. In this way, the predicted blood concentration from chronic oral administration of 250 μg of dofetilide can be easily evaluated while monitoring the QTc.

[0145] Example 4

[0146] A patient weighing 75 kg and with a CrCl of 45 mL / min presented with an arrhythmic storm after implantation of an implantable cardioverter-defibrillator. The attending physician decided to terminate the arrhythmic storm with an injection of dofetilide. The patient's electrocardiogram was continuously monitored. The patient then underwent the following treatment with dofetilide: (A) Time 0: IV loading dose: 450 μg administered over 1 hour. QTc, HR, and BP were measured every 15 minutes. (B) 4 hours later: Maintenance dose: 225 μg administered over 12 hours, 3 hours after the end of the IV loading dose. (C) 21 hours later: Oral administration begins. 250 μg is given orally every 12 hours, starting 5 hours after the end of IV maintenance infusion.

[0147] The present invention is susceptible to numerous modifications and variations in light of the above teachings, and it is therefore to be understood that, within the scope of the appended embodiments, the invention may be practiced other than as specifically described herein.

[0148] B. Arrhythmic Storm Termination 1. A method of terminating an arrhythmia storm in a patient after implantation of an implantable cardioverter-defibrillator, comprising: a Patients presenting with an arrhythmic storm after implantation of an implantable cardioverter-defibrillator were given a loading dose of dofetilide intravenously, where: (A) The loading dose is approximately 450–500 μg of dofetilide. (B) The loading dose is administered over approximately 30 to 60 minutes. b Approximately 0-4 hours after the IV loading dose is completed, administer a maintenance infusion of dofetilide intravenously over approximately 12 hours, based on the patient's creatinine clearance (CrCl) as shown in the table below: CrCl IV maintenance fluid oral dose (more than 12 hours) (every 12 hours) ≧60mL / min 450~500μg 500μg 40-<60mL / min 225-250μg 250μg 20ー<40mL / min 100~125μg 125μg <20mL / min Dofetilide not indicated Dofetilide not indicated c Once the patient has recovered from the arrhythmia episode, discontinue IV maintenance fluids and administer oral dofetilide. d Administer dofetilide orally every 12 hours, approximately 2 to 6 hours after discontinuing IV maintenance fluids. Dosage is determined based on the patient's CrCl, as shown in the table above. However, if the patient's QTc increases by 15% from baseline or if a QTc of >500 msec or >550 msec is measured if the patient has ventricular conduction abnormalities, the oral dose should be reduced from 500 mcg to 250 mcg, from 250 mcg to 125 mcg, or discontinued if originally at 125 mcg. 2. The method of embodiment 1, further comprising measuring the patient's QTc prior to the IV loading dose of dofetilide to establish a baseline QTc, and then measuring the QTc approximately every 15-30 minutes for 60 minutes, before the IV maintenance infusion, and before each oral dose. 3. The method of embodiment 1, wherein the loading dose is about 450 μg. 4. The method of embodiment 1, wherein the loading dose is about 460 μg. 5. The method of embodiment 1, wherein the loading dose is about 470 μg. 6. The method of embodiment 1, wherein the loading dose is about 480 μg. 7. The method of embodiment 1, wherein the loading dose is about 490 μg. 8. The method of embodiment 1, wherein the loading dose is about 500 μg. 9. A loading dose is administered over approximately 30 minutes. 10. The method of embodiment 1, wherein the loading dose is administered over about 40 minutes. 11. The method of embodiment 1, wherein the loading dose is administered over about 50 minutes. 12. The method of embodiment 1, wherein the loading dose is administered over about 60 minutes. 13. The method of embodiment 1, wherein the actual maintenance infusion dose begins at about 0 hours after completion of the loading dose. 14. The method of embodiment 1, wherein the maintenance infusion dose begins about 1 hour after completion of the loading dose. 15. The method of embodiment 1, wherein the maintenance infusion dose is initiated about 2 hours after completion of the loading dose. 16. The method of embodiment 1, wherein the maintenance infusion dose is initiated about 3 hours after completion of the loading dose. 17. The method of embodiment 1, wherein the maintenance infusion is initiated approximately 4 hours after completion of the loading dose. 18. The method of embodiment 1, wherein the patient's CrCl is ≥ 60 mL / min, the IV maintenance infusion is about 450-500 μg administered over about 12 hours, and the oral dose is 500 μg. 19. The method of embodiment 18, wherein the oral dose is reduced to 250 μg if the QTc increases by 15% over the baseline QTc or if a QTc of >500 msec is measured, or >550 msec if the patient has a ventricular conduction abnormality. 20. The method of embodiment 1, wherein the patient has a CrCl of 40-<60 mL / min, the IV maintenance infusion is about 225-250 μg administered over about 12 hours, and the oral dose is 250 μg. 21. The method of embodiment 20, wherein the oral dose is reduced to 125 μg if the QTc increases by 15% over baseline QTc or if a QTc of >500 msec or >550 msec (if the patient has a ventricular conduction abnormality) is measured. 22. The method of embodiment 1, wherein the patient has a CrCl of 20-<40 mL / min, the IV maintenance infusion is about 100-125 μg administered over about 12 hours, and the oral dose is 125 μg. 23. The method of embodiment 22, wherein the oral dosage is discontinued if the QTc increases by 15% over baseline QTc or if a QTc of >500 ms or >550 ms (if the patient has a ventricular conduction abnormality) is measured. Further Embodiments - B. Arrhythmia Termination 1. A method for rapidly terminating an arrhythmia storm in a patient and preventing its recurrence, comprising the steps of: a. A loading dose of approximately 450-500 μg of dofetilide is administered intravenously over approximately 30-60 minutes to patients in need thereof. b. Approximately 0-4 hours after completion of the loading dose, administer a maintenance dose of approximately 450-500 μg of dofetilide intravenously (the "IV maintenance dose") to patients with a creatine clearance of 60 mL / min or greater; c. The IV maintenance dose is administered over approximately 12 hours. d. For patients who have fully recovered from termination of the arrhythmia storm, discontinue IV maintenance doses and e. Approximately 2 to 6 hours after discontinuing the IV maintenance dose, administer dofetilide 500 μg orally every 12 hours to patients with a creatine clearance of 60 mL / min or greater. In patients with a QTc prolongation of 15% from baseline, a QTc of >500 msec, or a ventricular conduction abnormality with a QTc of >550 msec, the oral dofetilide dose was reduced to 250 μg. The loading dose is expected to achieve maximum serum concentrations at the end of the infusion, Patients are monitored to ensure that excessive QT prolongation does not lead to cardiac repolarization abnormalities that could result in life-threatening ventricular arrhythmias. 2. The method of claim 1 for terminating an arrhythmic storm in a patient after implantation of a cardiac defibrillator. 3. The method of embodiment 1, further comprising measuring the patient's QTc prior to intravenous administration of the loading dose of dofetilide to establish a baseline QTc, and then measuring QTc every 15 to 30 minutes during the infusion of the loading dose, and about every 60 minutes thereafter until the patient is stable. 4. The method of embodiment 3, wherein the patient's physician determines when the patient is stable. 5. The method of embodiment 4, wherein the patient can be stabilized after the loading dose of dofetilide is completed or after the first oral dose is administered. 6. The method of embodiment 1, wherein the loading dose is 450-500 μg of dofetilide. 7. The method of embodiment 1, wherein a maintenance dose of 450-500 μg of dofetilide (the "IV maintenance dose") is administered to patients with a creatine clearance of 60 mL / min or greater 1-3 hours after completion of the loading dose. 8. The method of embodiment 1, wherein the IV maintenance dose is about 450-500 μg of dofetilide. 9. The method of embodiment 1, wherein the creatine clearance is 60 mL / min or greater. 10. The method of embodiment 1, wherein 3 to 5 hours after discontinuation of the IV maintenance dose, dofetilide 500 μg is administered orally every 12 hours to patients with a creatine clearance of 60 mL / min or greater. 11. The method of embodiment 1, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) prior to administering the IV maintenance dose to determine the amount of dofetilide appropriate for the IV maintenance dose. 12. The method of embodiment 1, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) before orally administering dofetilide, and determining the amount of dofetilide appropriate for the oral dose. 13. The method of embodiment 1, wherein dofetilide is administered orally to a live patient who has sufficiently recovered from termination of an arrhythmic storm, is awake after surgery, and has an intact gag reflex. 14. The method of embodiment 1, wherein the intravenous loading dose is administered over about 30 to 60 minutes. 15. The method of embodiment 1, wherein the IV maintenance dose is administered over about 12 hours. 16. The method of embodiment 1, wherein the dofetilide is fully loaded within 3 days. 17. The method of embodiment 16, wherein dofetilide is fully loaded once a steady state blood concentration is reached. 18. The method of embodiment 1, wherein intravenous dofetilide is administered in an initial loading dose and a continuous IV maintenance dose. 19. The method of embodiment 1, wherein intravenous dofetilide administration prevents the possibility of arrhythmias by avoiding excessive blood dofetilide concentrations. 20. The method of embodiment 1, wherein the patient can be loaded with dofetilide by intravenous administration before the patient is awake after surgery, has an intact gag reflex, and is able to take oral dofetilide. 21. A method for rapidly terminating an arrhythmia storm in a patient and preventing its recurrence, comprising the steps of: a. A loading dose of approximately 450-500 μg of dofetilide is administered intravenously over approximately 30-60 minutes to patients in need of it. b. Approximately 0-4 hours after the completion of the loading dose, administer a maintenance dose of approximately 450-500 μg of dofetilide intravenously (hereinafter referred to as the "IV maintenance dose") to patients with a creatine clearance of 60 mL / min or greater; c. The IV maintenance dose is administered over approximately 12 hours. d. For patients who have fully recovered after the arrhythmia storm has subsided, discontinue IV maintenance doses and e. Approximately 2-6 hours after discontinuing the IV maintenance dose, administer dofetilide 250 μg orally every 12 hours to patients with creatine clearance of 40-<60 mL / min. The oral dofetilide dose was reduced to 125 μg for patients with a 15% increase in QTc from baseline, patients with a QTc >500 msec, or patients with a QTc >550 msec with ventricular conduction abnormalities. wherein the loading dose is predicted to achieve a maximum serum concentration at the end of the infusion; Here, patients are monitored to ensure that excessive QT prolongation does not lead to cardiac repolarization abnormalities that could result in life-threatening ventricular arrhythmias. 22. The method of embodiment 21 for terminating an arrhythmia storm in a patient after implantation of a cardioverter-defibrillator. 23. The method of embodiment 21, further comprising measuring the patient's QTc prior to intravenous administration of the loading dose of dofetilide to establish a baseline QTc, and then measuring the QTc every 15 to 30 minutes during the infusion of the loading dose, and about every 60 minutes thereafter until the patient is stable. 24. The method of embodiment 23, in which the patient's physician determines when the patient's condition is stable. 25. The method of embodiment 24, wherein the patient is stabilized after the loading dose of dofetilide is completed or after the first oral dose is administered. 26. The method of embodiment 21, wherein the loading dose is 450-500 μg of dofetilide. 27. The method of claim 21, wherein a maintenance dose of 450 to 500 μg of dofetilide ("IV maintenance dose") is administered to patients with a creatine clearance of 60 mL / min or greater 1 to 3 hours after completion of the loading dose. 28. The method of embodiment 21, wherein the IV maintenance dose is about 450-500 μg of dofetilide. 29. The method of embodiment 21, wherein creatine clearance is 60 mL / min or greater. 30. The method of embodiment 21, wherein the IV maintenance dose is discontinued 3 to 5 hours after the IV maintenance dose. 31. The method of embodiment 21, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) prior to administering the IV maintenance dose to determine the amount of dofetilide appropriate for the IV maintenance dose. 32. The method of embodiment 21, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) before orally administering dofetilide, and determining the amount of dofetilide appropriate for the oral dose. 33. The method of embodiment 21, wherein dofetilide is administered orally when the patient has sufficiently recovered from termination of the arrhythmia storm, is awake after surgery, and has an intact gag reflex. 34. The method of embodiment 21, wherein the intravenous loading dose is administered over about 30 to 60 minutes. 35. The method of embodiment 21, wherein the IV maintenance dose is administered over about 12 hours. 36. The method of embodiment 21, wherein dofetilide is fully loaded within 3 days. 37. The method of embodiment 36, wherein dofetilide is fully loaded once a steady state blood concentration is reached. 38. The method of embodiment 21, wherein intravenous dofetilide is administered in an initial loading dose and a continuous IV maintenance dose. 39. The method of embodiment 21, wherein intravenous dofetilide administration prevents the possibility of arrhythmias by avoiding excessive blood dofetilide concentrations. 40. The method of embodiment 21, wherein the patient can be loaded with dofetilide by intravenous administration before the patient is awake after surgery, has an intact gag reflex, and is able to take oral dofetilide. 41. A method for rapidly terminating an arrhythmia storm in a patient and preventing its recurrence, comprising the steps of: a. A loading dose of approximately 450-500 μg of dofetilide is administered intravenously over approximately 30-60 minutes to patients in need thereof. b. Approximately 0-4 hours after completion of the loading dose, administer a maintenance dose of approximately 450-500 μg of dofetilide intravenously (the "IV maintenance dose") to patients with a creatine clearance of 60 mL / min or greater; c. administer the above IV maintenance dose over approximately 12 hours; d. For patients who have fully recovered from termination of the arrhythmia storm, discontinue the above IV maintenance dose. e. Approximately 2-6 hours after discontinuing IV maintenance therapy, administer dofetilide 125 μg orally every 12 hours to patients with creatine clearance of 20-<40 mL / min. In patients with a 15% increase in QTc from baseline, patients with a QTc >500 msec, or patients with ventricular conduction abnormalities with a QTc >550 msec, oral dofetilide administration was discontinued. wherein the loading dose is expected to achieve a maximum serum concentration at the end of the infusion; Patients are monitored to ensure that excessive QT prolongation does not lead to cardiac repolarization abnormalities that could result in life-threatening ventricular arrhythmias. 42. The method of embodiment 41 for terminating an arrhythmia storm in a patient after implantation of a cardiac defibrillator. 43. The method of embodiment 41, further comprising measuring the patient's QTc prior to intravenous administration of the loading dose of dofetilide to establish a baseline QTc, and thereafter measuring the QTc every 15 to 30 minutes during the infusion of the loading dose, and about every 60 minutes thereafter until the patient is stable. 44. The method of embodiment 43, wherein the patient's physician determines when the patient's condition is stable. 45. The method of embodiment 44, wherein the patient may be stable after the loading dose of dofetilide is completed or after the first oral dose is administered. 46. ​​The method of embodiment 41, wherein the loading dose is 450 to 500 μg of dofetilide. 47. The method of embodiment 41, wherein a maintenance dose of 450-500 μg of dofetilide ("IV maintenance dose") is administered to patients with a creatine clearance of 60 mL / min or greater 1-3 hours after completion of the loading dose. 48. The method of embodiment 41, wherein the IV maintenance dose is 450-500 μg of dofetilide. 49. The method of embodiment 41, wherein creatine clearance is 60 mL / min or greater. 50. The method of embodiment 41, in which dofetilide 125 μg is administered orally every 12 hours to patients with a creatine clearance of less than 20 to 40 mL / min 3 to 5 hours after discontinuation of the IV maintenance dose. 51. The method of embodiment 41, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) prior to administering the IV maintenance dose to determine the amount of dofetilide appropriate for the IV maintenance dose. 52. The method of embodiment 41, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) before orally administering dofetilide, and determining the amount of dofetilide appropriate for the oral dose. 53. The method of embodiment 41, in which dofetilide is administered orally when the patient has sufficiently recovered from termination of the arrhythmia storm, is awake after surgery, and has an intact gag reflex. 54. The method of embodiment 41, wherein the intravenous loading dose is administered over about 30 to 60 minutes. 55. The method of embodiment 41, wherein the IV maintenance dose is administered over about 12 hours. 56. The method of embodiment 41, wherein dofetilide is fully loaded within 3 days. 57. The method of embodiment 56, wherein dofetilide is fully loaded once a steady state blood concentration is reached. 58. The method of embodiment 41, wherein intravenous dofetilide is administered in an initial loading dose and a continuous IV maintenance dose. 59. The method of embodiment 41, wherein intravenous dofetilide administration prevents the possibility of arrhythmia by avoiding excessive blood dofetilide concentrations. 60. The method of embodiment 41, wherein the patient can be loaded with dofetilide by intravenous administration before the patient wakes up after surgery, has an intact gag reflex, and is able to take oral dofetilide. 61. A method for rapidly terminating an arrhythmia storm in a patient and preventing its recurrence, comprising the steps of: a. A loading dose of approximately 450-500 μg of dofetilide is administered intravenously over approximately 30-60 minutes to patients in need thereof. b. Approximately 0-4 hours after completion of the loading dose, administer a maintenance dose of approximately 225-250 μg of dofetilide intravenously (the "IV maintenance dose") to patients with a creatine clearance of less than 40-60 mL / min; c. The IV maintenance dose is administered over approximately 12 hours. d. Discontinue IV maintenance doses for patients who have fully recovered from termination of the arrhythmia storm. e. Approximately 2 to 6 hours after discontinuing the IV maintenance dose, administer dofetilide 500 μg orally every 12 hours to patients with a creatine clearance of 60 mL / min or greater. In patients with a 15% increase in QTc from baseline, patients with a QTc >500 msec, or patients with a QTc >550 msec and ventricular conduction abnormalities, the oral dofetilide dose was reduced to 250 μg. The loading dose is expected to achieve maximum serum concentrations at the end of the infusion, Patients are monitored to ensure that excessive QT prolongation does not lead to cardiac repolarization abnormalities that could result in life-threatening ventricular arrhythmias. 62. The method of embodiment 61 for terminating an arrhythmia storm in a patient after implantation of a cardiac defibrillator. 63. The method of embodiment 61, further comprising measuring the patient's QTc prior to intravenous administration of the loading dose of dofetilide to establish a baseline QTc, and thereafter measuring the QTc every 15 to 30 minutes during the infusion of the loading dose, and about every 60 minutes thereafter until the patient is stable. 64. The method of embodiment 63, in which the patient's physician determines when the patient's condition is stable. 65. The method of embodiment 64, wherein the patient is stabilized after the loading dose of dofetilide is completed or after the first oral dose is administered. 66. The method of embodiment 61, wherein the loading dose is 450 to 500 μg of dofetilide. 67. The method of embodiment 61, wherein a maintenance dose of 450-500 μg of dofetilide ("IV maintenance dose") is administered to patients with a creatine clearance of 60 mL / min or greater 1-3 hours after completion of the loading dose. 68. The method of embodiment 61, wherein the IV maintenance dose is 225 to 250 μg of dofetilide. 69. The method of embodiment 61, wherein creatine clearance is 60 mL / min or greater. 70. The method of embodiment 61, in which dofetilide 500 μg is administered orally every 12 hours to patients with a creatine clearance of 60 mL / min or greater 3 to 5 hours after discontinuation of the IV maintenance dose. 71. The method of embodiment 61, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) prior to administering the IV maintenance dose to determine the amount of dofetilide indicated as the IV maintenance dose. 72. The method of embodiment 61, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) before orally administering dofetilide, and determining the amount of dofetilide appropriate for oral administration. 73. The method of embodiment 61, in which dofetilide is administered orally when the patient has sufficiently recovered from the termination of the arrhythmia episode, is awake after surgery, and has an intact gag reflex. 74. The method of embodiment 61, wherein the intravenous loading dose is administered over about 30 to 60 minutes. 75. The method of embodiment 61, wherein the IV maintenance dose is administered over about 12 hours. 76. The method of embodiment 61, in which dofetilide is fully loaded within 3 days. 77. The method of embodiment 76, wherein dofetilide is fully loaded once a steady state blood concentration of dofetilide is reached. 78. The method of embodiment 61, wherein intravenous dofetilide is administered in an initial loading dose and a continuous IV maintenance dose. 79. The method according to embodiment 61, in which intravenous dofetilide administration prevents the occurrence of arrhythmia by avoiding excessive dofetilide concentrations in the blood. 80. The method of embodiment 61, wherein the patient can be loaded with dofetilide by intravenous administration before the patient awakens after surgery, has an intact gag reflex, and is able to take oral dofetilide. 81. A method for rapidly terminating an arrhythmia storm in a patient and preventing its recurrence, comprising the steps of: a. A loading dose of approximately 450-500 μg of dofetilide is administered intravenously over approximately 30-60 minutes to patients in need thereof. b. Approximately 0-4 hours after completion of the loading dose, administer a maintenance dose of approximately 225-250 μg of dofetilide intravenously ("IV maintenance dose") to patients with a creatine clearance of 40-<60 mL / min; c. The IV maintenance dose is administered over approximately 12 hours. d. For patients who have fully recovered from termination of the arrhythmia storm, discontinue IV maintenance doses and e. Approximately 2 to 6 hours after discontinuing the IV maintenance dose, administer dofetilide 250 μg orally every 12 hours to patients with a creatine clearance of 40 to <60 mL / min. In this case, the oral dofetilide dose was reduced to 125 μg for patients with a 15% increase in QTc from baseline, patients with a QTc of >500 msec, or patients with ventricular conduction abnormalities with a QTc of >550 msec. The loading dose is expected to achieve maximum serum concentrations at the end of the infusion, Monitor patients to ensure that excessive QT prolongation does not lead to cardiac repolarization abnormalities that could result in life-threatening ventricular arrhythmias. 82. The method of embodiment 81 for terminating an arrhythmia storm in a patient after implantation of a cardiac defibrillator. 83. The method of embodiment 81, further comprising measuring the patient's QTc prior to intravenous administration of the loading dose of dofetilide to establish a baseline QTc, and then measuring QTc every 15 to 30 minutes during the infusion of the loading dose, and about every 60 minutes thereafter until the patient is stable. 84. The method of embodiment 83, in which the patient's physician determines the patient's stability. 85. The method of embodiment 84, wherein the patient may be stabilized after the loading dose of dofetilide is completed or after the first oral dose is administered. 86. The method of embodiment 81, wherein the loading dose is 450 to 500 μg of dofetilide. 87. The method of embodiment 81, wherein a maintenance dose of 450-500 μg of dofetilide ("IV maintenance dose") is administered to patients with a creatine clearance of 60 mL / min or greater 1-3 hours after completion of the loading dose. 88. The method of embodiment 81, wherein the IV maintenance dose is 225-250 μg of dofetilide. 89. The method of embodiment 81, in which dofetilide 250 μg is administered orally every 12 hours to patients with a creatine clearance of less than 40 to 60 mL / min 2 to 5 hours after discontinuation of the IV maintenance dose. 90. The method of embodiment 81, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) prior to administering the IV maintenance dose to determine the amount of dofetilide appropriate for the IV maintenance dose. 91. The method of embodiment 81, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) before orally administering dofetilide, and determining the amount of dofetilide appropriate for the oral dose. 92. The method of embodiment 81, wherein dofetilide is administered orally when the patient has sufficiently recovered from termination of the arrhythmia storm, is awake after surgery, and has an intact gag reflex. 93. The method of embodiment 81, wherein the intravenous loading dose is administered over about 30 to 60 minutes. 94. The method of embodiment 81, wherein the IV maintenance dose is administered over about 12 hours. 95. The method of embodiment 81, in which dofetilide is fully loaded within 3 days. 96. The method of embodiment 95, wherein dofetilide is fully loaded once a steady state blood concentration is reached. 97. The method of embodiment 81, wherein intravenous dofetilide is administered in an initial loading dose and a continuous IV maintenance dose. 98. The method of embodiment 81, wherein intravenous dofetilide administration prevents the possibility of arrhythmia by avoiding excessive blood dofetilide concentrations. 99. The method of embodiment 81, wherein the patient can be loaded with dofetilide by intravenous administration before the patient wakes up after surgery, has an intact gag reflex, and is able to take oral dofetilide. 100. A method for rapidly terminating an arrhythmia storm in a patient and preventing its recurrence, comprising the steps of: a. A loading dose of approximately 450-500 μg of dofetilide is administered intravenously over approximately 30-60 minutes to patients in need thereof. b. Approximately 0-4 hours after completion of the loading dose, administer a maintenance dose of approximately 225-250 μg intravenously (the "IV maintenance dose"); c. Administer the above IV maintenance dose over approximately 12 hours. d. For patients who have fully recovered from termination of the arrhythmia storm, discontinue IV maintenance doses and e. Approximately 2 to 6 hours after discontinuing the IV maintenance dose, administer dofetilide 125 mcg orally every 12 hours to patients with creatine clearance of 20-<60 mL / min. In patients with a 15% increase in QTc from baseline, patients with a QTc >500 msec, or patients with ventricular conduction abnormalities with a QTc >550 msec, oral dofetilide administration was discontinued. wherein the loading dose is expected to achieve a maximum serum concentration at the end of the infusion; Monitor patients to ensure that excessive QT prolongation does not lead to cardiac repolarization abnormalities that could result in life-threatening ventricular arrhythmias. 101. The method of embodiment 100 for terminating an arrhythmia storm in a patient after implantation of a cardiac defibrillator. 102. The method of embodiment 100, further comprising measuring the patient's QTc prior to intravenous administration of the loading dose of dofetilide to establish a baseline QTc, and then measuring the QTc every 15 to 30 minutes during the infusion of the loading dose, and then approximately every 60 minutes thereafter until the patient is stable. 103. The method of embodiment 102, in which the patient's physician determines whether the patient's condition is stable. 104. The method of embodiment 103, wherein the patient's condition may be stable after the loading infusion of dofetilide is completed or after the first oral dose is administered. 105. The method of embodiment 100, wherein the loading dose is 450 to 500 μg of dofetilide. 106. The method of embodiment 100, wherein a maintenance dose of 450-500 μg of dofetilide ("IV maintenance dose") is administered to patients with a creatine clearance of 60 mL / min or greater 1-3 hours after completion of the loading dose. 107. The method of embodiment 100, wherein the IV maintenance dose is 225 to 250 μg of dofetilide. 108. The method of embodiment 100, wherein 2 to 5 hours after discontinuation of the IV maintenance dose, dofetilide 125 μg is administered orally every 12 hours to patients with a creatine clearance of 20-<40 mL / min. 109. The method of embodiment 100, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) prior to administration of the IV maintenance dose to determine the amount of dofetilide appropriate for the IV maintenance dose. 110. The method of embodiment 100, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) before orally administering dofetilide, and determining the amount of dofetilide appropriate for the oral dose. 111. The method of embodiment 100, wherein dofetilide is administered orally when the patient has sufficiently recovered from termination of the arrhythmia storm, is awake after surgery, and has an intact gag reflex. 112. The method of embodiment 100, wherein the intravenous loading dose is administered over about 30 to 60 minutes. 113. The method of embodiment 100, wherein the IV maintenance dose is administered over approximately 12 hours. 114. The method of embodiment 100, in which dofetilide is fully loaded within 3 days. 115. The method of embodiment 114, wherein dofetilide is fully loaded when a steady-state concentration in the blood is reached. 116. The method of embodiment 100, wherein intravenous dofetilide is administered in an initial loading dose and a continuous IV maintenance dose. 117. The method according to embodiment 100, in which intravenous dofetilide administration prevents the occurrence of arrhythmia by avoiding excessive dofetilide concentrations in the blood. 118. The method of embodiment 100, in which a loading dose of dofetilide can be administered intravenously before the patient regains consciousness after surgery, has an intact gag reflex, and is able to take oral dofetilide. 119. A method for rapidly terminating an arrhythmia storm in a patient and preventing its recurrence, comprising the steps of: a. A loading dose of approximately 450-500 μg of dofetilide is administered intravenously over approximately 30-60 minutes to patients in need. b. Approximately 0-4 hours after completion of the loading dose, administer a maintenance dose of approximately 100-125 μg of dofetilide intravenously (the "IV maintenance dose") to patients with a creatine clearance of 20-<40 mL / min; c. The IV maintenance dose is administered over approximately 12 hours. d. For patients who have fully recovered after the arrhythmia storm has subsided, discontinue IV maintenance doses and e. Approximately 2 to 6 hours after discontinuing the IV maintenance dose, administer dofetilide 500 μg orally every 12 hours to patients with a creatine clearance of 60 mL / min or greater. The oral dofetilide dose was reduced to 250 μg for patients with a 15% increase in QTc from baseline, patients with a QTc >500 msec, or patients with ventricular conduction abnormalities with a QTc >550 msec. Here, the loading dose is expected to reach maximum serum concentrations at the end of the infusion, Patients are monitored to ensure that excessive QT prolongation does not lead to cardiac repolarization abnormalities that could result in life-threatening ventricular arrhythmias. 120. The method of embodiment 119 for terminating an arrhythmia storm in a patient after implantation of a cardioverter-defibrillator. 121. The method of embodiment 119, further comprising measuring the patient's QTc prior to intravenous administration of the loading dose of dofetilide to establish a baseline QTc, and then measuring the QTc every 15 to 30 minutes during the infusion of the loading dose, and about every 60 minutes thereafter until the patient is stable. 122. The method of embodiment 121, in which the patient's physician determines when the patient's condition is stable. 123. The method of embodiment 122, in which the patient may be stable after the loading dose of dofetilide is completed or after the first oral dose is administered. 124. The method of embodiment 119, wherein the loading dose is 450 to 500 μg of dofetilide. 125. The method of embodiment 119, wherein the loading dose of dofetilide is 450 to 500 μg. 126. The method of embodiment 119, wherein the loading dose of dofetilide is 450 to 500 μg. 127. The method of embodiment 119, wherein the loading dose of dofetilide is 450 to 500 μg. 128. The method of embodiment 119, wherein the loading dose of dofetilide is 450 to 500 μg. 129. The method of embodiment 119, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) prior to administering the IV maintenance dose to determine the amount of dofetilide appropriate for the IV maintenance dose. 130. The method of embodiment 119, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) before orally administering dofetilide, and determining the amount of dofetilide appropriate for the oral dose. 131. The method of embodiment 119, in which dofetilide is administered orally when the patient has sufficiently recovered from termination of the arrhythmia storm, is awake after surgery, and has an intact gag reflex. 132. The method of embodiment 119, wherein the intravenous loading dose is administered over about 30 to 60 minutes. 133. The method of embodiment 119, wherein the IV maintenance dose is administered over about 12 hours. 134. The method of embodiment 119, wherein dofetilide is fully loaded within 3 days. 135. The method of embodiment 134, wherein dofetilide is fully loaded once a steady state blood concentration is reached. 136. The method of embodiment 119, wherein intravenous dofetilide is administered in an initial loading dose and a continuous IV maintenance dose. 137. The method of embodiment 119, wherein intravenous dofetilide administration prevents the possibility of arrhythmia by avoiding excessive blood dofetilide concentrations. 138. The method of embodiment 119, wherein the patient can be loaded with dofetilide by intravenous administration before the patient wakes up after surgery, has an intact gag reflex, and is able to take oral dofetilide. 139. A method for rapidly terminating an arrhythmia storm in a patient and preventing its recurrence, comprising the steps of: a. A loading dose of approximately 450-500 μg of dofetilide is administered intravenously over approximately 30-60 minutes to patients in need thereof. b. Approximately 0-4 hours after completion of the loading dose, administer a maintenance dose of approximately 100-125 μg of dofetilide intravenously (the "IV maintenance dose") to patients with a creatine clearance of 20-<40 mL / min; c. administer the above IV maintenance dose over approximately 12 hours; d. For patients who have fully recovered from termination of the arrhythmia storm, discontinue IV maintenance doses and e. Approximately 2 to 6 hours after discontinuing the IV maintenance dose, administer dofetilide 250 μg orally every 12 hours to patients with a creatine clearance of 40 to <60 mL / min. In patients with a 15% increase in QTc from baseline, patients with a QTc >500 msec, or patients with ventricular conduction abnormalities with a QTc >550 msec, the oral dofetilide dose was reduced to 125 μg. Here, the loading dose is expected to reach maximum serum concentrations at the end of the infusion, Additionally, monitor patients for excessive QT prolongation, which may lead to cardiac repolarization abnormalities and potentially life-threatening ventricular arrhythmias. 140. The method of embodiment 139 for terminating an arrhythmia storm in a patient after implantation of a cardiac defibrillator. 141. The method of embodiment 139, further comprising measuring the patient's QTc prior to intravenous administration of the loading dose of dofetilide to establish a baseline QTc, and then measuring QTc every 15 to 30 minutes during the infusion of the loading dose, and about every 60 minutes thereafter until the patient is stable. 142. The method of embodiment 141, in which the patient's physician determines when the patient's condition is stable. 143. The method of embodiment 142, wherein the patient may be stable after the loading dose of dofetilide is completed or after the first oral dose is administered. 144. The method of embodiment 139, wherein the loading dose is 450 to 500 μg of dofetilide. 145. The method of embodiment 139, wherein a maintenance dose of 450-500 μg of dofetilide ("IV maintenance dose") is administered to patients with a creatine clearance of 60 mL / min or greater 1-3 hours after completion of the loading dose. 146. The method of embodiment 139, wherein the loading dose is 450 to 500 μg of dofetilide. 147. The method of embodiment 139, in which dofetilide 250 μg is administered orally every 12 hours to patients with a creatine clearance of less than 40 to 60 mL / min 2 to 5 hours after cessation of IV maintenance administration. 148. The method of embodiment 139, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) prior to administering the IV maintenance dose to determine the amount of dofetilide prescribed for the IV maintenance dose. 149. The method of embodiment 139, further comprising measuring the patient's creatine clearance as an approximation to determine the amount of dofetilide prescribed for the IV maintenance dose. 150. The method of embodiment 139, wherein dofetilide is administered orally to a patient who has sufficiently recovered from termination of the arrhythmia storm and whose gag reflex is intact upon awakening after surgery. 151. The method of embodiment 139, wherein the intravenous loading dose is administered over about 30 to 60 minutes. 152. The method of embodiment 139, wherein the IV maintenance dose is administered over about 12 hours. 153. The method of embodiment 139, wherein dofetilide is fully loaded within 3 days. 154. The method of embodiment 153, wherein dofetilide is fully loaded once a steady state blood concentration is reached. 155. The method of embodiment 139, wherein intravenous dofetilide is administered in an initial loading dose and a continuous IV maintenance dose. 156. The method of embodiment 139, wherein intravenous dofetilide administration prevents the possibility of arrhythmia by avoiding excessive blood dofetilide concentrations. 157. The method of embodiment 139, wherein the patient can be loaded with dofetilide by intravenous administration before the patient wakes up after surgery, has an intact gag reflex, and is able to take oral dofetilide. 158. A method for rapidly terminating an arrhythmia storm in a patient and preventing its recurrence, comprising the steps of: a. A loading dose of approximately 450-500 μg of dofetilide is administered intravenously over approximately 30-60 minutes to patients in need thereof. b. Approximately 0-4 hours after completion of the loading dose, administer a maintenance dose of approximately 100-125 μg of dofetilide intravenously ("IV maintenance dose") to patients with a creatine clearance of 20-<40 mL / min; c. administer the above IV maintenance dose over approximately 12 hours; d. For patients who have fully recovered from termination of the arrhythmia storm, discontinue IV maintenance doses and e. Approximately 2-6 hours after discontinuing IV maintenance therapy, administer dofetilide 125 mcg orally every 12 or 24 hours to patients with creatine clearance of 20-<40 mL / min. In patients with a 15% increase in QTc from baseline, patients with a QTc >500 msec, or patients with ventricular conduction abnormalities with a QTc >550 msec, oral dofetilide administration was discontinued. The loading dose is expected to achieve maximum serum concentrations at the end of the infusion, Patients are monitored to ensure that excessive QT prolongation does not lead to cardiac repolarization abnormalities that could result in life-threatening ventricular arrhythmias. 159. The method of embodiment 158 ​​for terminating an arrhythmia storm in a patient after implantation of a cardiac defibrillator. 160. The method of embodiment 158, further comprising measuring the patient's QTc prior to intravenous administration of the loading dose of dofetilide to establish a baseline QTc, and then measuring QTc every 15 to 30 minutes during the infusion of the loading dose, and about every 60 minutes thereafter until the patient is stable. 161. The method of embodiment 160, in which the patient's physician determines when the patient's condition is stable. 162. The method of embodiment 161, wherein the patient may be stable after the loading dose of dofetilide is completed or after the first oral dose is administered. 163. The method of embodiment 158, wherein the loading dose is 450 to 500 μg of dofetilide. 164. The method of embodiment 158, wherein a maintenance dose of 450-500 μg of dofetilide ("IV maintenance dose") is administered to patients with a creatine clearance of 60 mL / min or greater 1-3 hours after completion of the loading dose. 165. The method of embodiment 158, wherein the loading dose is 450 to 500 μg of dofetilide. 166. The method of embodiment 158, wherein the IV maintenance dose is discontinued after 3 to 5 hours. 167. The method of embodiment 158, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) prior to administering the IV maintenance dose to determine the amount of dofetilide appropriate for the IV maintenance dose. 168. The method of embodiment 158, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) before orally administering dofetilide, and determining the amount of dofetilide appropriate for oral administration. 169. The method of embodiment 158, in which dofetilide is administered orally when the patient has sufficiently recovered from the termination of the arrhythmia episode, is awake after surgery, and has an intact gag reflex. 170. The method of embodiment 158, wherein the intravenous loading dose is administered over about 30 to 60 minutes. 171. The method of embodiment 158, wherein the IV maintenance dose is administered over about 12 hours. 172. The method of embodiment 158, in which dofetilide is fully loaded within 3 days. 173. The method of embodiment 172, wherein dofetilide is fully loaded when a steady state blood concentration of dofetilide is reached. 174. The method of embodiment 158, wherein intravenous dofetilide is administered in an initial loading dose and a continuous IV maintenance dose. 175. The method according to embodiment 158 ​​of the embodiment, in which intravenous dofetilide administration prevents the occurrence of arrhythmia by avoiding excessive dofetilide concentrations in the blood. 176. The method of embodiment 158, in which dofetilide can be administered to the patient by intravenous administration before the patient is awake after surgery, has an intact gag reflex, and is able to take oral dofetilide. C. Intravenous dofetilide to improve atrial fibrillation / flutter

[0149] All references cited herein are incorporated by reference in their entirety.

[0150] definition

[0151] AF is atrial fibrillation.

[0152] AFL is atrial flutter and is very similar to AF. Patients with AFL usually experience more regular symptoms (e.g., a less irregular heart rate).

[0153] "About" is defined as ±10% of the numerical value.

[0154] BID or bid or bid refers to twice a day or once every 12 hours.

[0155] BP is blood pressure.

[0156]

[0156] HR is the heart rate.

[0157] IV means given intravenously or into a vein.

[0158] Severe AF / AFL refers to the degree of symptoms a patient exhibits. AF / AFL can be asymptomatic, symptomatic, or severe. Symptomatic patients may experience palpitations, dizziness, decreased exercise capacity, or presyncope. Severe AF / AFL refers to patients with symptoms reflecting more severe hemodynamic compromise. Severe AF / AFL may include shortness of breath (SOB), dyspnea, chest pain (angina), orthopnea, syncope (temporary loss of consciousness), and diaphoresis.

[0159] Dofetilide

[0160] Previous studies have reported that a single 1.5 μg / kg dose of dofetilide administered intravenously over 10 minutes resulted in a peak plasma concentration of 1.74 ng / mL (Sedgwick et al, Br. J. Clin Pharmacol 1991:31:515-519 and Rasmussen et al J. Cardiovascular Pharmacology 20:1992, S96-101). A 3.0 μg / mL infusion resulted in a plasma concentration of 5.35 ng / mL (Sedgwick et al. and Rasmussen et al.). Coz and associates (Clin. Pharmacology & Therapeutics, 1995;57(5) 533-54) reported a plasma Cmax of 1.9 ng / mL following oral administration of 500 μg of dofetilide. Therefore, if a single dose achieves 70% of the predicted steady-state concentration, then at steady state, a Cmax of 2.7 ng / mL can be estimated for at least five doses of 500 μg / mL twice daily. Given that a 1.5 μg / kg intravenous dose results in a peak concentration of 1.7 ng / mL, assuming linear kinetics, a 2.4 μg / kg dose would reach a peak concentration of 2.7 ng / mL, exposing the patient to the predicted peak serum concentration at steady state and, therefore, the greatest QTc prolongation. This potentially exposes the patient to the greatest risk of arrhythmias within a short period of inpatient monitoring.

[0161] Because IV dofetilide has linear kinetics, there is a direct relationship between the IV dose of dofetilide administered and the resulting serum concentration. Intravenous administration avoids serum concentration "overshoot," which can lead to excessive dofetilide blood concentrations and the associated arrhythmias. The relationship between serum concentration and QTc interval is well known and highly correlated.

[0162] AF / AFL conversion (Conversion)

[0163] In light of the above, the present invention provides a novel method for loading dofetilide that maximizes patient safety by carefully achieving the minimum necessary effective blood concentration to avoid excessive QT prolongation, which can cause abnormal cardiac repolarization and lead to life-threatening ventricular arrhythmias.

[0164] Accordingly, in one embodiment, the present invention provides a novel method for converting atrial fibrillation (AF) or atrial flutter (AFL) in critically ill patients, the method comprising administering dofetilide intravenously (IV).

[0165] In some embodiments, an IV dofetilide loading dose converts the patient to sinus rhythm. In these embodiments, the patient is then switched to oral dofetilide (e.g., BID).

[0166] In some embodiments, the patient does not return to sinus rhythm with an IV dofetilide loading dose. In these embodiments, cardioversion is performed. In some embodiments, the cardioversion patient is unable to take oral medications. In these embodiments, an IV maintenance dose is administered until the patient is able to take oral medications. At this point, the patient is switched to oral dofetilide (e.g., BID).

[0167] In another aspect, the present invention comprises a novel method of reversing atrial fibrillation (AF) or atrial flutter (AFL) in a patient presenting with severe AF or AFL, comprising the steps of: j Patients with severe atrial fibrillation or AFL received a loading dose of intravenous dofetilide. (A) The loading dose is approximately 450–500 μg of dofetilide. (B) The loading dose is administered over approximately 30 to 60 minutes. k Chemical transformation If the patient is converted to sinus rhythm, approximately 0-4 hours after completion of the IV loading dose, administer dofetilide orally every 12 hours, with the oral dose administered being determined based on the patient's creatinine clearance (CrCl), as shown in the table below: CrCl IV maintenance infusion oral dose (more than 12 hours) (every 12 hours) ≧60mL / min 450~500μg 500μg 40―<60mL / min 225~250μg 250μg 20―<40mL / min 100~125μg 125μg <20 mL / min Dofetilide not indicated Dofetilide not indicated l Chemical conversion failure Alternatively, if sinus rhythm does not occur after completion of IV stress injection, perform electrical cardioversion. Approximately 0-1 hour after cardioversion, administer a maintenance infusion of dofetilide over 3-12 hours, with the maintenance dose based on the patient's CrCl based on the 12-hour infusion shown in the table above. n Once the patient has recovered from cardioversion and is able to receive oral dofetilide, discontinue IV maintenance therapy; and Approximately 2-6 hours after discontinuing IV maintenance, administer dofetilide orally every 12 hours, with the oral dose administered based on the patient's CrCl as shown in the table above. However, if the patient's QTc increases by 15% from baseline or if the QTc is measured to be >500 msec or >550 msec if the patient has ventricular conduction abnormalities, reduce the oral dose from 500 mcg to 250 mcg, from 250 mcg to 125 mcg, or discontinue if initially at 125 mcg.

[0168] In some embodiments, QTc is measured before dofetilide administration to establish a baseline QTc value and compare it to subsequent QTc measurements. In some embodiments, QTc is measured during the initial infusion and approximately every 15 to 30 minutes thereafter for 60 minutes, before the IV maintenance infusion, and before each oral dose. These measurements can be discontinued once the physician confirms that the patient is receiving stable dofetilide. For example, QTc measurements can be discontinued after the loading infusion of dofetilide is complete. Alternatively, QTc measurements can be discontinued after the first oral dose is completed. The physician determines when to discontinue QTc measurements. Examples of sufficient oral doses include one, two, three, four, five, or six oral doses. After six oral doses, steady state is typically achieved, and no further changes in maximum serum dofetilide concentrations or QT prolongation are expected.

[0169] In another embodiment, the patient is monitored by electrocardiography to determine the patient's QTc.

[0170] In some embodiments, the IV loading dose is about 450-500 μg of dofetilide. Examples include about 450, 455, 460, 465, 470, 475, 480, 485, 490, 495-500 μg of dofetilide. Typically, an amount is selected that achieves the maximum serum concentration predicted by oral administration of 500 μg of dofetilide.

[0171] In some embodiments, the IV loading dose is administered over about 30-60 minutes, including about 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 30, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 30, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, etc.

[0172] Patients who are chemically converted by an IV dofetilide loading dose can usually receive oral dofetilide.

[0173] Patients who require cardioversion are usually unable to take oral medications immediately after the procedure. In these situations, an intravenous maintenance infusion of dofetilide is used. Once the patient is deemed sufficiently recovered from cardioversion to take oral dofetilide, the IV maintenance infusion of dofetilide can be discontinued and the patient can be switched to oral dofetilide. The patient's physician or representative determines when the patient can take oral dofetilide. Oral medications can usually be taken when the patient is awake and able to swallow with an intact swallowing reflex. In some cases, this occurs when the patient awakens after the procedure. In other cases, it may take longer for the patient to awaken and be able to swallow a tablet without aspiration.

[0174] In another embodiment, the IV maintenance infusion is initiated at the completion of the loading infusion. In another embodiment, the IV maintenance infusion is initiated about 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5 to 6 hours after the loading dose is completed.

[0175] IV maintenance infusions are typically administered for about 12 hours, but can be discontinued at any time. In other embodiments, maintenance infusions are administered for about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours. Additional examples include about 1.5, 2, 2.5, 3, 3.5, or 4 days (or possibly longer).

[0176] IV maintenance fluids can be discontinued if necessary (e.g., due to QTc prolongation). This is an advantage of intravenous administration compared with oral therapy. If the patient experiences side effects from dofetilide, IV maintenance fluids can be discontinued immediately.

[0177] The amount of IV maintenance fluid administered depends on the patient's CrCl, as shown in the table below: Creatinine clearance (CrCl) IV maintenance infusion of dofetilide (Over 12 hours) 60mL / min or more 450~500μg 40―<60mL / min 225~250μg 20―<40mL / min 100~125μg <20mL / min Dofetilide not indicated

[0178] For patients with CrCl ≥ 60 mL / min, the IV maintenance dose is typically about 450-500 μg of dofetilide, typically administered over about 12 hours (although this may vary as noted above). Examples include about 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, and 500 μg of dofetilide, which corresponds to about 0.625-0.694 μg / min of dofetilide (450 / 720-500 / 720). In other embodiments, the IV maintenance dose is about 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69-0.7 μg / min.

[0179] For patients with CrCl between 40 and <60 mL / min, the IV maintenance dose is typically about 225-250 μg of dofetilide, typically administered over about 12 hours (although this may vary as noted above). Examples include about 225, 230, 235, 240, and 245-250 μg of dofetilide. This corresponds to about 0.313-0.347 μg / min of dofetilide (225 / 720-250 / 720). In other embodiments, the IV maintenance dose is about 0.3, 0.31, 0.32, 0.33, or 0.34-0.35 μg / min.

[0180] For patients with CrCl between 20 and <40 mL / min, the IV maintenance dose is typically about 100-125 μg of dofetilide, typically administered over about 12 hours (although this may vary as noted above). Examples include about 100, 105, 110, 115, and 120-125 μg of dofetilide. This corresponds to about 0.139-0.174 μg / min of dofetilide (100 / 720-125 / 720). In other embodiments, the IV maintenance dose is about 0.13, 0.14, 0.15, 0.16, or 0.17-0.18 μg / min.

[0181] In another embodiment, oral administration is initiated about 1, 2, 3, 4, 5, 6, 7, 8, 9 to 10 hours after administration of the maintenance dose has stopped. In another embodiment, oral administration is initiated about 3 to 6 hours after administration of the maintenance dose has stopped.

[0182] Oral dofetilide is available in three capsule sizes: 125, 250, and 500 μg. In another embodiment, patients are orally administered dofetilide twice daily (every 12 hours). Examples of these doses include 125, 250, 375 (e.g., 125 capsules x 3, or 125 + 250 capsules), and 500 μg.

[0183] The standard dose for patients with a creatinine clearance (CrCl) (or calculated GFR (glomerular filtration rate)) of ≥ 60 mL / min is 500 μg, except that this dose is reduced if the patient's CrCl is < 60 mL / min, as shown in the table below. Creatinine clearance (CrCl) Starting oral dose of dofetilide ≧60mL / min 500μg bid 40-<60mL / min 250μg bid 20-<40mL / min 125μg bid <20mL / min Dofetilide not indicated

[0184] The oral dofetilide dose may be reduced based on the patient's QTc. For example, if the patient's QTc increases by 15% from baseline or if the QTc is measured to be >500 msec or >550 msec in patients with ventricular conduction abnormalities, the oral dofetilide dose should be reduced from 500 μg to 250 μg, or from 250 μg to 125 μg, or discontinued if the initial dose was 125 μg.

[0185] For patients with a CrCl ≥ 60 mL / min, the oral dose of dofetilide is 500 μg twice daily. In this embodiment, if the patient's QTc increases by 15% over baseline QTc or if the QTc is measured to be > 500 msec or > 550 msec if the patient has ventricular conduction abnormalities, the oral dose is reduced to 250 μg.

[0186] For patients with a CrCl of 40-<60 mL / min, the oral dose of dofetilide is 250 μg twice daily. In this embodiment, if the patient's QTc increases by 15% from baseline QTc or if the QTc is measured to be >500 msec or >550 msec if the patient has ventricular conduction abnormalities, the oral dose is reduced to 125 μg.

[0187] For patients with a CrCl of 20-<40 mL / min, the oral dose of dofetilide is 125 μg twice daily. In this embodiment, treatment is discontinued if the patient's QTc increases by 15% from baseline QTc or if the QTc measures >500 msec or >550 msec if the patient has ventricular conduction abnormalities.

[0188] In another embodiment, patients with a CrCl of 20-<40 mL / min are administered dofetilide 125 μg orally once daily. This once-daily dosing regimen is selected at the discretion of the patient's physician. In this embodiment, treatment is discontinued if the patient's QTc increases by 15% from baseline or if the QTc is measured to be >500 ms or >550 ms if the patient has ventricular conduction abnormalities.

[0189] In another embodiment, if the patient's CrCl is ≥ 60 mL / min, the IV maintenance dose is about 450-500 μg of dofetilide administered over about 12 hours and the oral dose is 500 μg of dofetilide twice daily, in which case if the patient's QTc increases by 15%, the oral dose is reduced to 250 μg.

[0190] In another embodiment, the patient's CrCl is 40-<60 mL / min, the IV maintenance dose is about 225-250 μg of dofetilide administered over about 12 hours, and the oral dose is 250 μg of dofetilide twice daily. In this embodiment, the oral dose is reduced to 125 μg if the patient's QTc increases by 15% from baseline QTc or if the QTc is measured to be >500 msec or >550 msec if the patient has ventricular conduction abnormalities.

[0191] In another embodiment, the patient's CrCl is 20-<40 mL / min, the IV maintenance dose is about 100-125 μg of dofetilide administered over about 12 hours, and the oral dose is 125 μg of dofetilide twice daily. In this embodiment, treatment is discontinued if the patient's QTc increases by 15% from baseline QTc or if the QTc measures >500 msec or >550 msec if the patient has ventricular conduction abnormalities.

[0192] In another embodiment, the patient's CrCl is 20-<40 mL / min, the IV maintenance dose is about 100-125 μg of dofetilide administered over about 12 hours, and the oral dofetilide dose is 125 μg once daily. In this embodiment, treatment is discontinued if the patient's QTc increases by 15% from baseline or if the patient's QTc is measured to be >500 milliseconds or, if the patient has ventricular conduction abnormalities, a QTcg >550 milliseconds.

[0193] A suitable intravenous formulation is described in US Pat. No. 11,364,213.

[0194] Examples of useful dofetilide intravenous solution concentrations include about 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95-100 μg / mL.

[0195] The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The present invention encompasses any and all combinations of the aspects of the present invention described herein. It is understood that any embodiment of the present invention can be combined with other embodiments to describe additional embodiments. It is also understood that each individual element of an embodiment is intended to be construed separately as its own independent embodiment. Furthermore, any element of an embodiment is intended to be combined with any other element of any embodiment to describe additional embodiments.

[0196] Other features of the present invention will become apparent from the following description of exemplary embodiments which are given by way of illustration and not by way of limitation. [Example]

[0197] Example 5

[0198] A 70 kg patient with CrCl >60 mL / min presented with severe atrial fibrillation (AF), and the treating physician determined that the AF needed to be terminated with an infusion of dofetilide. The patient was admitted to the hospital and continuously monitored with an electrocardiogram.

[0199] Chemical cardioversion with dofetilide :

[0200] The patient then undergoes the following treatment with dofetilide: (G) Time 0: Intravenous (IV) loading dose: 450 μg, infused over 1 hour, with QTc, HR, and BP measured every 15 minutes. (H) 1 Hour: Oral Dosage: If the patient is switched from an IV loading dose, 500 μg orally every 12 hours (BID) beginning 1 hour after the initiation of the IV loading infusion.

[0201] Electrical defibrillation :

[0202] The patient then undergoes the following treatment with dofetilide: (A) Time 0: Intravenous (IV) loading dose: 450 μg infused over 1 hour with QTc, HR, and BP measurements every 15 minutes. (B) 1 hour later: Cardioversion. If the patient is not switched off the dofetilide IV loading dose, the patient is cardioverted and restored to sinus rhythm. (C) 1.5 hours later: IV maintenance dose: 450 μg over 3 to 6 hours as needed after cardioversion. This maintenance dose is discontinued once the patient is able to take oral medications. (D) 4 to 7 hours later: Oral dose: 500 μg orally every 12 hours (BID), usually about 4 to 7 hours after the start of the IV loading dose.

[0203] Figure 1 shows the estimated blood dofetilide concentrations obtained with the above dosing regimen. This graph was obtained by modeling the above dosing regimen. Bayesian PK modeling was performed using the software packages NONMEM® version 7.4 (ICON, Hanover, MD, USA) and MWpharm (Mediware, Prague, CZ). PsN7 (Dept. of Pharmacy, Uppsala University, Uppsala, Sweden) was used for automated procedures. R (version 3.5.1, The R Foundation for Statistical Computing) was used for data preparation, graphical analysis, linear regression analysis, and statistical summaries. The R package "mrgsolve" was used for simulations.

[0204] Step (A): The loading dose (in this example, 450 μg of dofetilide administered IV over 1 hour) is predicted to achieve the maximum serum concentration expected from chronic oral administration of 500 μg of dofetilide. Oral administration peaks after six twice-daily doses of dofetilide. Peak dofetilide concentrations are achieved at the end of the infusion.

[0205] QTc is measured every 15 minutes during the infusion.

[0206] Step (B): At the end of the 1-hour loading IV infusion, begin an IV maintenance dose of 450 μg of dofetilide (0.625 μg / min) over 12 hours. This dose can be maintained until the patient is awake and able to take dofetilide orally.

[0207] Once the patient is able to tolerate oral dofetilide, IV dofetilide maintenance is discontinued. Approximately 3 hours after IV maintenance is discontinued, 500 μg of dofetilide is administered orally every 12 hours (BID).

[0208] If the QTc increases by 15% from baseline or if a QTc >500 msec (>550 msec in patients with ventricular conduction abnormalities) is observed, the subsequent oral dose should be reduced to 250 mcg BID (or lower if the initial oral dose is lower; see below).

[0209] If the patient's CrCl is below the normal range, the initial target concentration remains the same, but the oral (maintenance) dose is reduced to 250 μg or 125 μg BID (based on the table below). Creatinine clearance (CrCl) Oral dose of dofetilide ≧60mL / min 500μg bid 40-<60mL / min 250μg bid 20-<40mL / min 125μg bid <20mL / min Dofetilide not indicated

[0210] Furthermore, in patients who demonstrate excessive QTc prolongation (>500 msec or >550 msec in patients with ventricular conduction abnormalities) following the initial loading dose, the initial oral dose should be reduced to 250 μg (or 125 μg if the starting oral dose is 250 μg based on the table above), and the expected peak concentration should be reassessed 4 hours later. The longest QTc is measured at the peak concentration at the end of the loading dose and is equivalent to the peak concentration observed during chronic oral administration of 250 μg. This allows for the measurement of QTc responses at the highest concentrations of dofetilide that patients are expected to be chronically exposed to in order to maintain normal sinus rhythm, thereby establishing the safety of chronic dofetilide administration.

[0211] Example 6

[0212] A 75 kg patient with a CrCl of 45 mL / min presented with severe atrial fibrillation (AF), and the treating physician determined that the AF needed to be terminated with an infusion of dofetilide. The patient was admitted to the hospital and continuously monitored with an electrocardiogram.

[0213] Chemical cardioversion with dofetilide :

[0214] The patient then undergoes the following treatment with dofetilide: (A) Time 0: Intravenous (IV) loading dose: 450 μg, infused over 1 hour, with QTc, HR, and BP measured every 15 minutes. (B) 1 Hour: Oral Dosage: If the patient is switched from an IV loading dose, 250 μg orally every 12 hours (BID) beginning 1 hour after the initiation of the IV loading infusion.

[0215] Electrical defibrillation :

[0216] The patient then undergoes the following treatment with dofetilide: (A) Time 0: Intravenous (IV) loading dose: 450 μg infused over 1 hour with QTc, HR, and BP measurements every 15 minutes. (B) 1 hour later: Cardioversion. If the patient is not switched off the dofetilide IV loading dose, the patient is cardioverted and restored to sinus rhythm. (C) 1.5 hours later: IV maintenance dose: 225 μg over 3 to 6 hours as needed after cardioversion. This maintenance dose is discontinued once the patient is able to take oral medications. (D) After 4-7 hours: Oral dose: Once the post-defibrillation patient is able to take oral medications (usually about 4-7 hours after the start of the IV load), 250 μg orally every 12 hours (BID).

[0217] Many modifications and variations of the present invention are possible in light of the above teachings, and it is therefore to be understood that, within the scope of the appended embodiments, the invention may be practiced other than as specifically described herein. Embodiment C. Intravenous Dofetilide Administration to Improve Atrial Fibrillation / Atrial Flutter 1. A method for ameliorating atrial fibrillation (AF) or atrial flutter (AFL) in a patient presenting with severe atrial fibrillation (AF) or atrial flutter (AFL), comprising the steps of: a. Patients with severe atrial fibrillation or atrial flutter (AFL) receive a loading dose of dofetilide intravenously. (A) The loading dose is approximately 450–500 μg of dofetilide. (B) The loading dose is administered over approximately 30 to 60 minutes. b. If the patient is in sinus rhythm, approximately 0-4 hours after the completion of the intravenous loading dose, administer dofetilide orally every 12 hours at a dose determined based on the patient's creatinine clearance (CrCl) as shown in the table below: CrCl IV maintenance dose Oral dose (over 12 hours) (every 12 hours) ≧60mL / min 450~500μg 500μg 40―<60mL / min 225~250μg 250μg 20―<40mL / min 100~125μg 125μg <20mL / min Dofetilide is not indicated Dofetilide is not indicated c If the patient does not return to sinus rhythm after completion of the IV stress infusion, administer cardioversion and Approximately 0-1 hour after cardioversion, a maintenance dose of dofetilide is administered intravenously over approximately 3-12 hours, with the maintenance dose based on the patient's CrCl based on a 12-hour infusion as shown in the table above. e Once the patient has recovered from cardioversion and is able to receive oral dofetilide, discontinue the IV maintenance dose and f Approximately 2 to 6 hours after discontinuing the IV maintenance dose, administer dofetilide orally every 12 hours, with the oral dose determined based on the patient's CrCl as shown in the table above. However, if the patient's QTc increases by 15% from baseline or if the QTc is measured to be >500 msec or >550 msec if the patient has ventricular conduction abnormalities, reduce the oral dose from 500 mcg to 250 mcg, from 250 mcg to 125 mcg, or discontinue if initially at 125 mcg. 2. The method of embodiment 1, further comprising the steps of: Measure the patient's QTc before the IV loading dose of dofetilide to establish a baseline QTc, then measure QTc approximately every 15 to 30 minutes for 60 minutes, before the IV maintenance infusion, and before each oral dose. 3. The method of embodiment 1, wherein the loading dose is about 450 μg. 4. The method of embodiment 1, wherein the loading dose is about 460 μg. 5. The method of embodiment 1, wherein the loading dose is about 470 μg. 6. The method of embodiment 1, wherein the loading dose is about 480 μg. 7. The method of embodiment 1, wherein the loading dose is about 490 μg. 8. The method of embodiment 1, wherein the loading dose is about 500 μg. 9. The method of embodiment 1, wherein the loading dose is administered over about 30 minutes. 10. The method of embodiment 1, wherein the loading dose is administered over about 40 minutes. 11. The method of embodiment 1, wherein the loading dose is administered over about 50 minutes. 12. The method of embodiment 1, wherein the loading dose is administered over about 60 minutes. 13. The method of embodiment 1, wherein the maintenance dose begins at about 0 hours after completion of the loading dose. 14. The method of embodiment 1, wherein the maintenance dose is initiated about 1 hour after completion of the loading dose. 15. The method of embodiment 1, wherein the maintenance dose is initiated about 2 hours after completion of the loading dose. 16. The method of embodiment 1, wherein the maintenance dose is initiated about 3 hours after completion of the loading dose. 17. The method of embodiment 1, wherein the maintenance dose is initiated about 4 hours after completion of the loading dose. 18. The method of embodiment 1, wherein the patient's CrCl is greater than 60 mL / min, the IV maintenance dose is about 450-500 μg administered over about 12 hours, and the oral dose is 500 μg. 19. The method of embodiment 18, wherein the oral dose is reduced to 250 μg if the QTc increases by 15% over the baseline QTc or if a QTc of >500 ms or >550 ms is measured if the patient has a ventricular conduction abnormality. 20. The method of embodiment 1, wherein the patient has a CrCl of less than 40-60 mL / min, the IV maintenance dose is about 225-250 μg administered over about 12 hours, and the oral dose is 250 μg. 21. The method of embodiment 20, wherein the oral dose is reduced to 125 μg if the QTc increases by 15% over baseline QTc or if a QTc of >500 ms or >550 ms is measured if the patient has ventricular conduction abnormalities. 22. The method of embodiment 1, wherein the patient's CrCl is 20-<40 mL / min, the IV maintenance dose is about 100-125 μg administered over about 12 hours, and the oral dose is 125 μg. 23. The method of embodiment 22, wherein oral administration is discontinued if the QTc increases by 15% over baseline QTc or if a QTc of >500 ms is measured, or >550 ms if the patient has ventricular conduction abnormalities. Further Embodiments - C. Intravenous Dofetilide for Improved Atrial Fibrillation / Atrial Flutter 1. A method of treating a patient with severe symptomatic atrial fibrillation (AF) or atrial flutter (AFL), comprising: a. A loading dose of approximately 450-500 μg of dofetilide is administered intravenously over approximately 30-60 minutes to patients in need thereof. b. Approximately 0-4 hours after the completion of the loading dose, patients who have transitioned to sinus rhythm with creatine clearance of 60 mL / min or greater should receive oral dofetilide 500 μg every 12 hours. Here, the oral dofetilide dose was reduced to 250 μg for patients with a 15% increase in QTc from baseline, patients with a QTc >500 msec, or patients with a QTc >550 msec with ventricular conduction abnormalities. The loading dose is predicted to achieve maximum serum concentrations at the end of the infusion, Monitor patients to ensure that excessive QT prolongation does not lead to cardiac repolarization abnormalities that could result in life-threatening ventricular arrhythmias. 2. The method of embodiment 1, wherein atrial fibrillation (AF) or atrial flutter (AFL) is reversed. 3. The method of embodiment 1, wherein the severely symptomatic patient has severe hemodynamic impairment accompanied by symptoms such as shortness of breath, dyspnea, chest pain (angina), orthopnea, syncope, and sweating. 4. The method of embodiment 1, further comprising measuring the patient's QTc prior to intravenous administration of the loading dose of dofetilide to establish a baseline QTc, and then measuring the QTc every 15 to 30 minutes during the initial infusion and about every 60 minutes thereafter until the patient is stable. 5. The method of embodiment 4, wherein the patient's physician determines whether the patient's condition is stable. 6. The method of embodiment 5, wherein the patient may be stable after the loading dose of dofetilide is completed or the first oral dose is administered. 7. The method of embodiment 1, wherein the loading dose is 450-500 μg to 500 μg of dofetilide. 8. The method of embodiment 1, wherein a maintenance dose of 450-500 μg of dofetilide (the "IV maintenance dose") is administered to patients with a creatine clearance of 60 mL / min or greater 1-3 hours after completion of the loading dose. 9. The method of embodiment 1, wherein the creatine clearance is 60 mL / min or greater. 10. The method of embodiment 1, wherein the intravenous loading dose is administered over about 30 to 60 minutes. 11. The method of embodiment 1, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) before orally administering dofetilide to determine an amount of dofetilide appropriate for oral administration. 12. The method of embodiment 1, wherein the dofetilide is fully loaded within 3 days. 13. The method of embodiment 12, wherein dofetilide is fully loaded once a steady state blood concentration is reached. 14. The method of embodiment 1, wherein intravenous dofetilide administration prevents the occurrence of arrhythmia by avoiding excessive dofetilide concentrations in the blood. 15. A method of treating a patient with severe symptomatic atrial fibrillation (AF) or atrial flutter (AFL), comprising: a. Administer a loading dose of approximately 450-500 μg of dofetilide intravenously over approximately 30-60 minutes to patients in need. b. Approximately 0-4 hours after completion of the loading dose, patients with a creatine clearance of 40-<60 mL / min who have transitioned to sinus rhythm should receive dofetilide 250 μg orally every 12 hours. Here, the oral dofetilide dose was reduced to 125 μg for patients with a 15% increase in QTc from baseline, patients with a QTc of >500 msec, or patients with ventricular conduction abnormalities with a QTc of >550 msec. The loading dose is expected to reach peak serum concentrations at the end of the infusion. Monitor patients for excessive QT prolongation. 16. The method of embodiment 15 for treating atrial fibrillation (AF) or atrial flutter (AFL). 17. The method of embodiment 15, wherein the severely symptomatic patient has severe hemodynamic impairment accompanied by symptoms such as shortness of breath, dyspnea, chest pain (angina), orthopnea, syncope, and sweating. 18. The method of embodiment 15, further comprising measuring the patient's QTc prior to intravenous administration of the loading dose of dofetilide to establish a baseline QTc, and then measuring the QTc every 15 to 30 minutes during the initial infusion and about every 60 minutes thereafter until the patient is stable. 19. The method of embodiment 18, wherein the patient's physician determines the patient's stability. 20. The method of embodiment 19, wherein the patient's condition may be stable after the loading infusion of dofetilide is completed or after the first oral dose is administered. 21. The method of embodiment 15, wherein the loading dose is 450-500 μg to 500 μg of dofetilide. 22. The method of embodiment 15, wherein a maintenance dose of 450-500 μg of dofetilide (the "IV maintenance dose") is administered to patients with a creatine clearance of 60 mL / min or greater 1-3 hours after completion of the loading dose. 23. The method of embodiment 15, wherein the intravenous loading dose is administered over about 30 to 60 minutes. 24. The method of embodiment 15, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) before orally administering dofetilide to determine an amount of dofetilide appropriate for oral administration. 25. The method of embodiment 15, wherein dofetilide is fully loaded within 3 days. 26. The method of embodiment 25, wherein dofetilide is fully loaded once a steady-state blood concentration is reached. 27. The method of embodiment 15, wherein intravenous dofetilide administration prevents the possibility of arrhythmias by avoiding excessive blood dofetilide concentrations. 28. A method of treating a patient with severe symptoms of atrial fibrillation (AF) or atrial flutter (AFL), comprising: a. A loading dose of approximately 450-500 μg of dofetilide is administered intravenously over approximately 30-60 minutes to a patient in need thereof. b. Approximately 0-4 hours after completion of the loading dose, patients with a creatine clearance of 20-<40 mL / min who have transitioned to sinus rhythm receive 125 μg of dofetilide orally every 12 hours. Here, oral dofetilide was discontinued in patients with a 15% increase in QTc from baseline, patients with a QTc of >500 msec, or patients with ventricular conduction abnormalities with a QTc of >550 msec. Here, the loading dose is expected to reach maximum serum concentrations at the end of the infusion, Monitor patients to ensure that excessive QT prolongation does not lead to cardiac repolarization abnormalities that could result in life-threatening ventricular arrhythmias. 29. The method of embodiment 28 for converting atrial fibrillation (AF) or atrial flutter (AFL). 30. The method of embodiment 28, wherein the severely symptomatic patient has severe hemodynamic impairment with symptoms that may include shortness of breath, dyspnea, chest pain (angina), orthopnea, syncope, and sweating. 31. The method of embodiment 28, further comprising measuring the patient's QTc prior to intravenous administration of the loading dose of dofetilide to establish a baseline QTc, and then measuring the QTc every 15 to 30 minutes during the initial infusion and about every 60 minutes thereafter until the patient is stable. 32. The method of embodiment 31, in which the patient's physician determines when the patient's condition is stable. 33. The method of embodiment 32, wherein the patient may be stable after the loading dose of dofetilide is completed or after the first oral dose is administered. 34. The method of embodiment 28, wherein the loading dose is 450 to 500 μg of dofetilide. 35. The method of embodiment 28, wherein a maintenance dose of 450-500 μg of dofetilide ("IV maintenance dose") is administered to patients with a creatine clearance of 60 mL / min or greater 1-3 hours after completion of the loading dose. 36. The method of embodiment 28, wherein the intravenous loading dose is administered over about 30 to 60 minutes. 37. The method of embodiment 28, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) before orally administering dofetilide, to determine an amount of dofetilide appropriate for oral administration. 38. The method of embodiment 28, wherein dofetilide is fully loaded within 3 days. 39. The method of embodiment 38, wherein dofetilide is fully loaded when a steady-state blood concentration is reached. 40. The method according to embodiment 28, wherein intravenous dofetilide administration prevents the occurrence of arrhythmia by avoiding excessive dofetilide concentrations in the blood. 41. A method of treating a patient with severe symptomatic atrial fibrillation (AF) or atrial flutter (AFL), comprising: a. Administer a loading dose of approximately 450-500 μg of dofetilide intravenously over approximately 30-60 minutes to a patient in need thereof; b. After completion of the loading dose, cardioversion is performed on patients who have not been converted to sinus rhythm; c. Approximately 0-1 hour after cardioversion, administer a maintenance dose of approximately 450-500 μg of dofetilide intravenously over approximately 3-12 hours to patients with a creatine clearance of 60 mL / min or greater (the "IV maintenance dose"); d. Discontinue IV maintenance doses in patients who have adequately recovered from cardioversion e. Approximately 2 to 6 hours after discontinuing the IV maintenance dose, administer dofetilide 500 μg orally every 12 hours to patients with a creatine clearance of 60 mL / min or greater. Here, the oral dofetilide dose was reduced to 250 μg for patients with a 15% increase in QTc from baseline, patients with a QTc of >500 msec, or patients with ventricular conduction abnormalities with a QTc of >550 msec. Here, the loading dose is expected to reach maximum serum concentrations at the end of the infusion, Here, patients are monitored to ensure that excessive QT prolongation does not lead to cardiac repolarization abnormalities that could result in life-threatening ventricular arrhythmias. 42. The method of embodiment 41 for treating atrial fibrillation (AF) or atrial flutter (AFL). 43. The method of embodiment 41, wherein the severely symptomatic patient has severe hemodynamic disturbances accompanied by symptoms such as shortness of breath, dyspnea, chest pain (angina), orthopnea, syncope and sweating. 44. The method of embodiment 41, further comprising measuring the patient's QTc prior to intravenous administration of the loading dose of dofetilide to establish a baseline QTc, and then measuring the QTc every 15 to 30 minutes during the initial infusion and about every 60 minutes thereafter until the patient is stable. 45. The method of embodiment 44, in which the patient's physician determines the patient's stability. 46. ​​The method of embodiment 45, wherein the patient's condition may be stable after the loading infusion of dofetilide is completed or after the first oral dose is administered. 47. The method of embodiment 41, wherein the loading dose is 450 to 500 μg of dofetilide. 48. The method of embodiment 41, wherein a maintenance dose of 450-500 μg of dofetilide ("IV maintenance dose") is administered to patients with a creatine clearance of 60 mL / min or greater 1-3 hours after completion of the loading dose. 49. The method of embodiment 41, wherein the IV maintenance dose is about 450-500 μg of dofetilide. 50. The method of embodiment 41, wherein creatine clearance is 60 mL / min or greater. 51. The method of embodiment 41, wherein the dofetilide is administered orally 3 to 5 hours after discontinuing the IV maintenance dose. 52. The method of embodiment 41, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) prior to administering the IV maintenance dose to determine the amount of dofetilide appropriate for the IV maintenance dose. 53. The method of embodiment 41, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) before orally administering dofetilide, and determining the amount of dofetilide appropriate for the oral dose. 54. The method of embodiment 41, wherein dofetilide is administered orally to a patient who has sufficiently recovered from cardioversion, is awake after surgery, and has an intact gag reflex. 55. The method of embodiment 41, wherein the intravenous loading dose is administered over about 30 to 60 minutes. 56. The method of embodiment 41, wherein the IV maintenance dose is administered over about 3 to 12 hours. 57. The method of embodiment 41, wherein dofetilide is fully loaded within 3 days. 58. The method of embodiment 57, wherein dofetilide is fully loaded once a steady-state concentration in the blood is reached. 59. The method of embodiment 41, wherein intravenous dofetilide is administered in a first loading dose and a continuous IV maintenance dose. 60. The method of embodiment 41, wherein intravenous dofetilide administration prevents possible arrhythmias by avoiding excessive blood dofetilide concentrations. 61. A method of treating a patient with severe symptomatic atrial fibrillation (AF) or atrial flutter (AFL), comprising: a. Administer a loading dose of approximately 450-500 μg of dofetilide intravenously over approximately 30-60 minutes to patients in need. b. After completing the stress dose, cardioversion is performed on patients who have not yet converted to sinus rhythm. c. Approximately 0-1 hour after cardioversion, administer a maintenance dose of 450-500 μg of dofetilide intravenously over approximately 3-12 hours (the "IV maintenance dose") to patients with a creatine clearance of 60 mL / min or greater; d. Discontinue IV maintenance doses in patients who have adequately recovered from cardioversion; e. Approximately 2 to 6 hours after discontinuing the IV maintenance dose, administer dofetilide 250 μg orally every 12 hours to patients with a creatine clearance of 40 = < 60 mL / min. Here, the oral dofetilide dose was reduced to 125 μg for patients with a 15% increase in QTc from baseline, patients with a QTc of >500 msec, or patients with ventricular conduction abnormalities with a QTc of >550 msec. wherein the loading dose is expected to reach a maximum serum concentration at the end of the infusion; Monitor patients to ensure that excessive QT prolongation does not lead to cardiac repolarization abnormalities that could result in life-threatening ventricular arrhythmias. 62. The method of embodiment 61 for treating atrial fibrillation (AF) or atrial flutter (AFL). 63. The method of embodiment 61, wherein the severely symptomatic patient has severe hemodynamic impairment accompanied by symptoms such as shortness of breath, dyspnea, chest pain (angina), orthopnea, syncope, and sweating. 64. The method of embodiment 61, further comprising measuring the patient's QTc prior to intravenous administration of the loading dose of dofetilide to establish a baseline QTc, and then measuring the QTc every 15 to 30 minutes during the initial infusion and about every 60 minutes thereafter until the patient is stable. 65. A method for determining patient stability by a patient's physician. The method of embodiment 64. 66. The method of embodiment 65, wherein the patient's condition may be stable after the loading infusion of dofetilide is completed or after the first oral dose is administered. 67. The method of embodiment 61, wherein the loading dose is 450 to 500 μg of dofetilide. 68. The method of embodiment 61, wherein a maintenance dose of 450-500 μg of dofetilide ("IV maintenance dose") is administered to patients with a creatine clearance of 60 mL / min or greater 1-3 hours after completion of the loading dose. 69. The method of embodiment 61, wherein the IV maintenance dose is about 450-500 μg of dofetilide. 70. The method of embodiment 61, wherein creatine clearance is 60 mL / min or greater. 71. The method of embodiment 61, wherein dofetilide is administered orally about 2 to 6 hours after administration of the IV maintenance dose is discontinued. 72. The method of embodiment 61, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) before administering the IV maintenance dose to determine the amount of dofetilide appropriate for the IV maintenance dose. 73. The method of embodiment 61, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) before orally administering dofetilide, and determining the amount of dofetilide appropriate for the oral dose. 74. The method of embodiment 61, wherein dofetilide is administered orally when the patient has sufficiently recovered from cardioversion, is awake after surgery, and has a normal gag reflex. 75. The method of embodiment 61, wherein the intravenous loading dose is administered over about 30 to 60 minutes. 76. The method of embodiment 61, wherein the IV maintenance dose is administered over about 3 to 12 hours. 77. The method of embodiment 61, in which dofetilide is fully loaded within 3 days. 78. The method of embodiment 77, wherein dofetilide is fully loaded once a steady-state concentration in the blood is reached. 79. The method of embodiment 61, wherein intravenous dofetilide is administered in an initial loading dose and a continuous IV maintenance dose. 80. The method of embodiment 61, wherein intravenous dofetilide administration prevents possible arrhythmias by avoiding excessive blood dofetilide concentrations. 81. A method of treating a patient with severe symptomatic atrial fibrillation (AF) or atrial flutter (AFL), comprising: a. A loading dose of approximately 450-500 μg of dofetilide is administered intravenously over approximately 30-60 minutes. b. After the loading dose is complete, cardioversion is performed on patients who have not yet converted to sinus rhythm. c. Approximately 0 to 1 hour after conversion by electrical cardioversion, administer a maintenance dose ("IV maintenance dose") of 450 to 500 μg of dofetilide intravenously over approximately 3 to 12 hours to patients with a creatine clearance of 60 mL / min or greater; d. Discontinue IV maintenance doses in patients who have adequately recovered from cardioversion; e. Approximately 2 to 6 hours after discontinuation of the IV maintenance dose, administer 125 μg of dofetilide orally every 12 hours to patients with a creatine clearance of 20–<40 mL / min. Here, oral dofetilide was discontinued in patients with a 15% increase in QTc from baseline, patients with a QTc of >500 msec, or patients with ventricular conduction abnormalities with a QTc of >550 msec. Here, the loading dose is expected to reach a maximum serum concentration at the end of the infusion, Here, patients are monitored to ensure that excessive QT prolongation does not lead to cardiac repolarization abnormalities that could result in life-threatening ventricular arrhythmias. 82. The method of embodiment 81 for converting atrial fibrillation (AF) or atrial flutter (AFL). 83. The method of embodiment 81, wherein the severely symptomatic patient has severe hemodynamic impairment with symptoms that may include shortness of breath, dyspnea, chest pain (angina), orthopnea, syncope, and sweating. 84. The method of embodiment 81, further comprising measuring the patient's QTc prior to intravenous administration of the loading dose of dofetilide to establish a baseline QTc, and then measuring the QTc every 15 to 30 minutes during the initial infusion and about every 60 minutes thereafter until the patient is stable. 85. The method of embodiment 84, in which the patient's physician determines when the patient's condition is stable. 86. The method of embodiment 85, wherein the patient may be stable after the loading dose of dofetilide is completed or after the first oral dose is administered. 87. The method of embodiment 81, wherein the loading dose is 450 to 500 μg of dofetilide. 88. The method of embodiment 81, wherein a maintenance dose of 450-500 μg of dofetilide ("IV maintenance dose") is administered to patients with a creatine clearance of 60 mL / min or greater 1-3 hours after completion of the loading dose. 89. The IV maintenance dose is dofetilide 450-500 μg. 90. The method of embodiment 81, wherein creatine clearance is 60 mL / min or greater. 91. The method of embodiment 81, in which dofetilide 500 μg is administered orally every 12 hours to patients with a creatine clearance of 60 mL / min or greater 3 to 5 hours after discontinuation of the IV maintenance dose. 92. The method of embodiment 81, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) prior to administering the IV maintenance dose to determine the amount of dofetilide appropriate for the IV maintenance dose. 93. The method of embodiment 81, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) before orally administering dofetilide, and determining the amount of dofetilide appropriate for the oral dose. 94. The method of embodiment 81, in which dofetilide is administered orally to a patient who has sufficiently recovered from cardioversion, is awake after surgery, and has an intact gag reflex. 95. The method of embodiment 81, wherein the intravenous loading dose is administered over about 30 to 60 minutes. 96. The method of embodiment 81, wherein the IV maintenance dose is administered over about 3 to 12 hours. 97. The method of embodiment 81, wherein dofetilide is fully loaded within 3 days. 98. The method of embodiment 97, wherein dofetilide is fully loaded once a steady-state concentration in the blood is reached. 99. The method of embodiment 81, wherein intravenous dofetilide is administered in an initial loading dose and a continuous IV maintenance dose. 100. The method of embodiment 81, wherein intravenous dofetilide administration prevents the possibility of arrhythmia by avoiding excessive blood dofetilide concentrations. 101. A method of treating a patient with severe symptoms of atrial fibrillation (AF) or atrial flutter (AFL), comprising the steps of: a. A loading dose of approximately 450-500 μg of dofetilide is administered intravenously over approximately 30-60 minutes to a patient in need thereof; b. After the loading dose is complete, patients who have not been converted to sinus rhythm should be cardioverted. c. Approximately 0-1 hour after cardioversion, for patients with a creatine clearance of 40-<60 mL / min, administer a maintenance dose of 225-250 μg of dofetilide intravenously ("IV maintenance dose") over approximately 3-12 hours. d. For patients who have adequately recovered from cardioversion, discontinue IV maintenance doses and e. Approximately 2 to 6 hours after discontinuation of the IV maintenance dose, patients with creatine clearance ≥ 60 mL / min should receive dofetilide 500 μg orally every 12 hours. The oral dofetilide dose was reduced to 250 μg for patients with a 15% increase in QTc from baseline, patients with a QTc of >500 msec, or patients with ventricular conduction abnormalities with a QTc of >550 msec. Here, the loading dose is expected to reach maximum serum concentrations at the end of the infusion, Here, patients are monitored to ensure that excessive QT prolongation does not lead to cardiac repolarization abnormalities that could result in life-threatening ventricular arrhythmias. 102. The method of embodiment 101 for converting atrial fibrillation (AF) or atrial flutter (AFL). 103. The method of embodiment 101, wherein the severely symptomatic patient has severe hemodynamic impairment accompanied by symptoms such as shortness of breath, dyspnea, chest pain (angina), orthopnea, syncope, and sweating. 104. The method of embodiment 101, further comprising measuring the patient's QTc prior to intravenous administration of the loading dose of dofetilide to establish a baseline QTc, and then measuring the QTc every 15 to 30 minutes during the initial infusion and about every 60 minutes thereafter until the patient is stable. 105. The method of embodiment 104, in which the patient's physician determines when the patient's condition is stable. 106. The method of embodiment 105, wherein the patient may be stable after the loading dose of dofetilide is completed or after the first oral dose is administered. 107. The method of embodiment 101, wherein the loading dose is 450 to 500 μg of dofetilide. 108. The method of embodiment 101, wherein 1 to 3 hours after completion of the loading dose, 450 to 500 μg of dofetilide is administered as a maintenance dose ("IV maintenance dose") to patients with a creatine clearance of 60 mL / min or greater. 109. The method of embodiment 101, wherein the IV maintenance dose is 225 to 250 μg of dofetilide. 110. The method of embodiment 101, wherein the creatine clearance is 60 mL / min or greater. 111. The method of embodiment 101, in which dofetilide 500 μg is administered orally every 12 hours to patients with a creatine clearance of 60 mL / min or greater 3 to 5 hours after discontinuation of the IV maintenance dose. 112. The method of embodiment 101, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) prior to administration of the IV maintenance dose to determine the amount of dofetilide appropriate for the IV maintenance dose. 113. The method of embodiment 101, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) before orally administering dofetilide, and determining the amount of dofetilide appropriate for the oral dose. 114. Dofetilide is administered orally after the patient has sufficiently recovered from cardioversion and is conscious and has an intact gag reflex after surgery. 115. The method of embodiment 101, wherein the intravenous loading dose is administered over about 30 to 60 minutes. 116. The method of embodiment 101, wherein the IV maintenance dose is administered over about 3 to 12 hours. 117. The method of embodiment 101, in which dofetilide is fully loaded within 3 days. 118. The method of embodiment 101, wherein dofetilide is fully loaded when a steady-state concentration in the blood is reached. 119. The method of embodiment 101, wherein intravenous dofetilide is administered in an initial loading dose and a continuous IV maintenance dose. 120. The method according to embodiment 101, in which intravenous dofetilide administration prevents the occurrence of arrhythmia by avoiding excessive dofetilide concentrations in the blood. 121. A method of treating a patient with severe symptomatic atrial fibrillation (AF) or atrial flutter (AFL), comprising: a. A loading dose of approximately 450-500 μg of dofetilide is administered intravenously over approximately 30-60 minutes to patients in need thereof. b. After completion of the loading dose, cardioversion is performed on patients who have not been converted to sinus rhythm; c. Approximately 0-1 hour after cardioversion, administer a maintenance dose of 225-250 μg of dofetilide intravenously over approximately 3-12 hours (the "IV maintenance dose") to patients with a creatine clearance of 40-<60 mL / min. d. For patients who have fully recovered from cardioversion, discontinue IV maintenance doses and e. Approximately 2-6 hours after discontinuing the IV maintenance dose, administer dofetilide 250 mcg orally every 12 hours to patients with a creatine clearance of 40-<60 mL / min. For patients with a 15% increase in QTc from baseline, patients with a QTc >500 msec, or patients with ventricular conduction abnormalities with a QTc >550 msec, the oral dofetilide dose was reduced to 125 μg. Here, the loading dose is expected to reach maximum serum concentrations at the end of the infusion, Here, patients are monitored to ensure that excessive QT prolongation does not lead to cardiac repolarization abnormalities that could result in life-threatening ventricular arrhythmias. 122. The method of embodiment 121 for treating atrial fibrillation (AF) or atrial flutter (AFL). 123. The method of embodiment 121, wherein the severely symptomatic patient has severe hemodynamic impairment accompanied by symptoms such as shortness of breath, dyspnea, chest pain (angina), orthopnea, syncope, and sweating. 124. The method of embodiment 121, further comprising measuring the patient's QTc prior to intravenous administration of the loading dose of dofetilide to establish a baseline QTc, and then measuring the QTc every 15 to 30 minutes during the initial infusion and about every 60 minutes thereafter until the patient is stable. 125. The method of embodiment 124, in which the patient's physician determines when the patient's condition is stable. 126. The method of embodiment 125, in which the patient may be stable after the loading dose of dofetilide is completed or after the first oral dose is administered. 127. The method of embodiment 121, wherein the loading dose is 450 to 500 g of dofetilide. 128. The method of embodiment 121, wherein a maintenance dose of 450-500 μg of dofetilide ("IV maintenance dose") is administered to patients with a creatine clearance of 60 mL / min or greater 1-3 hours after completion of the loading dose. 129. The method of embodiment 121, wherein the IV maintenance dose is 225 to 250 μg of dofetilide. 130. The method of embodiment 121, wherein 3 to 5 hours after discontinuation of the IV maintenance dose, dofetilide 500 μg is administered orally every 12 hours to patients with a creatine clearance of 60 mL / min or greater. 131. The method of embodiment 121, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) prior to administering the IV maintenance dose to determine the amount of dofetilide appropriate for the IV maintenance dose. 132. The method of embodiment 121, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) before orally administering dofetilide, and determining the amount of dofetilide appropriate for the oral dose. 133. The method of embodiment 121, in which dofetilide is administered orally to a patient who has sufficiently recovered from cardioversion, is awake after surgery, and has an intact gag reflex. 134. The method of embodiment 121, wherein the intravenous loading dose is administered over about 30 to 60 minutes. 135. The method of embodiment 121, wherein the IV maintenance dose is administered over about 3 to 12 hours. 136. The method of embodiment 121, in which dofetilide is fully loaded within 3 days. 137. The method of embodiment 136, wherein dofetilide is fully loaded once a steady-state concentration in the blood is reached. 138. The method of embodiment 121, wherein intravenous dofetilide is administered in a first loading dose and a continuous IV maintenance dose. 139. The method of embodiment 121, wherein intravenous dofetilide administration prevents possible arrhythmias by avoiding excessive blood dofetilide concentrations. 140. A method of treating a patient with severe symptomatic atrial fibrillation (AF) or atrial flutter (AFL), comprising: a. Administer a loading dose of approximately 450-500 μg of dofetilide intravenously over approximately 30-60 minutes to patients in need. b. After completing the stress dose, cardioversion is performed on patients who have not yet converted to sinus rhythm. c. Approximately 0-1 hour after cardioversion, administer a maintenance dose of 225-250 μg of dofetilide intravenously over approximately 3-12 hours (the "IV maintenance dose") to patients with a creatine clearance of 40-<60 mL / min; d. For patients who have fully recovered from cardioversion, discontinue IV maintenance doses and e. Approximately 2-6 hours after discontinuing IV maintenance therapy, administer dofetilide 125 μg orally every 12 hours to patients with creatine clearance of 20-<40 mL / min. In this study, oral dofetilide was discontinued in patients with a 15% increase in QTc from baseline, patients with a QTc of >500 msec, or patients with ventricular conduction abnormalities with a QTc of >550 msec. The loading dose is expected to achieve maximum serum concentrations at the end of the infusion, Monitor patients to ensure that excessive QT prolongation does not lead to cardiac repolarization abnormalities that could result in life-threatening ventricular arrhythmias. 141. The method of embodiment 140 for treating atrial fibrillation (AF) or atrial flutter (AFL). 142. The method of embodiment 140, wherein the severely symptomatic patient has severe hemodynamic impairment accompanied by symptoms such as shortness of breath, dyspnea, chest pain (angina), orthopnea, syncope, and sweating. 143. The method of embodiment 140, further comprising measuring the patient's QTc prior to intravenous administration of the loading dose of dofetilide to establish a baseline QTc, and then measuring the QTc every 15 to 30 minutes during the initial infusion and about every 60 minutes thereafter until the patient is stable. 144. The method of embodiment 143, in which the patient's physician determines the patient's stability. 145. The method of embodiment 144, wherein the patient's condition may be stable after the loading infusion of dofetilide is completed or after the first oral dose is administered. 146. The method of embodiment 140, wherein the loading dose is about 450 to 500 μg of dofetilide. 147. The method of embodiment 140, wherein a maintenance dose of 450 to 500 μg of dofetilide ("IV maintenance dose") is administered to patients with a creatine clearance of 60 mL / min or greater 1 to 3 hours after completion of the loading dose. 148. The method of embodiment 140, wherein the IV maintenance dose is 225 to 250 μg of dofetilide. 149. The method of embodiment 140, in which dofetilide 500 μg is administered orally every 12 hours to patients with a creatine clearance of 60 mL / min or greater 3 to 5 hours after discontinuation of the IV maintenance dose. 150. The method of embodiment 140, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) prior to administration of the IV maintenance dose to determine the amount of dofetilide appropriate for the IV maintenance dose. 151. The method of embodiment 140, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) before orally administering dofetilide, and determining the amount of dofetilide appropriate for the oral dose. 152. The method according to embodiment 140, in which dofetilide is administered orally to a patient who has sufficiently recovered from cardioversion and is conscious and has an intact gag reflex after surgery. 153. The method of embodiment 140, wherein the actual intravenous loading dose is administered over about 30 to 60 minutes. 154. The method of embodiment 140, wherein the IV maintenance dose is administered over about 3 to 12 hours. 155. The method of embodiment 140, in which dofetilide is fully loaded within 3 days. 156. The method of embodiment 155, wherein dofetilide is fully loaded when a steady-state concentration in the blood is reached. 157. The method of embodiment 140, wherein intravenous dofetilide is administered in an initial loading dose and a continuous IV maintenance dose. 158. The method according to embodiment 140, in which intravenous dofetilide administration prevents the occurrence of arrhythmia by avoiding excessive dofetilide concentrations in the blood. 159. A method of treating a patient with severe symptomatic atrial fibrillation (AF) or atrial flutter (AFL), comprising: a. A loading dose of approximately 450-500 μg of dofetilide is administered intravenously over approximately 30-60 minutes. b. After the loading dose is complete, the patient is cardioverted; c. Approximately 0 to 1 hour after electrical cardioversion, in patients with a creatine clearance of 20 to <40 mL / min, a maintenance dose ("IV maintenance dose") of 100 to 125 μg of dofetilide is administered intravenously over approximately 3 to 12 hours. d. For patients who have adequately recovered from cardioversion, discontinue IV maintenance doses and e. Approximately 2 to 6 hours after discontinuing the IV maintenance dose, administer dofetilide 500 μg orally every 12 hours to patients with a creatine clearance of 60 mL / min or greater. Here, the oral dofetilide dose was reduced to 250 μg for patients with a 15% increase in QTc from baseline, patients with a QTc of >500 msec, or patients with ventricular conduction abnormalities of >550 msec. wherein the loading dose is expected to achieve a maximum serum concentration at the end of the infusion; Here, patients are monitored to ensure that excessive QT prolongation does not lead to cardiac repolarization abnormalities that could result in life-threatening ventricular arrhythmias. 160. The method of embodiment 159 for converting atrial fibrillation (AF) or atrial flutter (AFL). 161. The method of embodiment 159, wherein the severely symptomatic patient has severe hemodynamic impairment accompanied by symptoms such as shortness of breath, dyspnea, chest pain (angina), orthopnea, syncope, and sweating. 162. The method of embodiment 159, further comprising measuring the patient's QTc prior to intravenous administration of the loading dose of dofetilide to establish a baseline QTc, and then measuring the QTc every 15 to 30 minutes during the initial infusion and about every 60 minutes thereafter until the patient is stable. 163. The method of embodiment 162, in which the patient's physician determines when the patient's condition is stable. 164. The method of embodiment 163, in which the patient may be stable after the loading dose of dofetilide is completed or after the first oral dose is administered. 165. The method of embodiment 159, wherein the loading dose is 450 to 500 μg of dofetilide. 166. The method of embodiment 159, wherein a maintenance dose of 450-500 μg of dofetilide ("IV maintenance dose") is administered to patients with a creatine clearance of 60 mL / min or greater 1-3 hours after completion of the loading dose. 167. The method of embodiment 159, wherein the loading dose is 450 μg. 168. The method of embodiment 159, wherein creatine clearance is 60 mL / min or greater. 169. The method of embodiment 159, wherein 450-500 μg of dofetilide is administered as an IV maintenance dose approximately 2-6 hours after cessation of administration of the IV maintenance dose. 170. The method of embodiment 159, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) prior to administering the IV maintenance dose to determine the amount of dofetilide appropriate for the IV maintenance dose. 171. The method of embodiment 159, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) before orally administering dofetilide, and determining the amount of dofetilide appropriate for the oral dose. 172. The method of embodiment 159, wherein dofetilide is administered orally to a patient who has sufficiently recovered from cardioversion, is awake after surgery, and has an intact gag reflex. 173. The method of embodiment 159, wherein the intravenous loading dose is administered over about 30 to 60 minutes. 174. The method of embodiment 159, wherein the IV maintenance dose is administered over about 3 to 12 hours. 175. The method of embodiment 159, wherein dofetilide is fully loaded within 3 days. 176. The method of embodiment 175, wherein dofetilide is fully loaded once a steady-state concentration in the blood is reached. 177. The method of embodiment 159, wherein intravenous dofetilide is administered in an initial loading dose and a continuous IV maintenance dose. 178. The method of embodiment 159, wherein intravenous dofetilide administration prevents the possibility of arrhythmia by avoiding excessive blood dofetilide concentrations. 179. A method of treating a patient with severe symptoms of atrial fibrillation (AF) or atrial flutter (AFL), comprising the steps of: a. A loading dose of approximately 450-500 μg of dofetilide is administered intravenously over approximately 30-60 minutes to a patient in need thereof; b. After the loading dose is complete, patients who have not been converted to sinus rhythm should be cardioverted. c. Approximately 0-1 hour after cardioversion, for patients with a creatine clearance of 20-<40 mL / min, administer a maintenance dose of 100-125 μg of dofetilide intravenously ("IV maintenance dose") over approximately 3-12 hours. d. Discontinue IV maintenance doses in patients who have adequately recovered from cardioversion e. Approximately 2-6 hours after discontinuation of the IV maintenance dose, for patients with creatine clearance of 40-<60 mL / min, administer dofetilide 250 mcg orally every 12 hours. The oral dofetilide dose was reduced to 25 μg for patients with a 15% increase in QTc from baseline, patients with a QTc of >500 milliseconds, or patients with ventricular conduction abnormalities with a QTc of >550 milliseconds. where the loading dose is expected to reach a maximum serum concentration at the end of the infusion, Here, patients are monitored to ensure that excessive QT prolongation does not lead to cardiac repolarization abnormalities that could result in life-threatening ventricular arrhythmias. 180. The method of embodiment 179 for converting atrial fibrillation (AF) or atrial flutter (AFL). 181. The method of embodiment 179, wherein the severely affected patient has severe hemodynamic impairment accompanied by symptoms such as shortness of breath, dyspnea, chest pain (angina), orthopnea, syncope, and sweating. 182. The method of embodiment 179, further comprising measuring the patient's QTc prior to intravenous administration of the loading dose of dofetilide to establish a baseline QTc, and then measuring the QTc every 15 to 30 minutes during the initial infusion and about every 60 minutes thereafter until the patient is stable. 183. The method of embodiment 182, in which the patient's physician determines when the patient's condition is stable. 184. The method of embodiment 183, in which the patient may be stable after the loading dose of dofetilide is completed or after the first oral dose is administered. 185. The method of embodiment 179, wherein the loading dose is 450 to 500 μg of dofetilide. 186. The method of embodiment 179, wherein a maintenance dose of 450-500 μg of dofetilide ("IV maintenance dose") is administered to patients with a creatine clearance of 60 mL / min or greater 1-3 hours after completion of the loading dose. 187. The method of embodiment 179, wherein the IV maintenance dose is 100 to 125 μg of dofetilide. 188. The method of embodiment 179, in which dofetilide 250 μg is administered orally every 12 hours to patients with a creatine clearance of less than 40 to 60 mL / min 3 to 5 hours after discontinuation of the IV maintenance dose. 189. The method of embodiment 179, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) prior to administering the IV maintenance dose to determine the amount of dofetilide appropriate for the IV maintenance dose. 190. The method of embodiment 179, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) before orally administering dofetilide, and determining the amount of dofetilide appropriate for the oral dose. 191. The method of embodiment 179, wherein dofetilide is administered orally once the patient has sufficiently recovered from cardioversion, is awake after surgery, and has an intact gag reflex. 192. The method of embodiment 179, wherein the intravenous loading dose is administered over about 30 to 60 minutes. 193. The method of embodiment 179, wherein the IV maintenance dose is administered over about 3 to 12 hours. 194. How dofetilide get fully loaded within 3 days? 195. The method of embodiment 194, wherein dofetilide is fully loaded once a steady-state concentration in the blood is reached. 196. The method of embodiment 179, wherein intravenous dofetilide is administered in an initial loading dose and a continuous IV maintenance dose. 197. The method of embodiment 179, wherein intravenous dofetilide administration prevents the possibility of arrhythmia by avoiding excessive blood dofetilide concentrations. 198. A method of treating a patient with severe symptoms of atrial fibrillation (AF) or atrial flutter (AFL), comprising the steps of: a. Administer a loading dose of approximately 450-500 μg of dofetilide intravenously over approximately 30-60 minutes to a patient in need thereof; b. After completion of the stress dose, patients who have not yet converted to sinus rhythm should be cardioverted. c. Approximately 0-1 hour after cardioversion, administer a maintenance dose of 100-125 μg of dofetilide intravenously over approximately 3-12 hours (the "IV maintenance dose") to patients with a creatine clearance of 20-<40 mL / min; d. For patients who have fully recovered from cardioversion, discontinue IV maintenance medication and e. Approximately 2-6 hours after discontinuing IV maintenance therapy, administer dofetilide 125 mcg orally every 12 or 24 hours to patients with creatine clearance of 20-<40 mL / min. In patients with a 15% increase in QTc from baseline, patients with a QTc >500 msec, or patients with ventricular conduction abnormalities with a QTc >550 msec, oral dofetilide administration was discontinued. The loading dose is expected to achieve maximum serum concentrations at the end of the infusion. Patients are monitored to ensure that excessive QT prolongation does not lead to cardiac repolarization abnormalities that could result in life-threatening ventricular arrhythmias. 199. The method of embodiment 198 described in embodiment 198 for treating atrial fibrillation (AF) or atrial flutter (AFL). 200. The method of embodiment 198, wherein the severely symptomatic patient has severe hemodynamic impairment accompanied by symptoms such as shortness of breath, dyspnea, chest pain (angina), orthopnea, syncope, and sweating. 201. The method of embodiment 198, further comprising measuring the patient's QTc prior to intravenous administration of the loading dose of dofetilide to establish a baseline QTc, and then measuring the QTc every 15 to 30 minutes during the initial infusion and about every 60 minutes thereafter until the patient is stable. 202. The method of embodiment 201, in which the patient's physician determines whether the patient's condition is stable. 203. The method of embodiment 202, wherein the patient's condition may be stable after the loading infusion of dofetilide is completed or after the first oral dose is administered. 204. The method of embodiment 198, wherein the loading dose is 450 to 500 μg of dofetilide. 205. The method of embodiment 198, wherein a maintenance dose of 450-500 μg of dofetilide ("IV maintenance dose") is administered to patients with a creatine clearance of 60 mL / min or greater 1-3 hours after completion of the loading dose. 206. The method of embodiment 198, wherein the IV maintenance dose is 100 to 125 μg of dofetilide. 207. The method of embodiment 198, in which dofetilide 500 μg is administered orally every 12 hours to patients with a creatine clearance of 60 mL / min or greater 3 to 5 hours after discontinuation of the IV maintenance dose. 208. The method of embodiment 198, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) prior to administration of the IV maintenance dose to determine the amount of dofetilide appropriate for the IV maintenance dose. 209. The method of embodiment 198, further comprising measuring the patient's creatine clearance as an approximation of glomerular filtration rate (GFR) before orally administering dofetilide, and determining the amount of dofetilide appropriate for the oral dose. 210. The method of embodiment 198, wherein dofetilide is administered orally once the patient has sufficiently recovered from cardioversion, is awake after surgery, and has an intact gag reflex. 211. The method of embodiment 198, wherein the intravenous loading dose is administered over about 30 to 60 minutes. 212. The method of embodiment 198, wherein the IV maintenance dose is administered over about 3 to 12 hours. 213. The method of embodiment 198, wherein dofetilide is fully loaded within 3 days. 214. The method of embodiment 213, wherein dofetilide is fully loaded once a steady-state concentration in the blood is reached. 215. The method of embodiment 198, wherein intravenous dofetilide is administered in a first loading dose and a continuous IV maintenance dose. 216. The method of embodiment 198, wherein intravenous dofetilide administration prevents possible arrhythmias by avoiding excessive blood dofetilide concentrations.

Claims

1. 1. A pharmaceutical dofetilide IV composition for use in treating a patient in need thereof, comprising the steps of: I. The patient is administered a loading dose of dofetilide intravenously, the loading dose being administered over 30-60 minutes; II. 0-4 hours after the completion of the IV loading dose, administer a maintenance infusion of dofetilide intravenously over 12 hours; III. Once the patient is able to take oral dofetilide, discontinue the IV maintenance infusion dose; IV. 2-6 hours after discontinuing the IV maintenance infusion, administer dofetilide orally every 12 hours. V. The above maintenance fluid regimens will be based on the patient's creatinine clearance (CrCl) as shown in the table below: CrCl IV maintenance fluid oral dose (Over 12 hours) (Every 12 hours) ≧60mL / min 450-500μg 500μg 40-<60mL / min 225-250μg 250μg 20-<40mL / min 100-125μg 125μg <20 mL / min Dofetilide not indicated Dofetilide not indicated VI. Measure the patient's QTc before the IV loading dose of dofetilide to establish a baseline QTc, and then measure QTc every 15-30 minutes for 60 minutes before the IV maintenance infusion and before each oral dose; VII. However, if the patient's QTc increases by 15% over baseline QTc or if a QTc of >500 msec or >550 msec is measured if the patient has ventricular conduction abnormalities, reduce the oral dose from 500 μg to 250 μg, from 250 μg to 125 μg, or discontinue if initially at 125 μg.

2. 10. The dofetilide IV pharmaceutical composition according to claim 1, which is used to reduce the risk of developing atrial fibrillation (AF) and / or atrial flutter (AFL) in patients who have undergone coronary artery bypass surgery (CABS).

3. 10. The pharmaceutical dofetilide IV composition of claim 1 for use in treating patients in need of termination of an arrhythmic storm in patients after implantation of an implantable cardioverter defibrillator.

4. 10. The pharmaceutical dofetilide IV composition of claim 1 for use in treating patients with severe atrial fibrillation (AF) or atrial flutter (AFL) in need of amelioration of AF or AFL.

5. 10. The pharmaceutical dofetilide IV composition of claim 1 for use in treating a patient in need thereof, wherein the patient is administered a loading dose of 450-500 μg of dofetilide intravenously.

6. 10. The pharmaceutical dofetilide IV composition of claim 1 for use in treating a patient in need thereof, comprising an intravenous maintenance infusion of 100-500 μg of dofetilide over 12 hours. And,

7. 7. The pharmaceutical dofetilide IV composition of any one of claims 1 to 6 for use in treating a patient in need thereof, wherein the time between the Cmax dofetilide concentration achieved after an IV loading dose of dofetilide and the Cmax dofetilide concentration achieved after the first oral dose of dofetilide is 14 to 18 hours.

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