Intravenous dofeliid and uses thereof

Abstract

The present invention relates to a safe dosage regimen comprising administering a dose of dofelilide IV followed by oral administration of dofelilide. In a first aspect, the present invention relates to a method of reducing the risk of atrial fibrillation (AF) and / or atrial flutter (AFL) following coronary artery bypass surgery (CABS) by intravenously administering a loaded dose and a sustaining dose of dofililide followed by an oral dose. In a second aspect, the present invention relates to a method of terminating an arrhythmic storm in a patient after implementation of an implantable defibrillator by loading and maintaining infusion and then oral administration of doferide intravenously. In a third aspect, the present invention also relates to a method of transforming atrial fibrillation (AF) or atrial flutter (AFL) in a patient suffering from highly symptomatic AF or AFL by intravenous administration of at least a loading dose of dofililide, or if it fails, cardioversion and maintenance of infusion, followed by long term oral administration.

Description

TECHNICAL FIELD

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

[0002] The present invention also relates to a novel method of terminating a patient's arrhythmic storm after implantation of a cardiac defibrillator by intravenous administration of dofetilide.

[0003] The present invention also relates to a novel method of converting atrial fibrillation (AF) or atrial flutter (AFL) in a patient presenting with highly symptomatic AF or AFL by intravenous administration of dofetilide. BACKGROUND

[0004] Dofetilide is a Vaughn Williams Class III antiarrhythmic drug. Its action is to prolong the action potential duration, particularly by prolonging the repolarization time. Dofetilide does this by blocking the outward potassium channel, IKr (rapidly activating potassium rectifier current). This action is both antiarrhythmic and proarrhythmic. Excessive prolongation of the repolarization time can cause life threatening arrhythmias, particularly those known as Torsade de Pointe ventricular tachycardia (Tpd). The repolarization time of the heart cell can be manifested on the body surface ECG (electrocardiogram) by an increase in the QT interval. Since the QT interval varies with heart rate, the QT interval is usually measured as the heart rate corrected QT, called the QTc. Prolongation of the QTc interval by a drug can cause arrhythmias. Thus, during the initial loading phase, or in a dose escalation program, it is critical to monitor the QTc interval to avoid excessive QTc prolongation, and thus the potential development of life threatening ventricular tachycardia, particularly of the Tdp variety. For these reasons, the FDA has required inpatient QTc monitoring during the initial dofetilide loading or dose escalation. However, for patients who require chronic dofetilide therapy (e.g., patients with intermittent AF but who are currently in sinus rhythm), it takes at least 3 days for oral dofetilide to reach steady state concentrations, and thus for the QTc prolongation to be fully expressed. Thus, patients typically require a 3 day hospitalization to prevent the potential arrhythmias from occurring outside the hospital where help is not usually available.

[0005] The relationship between blood concentration of dofetilide and QTc can be expressed as: QTc = baseline QTc + (slope relationship x blood dofetilide concentration). The relationship between dofetilide plasma concentration and QTc has been established previously. As reported by Sedgwick et al., Br J. Clin Pharmacol 1991 : 31 : 515-519, QTc varies between 15-25 msec / ng / mL (mean = 20 msec). Thus, for a patient with an initial QTc of 405 msec QT, who receives a IV dose of 2.4 μg / kg, which would be similar to a chronic dose of 500 μg BID, one would expect to show a QTc of 459 msec, an increase of 13% over baseline, within acceptable limits.

[0006] QTc = 405 msec + (20 msec / ng / mL x 2.7 ng / mL) = 459 msec

[0007] When dofetilide is administered, the physician first assesses the QTc interval. If the QTc is greater than 440 msec (500 msec for patients with ventricular conduction abnormalities), dofetilide is not indicated. The physician then calculates the patient's creatinine clearance (CrCl, which is a useful approximation of glomerular filtration rate (GFR)) using the following formula:

[0008] Creatinine clearance (male) = ((140 - age) x weight (kg)) / (72 x serum creatinine (mg / dL))

[0009] Creatinine clearance (female) = Creatinine clearance (male) x 0.85

[0010] After calculating the CrCl, the initial dose of dofetilide is determined as follows.

[0011]

[0012] The physician must then monitor the QTc until steady state is achieved, which in this case is 5-6 doses, or ECG monitoring in the hospital for 3 days. When the goal is to rapidly load dofetilide immediately after surgery to prevent AF / AFL, this is an expensive, time-consuming procedure and is impractical.

[0013] U.S. Patent No. 11,364,213 (U.S. '213) relates to a method of reducing the 3-day loading period for patients requiring chronic oral dofetilide. Typically, these patients, who usually present with intermittent AF but are in current sinus rhythm, are given a first intravenous dose of dofetilide and then oral dofetilide twice a day (BID). U.S. '213 describes how the claimed method can assess the risk of dofetilide in a patient in one day or less, thereby reducing the cost, e.g., hospital cost, of initiating chronic oral dofetilide therapy.

[0014] In the United States, approximately 400,000 cases of open heart coronary artery bypass surgery and another 100,000 cases of heart valve surgery are performed each year. Due to the opening of the pericardial space, manipulation of the heart, and placement of temporary atrial pacing leads, the incidence of postoperative AF / AFL is between 30-50% at 3 to 5 days postoperatively. AF / AFL can be very rapid, causing symptomatic and hemodynamic patient compromise. Postoperative AF / AFL can lead to serious complications and significantly prolong patient hospitalization.

[0015] Dofetilide is an effective agent for preventing AF / AFL. However, the time required for oral loading of dofetilide, the only approved method of administration, makes its use less effective in preventing early onset AF / AFL. IV loading doses can rapidly achieve effective concentrations. However, dofetilide can cause QT prolongation, which can lead to the development of life-threatening ventricular arrhythmias when overdosed.

[0016] Therefore, it would be beneficial to develop a method of using dofetilide to prevent AF and / or AFL in patients undergoing open heart coronary artery bypass surgery.

[0017] The above situation applies to patients requiring chronic dofetilide therapy, particularly patients in an arrhythmic storm. Currently, oral dofetilide requires at least 3 days to achieve steady state concentrations. This is unsatisfactory.

[0018] The physician must then monitor the QTc until steady state is achieved, in this case 5-6 doses, or ECG monitoring in the hospital for 3 days. This is impractical when the goal is to rapidly terminate the arrhythmic storm and prevent its recurrence.

[0019] The availability of implantable defibrillators for patients who have had a "sudden death" stoppage or for patients at high risk of life-threatening ventricular arrhythmias has greatly benefited patients. Implantable defibrillators (IDs) have significantly reduced the incidence of arrhythmic death in patients at high risk of cardiac arrest. Patients with severe heart failure, patients who have survived a cardiac arrest, and patients with recent ventricular tachycardia have all benefited from the availability of IDs.

[0020] However, the process of implementation and testing of the ID can result in recurrent, sustained ventricular tachycardia (VT) and ventricular fibrillation (VF). At times, termination of these sustained arrhythmias can be very difficult to treat, with many of the currently available medications being ineffective. The sustained, recurrent nature of the arrhythmia storm is particularly prevalent in patients with poor left ventricular function. Patients with poor cardiac function are also among those in which many antiarrhythmic medications promote arrhythmia (proarrhythmia). Dofetilide, a Vaughan Williams class III antiarrhythmic that prolongs cardiac repolarization, has been shown to be safe in patients with poor cardiac function (Diamond study (Torp-Pedersen et al. NEJM 1999; 341 :857-65)). However, the use of oral dofetilide to treat an arrhythmia storm is impractical, as oral dofetilide requires 3 days in a hospital loading regimen, while an arrhythmia storm is a condition that requires immediate treatment.

[0021] Therefore, it would be beneficial to develop a method of intravenous administration of dofetilide in a rapid loading paradigm to treat an arrhythmia storm. An important aspect is patient safety.

[0022] Atrial fibrillation (AF) or atrial flutter (AFL) can be highly symptomatic and in patients with impaired myocardial function can lead to heart decompensation and possible death. Symptomatic AF / AFL can be terminated by the patient either by drug therapy or electrical cardioversion to restore normal sinus rhythm. Dofetilide is known to be effective in converting AF / AFL and preventing recurrence of arrhythmia. Dofetilide is approved in the United States. The U.S. Food and Drug Administration for conversion of symptomatic AF / AFL. However, oral administration of the drug over several days (the currently approved method) is a substantial barrier to conversion, particularly in urgent situations where conversion is considered in light of the patient's condition. IV formulations of dofetilide that are rapidly infused are effective in conversion, but dofetilide can cause excessive QT prolongation, which can lead to the development of serious life-threatening type of ventricular arrhythmia, torsades de pointes.

[0023] Therefore, it would be beneficial to develop a method of effective administration of an IV formulation of dofetilide that can be administered in a controlled manner and with careful patient assessment to avoid the precipitation of life-threatening drug-induced arrhythmia (proarrhythmia). This is particularly needed in patients with reduced cardiac function, as many drugs are more likely to cause life-threatening arrhythmias in heart failure patients. AF / AFL is common in patients with reduced cardiac function, and in clinical studies it was found that dofetilide does not increase life-threatening arrhythmias in this heart failure population. SUMMARY

[0024] Accordingly, the present invention relates to a novel and safe method of intravenous loading and maintenance of dofetilide in a patient and safely transitioning to oral dofetilide intake.

[0025] In particular, the present invention provides a pharmaceutical dofetilide IV combination (composition) for treating a patient in need thereof, comprising the steps of:

[0026] I. intravenously administering a loading dose of dofetilide to the patient, wherein the loading dose is administered over 30-60 minutes,

[0027] II. intravenously administering a maintenance infusion of dofetilide over 12 hours 0-4 hours after completion of the IV loading dose,

[0028] III. discontinuing the IV maintenance infusion when the patient is able to take oral dofetilide; and,

[0029] IV. orally administering dofetilide every 12 hours 2-6 hours after discontinuing the IV maintenance infusion;

[0030] V. wherein the maintenance infusion is given based on the patient's creatinine clearance (CrCl) as given in the following table

[0031]

[0032] VI. and wherein prior to the IV maintenance infusion and prior to each oral dose, the patient's QTc is measured prior to the IV loading dose of dofetilide to establish a baseline QTc, and then the QTc is measured every 15-30 minutes for 60 minutes;

[0033] VII. with the proviso that if the patient's QTc increases by 15% from the baseline QTc, or if the QTc measurement is > 500 msec or > 550 msec, the oral dose is reduced from 500 μg to 250 μg, from 250 μg to 125 μg, or if initially 125 μg, discontinued if the patient has a ventricular conduction abnormality.

[0034] In a preferred embodiment, the present invention relates to a novel method of intravenous loading and maintenance of dofetilide in a patient after coronary artery bypass surgery with the aim of reducing the risk of postoperative AF / AFL.

[0035] In an alternative preferred embodiment, the present invention relates to a novel method of intravenous loading of dofetilide in a patient with a cardiac rhythm storm after implantation of an implantable defibrillator.

[0036] In another alternative embodiment, the method comprises intravenous administration of a loading dose of dofetilide to a patient suffering from a cardiac storm followed by intravenous maintenance infusion of dofetilide and then switching to oral administration for maintenance after implantation of an implantable defibrillator.

[0037] These and other objects which will become apparent during the following detailed description have been realized by the inventor's discovery that intravenous dofetilide can be safely administered until the patient is able to take oral dofetilide and then safely switched to oral doses.

[0038] Preferably, the pharmaceutical dofetilide IV combination according to an embodiment of the present application for use in the treatment of a patient in need thereof, wherein the risk of developing atrial fibrillation (AF) and / or atrial flutter (AFL) is reduced in patients undergoing coronary artery bypass surgery (CABS).

[0039] Preferably, the pharmaceutical dofetilide IV combination according to an embodiment for use in the treatment of a patient in need thereof, wherein the cardiac storm in the patient after implantation of an implantable defibrillator is terminated.

[0040] Preferably, the pharmaceutical dofetilide IV combination according to an embodiment for use in the treatment of a patient in need thereof, wherein the atrial fibrillation (AF) or atrial flutter (AFL) is converted in patients presenting with highly symptomatic AF or AFL.

[0041] Preferably, the pharmaceutical dofetilide IV combination according to an embodiment of the present application for use in the treatment of a patient in need thereof, wherein the intravenous administration of a loading dose of dofetilide is 450 ~ 500 μg dofetilide.

[0042] Preferably, the pharmaceutical dofetilide IV combination according to an embodiment of the present application for use in the treatment of a patient in need thereof, wherein the intravenous administration of a maintenance infusion of dofetilide to the patient is 100 ~ 500 μg dofetilide over 12 hours.

[0043] Preferably, the pharmaceutical dofetilide IV combination according to any one of claims 1 to 6 for use in the treatment of a patient in need thereof, wherein the time duration between the Cmax dofetilide concentration obtained after administration of the IV loading dose of dofetilide and the Cmax dofetilide concentration obtained after the first oral dose administration of dofetilide is between 14 and 18 hours.

[0044] These and other objects which will become apparent during the following detailed description have been realized by the inventor's discovery that intravenous dofetilide can be used to treat the cardiac storm in the patient after implantation of an implantable defibrillator. DETAILED DESCRIPTION

[0045] A. Intravenous dofetilide to reduce the risk of AF / AFL after coronary artery bypass graft surgery

[0046] All references cited herein are incorporated by reference in their entirety.

[0047] Definitions

[0048] About is defined as + / - 10% of the stated value.

[0049] BID or bid or b.i.d. means twice a day or every 12 hours.

[0050] BP is blood pressure.

[0051] HR is heart rate.

[0052] IV means intravenously or intravenous.

[0053] Dofetilide

[0054] Previous studies have reported that a single dose of dofetilide after a 10 minute infusion of 1.5 μg / kg 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.) An infusion of 3.0 μg / mL resulted in a plasma concentration of 5.35 ng / mL. (Sedgwick et al. and Rasmussen et al.) Coz and colleagues (Clin. Pharmacology & Therapeutics, 1995; 57(5) 533-54) reported that a 500 μg oral dose of dofetilide resulted in a plasma concentration Cmax of 1.9 ng / mL. Therefore, if a single dose achieves 70% of predicted steady state, then at steady state, if 500 μg / mL is administered twice a day for at least 5 doses, the Cmax ss can be estimated to be 2.7 ng / mL. If a 1.5 μg / kg IV dose is known to result in a peak level of 1.7 ng / mL, then assuming linear kinetics, a dose of 2.4 μg / kg would achieve a peak concentration of 2.7 ng / mL, exposing the patient to the peak serum concentration predicted at steady state, and thus to the maximum QTc prolongation. This would expose the patient to the potential maximum risk of arrhythmia for a short period of time when monitored in the hospital.

[0055] IV dofetilide pharmacokinetics is linear, allowing a direct relationship between the IV dose of dofetilide administered and the serum concentration achieved. With IV administration, "overshoot" of serum concentration is avoided, avoiding excessive dofetilide blood levels and thus the potential for cardiac arrhythmias. The relationship between serum concentration and QTc interval is well known, with a high degree of correlation.

[0056] CABS: coronary artery bypass surgery

[0057] It is generally preferred that the heart undergoing surgery not be exposed to unnecessary antiarrhythmic drugs that can result in adverse outcomes. It is also known that the incidence of atrial fibrillation (AF) and / or atrial flutter (AFL) in CABS patients is 30-50% within 3 to 5 days postoperatively.

[0058] In view of the foregoing, the present invention is directed to a novel method of loading dofetilide that ensures that there is no excessive QT prolongation that can lead to abnormal cardiac repolarization and thus life-threatening ventricular arrhythmias by carefully achieving the minimally necessary effective drug blood concentration, thus maximizing patient safety.

[0059] Thus, in one aspect, the present invention is directed to a novel method of reducing the risk of developing AF and / or AFL after CABS by intravenously administering dofetilide to a patient who has undergone 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 and switching to oral dose maintenance.

[0060] Reducing the risk means reducing the risk of developing AF / AFL within 3-5 minutes after CABS surgery by 30-50%. Examples include reducing the risk of developing AF and / or AFL to about 25%, 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1% to 0%.

[0061] In another aspect, the present invention is directed to a novel method of 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:

[0062] a measuring the QTc of the patient to establish a baseline QTc, and then measuring the QTc thereafter about every 15-30 minutes;

[0063] b intravenously administering a loading dose of dofetilide to a patient who has undergone CABS, wherein:

[0064] (A) a loading dose of about 450-500 μg of dofetilide; and

[0065] (B) administering the loading dose over about 30-60 minutes;

[0066] c intravenously administering a maintenance dose of dofetilide over about 12 hours after the IV loading dose is completed, the maintenance dose given based on the creatinine clearance of the CABS patient as shown in the following table;

[0067]

[0068] d discontinuing the IV maintenance dose once the patient has recovered from CABS sufficiently to take dofetilide orally.

[0069] In another aspect, the method further comprises:

[0070] e orally administering dofetilide every 12 hours after discontinuing the maintenance dose, the oral dose given based on the creatinine clearance of the CABS patient as given in the following table;

[0071]

[0072] provided that the oral dose of dofetilide is reduced from 500 μg to 250 μg, from 250 μg to 125 μg, or discontinued if the initial oral dose is 125 μg, if the patient's QTc is increased by 15% from baseline QTc, or if the QTc measurement is > 500 msec or > 550 msec in patients with ventricular conduction abnormalities.

[0073] Generally, QTc is measured prior to administering dofetilide to establish a baseline QTc, and further QTc measurements can be compared to the baseline QTc. QTc is generally measured about every 15, 20, 25, to 30 minutes. These measurements can be discontinued once the patient's medical staff is 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 number of oral doses are administered. The medical care provided can determine when to discontinue QTc measurements. Examples of a sufficient number of oral doses include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, to 20 oral doses.

[0074] In another aspect, the patient is monitored by electrocardiogram to determine the patient's QTc.

[0075] The IV loading dose is typically about 450-500 pg of dofetilide. Examples include about 450, 455, 460, 465, 470, 475, 480, 485, 490, 495 to 500 pg of dofetilide. Typically, the loading dose selected is an amount that achieves a predicted maximum serum concentration from oral administration of 500 pg of dofetilide.

[0076] The IV loading dose is typically administered over about 30-60 minutes. Examples include 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 to 60 minutes.

[0077] In another aspect, the IV maintenance dose begins about 0 h, 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 3.5 h, 4 h, 4.5 h, 5 h, 5.5 h to 6 h after completion of the loading dose.

[0078] Typically, the IV maintenance dose of about 12 h can be interrupted at any time. In another aspect, the maintenance dose is administered about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 to 24 h. Additional examples include about 1.5, 2, 2.5, 3, 3.5 to 4 days (or sometimes longer).

[0079] The IV maintenance dose can be interrupted if needed (e.g., QTc elevation is measured). This is an advantage of the IV versus the oral dose. If the patient has an adverse effect to dofetilide, the IV administration can be quickly stopped.

[0080] The IV maintenance dose administered depends on the patient's CrCl, as shown in the following table.

[0081]

[0082] For patients with CrCl > 60 mL / min, the IV maintenance dose is typically about 450-500 μg of dofetilide, and is typically administered over about 12 h (but can vary as described above). Examples include about 450, 455, 460, 465, 470, 475, 480, 485, 490, 495 to 500 μg of dofetilide. This corresponds to about 0.625-0.694 μg / min of dofetilide (450 / 720-500 / 720). In another aspect, the IV maintenance dose is about 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 069 to 0.7 μg / min.

[0083] For patients with CrCl of 40-<60 mL / min, the IV maintenance dose is typically about 225-250 μg of dofetilide, and is typically administered over about 12 h (but can vary as described above). Examples include about 225, 230, 235, 240, 245 to 250 μg of dofetilide. This corresponds to about 0.313-0.347 μg / min of dofetilide (225 / 720 to 250 / 720). In another aspect, the IV maintenance dose is about 0.3, 0.31, 0.32, 0.33, 0.34 to 0.35 μg / min.

[0084] For patients with CrCl of 20-<40 mL / min, the IV maintenance dose is typically about 100-125 μg of dofetilide, and is typically administered over about 12 h (but can vary as described above). Examples include about 100 μg, 105 μg, 110 μg, 115 μg, 120 μg to 125 μg of dofetilide. This corresponds to about 0.139-0.174 μg / min of dofetilide (100 / 720-125 / 720). In another aspect, the IV maintenance dose is about 0.13, 0.14, 0.15, 0.16, 0.17 to 0.18 μg / min.

[0085] Because the patient is not conscious during and shortly after CABS, oral doxepin cannot be administered. Therefore, it is an advantage of the present application that a patient who has undergone CABS can be loaded with doxepin before the patient is typically able to take oral doxepin. Once it is determined that the patient has recovered from CABS enough to take oral doxepin, the doxepin IV maintenance dose can be discontinued and the transition to oral doxepin can be achieved. The patient's medical staff (e.g., surgeon, physician, nurse, etc.) determines when the patient can take oral doxepin. Typically, the patient can take the oral medication when they are coherent. In some aspects, this will be when the patient wakes up after surgery. In other aspects, the patient can need more time to be coherent and able to swallow the pill after waking up.

[0086] In another aspect, the oral dose is initiated about 1, 2, 3, 4, 5, 6, 7, 8, 9 to 10 hours after the maintenance dose is discontinued. In another aspect, the oral dose is initiated about 3-6 hours after the maintenance dose is discontinued.

[0087] Oral doxepin is available in capsule form in three sizes, 125, 250, and 500 μg. In another aspect, the patient is orally administered doxepin BID (once every 12 hours). Examples of these doses include 125 μg, 250 μg, 375 μg (e.g., 3 x 125 capsules or 125 + 250 capsules), and 500 μg.

[0088] The standard dose for patients with creatinine clearance (CrCl) (or calculated GFR (glomerular filtration rate)) > 60 mL / min is 500 μg. However, if the patient's CRCL is < 60 mL / min, the dose is reduced according to the following table.

[0089]

[0090] The oral dose of doxepin is also reduced if the patient's QTc is assured. For example, if the patient's QTc is increased by 15% from baseline QTc, or if the QTc is measured to be > 500 msec or > 550 msec in patients with ventricular conduction abnormalities, the oral dose of doxepin is reduced from 500 μg to 250 μg, or from 250 μg to 125 μg, or discontinued if the original dose was 125 μg.

[0091] For CrCl >For patients with CrCl 40-<60 mL / min, the twice-daily oral dose of dofetilide is 250 μg. In this regard, if the patient's QTc increases by 15% from baseline QTc, or if the QTc is measured at >500 msec or >550 msec, the oral dose is reduced to 125 μg if the patient has a ventricular conduction abnormality.

[0092] For patients with CrCl 40-<60 mL / min, the twice-daily oral dose of dofetilide is 250 μg. In this regard, if the patient's QTc increases by 15% from baseline QTc, or if the QTc is measured at >500 msec or >550 msec, the oral dose is reduced to 125 μg if the patient has a ventricular conduction abnormality.

[0093] For patients with CrCl 20-<40 mL / min, the twice-daily oral dose of dofetilide is 125 μg. In this regard, if the patient's QTc increases by 15% from baseline QTc, or if the QTc is measured at >500 msec or >550 msec, the treatment is discontinued if the patient has a ventricular conduction abnormality.

[0094] In an alternative aspect, patients with CrCl 20-<40 mL / min are administered 125 μg of dofetilide once daily orally. This once-daily regimen is selected based on the judgment of the patient's health care provider (e.g., physician, surgeon, doctor, etc.). In this regard, if the patient's QTc increases by 15% from baseline QTc, or if the QTc is measured at >500 msec or >550 msec, the treatment is discontinued if the patient has a ventricular conduction abnormality.

[0095] In another aspect, patients with CrCl >60 mL / min are administered an IV maintenance dose of about 450-500 μg of dofetilide and over about 12 h, and the twice-daily oral dose of dofetilide is 500 μg. In this regard, if the patient's QTc increases by 15% from baseline QTc, or if the QTc is measured at >500 msec or >550 msec, the oral dose is reduced to 250 μg if the patient has a ventricular conduction abnormality.

[0096] In another aspect, patients with CrCl 40-<60 mL / min are administered an IV maintenance dose of about 225-250 μg of dofetilide and over about 12 h, and the twice-daily oral dose of dofetilide is 250 μg. In this regard, if the patient's QTc increases by 15% from baseline QTc, or if the QTc is measured at >500 msec or >550 msec, the oral dose is reduced to 125 μg if the patient has a ventricular conduction abnormality.

[0097] In another aspect, the patient has a CrCl of 20-<40 ml / min, the IV maintenance dose is about 100-125 μg of dofetilide and is administered over about 12 h, and the twice daily oral dose of dofetilide is 125 μg. In this aspect, treatment is discontinued if the patient's QTc increases by >15% from baseline QTc, or if the QTc is measured at >500 msec or >550 msec, or if the patient has a ventricular conduction abnormality.

[0098] In another aspect, the patient has a CrCl of 20-<40 ml / min, the IV maintenance dose is about 100-125 μg of dofetilide and is administered over about 12 h, and the once daily oral dose of dofetilide is 125 μg. In this aspect, treatment is discontinued if the patient's QTc increases by >15% from baseline QTc, or if the QTc is measured at >500 msec or >550 msec, or if the patient has a ventricular conduction abnormality.

[0099] Suitable intravenous formulations are described in U.S. Patent No. 11,364,213.

[0100] Examples of useful concentrations of intravenous solutions of dofetilide include about 1 μg / mL, 2 μg / mL, 3 μg / mL, 4 μg / mL, 5 μg / mL, 10 μg / mL, 15 μg / mL, 20 μg / mL, 25 μg / mL, 30 μg / mL, 35 μg / mL, 40 μg / mL, 45 μg / mL, 50 μg / mL, 55 μg / mL, 60 μg / mL, 65 μg / mL, 70 μg / mL, 75 μg / mL, 80 μg / mL, 85 μg / mL, 90 μg / mL, 95 μg / mL to 100 μg / mL.

[0101] The application can be implemented in other specific forms without departing from the spirit or essential attributes of the application. The application encompasses all combinations of aspects of the application described herein. It will be understood that any and all embodiments of the application can be combined with any one or more other embodiments to describe additional embodiments. It will also be understood that each individual element of the embodiments is intended to be separately considered an independent embodiment on its own. Furthermore, any element of the embodiments is intended to be combined with any and all other elements from any embodiment to describe additional embodiments.

[0102] Other features of the application will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the application and are not intended to limit the application.

[0103] Examples

[0104] Example 1

[0105] A 70 kg patient with CrCl > 90 mL / min occurs after coronary artery bypass surgery. To reduce the likelihood of post-operative AF, the patient receives a loading dose of dofetilide after the surgery is complete. The patient has continuous monitoring of ECG. The patient is then treated with dofetilide as follows.

[0106] (A) Hour 0: Intravenous (IV) loading dose: 450 μg infused over 1 hour. Measure QTc, HR, and BP every 15 minutes.

[0107] (B) Hour 1: IV maintenance dose: 450 μg infused over 12 hours, starting at the end of the loading dose infusion; and,

[0108] (C) Hour 16: Oral dose: 500 μg orally every 12 hours (BID), starting 3 hours after the IV maintenance infusion is terminated.

[0109] Figure 1 Estimated dofetilide plasma concentrations obtained with the above dosing regimen are shown. The figure was obtained by modeling the above dosing regimen. Software packages NONMEM™ version 7.4 (ICON, Hanover, MD, USA) and MWpharm (Mediware, Prague, CZ) 6 were used for Bayesian PK modeling. PsN 7 (Dept. of Pharmacy, Uppsala University, Uppsala, Sweden) was used for automation of the program. R (version 3.5.1, R Foundation for Statistical Computing) was used for data preparation, graphical analysis, linear regression analysis, and statistical summary. R package ‘mrgsolve’ was used for simulation.

[0110] Step (A): The expected loading dose (450 μg dofetilide infused over 1 hour in this example) is expected to reach the expected maximum serum concentration that is expected for an oral 500 μg dose of dofetilide. This would reach a peak after 6 doses of dofetilide twice a day orally. The peak concentration is typically reached at the end of the infusion.

[0111] QTc is measured every 15 minutes.

[0112] Step (B): At the end of the 1 hour IV loading, an IV maintenance dose of 450 μg dofetilide (0.625 μg / min) is started over 12 hours. This dose can be maintained until the patient is awake and able to take dofetilide orally.

[0113] Once the patient can take oral dofetilide, the dofetilide maintenance IV is discontinued. Starting approximately 3 hours after the maintenance IV is discontinued, a 500 μg oral dose of dofetilide is administered every 12 hours (BID).

[0114] If the QTc increases by 15% from baseline QTc, or if a QTc > 500 msec (550 msec in patients with ventricular conduction abnormalities) is observed, subsequent oral doses will be reduced to 250 μg BID (or lower if the original oral dose required was lower, see below).

[0115] It should be noted that if the patient has a CrCl below normal, the initial target concentration will be the same, but the oral (maintenance) dose administered will be lower; 250 μg or 125 μg BID (based on the figure below).

[0116]

[0117] In addition, in patients who show excessive QTc prolongation on the initial loading (in > 500 msec or > 550 msec in patients with ventricular conduction abnormalities), the first oral dose will be reduced to 250 μg (or 125 μg if the starting oral dose was 250 μg, based on the figure above), and the peak concentration is expected within 4 hours, and the QTc is re-evaluated. In this way, the concentration prediction from chronic oral dosing of dofetilide at 250 μg can be easily assessed by QTc observations.

[0118] Example 2

[0119] A 75 kg patient with a CrCl of 45 ml / min undergoing CABGS, which occurs after a coronary artery bypass surgery. To reduce the likelihood of post-operative AF, the patient receives a loading dose of dofetilide after the surgery is complete. The patient has continuous monitoring of ECG. The patient is then treated with dofetilide as follows.

[0120] (A) Hour 0: IV loading dose: 450 μg infused over 1 hour, with QTc, HR, and BP measured every 15 minutes.

[0121] (B) Hour 4: Maintenance infusion: 225 μg infused over 12 hours, starting 3 hours after the IV loading dose is complete.

[0122] (C) Hour 21: Oral dose starts 250 μg, given orally every 12 hours, starting 5 hours after the IV maintenance infusion is terminated.

[0123] Many modifications and variations of this application are possible in light of the above teachings. It is, therefore, to be understood that within the scope of the appended claims, the application can be practiced otherwise than as specifically described.

[0124] Embodiment-A. Preventing AF after CAB (L)

[0125] 1. A method of reducing the risk of developing atrial fibrillation (AF) and / or atrial flutter (AFL) in a patient undergoing coronary artery bypass surgery (CABS), comprising:

[0126] a measuring the patient's QTc to establish a baseline QTc, and then measuring the QTc thereafter about every 15-30 minutes;

[0127] b intravenously administering to the patient who has undergone CAB a loading dose of dofetilide, wherein:

[0128] (A) the loading dose is about 450-500 μg dofetilide; and,

[0129] (B) the loading dose is administered over about 30-60 minutes;

[0130] c intravenously administering a maintenance dose of dofetilide over about 12 hours, about 0-4 hours after completion of the IV loading dose, the maintenance dose given based on the creatinine clearance (CrCl) of the CABS patient given in the following table;

[0131]

[0132] d discontinuing the IV maintenance dose when the patient has recovered sufficiently from CABS to take dofetilide orally; and,

[0133] e orally administering dofetilide every 12 hours, about 2-6 hours after discontinuing the IV maintenance dose, the oral dose given based on the CrCl of the CABS patient given in the above table;

[0134] with the proviso that if the patient's QTc increases by 15% from the baseline QTc, or if the QTc measurement is >500 msec or >550 msec, the oral dose is reduced from 500 μg to 250 μg, from 250 μg to 125 μg, or if initially 125 μg, discontinued, if the patient has a ventricular conduction abnormality.

[0135] 2. The method of embodiment 1, wherein the loading dose is about 450 μg.

[0136] 3. The method of embodiment 1, wherein the loading dose is about 460 μg.

[0137] 4. The method of embodiment 1, wherein the loading dose is about 470 μg.

[0138] 5. The method of embodiment 1, wherein the loading dose is about 480 μg.

[0139] 6. The method of embodiment 1, wherein the loading dose is about 490 μg.

[0140] 7. The method of embodiment 1, wherein the loading dose is about 500 μg.

[0141] 8. The method of embodiment 1, wherein the loading dose is administered over about 30 minutes.

[0142] 9. The method of embodiment 1, wherein the loading dose is administered over about 40 minutes.

[0143] 10. The method of embodiment 1, wherein the loading dose is administered over about 50 minutes.

[0144] 11. The method of embodiment 1, wherein the loading dose is administered over about 60 minutes.

[0145] 12. The method of embodiment 1, wherein the maintenance dose begins about Oh after completion of the loading dose.

[0146] 13. The method of embodiment 1, wherein the maintenance dose begins about Ih after completion of the loading dose.

[0147] 14. The method of embodiment 1, wherein the maintenance dose begins about 2h after completion of the loading dose.

[0148] 15. The method of embodiment 1, wherein the maintenance dose begins about 3h after completion of the loading dose.

[0149] 16. The method of embodiment 1, wherein the maintenance dose begins about 4h after completion of the loading dose.

[0150] 17. The method of embodiment 1, wherein the patient has a CrCl > 60 mL / min, the IV maintenance dose is about 450-500 μg given over about 12h and the oral dose is 500 μg.

[0151] 18. The method of embodiment 17, wherein the oral dose is reduced to 250 μg if the patient has a QTc increase of 15% from baseline QTc, or a QTc measurement of > 500 msec or > 550 msec.

[0152] 19. The method of embodiment 1, wherein the patient has a CrCl of 40-<60 mL / min, the IV maintenance dose is about 225-250 μg administered over about 12 h, and the oral dose is 250 μg.

[0153] 20. The method of embodiment 19, wherein the oral dose is reduced to 125 μg if the patient has a ventricular conduction abnormality due to a 15% increase in QTc from baseline QTc, or if QTc is measured as >500 msec or >550 msec.

[0154] 21. The method of embodiment 1, wherein the patient has a CrCl of 20-<40 mL / min, the IV maintenance dose is about 100-125 μg administered over about 12 h, and the oral dose is 125 μg.

[0155] 22. The method of embodiment 21, wherein the oral dose is discontinued if the patient has a ventricular conduction abnormality due to a 15% increase in QTc from baseline QTc, or if QTc is measured as >500 msec, or >550 msec is observed.

[0156] 23. A method of reducing the risk of a patient developing atrial fibrillation (AF) and / or atrial flutter (AFL), the patient having undergone coronary artery bypass surgery (CABS) and having a creatinine clearance (CrCl) of 20-<40 mL / min, the method comprising:

[0157] a measuring the patient's QTc to establish a baseline QTc, and then measuring the QTc thereafter about every 15-30 minutes;

[0158] b intravenously administering a loading dose of dofetilide to the patient who has received CAB, wherein:

[0159] (A) the loading dose is about 450-500 μg dofetilide; and,

[0160] (B) the loading dose is administered over about 30-60 minutes;

[0161] c intravenously administering a maintenance dose of 100-125 μg dofetilide over about 12 h, based on the CrCl of the CABS patient, about 0-4 h after completion of the IV loading dose;

[0162] d discontinuing the IV maintenance dose once the patient has recovered sufficiently from the CABS to take dofetilide orally; and,

[0163] e orally administering 125 μg dofetilide every 24 h about 2-6 h after discontinuing the IV maintenance dose;

[0164] with the proviso that if the patient's QTc is increased by 15% from baseline QTc, or if the QTc measurement is > 500 msec or > 550 msec, the oral dose is discontinued if the patient has a ventricular conduction abnormality.

[0165] Further Embodiment - A. Prevention of AF after CAB (L)

[0166] 1. A method of treating a patient who has undergone coronary artery bypass surgery (CABS), comprising:

[0167] a. intravenously administering to a patient in need thereof a loading dose of about 450-500 μg of dofetilide over about 30-60 minutes;

[0168] b. intravenously administering to a patient with a creatinine clearance of 60 ml / min or greater a maintenance dose ("IV maintenance dose") of about 450-500 μg of dofetilide about 0-4 hours after completion of the loading dose;

[0169] c. administering the IV maintenance dose over about 12 hours;

[0170] d. discontinuing the IV maintenance dose for those patients who have sufficiently recovered from the CAB; and

[0171] e. orally administering 500 μg of dofetilide every 12 hours to a patient with a creatinine clearance of 60 ml / min or greater about 2-6 hours after discontinuing the IV maintenance dose;

[0172] wherein the oral dose of dofetilide is reduced to 250 μg for those patients with a QTc increase of 15% from baseline, those patients with a QTc > 500 msec, or those patients with a ventricular conduction abnormality and a QTc > 550 msec; and wherein the loading dose is expected to reach maximum serum concentration at the end of the infusion; and

[0173] wherein the patient is monitored to ensure that there is no excessive QT prolongation leading to abnormal cardiac repolarization resulting in life threatening ventricular arrhythmias.

[0174] 2. The method of embodiment 1, which is a method of reducing the risk of developing atrial fibrillation (AF) and / or atrial flutter (AFL) in a patient who has undergone coronary artery bypass surgery (CABS), wherein reducing the risk means reducing the risk of developing AF / AFL by 30-50% within three to five days directly after the CABS procedure.

[0175] 3. The method of embodiment 1, further comprising measuring the patient's QTc prior to intravenously administering a loading dose of dofetilide, and thereafter measuring the QTc every 15-30 minutes until the IV maintenance dose of dofetilide is discontinued or after a sufficient number of oral doses are administered.

[0176] 4. The method of embodiment 3, wherein the patient's medical staff determines when the sufficient number of oral doses is administered.

[0177] 5. The method of embodiment 4, wherein the patient's medical staff is the patient's surgeon, physician and / or nurse.

[0178] 6. The method of embodiment 1, wherein the loading dose is about 450-500 μg dofetilide.

[0179] 7. The method of embodiment 1, wherein 1-3 hours after the completion of the loading dose, a 450-500 μg maintenance dose ("IV maintenance dose") of dofetilide is administered to a patient having a creatinine clearance of 60 ml / min or greater.

[0180] 8. The method of embodiment 1, wherein the IV maintenance dose is about 450-500 μg dofetilide.

[0181] 9. The method of embodiment 1, wherein the creatinine clearance is 60 mL / min or greater.

[0182] 10. The method of embodiment 1, wherein the IV maintenance dose is discontinued after 2-6 hours.

[0183] 11. The method of embodiment 1, further comprising measuring the patient's creatinine clearance as an approximation of glomerular filtration rate (GFR) prior to administering the IV maintenance dose to determine the amount of dofetilide indicated for the IV maintenance dose.

[0184] 12. The method of embodiment 1, further comprising measuring the patient's creatinine clearance as an approximation of glomerular filtration rate (GFR) prior to orally administering dofetilide to determine the amount of dofetilide indicated for the oral dose.

[0185] 13. The method of embodiment 1, wherein the patient has sufficiently recovered from the CABS and orally administers dofetilide when the patient is awake and coherent after surgery, as determined by the patient's medical staff.

[0186] 14. The method of embodiment 13, wherein the patient's medical staff is the patient's surgeon, physician and / or nurse.

[0187] 15. The method of embodiment 1, wherein the intravenous loading dose is administered over about 40-50 minutes.

[0188] 16. The method of embodiment 1, wherein the IV maintenance dose is administered over 12 hours.

[0189] 17. The method of embodiment 1, wherein the dofetilide is completely loaded in less than 3 days.

[0190] 18. The method of embodiment 17, wherein the dofetilide is completely loaded when the dofetilide reaches a steady state concentration in the blood.

[0191] 19. The method of embodiment 1, wherein the intravenous dofetilide is administered as a first loading dose and a continuous IV maintenance dose.

[0192] 20. The method of embodiment 1, wherein the intravenous dofetilide administration prevents possible arrhythmias by avoiding excessive dofetilide blood levels.

[0193] 21. The method of embodiment 1, wherein the patient is loaded with dofetilide by intravenous administration prior to the patient being consecutively awake after surgery and able to take dofetilide orally.

[0194] 22. A method of treating a patient who has undergone coronary artery bypass surgery (CABS), comprising:

[0195] a. intravenously administering to a patient in need thereof a loading dose of about 450-500 μg dofetilide over about 30-60 minutes;

[0196] b. intravenously administering to a patient with a creatinine clearance of 60 ml / min or greater a maintenance dose ("IV maintenance dose") of about 450-500 μg dofetilide about 0-4 hours after completion of the loading dose;

[0197] c. administering the IV maintenance dose over about 12 hours;

[0198] d. discontinuing the IV maintenance dose for those patients who have sufficiently recovered from the CAB; and

[0199] e. orally administering 250 μg dofetilide every 12 hours to a patient with a creatinine clearance of 40-<60 ml / min about 2-6 hours after discontinuing the IV maintenance dose;

[0200] wherein the oral dofetilide dose is reduced to 125 μg for those patients with a 15% increase in QTc from baseline, those patients with a QTc > 500 msec, or those patients with a ventricular conduction abnormality with a QTc > 550 msec; and

[0201] wherein the loading dose is expected to reach a maximum serum concentration at the end of the infusion; and

[0202] wherein the patient is monitored to ensure that there is no excessive QT prolongation leading to abnormal cardiac repolarization leading to life threatening ventricular arrhythmias.

[0203] 23. The method of embodiment 22, which is a method of reducing the risk of developing atrial fibrillation (AF) and / or atrial flutter (AFL) in a patient who has undergone coronary artery bypass surgery (CABS), wherein reducing the risk means reducing the risk of developing AF / AFL by 30-50% directly within three to five days after the CABS surgery.

[0204] 24. The method of embodiment 22, further comprising measuring the patient's QTc prior to intravenously administering a loading dose of dofetilide, and thereafter measuring the QTc every 15-30 minutes until the IV maintenance dose of dofetilide is discontinued or after administration of a sufficient number of oral doses.

[0205] 25. The method of embodiment 24, wherein the patient's medical staff determines when the sufficient number of oral doses is administered.

[0206] 26. The method of embodiment 25, wherein the patient's medical staff is the patient's surgeon, physician, and / or nurse.

[0207] 27. The method of embodiment 22, wherein the loading dose is 450-500 μg dofetilide.

[0208] 28. The method of embodiment 22, wherein 1-3 hours after completion of the loading dose, a 450-500 μg maintenance dose ("IV maintenance dose") of dofetilide is administered to a patient having a creatinine clearance of 60 ml / min or more.

[0209] 29. The method of embodiment 22, wherein the IV maintenance dose is 450-500 μg dofetilide.

[0210] 30. The method of embodiment 22, wherein the creatinine clearance is 60 mL / min or more.

[0211] 31. The method of embodiment 22, wherein the IV maintenance dose is discontinued after 3-5 hours.

[0212] 32. The method of embodiment 22, further comprising measuring the patient's creatinine clearance as an approximation of glomerular filtration rate (GFR) prior to administering the IV maintenance dose to determine the amount of dofetilide indicated for the IV maintenance dose.

[0213] 33. The method of embodiment 22, further comprising measuring the patient's creatinine clearance rate as an approximation of glomerular filtration rate (GFR) prior to orally administering the dofetilide to determine the amount of dofetilide indicated for the oral dose.

[0214] 34. The method of embodiment 22, wherein the patient has sufficiently recovered from the CABS and the dofetilide is orally administered when the patient is awake and coherent after the surgery, as determined by the patient's medical staff.

[0215] 35. The method of embodiment 34, wherein the patient's medical staff is the patient's surgeon, physician and / or nurse.

[0216] 36. The method of embodiment 22, wherein the intravenous loading dose is administered over about 30-60 minutes.

[0217] 37. The method of embodiment 22, wherein the IV maintenance dose is administered over about 12 hours.

[0218] 38. The method of embodiment 22, wherein the dofetilide is fully loaded in less than 3 days.

[0219] 39. The method of embodiment 38, wherein the dofetilide is fully loaded when the dofetilide reaches a steady state concentration in the blood.

[0220] 40. The method of embodiment 22, wherein the intravenous dofetilide is administered as a first loading dose and a continuous IV maintenance dose.

[0221] 41. The method of embodiment 22, wherein the intravenous dofetilide administration prevents possible arrhythmias by avoiding excessive dofetilide blood levels.

[0222] 42. The method of embodiment 22, wherein the patient is loaded with dofetilide by intravenous administration prior to the patient remaining coherent and awake after the surgery and being able to orally take dofetilide.

[0223] 43. A method of treating a patient who has undergone coronary artery bypass surgery (CABS), comprising:

[0224] a. intravenously administering to a patient in need thereof a loading dose of about 450-500 μg of dofetilide over about 30-60 minutes;

[0225] b. intravenously administering to a patient with a creatinine clearance rate of 60 ml / min or greater a maintenance dose ("IV maintenance dose") of about 450-500 μg of dofetilide about 0-4 hours after completion of the loading dose.

[0226] c. administering an IV maintenance dose over about 12 hours;

[0227] d. discontinuing the IV maintenance dose for those patients who have fully recovered from CAB;

[0228] e. orally administering 125 μg of dofetilide to patients with creatinine clearance of 20 to < 40 ml / min every 12 hours about 2 to 6 hours after discontinuing the IV maintenance dose;

[0229] wherein the oral dofetilide dose is discontinued for those patients with a 15% increase in QTc from baseline, those patients with a QTc > 500 msec, or those patients with a ventricular conduction abnormality with a QTc > 550 msec; and

[0230] wherein the loading dose is expected to reach a maximum serum concentration at the end of the infusion; and

[0231] wherein the patient is monitored to ensure that there is no excessive QT prolongation leading to abnormal cardiac repolarization resulting in life threatening ventricular arrhythmias.

[0232] 44. The method of embodiment 43, which is a method of reducing the risk of atrial fibrillation (AF) and / or atrial flutter (AFL) in a patient who has undergone coronary artery bypass surgery (CABS), wherein reducing the risk means reducing the risk of AF / AFL by 30-50% within three to five days directly after the CABS surgery.

[0233] 45. The method of embodiment 43, further comprising measuring the QTc of the patient prior to intravenously administering the loading dose of dofetilide, and thereafter measuring the QTc every 15-30 minutes until the IV maintenance dose of dofetilide is discontinued or after a sufficient number of oral doses are administered.

[0234] 46. The method of embodiment 45, wherein the medical staff of the patient determines when the sufficient number of oral doses is administered.

[0235] 47. The method of embodiment 46, wherein the medical staff of the patient is the surgeon, physician and / or nurse of the patient.

[0236] 48. The method of embodiment 43, wherein the loading dose is about 450-500 μg of dofetilide.

[0237] 49. The method of embodiment 43, wherein 1-3 hours after the completion of the loading dose, a 450-500 μg maintenance dose ("IV maintenance dose") of dofetilide is administered to the patient with a creatinine clearance of 60 ml / min or greater.

[0238] 50. The method of embodiment 43, wherein the IV maintenance dose is about 450-500 μg of dofetilide.

[0239] 51. The method of embodiment 43, wherein the creatinine clearance rate is 60 mL / min or greater.

[0240] 52. The method of embodiment 43, wherein a 450-500 μg maintenance dose ("IV maintenance dose") of dofetilide is administered to a patient having a creatinine clearance rate of 60 ml / min or greater 1-3 hours after completion of the loading dose.

[0241] 53. The method of embodiment 43, further comprising measuring the patient's creatinine clearance rate as an approximation of glomerular filtration rate (GFR) prior to administering the IV maintenance dose to determine the amount of dofetilide indicated for the IV maintenance dose.

[0242] 54. The method of embodiment 43, further comprising measuring the patient's creatinine clearance rate as an approximation of glomerular filtration rate (GFR) prior to orally administering dofetilide to determine the amount of dofetilide indicated for the oral dose.

[0243] 55. The method of embodiment 43, wherein the patient has sufficiently recovered from the CABS and is orally administered dofetilide when the patient is awake and coherent after surgery, as determined by the patient's medical staff.

[0244] 56. The method of embodiment 55, wherein the patient's medical staff is the patient's surgeon, physician and / or nurse.

[0245] 57. The method of embodiment 43, wherein the intravenous loading dose is administered over about 30-60 minutes.

[0246] 58. The method of embodiment 43, wherein the IV maintenance dose is administered over about 12 hours.

[0247] 59. The method of embodiment 43, wherein the dofetilide is fully loaded in less than 3 days.

[0248] 60. The method of embodiment 59, wherein the dofetilide is fully loaded when the dofetilide reaches a steady state concentration in the blood.

[0249] 61. The method of embodiment 43, wherein the intravenous dofetilide is administered in a first loading dose and a continuing IV maintenance dose.

[0250] 62. The method of embodiment 43, wherein the intravenous dofetilide administration prevents possible cardiac arrhythmias by avoiding excessive dofetilide blood levels.

[0251] 63. The method of embodiment 43, wherein the patient is loaded with dofetilide by intravenous administration before the patient remains coherent and awake and is able to take oral dofetilide after surgery.

[0252] 64. A method of treating a patient who has undergone coronary artery bypass surgery (CABS), comprising:

[0253] a. intravenously administering to a patient in need thereof a loading dose of about 450-500 μg of dofetilide over about 30-60 minutes;

[0254] b. intravenously administering to a patient with a creatinine clearance of 40-<60 mL / min a maintenance dose ("IV maintenance dose") of about 225-250 μg of dofetilide about 0-4 hours after completion of the loading dose;

[0255] c. administering the IV maintenance dose over about 12 hours;

[0256] d. discontinuing the IV maintenance dose for those patients who have sufficiently recovered from CAB; and

[0257] e. orally administering 500 μg of dofetilide every 12 hours to a patient with a creatinine clearance of 60 ml / min or greater about 2-6 hours after discontinuing the IV maintenance dose;

[0258] wherein the oral dofetilide dose is reduced to 250 μg for those patients with a 15% increase in QTc from baseline, those patients with a QTc > 500 msec, or those patients with a ventricular conduction abnormality with a QTc > 550 msec; and

[0259] wherein the loading dose is expected to reach a maximum serum concentration at the end of the infusion; and

[0260] wherein the patient is monitored to ensure no excessive QT prolongation leading to abnormal cardiac repolarization resulting in life threatening ventricular arrhythmias.

[0261] 65. The method of embodiment 64, which is a method of reducing the risk of atrial fibrillation (AF) and / or atrial flutter (AFL) in a patient who has undergone coronary artery bypass surgery (CABS), wherein reducing the risk means reducing the risk of 30-50% of developing AF / AFL within three to five days directly after the CABS procedure.

[0262] 66. The method of embodiment 64, further comprising measuring the patient's QTc prior to intravenous administration of the loading dose of dofetilide, and thereafter measuring the QTc every 15-30 minutes until discontinuing the IV maintenance dose of dofetilide or after administration of a sufficient number of oral doses.

[0263] 67. The method of embodiment 66, wherein the patient's medical personnel determine when the sufficient number of oral doses has been administered.

[0264] 68. The method of embodiment 67, wherein the patient's medical personnel are the patient's surgeon, physician, and / or nurse.

[0265] 69. The method of embodiment 66, wherein the loading dose is 450-500 μg of dofetilide.

[0266] 70. The method of embodiment 66, wherein 1-3 hours after completion of the loading dose, a patient with a creatinine clearance of 60 ml / min or more is administered a 450-500 μg maintenance dose ("IV maintenance dose") of dofetilide.

[0267] 71. The method of embodiment 66, wherein the IV maintenance dose is 225-250 μg of dofetilide.

[0268] 72. The method of embodiment 66, wherein the creatinine clearance is 60 mL / min or more.

[0269] 73. The method of embodiment 66, wherein 1-3 hours after completion of the loading dose, a patient with a creatinine clearance of 60 ml / min or more is administered a 450-500 μg maintenance dose ("IV maintenance dose") of dofetilide.

[0270] 74. The method of embodiment 66, further comprising measuring the patient's creatinine clearance as a proxy for glomerular filtration rate (GFR) prior to administration of the IV maintenance dose to determine the amount of dofetilide indicated for the IV maintenance dose.

[0271] 75. The method of embodiment 66, further comprising measuring the patient's creatinine clearance as a proxy for glomerular filtration rate (GFR) prior to oral administration of dofetilide to determine the amount of dofetilide indicated for the oral dose.

[0272] 76. The method of embodiment 66, wherein the patient has sufficiently recovered from the CABS and oral administration of dofetilide occurs when the patient is awake and coherent after surgery, as determined by the patient's medical personnel.

[0273] 77. The method of embodiment 76, wherein the patient's medical personnel are the patient's surgeon, physician, and / or nurse.

[0274] 78. The method of embodiment 66, wherein the intravenous loading dose is administered over about 30-60 minutes.

[0275] 79. The method of embodiment 66, wherein the IV maintenance dose is administered over about 12 hours.

[0276] 80. The method of embodiment 66, wherein the multiple doses of dofetilide are completed in less than 3 days.

[0277] 81. The method of embodiment 80, wherein the multiple doses of dofetilide are completed when the dofetilide reaches a steady state concentration in the blood.

[0278] 82. The method of embodiment 66, wherein the intravenous dofetilide is administered as a first loading dose and a continuous IV maintenance dose.

[0279] 83. The method of embodiment 66, wherein the intravenous dofetilide administration prevents possible arrhythmias by avoiding excessive dofetilide blood levels.

[0280] 84. The method of embodiment 66, wherein the patient is loaded with dofetilide by intravenous administration prior to the patient remaining coherent and awake after surgery and being able to take dofetilide orally.

[0281] 85. A method of treating a patient who has undergone coronary artery bypass surgery (CABS), comprising:

[0282] a. intravenously administering to a patient in need thereof a loading dose of about 450-500 μg dofetilide over about 30-60 minutes;

[0283] b. intravenously administering to a patient with a creatinine clearance of 40-<60 mL / min a maintenance dose ("IV maintenance dose") of about 225-250 μg dofetilide about 0-4 hours after completion of the loading dose;

[0284] c. administering the IV maintenance dose over about 12 hours;

[0285] d. discontinuing the IV maintenance dose for those patients who have sufficiently recovered from the CAB; and

[0286] e. orally administering 250 μg dofetilide to a patient with a creatinine clearance of 40-<60 mL / min every 12 hours about 2-6 hours after discontinuing the IV maintenance dose;

[0287] wherein the oral dofetilide dose is reduced to 125 μg for those patients with a QTc increase of 15% from baseline, those patients with a QTc > 500 msec, or those patients with a ventricular conduction abnormality of QTc > 550 msec; and

[0288] wherein the loading dose is expected to reach a maximum serum concentration at the end of the infusion; and

[0289] wherein the patient is monitored to ensure that there is no excessive QT prolongation leading to abnormal cardiac repolarization leading to life threatening ventricular arrhythmias.

[0290] 86. The method of embodiment 85, which is a method of reducing the risk of atrial fibrillation (AF) and / or atrial flutter (AFL) in a patient who has undergone coronary artery bypass surgery (CABS), wherein reducing the risk means reducing the risk of AF / AFL by 30-50% within three to five days immediately after the CABS surgery.

[0291] 87. The method of embodiment 85, further comprising measuring the patient's QTc prior to intravenous administration of a loading dose of dofetilide, and thereafter measuring the QTc every 15-30 minutes until the IV maintenance dose of dofetilide is discontinued or after administration of a sufficient number of oral doses.

[0292] 88. The method of embodiment 87, wherein the patient's medical staff determines when the sufficient number of oral doses is administered.

[0293] 89. The method of embodiment 88, wherein the patient's medical staff is the patient's surgeon, physician and / or nurse.

[0294] 90. The method of embodiment 85, wherein the loading dose is 450-500 μg dofetilide.

[0295] 91. The method of embodiment 85, wherein 1-3 hours after completion of the loading dose, a patient with a creatinine clearance of 60 ml / min or greater is administered a maintenance dose ("IV maintenance dose") of 450-500 μg dofetilide.

[0296] 92. The method of embodiment 85, wherein the IV maintenance dose is 225-250 μg dofetilide.

[0297] 93. The method of embodiment 85, wherein 1-3 hours after completion of the loading dose, a patient with a creatinine clearance of 60 ml / min or greater is administered a maintenance dose ("IV maintenance dose") of 450-500 μg dofetilide.

[0298] 94. The method of embodiment 85, further comprising measuring the patient's creatinine clearance as a proxy for glomerular filtration rate (GFR) prior to administration of the IV maintenance dose to determine the amount of dofetilide indicated by the IV maintenance dose.

[0299] 95. The method of embodiment 85, further comprising measuring the patient's creatinine clearance rate as an approximation of glomerular filtration rate (GFR) prior to orally administering the dofetilide to determine the amount of dofetilide indicated for the oral dose.

[0300] 96. The method of embodiment 85, wherein the patient has sufficiently recovered from the CABS and the dofetilide is orally administered when the patient is awake and coherent after surgery, as determined by the patient's medical staff.

[0301] 97. The method of embodiment 96, wherein the patient's medical staff is the patient's surgeon, physician and / or nurse.

[0302] 98. The method of embodiment 85, wherein the intravenous loading dose is administered over about 30-60 minutes.

[0303] 99. The method of embodiment 85, wherein the IV maintenance dose is administered over about 12 hours.

[0304] 100. The method of embodiment 85, wherein the dofetilide is fully loaded in less than 3 days.

[0305] 101. The method of embodiment 100, wherein the dofetilide is fully loaded when the dofetilide reaches a steady state concentration in the blood.

[0306] 102. The method of embodiment 85, wherein the intravenous dofetilide is administered as a first loading dose and a continuous IV maintenance dose.

[0307] 103. The method of embodiment 85, wherein the intravenous dofetilide administration prevents possible arrhythmias by avoiding excessive dofetilide blood levels.

[0308] 104. The method of embodiment 85, wherein the patient is loaded with dofetilide by intravenous administration prior to the patient being coherent and awake after surgery and able to orally take dofetilide.

[0309] 105. A method of treating a patient who has undergone coronary artery bypass surgery (CABS), comprising:

[0310] a. intravenously administering to a patient in need thereof a loading dose of about 450-500 μg dofetilide over about 30-60 minutes;

[0311] b. intravenously administering to a patient with a creatinine clearance rate of 40-<60 mL / min a maintenance dose ("IV maintenance dose") of about 225-250 μg dofetilide about 0-4 hours after completion of the loading dose;

[0312] c. administering an IV maintenance dose over about 12 hours;

[0313] d. discontinuing the IV maintenance dose for those patients who have fully recovered from CAB;

[0314] e. orally administering 125 μg of dofetilide to patients with creatinine clearance of 20-<40 ml / min every 12 hours about 2-6 hours after discontinuing the IV maintenance dose;

[0315] wherein the oral dofetilide dose is discontinued for those patients with a QTc increase of 15% from baseline, those patients with a QTc > 500 msec, or those patients with a ventricular conduction abnormality with a QTc > 550 msec; and

[0316] wherein the loading dose is expected to reach a maximum serum concentration at the end of the infusion; and

[0317] wherein the patient is monitored to ensure that there is no excessive QT prolongation leading to abnormal cardiac repolarization resulting in life threatening ventricular arrhythmias.

[0318] 106. The method of embodiment 105, which is a method of reducing the risk of atrial fibrillation (AF) and / or atrial flutter (AFL) in a patient who has undergone coronary artery bypass surgery (CABS), wherein reducing the risk means reducing the risk of AF / AFL by 30-50% within three to five days directly after CABS surgery.

[0319] 107. The method of embodiment 105, further comprising measuring the QTc of the patient prior to intravenously administering the loading dose of dofetilide, and thereafter measuring the QTc every 15-30 minutes until the IV maintenance dose of dofetilide is discontinued or after a sufficient number of oral doses are administered.

[0320] 108. The method of embodiment 107, wherein the patient's medical staff determines when the sufficient number of oral doses is administered.

[0321] 109. The method of embodiment 108, wherein the patient's medical staff is the patient's surgeon, physician, and / or nurse.

[0322] 110. The method of embodiment 105, wherein the loading dose is 450-500 μg of dofetilide.

[0323] 111. The method of embodiment 105, wherein 1-3 hours after the completion of the loading dose, a 450-500 μg maintenance dose ("IV maintenance dose") of dofetilide is administered to the patient with a creatinine clearance of 60 ml / min or greater.

[0324] 112. The method of embodiment 105, wherein the IV maintenance dose is 225-250 μg of dofetilide.

[0325] 113. The method of embodiment 105, wherein 1-3 hours after completion of the loading dose, a patient with a creatinine clearance of 60 ml / min or greater is administered a maintenance dose ("IV maintenance dose") of 450-500 μg of dofetilide.

[0326] 114. The method of embodiment 105, further comprising measuring the patient's creatinine clearance as a proxy for glomerular filtration rate (GFR) prior to administering the IV maintenance dose to determine the amount of dofetilide indicated for the IV maintenance dose.

[0327] 115. The method of embodiment 105, further comprising measuring the patient's creatinine clearance as a proxy for glomerular filtration rate (GFR) prior to orally administering dofetilide to determine the amount of dofetilide indicated for the oral dose.

[0328] 116. The method of embodiment 105, wherein the patient has sufficiently recovered from the CABS and the dofetilide is orally administered when the patient is awake and coherent after surgery, as determined by the patient's medical staff.

[0329] 117. The method of embodiment 116, wherein the patient's medical staff is the patient's surgeon, physician and / or nurse.

[0330] 118. The method of embodiment 105, wherein the intravenous loading dose is administered over about 30-60 minutes.

[0331] 119. The method of embodiment 105, wherein the IV maintenance dose is administered over about 12 hours.

[0332] 120. The method of embodiment 105, wherein the dofetilide is fully loaded in less than 3 days.

[0333] 121. The method of embodiment 120, wherein the dofetilide is fully loaded when the dofetilide reaches a steady state concentration in the blood.

[0334] 122. The method of embodiment 105, wherein the intravenous dofetilide is administered in a first loading dose and a continuing IV maintenance dose.

[0335] 123. The method of embodiment 105, wherein the intravenous dofetilide administration prevents possible cardiac arrhythmias by avoiding excessive dofetilide blood levels.

[0336] 124. The method of embodiment 105, wherein the patient is loaded with dofetilide by intravenous administration prior to the patient remaining coherent and awake and able to take oral dofetilide after surgery.

[0337] 125. A method of treating a patient who has undergone coronary artery bypass surgery (CABS), comprising:

[0338] a. intravenously administering to a patient in need thereof a loading dose of about 450-500 μg of dofetilide over about 30-60 minutes;

[0339] b. intravenously administering to a patient with a creatinine clearance of 20-<40 mL / min a maintenance dose ("IV maintenance dose") of about 100-125 μg of dofetilide about 0-4 hours after completion of the loading dose;

[0340] c. administering the IV maintenance dose over about 12 hours;

[0341] d. discontinuing the IV maintenance dose for those patients who have sufficiently recovered from CAB; and

[0342] e. orally administering 500 μg of dofetilide every 12 hours to a patient with a creatinine clearance of 60 ml / min or greater about 2-6 hours after discontinuing the IV maintenance dose;

[0343] wherein the oral dose of dofetilide is reduced to 250 μg for those patients with a 15% increase in QTc from baseline, those patients with a QTc > 500 msec, or those patients with a ventricular conduction abnormality with a QTc > 550 msec; and

[0344] wherein the loading dose is expected to reach a maximum serum concentration at the end of the infusion; and

[0345] wherein the patient is monitored to ensure no excessive QT prolongation leading to abnormal cardiac repolarization resulting in life threatening ventricular arrhythmias.

[0346] 126. The method of embodiment 125, which is a method of reducing the risk of atrial fibrillation (AF) and / or atrial flutter (AFL) in a patient who has undergone coronary artery bypass surgery (CABS), wherein reducing the risk means reducing the risk of 30-50% of developing AF / AFL within three to five days directly after the CABS procedure.

[0347] 127. The method of embodiment 125, further comprising measuring the patient's QTc prior to intravenous administration of the loading dose of dofetilide, and thereafter measuring the QTc every 15-30 minutes until discontinuing the IV maintenance dose of dofetilide or after administration of a sufficient number of oral doses.

[0348] 128. The method of embodiment 127, wherein the patient's medical staff determines when the sufficient number of oral doses has been administered.

[0349] 129. The method of embodiment 128, wherein the patient's medical staff is the patient's surgeon, physician, and / or nurse.

[0350] 130. The method of embodiment 125, wherein the loading dose is 450-500 μg of dofetilide.

[0351] 131. The method of embodiment 125, wherein 1-3 hours after completion of the loading dose, a patient with a creatinine clearance of 60 ml / min or more is administered a 450-500 μg maintenance dose ("IV maintenance dose") of dofetilide.

[0352] 132. The method of embodiment 125, wherein the IV maintenance dose is 100-125 μg of dofetilide.

[0353] 133. The method of embodiment 125, wherein the creatinine clearance is 60 mL / min or more.

[0354] 134. The method of embodiment 125, 1. wherein 3-5 hours after discontinuation of the IV maintenance dose, a patient with a creatinine clearance of 60 ml / min or more is orally administered 500 μg of dofetilide every 12 hours.

[0355] 135. The method of embodiment 125, further comprising measuring the patient's creatinine clearance as a proxy for glomerular filtration rate (GFR) prior to administering the IV maintenance dose to determine the amount of dofetilide indicated for the IV maintenance dose.

[0356] 136. The method of embodiment 125, further comprising measuring the patient's creatinine clearance as a proxy for glomerular filtration rate (GFR) prior to orally administering dofetilide to determine the amount of dofetilide indicated for the oral dose.

[0357] 137. The method of embodiment 125, wherein the patient has sufficiently recovered from the CABS and the dofetilide is orally administered when the patient is awake and coherent after surgery, as determined by the patient's medical staff.

[0358] 138. The method of embodiment 137, wherein the patient's medical staff is the patient's surgeon, physician, and / or nurse.

[0359] 139. The method of embodiment 125, wherein the intravenous loading dose is administered over about 30-60 minutes.

[0360] 140. The method of embodiment 125, wherein the IV maintenance dose is administered over about 12 hours.

[0361] 141. The method of embodiment 125, wherein the donepezil is fully loaded in less than 3 days.

[0362] 142. The method of embodiment 141, wherein the donepezil is fully loaded when the donepezil reaches a steady state concentration in the blood.

[0363] 143. The method of embodiment 125, wherein the intravenous donepezil is administered as a first loading dose and a continuous IV maintenance dose.

[0364] 144. The method of embodiment 125, wherein the intravenous donepezil administration prevents possible arrhythmias by avoiding excessive donepezil blood levels.

[0365] 145. The method of embodiment 125, wherein the patient is loaded with donepezil by intravenous administration before the patient remains coherent and awake after surgery and is able to take donepezil orally.

[0366] 146. A method of treating a patient who has undergone coronary artery bypass surgery (CABS), comprising:

[0367] a. intravenously administering to a patient in need thereof a loading dose of about 450-500 μg of donepezil over about 30-60 minutes;

[0368] b. intravenously administering to a patient with a creatinine clearance of 20-<40 mL / min a maintenance dose ("IV maintenance dose") of about 100-125 μg of donepezil about 0-4 hours after the completion of the loading dose;

[0369] c. administering the IV maintenance dose over about 12 hours;

[0370] e. discontinuing the IV maintenance dose for those patients who have sufficiently recovered from the CAB; and

[0371] orally administering 250 μg of donepezil every 12 hours to a patient with a creatinine clearance of 40-<60 ml / min about 2-6 hours after the IV maintenance dose is discontinued;

[0372] wherein the oral donepezil dose is reduced to 125 μg for those patients with a 15% increase in QTc from baseline, those patients with a QTc > 500 msec, or those patients with a ventricular conduction abnormality with a QTc > 550 msec; and

[0373] wherein the loading dose is expected to reach a maximum serum concentration at the end of the infusion; and

[0374] wherein the patient is monitored to ensure that there is no excessive QT prolongation leading to abnormal cardiac repolarization leading to life threatening ventricular arrhythmias.

[0375] 147. The method of embodiment 146, which is a method of reducing the risk of atrial fibrillation (AF) and / or atrial flutter (AFL) in a patient who has undergone coronary artery bypass surgery (CABS), wherein reducing the risk means reducing the risk of AF / AFL by 30-50% within three to five days directly after the CABS surgery.

[0376] 148. The method of embodiment 146, further comprising measuring the patient's QTc prior to intravenous administration of a loading dose of dofetilide, and thereafter measuring the QTc every 15-30 minutes until the IV maintenance dose of dofetilide is discontinued or after administration of a sufficient number of oral doses.

[0377] 149. The method of embodiment 148, wherein the patient's medical staff determines when the sufficient number of oral doses has been administered.

[0378] 150. The method of embodiment 149, wherein the patient's medical staff is the patient's surgeon, physician, and / or nurse.

[0379] 151. The method of embodiment 146, wherein the loading dose is 450-500 μg dofetilide.

[0380] 152. The method of embodiment 146, wherein 1-3 hours after completion of the loading dose, a 450-500 μg maintenance dose ("IV maintenance dose") of dofetilide is administered to a patient having a creatinine clearance of 60 ml / min or greater.

[0381] 153. The method of embodiment 146, wherein the IV maintenance dose is 100-125 μg dofetilide.

[0382] 154. The method of embodiment 146, 1. wherein the IV maintenance dose is discontinued after 3-5 hours. IV maintenance dose.

[0383] 155. The method of embodiment 146, further comprising, prior to administration of the IV maintenance dose, measuring the patient's creatinine clearance as an approximation of glomerular filtration rate (GFR) to determine the amount of dofetilide indicated for the IV maintenance dose.

[0384] 156. The method of embodiment 146, further comprising measuring the patient's creatinine clearance rate as an approximation of glomerular filtration rate (GFR) prior to orally administering the dofetilide to determine the amount of dofetilide indicated for the oral dose.

[0385] 157. The method of embodiment 146, wherein the patient has sufficiently recovered from the CABS and the dofetilide is orally administered when the patient is awake and coherent after surgery, as determined by the patient's medical staff.

[0386] 158. The method of embodiment 157, wherein the patient's medical staff is the patient's surgeon, physician, and / or nurse.

[0387] 159. The method of embodiment 146, wherein the intravenous loading dose is administered over about 30-60 minutes.

[0388] 160. The method of embodiment 146, wherein the IV maintenance dose is administered over about 12 hours.

[0389] 161. The method of embodiment 146, wherein the dofetilide is fully loaded in less than 3 days.

[0390] 162. The method of embodiment 161, wherein the dofetilide is fully loaded when the dofetilide reaches a steady state concentration in the blood.

[0391] 163. The method of embodiment 146, wherein the intravenous dofetilide is administered as a first loading dose and a continuous IV maintenance dose.

[0392] 164. The method of embodiment 146, wherein the intravenous dofetilide administration prevents possible arrhythmias by avoiding excessive dofetilide blood levels.

[0393] 165. The method of embodiment 146, wherein the patient is loaded with dofetilide by intravenous administration prior to the patient being coherent and awake after surgery and able to orally administer dofetilide.

[0394] 166. A method of treating a patient who has undergone coronary artery bypass surgery (CABS), comprising:

[0395] a. intravenously administering to a patient in need thereof a loading dose of about 450-500 μg dofetilide over about 30-60 minutes;

[0396] b. intravenously administering to a patient with a creatinine clearance rate of 20-<40 mL / min a maintenance dose ("IV maintenance dose") of about 100-125 μg dofetilide about 0-4 hours after completion of the loading dose;

[0397] c. administering an IV maintenance dose over about 12 hours;

[0398] d. discontinuing the IV maintenance dose for those patients who have fully recovered from CAB;

[0399] e. orally administering 125 μg of dofetilide to patients with creatinine clearance of 20-<40 ml / min every 12 hours or every 24 hours about 2-6 hours after discontinuing the IV maintenance dose;

[0400] wherein the oral dofetilide dose is discontinued for those patients with a QTc increase of 15% from baseline, those patients with a QTc > 500 msec, or those patients with a ventricular conduction abnormality with a QTc > 550 msec; and

[0401] wherein the loading dose is expected to reach a maximum serum concentration at the end of the infusion; and

[0402] wherein the patient is monitored to ensure that there is no excessive QT prolongation leading to abnormal cardiac repolarization resulting in life threatening ventricular arrhythmias.

[0403] 167. The method of embodiment 166, which is a method of reducing the risk of atrial fibrillation (AF) and / or atrial flutter (AFL) in a patient who has undergone coronary artery bypass surgery (CABS), wherein reducing the risk means reducing the risk of AF / AFL by 30-50% within three to five days directly after the CABS surgery.

[0404] 168. The method of embodiment 166, further comprising measuring the QTc of the patient prior to intravenously administering the loading dose of dofetilide, and thereafter measuring the QTc every 15-30 minutes until the IV maintenance dose of dofetilide is discontinued or after a sufficient number of oral doses have been administered.

[0405] 169. The method of embodiment 168, wherein the patient's medical staff determines when the sufficient number of oral doses has been administered.

[0406] 170. The method of embodiment 169, wherein the patient's medical staff is the patient's surgeon, physician, and / or nurse.

[0407] 171. The method of embodiment 166, wherein the loading dose is 450-500 μg of dofetilide.

[0408] 172. The method of embodiment 166, wherein 1-3 hours after completion of the loading dose, the patient is administered a 450-500 μg maintenance dose ("IV maintenance dose") of dofetilide if the patient has a creatinine clearance of 60 ml / min or greater.

[0409] 173. The method of embodiment 166, wherein the IV maintenance dose is about 100-125 μg of dofetilide.

[0410] 174. The method of embodiment 166, 1. wherein the IV maintenance dose is discontinued after 3-5 hours. IV maintenance dose.

[0411] 175. The method of embodiment 166, further comprising measuring the patient's creatinine clearance rate as an approximation of glomerular filtration rate (GFR) prior to administering the IV maintenance dose to determine the amount of dofetilide indicated for the IV maintenance dose.

[0412] 176. The method of embodiment 166, further comprising measuring the patient's creatinine clearance rate as an approximation of glomerular filtration rate (GFR) prior to orally administering dofetilide to determine the amount of dofetilide indicated for the oral dose.

[0413] 177. The method of embodiment 166, wherein the patient has sufficiently recovered from the CABS and the dofetilide is orally administered when the patient is awake and coherent after surgery, as determined by the patient's medical staff.

[0414] 178. The method of embodiment 177, wherein the patient's medical staff is the patient's surgeon, physician, and / or nurse.

[0415] 179. The method of embodiment 166, wherein the intravenous loading dose is administered over about 30-60 minutes.

[0416] 180. The method of embodiment 166, wherein the IV maintenance dose is administered over about 12 hours.

[0417] 181. The method of embodiment 166, wherein the dofetilide is fully loaded in less than 3 days.

[0418] 182. The method of embodiment 181, wherein the dofetilide is fully loaded when the dofetilide reaches a steady state concentration in the blood.

[0419] 183. The method of embodiment 166, wherein the intravenous dofetilide is administered in a first loading dose and a continuous IV maintenance dose.

[0420] 184. The method of embodiment 166, wherein the intravenous dofetilide administration prevents possible cardiac arrhythmias by avoiding excessive dofetilide blood levels.

[0421] 185. The method of embodiment 166, wherein the patient is loaded with dofetilide by intravenous administration before the patient is coherent and awake and able to take dofetilide orally after surgery.

[0422] B. Intravenous dofetilide to terminate arrhythmia storm after implantation of a cardiac defibrillator

[0423] All references cited herein are incorporated by reference in their entirety.

[0424] Definitions

[0425] About is defined as + / - 10% of the stated value.

[0426] Arrhythmia storm (AS) is defined as three or more episodes of sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) within 24 hours.

[0427] BID or bid or b.i.d. means twice a day or every 12 hours.

[0428] BP is blood pressure.

[0429] HR is heart rate.

[0430] IV means intravenously or intravenously.

[0431] Dofetilide

[0432] Previous studies have reported that a single dose of propafenone produces a peak plasma concentration of 1.74 ng / mL after a 10 minute infusion of 1.5 μg / kg. (Sedgwick et al., Br. J. Clin Pharmacol 1991 : 31 : 515-519 and Rasmussen et al., J. Cardiovascular Pharmacology 20: 1992, S96-101.) An infusion of 3.0 μg / mL resulted in a plasma concentration of 5.35 ng / mL. (Sedgwick et al. and Rasmussen et al.) Coz and colleagues (Clin. Pharmacology & Therapeutics, 1995; 57(5) 533-54) reported a plasma concentration Cmax of 1.9 ng / mL after a 500 μg oral dose of propafenone. Therefore, if a single dose achieves 70% of predicted steady state, then at steady state, if 500 μg / mL is administered twice daily for at least 5 doses, the Cmax ss can be estimated to be 2.7 ng / mL. If an IV dose of 1.5 μg / kg is known to result in a peak level of 1.7 ng / mL, then assuming linear kinetics, a dose of 2.4 μg / kg would achieve a peak concentration of 2.7 ng / mL, exposing the patient to the peak serum concentration predicted at steady state, and thus to the maximum QTc prolongation. This would expose the patient to the potential maximum risk of arrhythmia for a short period of time when monitored in a hospital setting.

[0433] IV propafenone kinetics are linear, allowing a direct relationship between the IV dose of propafenone administered and the serum concentration achieved. By IV administration, the "overshoot" of serum concentration can be avoided, avoiding excessive blood levels of propafenone and thus the potential for arrhythmia. The relationship between serum concentration and QTc interval is well known, with a high degree of correlation.

[0434] Arrhythmia storm

[0435] In view of the above, the present invention is directed to a novel method of loading propafenone that maximizes patient safety by carefully achieving the necessary effective blood concentration of the drug and determining that at that propafenone concentration there is no excessive QT prolongation that can lead to abnormal cardiac repolarization and thus life threatening ventricular arrhythmias.

[0436] Thus, in one aspect, the present application relates to a novel method of terminating a patient's cardiac storm following implantation of an implantable defibrillator. In another aspect, the method comprises intravenous administration of a loading dose and a maintenance infusion of dofetilide. In another aspect, the method comprises oral administration of dofetilide BID. In another aspect, the method comprises intravenous administration of a loading dose and at least one maintenance infusion of dofetilide, and conversion to oral dosing.

[0437] In another aspect, the present application relates to a novel method of terminating a patient's cardiac storm following implantation of an implantable defibrillator, comprising:

[0438] f. intravenously administering a loading dose of dofetilide to a patient who has developed a cardiac storm following implantation of an implantable defibrillator, wherein:

[0439] (A) the loading dose is about 450-500 μg dofetilide; and,

[0440] (B) the loading dose is administered over about 30-60 minutes;

[0441] g. intravenously administering a maintenance infusion of dofetilide over about 12 hours, about 0-4 hours after completion of the IV loading dose, the maintenance infusion given based on the patient's creatinine clearance (CrCl) as given in the following table:

[0442]

[0443] h. discontinuing the IV maintenance infusion once the patient has recovered from the termination of the cardiac storm sufficient to take oral dofetilide;

[0444] with the proviso that if the patient's QTc increases by 15% from baseline QTc, or if the QTc is measured as > 500 msec or > 550 msec, the oral dose is reduced from 500 μg to 250 μg, from 250 μg to 125 μg, or if initially 125 μg, discontinued, if the patient has a ventricular conduction abnormality.

[0445] In another aspect, the method further comprises:

[0446] i. orally administering dofetilide every 12 hours, about 2-6 hours after discontinuing the maintenance infusion, the oral dose given based on the patient's creatinine clearance as given in the following table:

[0447]

[0448] provided that if the patient's QTc increases by 15% from baseline QTc, or if the QTc measurement is > 500 msec or > 550 msec in patients with ventricular conduction abnormalities, the oral dose of dofetilide is reduced from 500 μg to 250 μg, from 250 μg to 125 μg, or if initially 125 μg, the dose is discontinued.

[0449] In some aspects, QTc is measured prior to administration of dofetilide to establish a baseline QTc, and further QTc measurements can be compared to the baseline QTc. In some aspects, QTc is measured during the initial infusion, thereafter about every 15-30 minutes for 60 minutes, and prior to the IV maintenance infusion and prior to each oral dose. These measurements can be discontinued once the physician observes that the patient is stable to dofetilide. For example, QTc measurements can be stopped after the completion of the loading infusion of dofetilide. Alternatively, QTc measurements can be discontinued after the first oral dose is administered. The physician determines when to discontinue the QTc measurements. Examples of a sufficient number of oral doses include 1, 2, 3, 4, 5 to 6 oral doses. After 6 oral doses, steady state is generally achieved, and the maximum serum dofetilide concentration or QT prolongation is not expected to change further.

[0450] In another aspect, the patient has poor left ventricular function.

[0451] In another aspect, the patient is monitored by electrocardiogram to determine the patient's QTc.

[0452] The IV loading dose is typically about 450-500 μg of dofetilide. Examples include about 450, 455, 460, 465, 470, 475, 480, 485, 490, 495 to 500 μg of dofetilide. Typically, the loading dose selected is an amount that achieves a predicted maximum serum concentration from oral administration of 500 μg of dofetilide.

[0453] The IV loading dose is typically administered over about 30-60 minutes. Examples include 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 to 60 minutes.

[0454] In another aspect, the IV maintenance infusion is initiated after completion of the loading dose. In another aspect, 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 h after completion of the loading dose.

[0455] The IV maintenance infusion is typically given for about 12 hours, which can be interrupted at any time. In another aspect, the maintenance infusion 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 to 24 h. Additional examples include about 1.5, 2, 2.5, 3, 3.5 to 4 days (or sometimes longer).

[0456] If needed, the IV maintenance infusion can be interrupted (e.g., excessive QTc prolongation is measured). This is an advantage of IV over oral dosing. If the patient has an adverse effect to dofetilide, the IV infusion can be stopped quickly.

[0457] The IV maintenance infusion dose given depends on the patient's CrCl, as shown in the following table.

[0458]

[0459] For patients with CrCl > 60 ml / min, the IV maintenance infusion is typically about 450-500 μg dofetilide, and is typically given over about 12 hours (but can vary as described above). Examples include about 450, 455, 460, 465, 470, 475, 480, 485, 490, 495 to 500 μg dofetilide. This corresponds to about 0.625-0.694 μg / min dofetilide (450 / 720-500 / 720). In another aspect, the IV maintenance infusion is about 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 069 to 0.7 μg / min.

[0460] For patients with CrCl of 40-<60 mL / min, the IV maintenance infusion is typically about 225-250 μg dofetilide, and is typically given over about 12 h (but can vary as described above). Examples include about 225, 230, 235, 240, 245 to 250 μg dofetilide. This corresponds to about 0.313-0.347 μg / min dofetilide (225 / 720 to 250 / 720). In another aspect, the IV maintenance infusion is about 0.3, 0.31, 0.32, 0.33, 0.34, 0.35 μg / min.

[0461] For patients with CrCl of 20-<40 mL / min, the IV maintenance infusion is typically about 100-125 μg of dofetilide, and is typically administered over about 12 h (but can vary as described above). Examples include about 100 μg, 105 μg, 110 μg, 115 μg, 120 μg to 125 μg of dofetilide. This corresponds to about 0.139-0.174 μg / min of dofetilide (100 / 720 to 125 / 720). In another aspect, the IV maintenance infusion is about 0.13, 0.14, 0.15, 0.16, 0.17 to 0.18 μg / min.

[0462] After the termination of the arrhythmic storm (after implantation of an implantable defibrillator), the patient is typically unable to take oral medications. Thus, one advantage of the present application is that a patient who has experienced termination of an arrhythmic storm can be administered dofetilide prior to the time that the patient would normally be able to take dofetilide orally. Once it is determined that the patient has recovered sufficiently from the termination of the arrhythmic storm (and implantation of an implantable defibrillator) to take dofetilide orally, the IV maintenance infusion of dofetilide can be discontinued and conversion to oral dofetilide can be effected. The patient's physician determines when the patient can take dofetilide orally. Typically, the patient can take oral medications when they are awake with an intact gag reflex. In some aspects, this will be when the patient wakes up after surgery. In other aspects, the patient can need more time to swallow the pill without aspiration after waking up.

[0463] In another aspect, the oral dose is initiated about 1, 2, 3, 4, 5 to 6 hours after the maintenance infusion is stopped. In another aspect, the oral dose is initiated about 3-6 hours after the maintenance infusion is stopped.

[0464] Oral dofetilide is available in capsule form in three sizes, 125, 250 and 500 μg. In another aspect, the patient is given dofetilide orally BID (once every 12 hours). Examples of these doses include 125 μg, 250 μg, 375 μg (e.g., 3 x 125 capsules or 125 + 250 capsules) and 500 μg.

[0465] The standard dose for patients with creatinine clearance (CrCl) (or calculated GFR (glomerular filtration rate)) of >60 mL / min is 500 μg. However, if the patient has a CRCL of <60 mL / min, the dose is reduced according to the following table.

[0466]

[0467] If the patient's QTc is assured, the oral dose of domperidone is also reduced. For example, if the patient's QTc is increased by 15% from baseline QTc, or if the QTc is measured at > 500 msec or > 550 msec in patients with ventricular conduction abnormalities, the oral dose of domperidone is reduced from 500 μg to 250 μg, or from 250 μg to 125 μg, or if the original dose was 125 μg, the treatment is discontinued.

[0468] For patients with CrCl > For patients with CrCl of 40-< 60 mL / min, the twice daily oral dose of domperidone is 250 μg. In this regard, if the patient's QTc is increased by 15% from baseline QTc, or if the QTc is measured at > 500 msec or > 550 msec in patients with ventricular conduction abnormalities, the oral dose is reduced to 125 μg.

[0469] For patients with CrCl of 40-< 60 mL / min, the twice daily oral dose of domperidone is 250 μg. In this regard, if the patient's QTc is increased by 15% from baseline QTc, or if the QTc is measured at > 500 msec or > 550 msec in patients with ventricular conduction abnormalities, the oral dose is reduced to 125 μg.

[0470] For patients with CrCl of 20-< 40 mL / min, the twice daily oral dose of domperidone is 125 μg. In this regard, if the patient's QTc is increased by 15% from baseline QTc, or if the QTc is measured at > 500 msec or > 550 msec in patients with ventricular conduction abnormalities, the treatment is discontinued.

[0471] In an alternative aspect, patients with CrCl of 20-< 40 mL / min are administered 125 μg of domperidone orally once daily. This once daily regimen is selected based on the judgment of the patient's physician. In this regard, if the patient's QTc is increased by 15% from baseline QTc, or if the QTc is measured at > 500 msec or > 550 msec in patients with ventricular conduction abnormalities, the treatment is discontinued.

[0472] In another aspect, patients with CrCl of > 60 mL / min are administered an IV maintenance infusion of about 450-500 μg of domperidone over about 12 h, and the twice daily oral dose of domperidone is 500 μg. In this regard, if the patient's QTc is increased by 15% from baseline QTc, or if the QTc is measured at > 500 msec or > 550 msec in patients with ventricular conduction abnormalities, the oral dose is reduced to 250 μg.

[0473] In another aspect, the patient has a CrCl of 40-<60 ml / min, the IV maintenance infusion is about 225-250 μg of dofetilide, and is given over about 12 h, and the twice daily oral dose of dofetilide is 250 μg. In this aspect, if the patient's QTc increases by 15% from baseline QTc, or if the QTc is measured as >500 msec or >550 msec, the oral dose is reduced to 125 μg if the patient has a ventricular conduction abnormality.

[0474] In another aspect, the patient has a CrCl of 20-<40 ml / min, the IV maintenance infusion is about 100-125 μg of dofetilide, and is given over about 12 h, and the twice daily oral dose of dofetilide is 125 μg. In this aspect, if the patient's QTc increases by 15% from baseline QTc, or if the QTc is measured as >500 msec or >550 msec, the treatment is discontinued if the patient has a ventricular conduction abnormality.

[0475] In an alternative aspect, the patient has a CrCl of 20-<40 ml / min, the IV maintenance infusion is about 100-125 μg of dofetilide and is given over about 12 h, and the once daily oral dose of dofetilide is 125 μg. In this aspect, if the patient's QTc increases by 15% from baseline QTc, or if the QTc is measured as >500 msec or >550 msec, the treatment is discontinued if the patient has a ventricular conduction abnormality.

[0476] Suitable intravenous formulations are described in U.S. Patent No. 11,364,213.

[0477] Examples of concentrations of dofetilide useful in intravenous solutions include about 1 μg / mL, 2 μg / mL, 3 μg / mL, 4 μg / mL, 5 μg / mL, 10 μg / mL, 15 μg / mL, 20 μg / mL, 25 μg / mL, 30 μg / mL, 35 μg / mL, 40 μg / mL, 45 μg / mL, 50 μg / mL, 55 μg / mL, 60 μg / mL, 65 μg / mL, 70 μg / mL, 75 μg / mL, 80 μg / mL, 85 μg / mL, 90 μg / mL, 95 μg / mL to 100 μg / mL.

[0478] The application can be implemented in other specific forms without departing from the spirit or essential attributes of the application. The application encompasses all combinations of aspects of the application described herein. It will be understood that any and all embodiments of the application can be combined with any other one or more embodiments to describe additional embodiments. It will also be understood that each individual element of the embodiments is intended to be separately considered an independent embodiment on its own. Furthermore, any element of the embodiments is intended to be combined with any and all other elements from any embodiment to describe additional embodiments.

[0479] Other features of the application will become apparent in the course of the following descriptions of exemplary embodiments, which are given for illustration of the application and are not intended to be limiting thereof.

[0480] Embodiments

[0481] Example 3

[0482] A 70 kg patient with CrCl > 60 ml / min presented with a Torsades de Pointes storm after implantation of an implantable defibrillator. The patient's physician decided to terminate the Torsades de Pointes storm by infusion of dofetilide. The patient had continuous monitoring of ECG. The patient was then treated with dofetilide as follows.

[0483] (D) Hour 0: Intravenous (IV) loading dose: 450 μg infused over 1 hour, measuring QTc, HR, and BP every 15 minutes;

[0484] (E) Hour 1 : IV maintenance infusion: 450 μg infused over 12 h, starting at the end of the loading dose infusion; and,

[0485] (F) Hour 16: Oral dose: 500 μg orally every 12 hours (BID), starting 3 h after termination of the IV maintenance infusion.

[0486] Figure 1Estimated blood plasma concentrations of dofetilide obtained with the above dosing regimen are shown. The plot was obtained by modeling the above dosing regimen. Software packages NONMEM™ version 7.4 (ICON, Hanover, MD, USA) and MWpharm (Mediware, Prague, CZ) 6 were used for Bayesian PK modeling. PsN7 (Dept. of Pharmacy, Uppsala University, Uppsala, Sweden) was used for automation of the procedure. R (version 3.5.1, R Foundation for Statistical Computing) was used for data preparation, graphical analysis, linear regression analysis, and statistical summary. R package ‘mrgsolve’ was used for simulation.

[0487] Step (A): The expected loading dose (in this example, a 450 μg dofetilide IV infusion over 1 hour) reaches the expected maximum serum concentration, which is expected from chronic oral dosing of 500 μg dofetilide. This would reach a peak after 6 dofetilide doses twice daily if dosed orally. Peak concentration is typically reached at the end of the infusion.

[0488] QTc is measured every 15 minutes during the infusion.

[0489] Step (B): At the end of the 1-hour IV loading, an IV maintenance infusion of 450 μg dofetilide (0.625 μg / min) over 12 hours is started. This dose can be maintained until the patient is awake and able to take dofetilide orally.

[0490] Once the patient can take dofetilide orally, the dofetilide maintenance IV is discontinued. Starting about 3 h after the IV maintenance infusion is discontinued, 500 μg oral doses of dofetilide are administered every 12 h (BID) thereafter.

[0491] If the QTc increases by 15% from the baseline QTc, or if a QTc > 500 msec (550 msec in patients with ventricular conduction abnormalities) is observed, subsequent oral doses will be reduced to 250 μg BID (or lower if the original oral dose required was lower, see below).

[0492] It should be noted that if the patient exhibits a CrCl that is lower than normal, the initial target concentration will be the same, but the oral (maintenance) dose administered will be lower; 250 μg or 125 μg BID (based on the figure below).

[0493]

[0494] Further, in patients who show excessive QTc prolongation under initial loading (at > 500 msec or > 550 msec, in patients with ventricular conduction abnormalities), the first oral dose will be reduced to 250 μg (or 125 μg if the initial oral dose was 250 μg, based on the chart above), and the peak concentration is expected within 4 hours, and the QTc is re-evaluated. In this way, the concentration prediction from chronic oral dosing of dofetilide at 250 μg can be easily assessed by QTc observations.

[0495] Example 4

[0496] A 75 kg patient with CrCl of 45 mL / min presents with a tachyarrhythmia storm after implantation of an implantable defibrillator. The patient's physician decides to terminate the tachyarrhythmia storm by infusion of dofetilide. The patient's ECG is continuously monitored. The patient is then treated with dofetilide as follows.

[0497] (A) Hour 0: IV loading dose: 450 μg infused over 1 hour, measuring QTc, HR, and BP every 15 minutes.

[0498] (B) Hour 4: Maintenance infusion: 225 μg infused over 12 hours starting 3 hours after the IV loading dose is completed.

[0499] (C) Hour 21: Oral dose initiation 250 μg, given orally every 12 hours, starting 5 hours after the IV maintenance infusion is terminated.

[0500] Many modifications and variations of this application are possible in light of the above teachings. It is, therefore, to be understood that within the scope of the appended embodiments, the application can be practiced otherwise than as specifically described.

[0501] Embodiment-B. Termination of tachyarrhythmia storm

[0502] 1. A method of terminating a tachyarrhythmia storm in a patient after implantation of an implantable defibrillator, comprising:

[0503] a intravenously administering a loading dose of dofetilide to a patient who presents with a tachyarrhythmia storm after implantation of an implantable defibrillator, wherein:

[0504] (A) the loading dose is about 450-500 μg of dofetilide; and,

[0505] (B) the loading dose is administered over about 30-60 minutes;

[0506] b intravenously administering a maintenance infusion of dofetilide over about 12 h, about 0-4 h after the IV loading dose is completed, the maintenance infusion given based on the patient's creatinine clearance (CrCl) given in the following table;

[0507]

[0508] c Once the patient has recovered from the termination of the arrhythmic storm, oral dofetilide is administered; and,

[0509] d Oral dofetilide is administered every 12 h, about 2-6 h after the IV maintenance infusion is stopped, the oral dose given based on the patient's CrCl given in the table above;

[0510] with the proviso that if the patient's QTc increases by 15% from the baseline QTc, or if the QTc is measured as > 500 msec or > 550 msec, the oral dose is reduced from 500 μg to 250 μg, from 250 μg to 125 μg, or if initially 125 μg, discontinued, if the patient has a ventricular conduction abnormality.

[0511] 2. The method of embodiment 1, further comprising:

[0512] measuring the patient's QTc prior to the IV loading dose of dofetilide to establish a baseline QTc, then measuring the QTc thereafter about every 15-30 minutes for 60 min, and prior to the IV maintenance infusion and prior to each oral dose.

[0513] 3. The method of embodiment 1, wherein the loading dose is about 450 μg.

[0514] 4. The method of embodiment 1, wherein the loading dose is about 460 μg.

[0515] 5. The method of embodiment 1, wherein the loading dose is about 470 μg.

[0516] 6. The method of embodiment 1, wherein the loading dose is about 480 μg.

[0517] 7. The method of embodiment 1, wherein the loading dose is about 490 μg.

[0518] 8. The method of embodiment 1, wherein the loading dose is about 500 μg.

[0519] 9. The method of embodiment 1, wherein the loading dose is administered over about 30 minutes.

[0520] 10. The method of embodiment 1, wherein the loading dose is administered over about 40 minutes.

[0521] 11. The method of embodiment 1, wherein the loading dose is administered over about 50 minutes.

[0522] 12. The method of embodiment 1, wherein the loading dose is administered over about 60 minutes.

[0523] 13. The method of embodiment 1, wherein the maintenance infusion is initiated about Oh after completion of the loading dose.

[0524] 14. The method of embodiment 1, wherein the maintenance infusion is initiated about Ih after completion of the loading dose.

[0525] 15. The method of embodiment 1, wherein the maintenance infusion is initiated about 2h after completion of the loading dose.

[0526] 16. The method of embodiment 1, wherein the maintenance infusion is initiated about 3h after completion of the loading dose.

[0527] 17. The method of embodiment 1, wherein the maintenance infusion is initiated about 4h after completion of the loading dose.

[0528] 18. The method of embodiment 1, wherein the patient has a CrCl > 60 ml / min, the IV maintenance infusion is about 450-500 μg given over about 12h, and the oral dose is 500 μg.

[0529] 19. The method of embodiment 18, wherein the oral dose is reduced to 250 μg if the patient has a ventricular conduction abnormality due to a QTc increase of 15% from baseline QTc, or if the QTc is measured as > 500 msec or > 550 msec.

[0530] 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 given over about 12h, and the oral dose is 250 μg.

[0531] 21. The method of embodiment 20, wherein the oral dose is reduced to 125 μg if the patient has a ventricular conduction abnormality due to a QTc increase of 15% from baseline QTc, or if the QTc is measured as > 500 msec or > 550 msec.

[0532] 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 given over about 12h, and the oral dose is 125 μg.

[0533] 23. The method of embodiment 22, wherein the oral dose is discontinued if the patient has a ventricular conduction abnormality due to a QTc increase of 15% from baseline QTc, or if the QTc is measured as > 500 msec or > 550 msec.

[0534] Further embodiments - B. Termination of arrhythmic storm

[0535] 1. A method of terminating an arrhythmic storm in a patient to rapidly terminate the arrhythmic storm and prevent its recurrence, comprising:

[0536] a. intravenously administering to a patient in need thereof a loading dose of about 450-500 μg of dofetilide over about 30-60 minutes;

[0537] b. intravenously administering to a patient with a creatinine clearance of 60 ml / min or greater about 450-500 μg of a maintenance dose ("IV maintenance dose") of dofetilide about 0-4 hours after completion of the loading dose;

[0538] c. administering the IV maintenance dose over about 12 hours;

[0539] d. discontinuing the IV maintenance dose for those patients who have sufficiently recovered from the arrhythmic storm termination; and

[0540] e. orally administering 500 μg of dofetilide to a patient with a creatinine clearance of 60 ml / min or greater every 12 hours about 2-6 hours after discontinuing the IV maintenance dose;

[0541] wherein the oral dofetilide dose is reduced to 250 μg for those patients with a QTc increase of 15% from baseline, those patients with a QTc > 500 msec, or those patients with ventricular conduction abnormalities with a QTc > 550 msec; and

[0542] wherein the loading dose is expected to reach a maximum serum concentration at the termination of the infusion; and

[0543] wherein the patient is monitored to ensure no excessive QT prolongation leading to abnormal cardiac repolarization resulting in life threatening ventricular arrhythmias.

[0544] 2. The method of claim 1 which is a method of terminating an arrhythmic storm in a patient after implantation of a cardiac defibrillator.

[0545] 3. The method of embodiment 1 further comprising measuring the patient's QTc to establish a baseline QTc prior to intravenously administering the loading dose of dofetilide, thereafter measuring the QTc every 15-30 minutes during the infusion of the loading dose, and thereafter measuring the QTc about every 60 minutes until the patient is stable.

[0546] 4. The method of embodiment 3 wherein the patient's physician determines when the patient is stable.

[0547] 5. The method of embodiment 4, wherein the patient can be stable after completion of the loading infusion of dofetilide or after administration of the first oral dose.

[0548] 6. The method of embodiment 1, wherein the loading dose is 450-500 μg dofetilide.

[0549] 7. The method of embodiment 1, wherein a maintenance dose ("IV maintenance dose") of 450-500 μg dofetilide is administered to a patient with a creatinine clearance of 60 ml / min or greater 1-3 hours after completion of the loading dose.

[0550] 8. The method of embodiment 1, wherein the IV maintenance dose is about 450-500 μg dofetilide.

[0551] 9. The method of embodiment 1, wherein the creatinine clearance is 60 mL / min or greater.

[0552] 10. The method of embodiment 1, wherein 500 μg dofetilide is orally administered to a patient with a creatinine clearance of 60 ml / min or greater every 12 hours 3-5 hours after discontinuing the IV maintenance dose.

[0553] 11. The method of embodiment 1, further comprising measuring the patient's creatinine clearance as an approximation of glomerular filtration rate (GFR) prior to administration of the IV maintenance dose to determine the amount of dofetilide indicated for the IV maintenance dose.

[0554] 12. The method of embodiment 1, further comprising measuring the patient's creatinine clearance as an approximation of glomerular filtration rate (GFR) prior to oral administration of dofetilide to determine the amount of dofetilide indicated for the oral dose.

[0555] 13. The method of embodiment 1, wherein the patient has sufficiently recovered from the termination of the arrhythmic storm and oral administration of dofetilide occurs while the patient is awake postoperatively with an intact gag reflex.

[0556] 14. The method of embodiment 1, wherein the intravenous loading dose is administered over about 30-60 minutes.

[0557] 15. The method of embodiment 1, wherein the IV maintenance dose is administered over about 12 hours.

[0558] 16. The method of embodiment 1, wherein the dofetilide is fully loaded in less than 3 days.

[0559] 17. The method of embodiment 16, wherein the dofetilide is fully loaded when the dofetilide reaches a steady state concentration in the blood.

[0560] 18. The method of embodiment 1, wherein the intravenous dofetilide is administered as a first loading dose and a continuous IV maintenance dose.

[0561] 19. The method of embodiment 1, wherein the intravenous dofetilide administration prevents possible arrhythmias by avoiding excessive dofetilide blood levels.

[0562] 20. The method of embodiment 1, wherein the patient is loaded with dofetilide by intravenous administration before the patient is awake after surgery and has intact emetic reflexes and is able to take dofetilide orally.

[0563] 21. A method of terminating a patient's arrhythmic storm to rapidly terminate the arrhythmic storm and prevent its recurrence, comprising:

[0564] a. intravenously administering to a patient in need thereof a loading dose of about 450-500 μg of dofetilide over about 30-60 minutes;

[0565] b. intravenously administering to a patient with a creatinine clearance of 60 ml / min or greater a maintenance dose ("IV maintenance dose") of about 450-500 μg of dofetilide about 0-4 hours after completion of the loading dose;

[0566] c. administering the IV maintenance dose over about 12 hours;

[0567] d. discontinuing the IV maintenance dose for those patients who have sufficiently recovered from the arrhythmic storm termination; and

[0568] e. orally administering 250 μg of dofetilide every 12 hours to a patient with a creatinine clearance of 40-<60 ml / min about 2-6 hours after discontinuing the IV maintenance dose;

[0569] wherein the oral dofetilide dose is reduced to 125 μg for those patients with a QTc increase of 15% from baseline, those patients with a QTc > 500 msec, or those patients with ventricular conduction abnormalities with a QTc > 550 msec; and

[0570] wherein the loading dose is expected to reach a maximum serum concentration at the end of the infusion; and

[0571] wherein the patient is monitored to ensure that there is no excessive QT prolongation leading to abnormal cardiac repolarization leading to life threatening ventricular arrhythmias.

[0572] 22. The method of embodiment 21, which is a method of terminating a patient's arrhythmic storm after implantation of a cardiac defibrillator.

[0573] 23. The method of embodiment 21, further comprising measuring the patient's QTc to establish a baseline QTc prior to intravenous administration of the loading dose of dofetilide, thereafter measuring the QTc every 15-30 minutes during the infusion of the loading dose, thereafter measuring the QTc about every 60 minutes until the patient is stable.

[0574] 24. The method of embodiment 23, wherein the patient's physician determines when the patient is stable.

[0575] 25. The method of embodiment 24, wherein the patient can be stable after completion of the loading infusion of dofetilide or after administration of the first oral dose.

[0576] 26. The method of embodiment 21, wherein the loading dose is 450-500 μg dofetilide.

[0577] 27. The method of claim 21, wherein 1-3 hours after completion of the loading dose, a patient with a creatinine clearance of 60 ml / min or greater is administered a maintenance dose ("IV maintenance dose") of 450-500 μg dofetilide.

[0578] 28. The method of embodiment 21, wherein the IV maintenance dose is about 450-500 μg dofetilide.

[0579] 29. The method of embodiment 21, wherein the creatinine clearance is 60 mL / min or greater.

[0580] 30. The method of embodiment 21, 1. wherein the IV maintenance dose is discontinued after 3-5 hours. IV maintenance dose.

[0581] 31. The method of embodiment 21, further comprising measuring the patient's creatinine clearance as an approximation of glomerular filtration rate (GFR) prior to administration of the IV maintenance dose to determine the amount of dofetilide indicated for the IV maintenance dose.

[0582] 32. The method of embodiment 21, further comprising measuring the patient's creatinine clearance as an approximation of glomerular filtration rate (GFR) prior to oral administration of dofetilide to determine the amount of dofetilide indicated for the oral dose.

[0583] 33. The method of embodiment 21, wherein the patient has sufficiently recovered from the termination of the arrhythmic storm and has an intact gag reflex when orally administered dofetilide while awake postoperatively.

[0584] 34. The method of embodiment 21, wherein the intravenous loading dose is administered over about 30-60 minutes.

[0585] 35. The method of embodiment 21, wherein the IV maintenance dose is administered over about 12 hours.

[0586] 36. The method of embodiment 21, wherein the dofetilide is fully loaded in less than 3 days.

[0587] 37. The method of embodiment 36, wherein the dofetilide is fully loaded when the dofetilide reaches a steady state concentration in the blood.

[0588] 38. The method of embodiment 21, wherein the intravenous dofetilide is administered as a first loading dose and a continuous IV maintenance dose.

[0589] 39. The method of embodiment 21, wherein the intravenous dofetilide administration prevents possible arrhythmias by avoiding excessive dofetilide blood levels.

[0590] 40. The method of embodiment 21, wherein the patient is loaded with dofetilide by intravenous administration before the patient is awake after surgery and the vomiting reflex is intact and able to take dofetilide orally.

[0591] 41. A method of terminating a patient's arrhythmic storm to rapidly terminate the arrhythmic storm and prevent its recurrence, comprising:

[0592] a. intravenously administering to a patient in need thereof a loading dose of about 450-500 μg dofetilide over about 30-60 minutes;

[0593] b. intravenously administering to a patient with a creatinine clearance of 60 ml / min or greater a maintenance dose ("IV maintenance dose") of about 450-500 μg dofetilide about 0-4 hours after completion of the loading dose;

[0594] c. administering the IV maintenance dose over about 12 hours;

[0595] d. discontinuing the IV maintenance dose for those patients who have sufficiently recovered from the arrhythmic storm termination; and

[0596] e. orally administering 125 μg dofetilide to a patient with a creatinine clearance of 20-<40 ml / min every 12 hours about 2-6 hours after discontinuing the IV maintenance dose;

[0597] wherein the oral dofetilide dose is discontinued for those patients with a QTc increase of 15% from baseline, those patients with a QTc > 500 msec, or those patients with a ventricular conduction abnormality with a QTc > 550 msec; and

[0598] wherein the loading dose is expected to reach a maximum serum concentration at the end of the infusion; and

[0599] wherein the patient is monitored to ensure that there is no excessive QT prolongation leading to abnormal cardiac repolarization leading to life threatening ventricular arrhythmias.

[0600] 42. The method of embodiment 41, which is a method of terminating a patient's arrhythmic storm after implantation of a cardiac defibrillator.

[0601] 43. The method of embodiment 41, further comprising measuring the patient's QTc to establish a baseline QTc prior to intravenous administration of a loading dose of dofetilide, thereafter measuring the QTc every 15-30 minutes during infusion of the loading dose, thereafter measuring the QTc about every 60 minutes until the patient is stabilized.

[0602] 44. The method of embodiment 43, wherein the patient's physician determines when the patient is stabilized.

[0603] 45. The method of embodiment 44, wherein the patient can be stabilized after completion of the loading infusion of dofetilide or after administration of the first oral dose.

[0604] 46. The method of embodiment 41, wherein the loading dose is 450-500 μg dofetilide.

[0605] 47. The method of embodiment 41, wherein 1-3 hours after completion of the loading dose, a patient with a creatinine clearance of 60 ml / min or greater is administered a maintenance dose ("IV maintenance dose") of 450-500 μg dofetilide.

[0606] 48. The method of embodiment 41, wherein the IV maintenance dose is 450-500 μg dofetilide.

[0607] 49. The method of embodiment 41, wherein the creatinine clearance is 60 mL / min or greater.

[0608] 50. The method of embodiment 41, 1. wherein 3-5 hours after discontinuing the IV maintenance dose, a patient with a creatinine clearance of 20-<40 ml / min is administered 125 μg dofetilide orally every 12 hours.

[0609] 51. The method of embodiment 41, further comprising measuring the patient's creatinine clearance as a proxy for glomerular filtration rate (GFR) prior to administration of the IV maintenance dose to determine the amount of dofetilide indicated for the IV maintenance dose.

[0610] 52. The method of embodiment 41, further comprising measuring the patient's creatinine clearance rate as an approximation of glomerular filtration rate (GFR) prior to orally administering dofetilide to determine the amount of dofetilide indicated for the oral dose.

[0611] 53. The method of embodiment 41, wherein the patient has sufficiently recovered from the termination of the arrhythmic storm and orally administered dofetilide while awake postoperatively with an intact gag reflex.

[0612] 54. The method of embodiment 41, wherein the intravenous loading dose is administered over about 30-60 minutes.

[0613] 55. The method of embodiment 41, wherein the IV maintenance dose is administered over about 12 hours.

[0614] 56. The method of embodiment 41, wherein the dofetilide is fully loaded in less than 3 days.

[0615] 57. The method of embodiment 56, wherein the dofetilide is fully loaded when the dofetilide reaches a steady state concentration in the blood.

[0616] 58. The method of embodiment 41, wherein the intravenous dofetilide is administered as a first loading dose and a continuous IV maintenance dose.

[0617] 59. The method of embodiment 41, wherein the intravenous dofetilide administration prevents possible arrhythmias by avoiding excessive dofetilide blood levels.

[0618] 60. The method of embodiment 41, wherein the patient is loaded with dofetilide by intravenous administration prior to the patient being awake postoperatively and having an intact gag reflex and being able to orally administer dofetilide.

[0619] 61. A method of terminating an arrhythmic storm in a patient to rapidly terminate the arrhythmic storm and prevent its recurrence, comprising:

[0620] a. intravenously administering to a patient in need thereof a loading dose of about 450-500 μg of dofetilide over about 30-60 minutes;

[0621] b. intravenously administering to a patient with a creatinine clearance rate of 40-<60 mL / min a maintenance dose ("IV maintenance dose") of about 225-250 μg of dofetilide about 0-4 hours after completion of the loading dose;

[0622] c. administering the IV maintenance dose over about 12 hours;

[0623] d. for those patients who are fully recovered from the arrhythmic storm termination, discontinuing the IV maintenance dose; and

[0624] e. about 2-6 hours after discontinuing the IV maintenance dose, orally administering 500 μg of dofetilide to patients with a creatinine clearance of 60 ml / min or greater every 12 hours;

[0625] wherein for those patients with a QTc increase of 15% from baseline, those patients with a QTc > 500 msec, or those patients with a ventricular conduction abnormality with a QTc > 550 msec, the oral dofetilide dose is reduced to 250 μg; and

[0626] wherein the loading dose is expected to reach a maximum serum concentration at the termination of the infusion; and

[0627] wherein the patient is monitored to ensure that there is no excessive QT prolongation leading to abnormal cardiac repolarization resulting in life threatening ventricular arrhythmias.

[0628] 62. The method of embodiment 61, which is a method of terminating an arrhythmic storm in a patient after implantation of a cardiac defibrillator.

[0629] 63. The method of embodiment 61, further comprising measuring the QTc of the patient to establish a baseline QTc prior to intravenously administering a loading dose of dofetilide, thereafter measuring the QTc every 15-30 minutes during the infusion of the loading dose, and thereafter measuring the QTc about every 60 minutes until the patient is stable.

[0630] 64. The method of embodiment 63, wherein the patient's physician determines when the patient is stable.

[0631] 65. The method of embodiment 64, wherein the patient can be stable after completion of the loading infusion of dofetilide or after administration of the first oral dose.

[0632] 66. The method of embodiment 61, wherein the loading dose is 450-500 μg of dofetilide.

[0633] 67. The method of embodiment 61, wherein 1-3 hours after completion of the loading dose, a maintenance dose ("IV maintenance dose") of 450-500 μg of dofetilide is administered to patients with a creatinine clearance of 60 ml / min or greater.

[0634] 68. The method of embodiment 61, wherein the IV maintenance dose is 225-250 μg of dofetilide.

[0635] 69. The method of embodiment 61, wherein the creatinine clearance is 60 mL / min or greater.

[0636] 70. The method of embodiment 61, wherein 500 μg of dofetilide is orally administered to a patient with a creatinine clearance of 60 ml / min or greater every 12 hours 3-5 hours after the IV maintenance dose is discontinued.

[0637] 71. The method of embodiment 61, further comprising measuring the patient's creatinine clearance as a proxy for glomerular filtration rate (GFR) prior to administering the IV maintenance dose to determine the amount of dofetilide indicated for the IV maintenance dose.

[0638] 72. The method of embodiment 61, further comprising measuring the patient's creatinine clearance as a proxy for glomerular filtration rate (GFR) prior to orally administering dofetilide to determine the amount of dofetilide indicated for the oral dose.

[0639] 73. The method of embodiment 61, wherein the patient has sufficiently recovered from the termination of the arrhythmic storm and the dofetilide is orally administered when the patient is awake postoperatively with an intact gag reflex.

[0640] 74. The method of embodiment 61, wherein the IV loading dose is administered over about 30-60 minutes.

[0641] 75. The method of embodiment 61, wherein the IV maintenance dose is administered over about 12 hours.

[0642] 76. The method of embodiment 61, wherein the dofetilide is fully loaded in less than 3 days.

[0643] 77. The method of embodiment 76, wherein the dofetilide is fully loaded when the dofetilide reaches a steady state concentration in the blood.

[0644] 78. The method of embodiment 61, wherein the IV dofetilide is administered as a first loading dose and a continuing IV maintenance dose.

[0645] 79. The method of embodiment 61, wherein IV dofetilide administration prevents possible arrhythmias by avoiding excessive dofetilide blood levels.

[0646] 80. The method of embodiment 61, wherein the patient can be loaded with dofetilide intravenously prior to the patient being awake postoperatively and having an intact gag reflex and being able to orally administer dofetilide.

[0647] 81. A method of terminating an arrhythmic storm in a patient to rapidly terminate the arrhythmic storm and prevent its recurrence, comprising:

[0648] a. intravenously administering to a patient in need thereof a loading dose of about 450-500 μg of dofetilide over about 30-60 minutes;

[0649] b. about 0-4 hours after completion of the loading dose, intravenously administering to a patient with a creatinine clearance of 40-<60 mL / min a maintenance dose ("IV maintenance dose") of about 225-250 μg of dofetilide;

[0650] c. administering the IV maintenance dose over about 12 hours;

[0651] d. discontinuing the IV maintenance dose for those patients who have sufficiently recovered from the arrhythmic storm termination; and

[0652] e. about 2-6 hours after discontinuing the IV maintenance dose, orally administering 250 μg of dofetilide to a patient with a creatinine clearance of 40-<60 ml / min every 12 hours.

[0653] wherein the oral dose of dofetilide is reduced to 125 μg for those patients with a QTc increase of 15% from baseline, those patients with a QTc > 500 msec, or those patients with a ventricular conduction abnormality with a QTc > 550 msec; and

[0654] wherein the loading dose is expected to reach a maximum serum concentration at the end of the infusion; and

[0655] wherein the patient is monitored to ensure that there is no excessive QT prolongation leading to abnormal cardiac repolarization leading to life threatening ventricular arrhythmias.

[0656] 82. The method of embodiment 81, which is a method of terminating an arrhythmic storm in a patient after implantation of a cardiac defibrillator.

[0657] 83. The method of embodiment 81, further comprising measuring the QTc of the patient to establish a baseline QTc prior to intravenously administering the loading dose of dofetilide, thereafter measuring the QTc every 15-30 minutes during the infusion of the loading dose, and thereafter measuring the QTc about every 60 minutes until the patient is stable.

[0658] 84. The method of embodiment 83, wherein the patient's physician determines when the patient is stable.

[0659] 85. The method of embodiment 84, wherein the patient can be stable after completion of the loading infusion of dofetilide or after administration of the first oral dose.

[0660] 86. The method of embodiment 81, wherein the loading dose is 450-500 μg of dofetilide.

[0661] 87. The method of embodiment 81, wherein 450 to 500 μg of a maintenance dose ("IV maintenance dose") of dofetilide is administered to a patient having a creatinine clearance of 60 ml / min or greater 1 to 3 hours after completion of the loading dose.

[0662] 88. The method of embodiment 81, wherein the IV maintenance dose is 225 to 250 μg of dofetilide.

[0663] 89. The method of embodiment 81, wherein 250 μg of dofetilide is administered orally to a patient having a creatinine clearance of 40 to < 60 ml / min every 12 hours 2 to 5 hours after discontinuing the IV maintenance dose.

[0664] 90. The method of embodiment 81, further comprising measuring the patient's creatinine clearance as an approximation of glomerular filtration rate (GFR) prior to administering the IV maintenance dose to determine the amount of dofetilide indicated for the IV maintenance dose.

[0665] 91. The method of embodiment 81, further comprising measuring the patient's creatinine clearance as an approximation of glomerular filtration rate (GFR) prior to administering dofetilide orally to determine the amount of dofetilide indicated for the oral dose.

[0666] 92. The method of embodiment 81, wherein the patient has recovered sufficiently from the termination of the arrhythmic storm and the dofetilide is administered orally while the patient is awake postoperatively with an intact gag reflex.

[0667] 93. The method of embodiment 81, wherein the intravenous loading dose is administered over about 30 to 60 minutes.

[0668] 94. The method of embodiment 81, wherein the IV maintenance dose is administered over about 12 hours.

[0669] 95. The method of embodiment 81, wherein the dofetilide is fully loaded in less than 3 days.

[0670] 96. The method of embodiment 95, wherein the dofetilide is fully loaded when the dofetilide reaches a steady state concentration in the blood.

[0671] 97. The method of embodiment 81, wherein the intravenous dofetilide is administered as a first loading dose and a continuing IV maintenance dose.

[0672] 98. The method of embodiment 81, wherein the administration of intravenous dofetilide prevents possible arrhythmias by avoiding excessive blood levels of dofetilide.

[0673] 99. The method of embodiment 81, wherein the patient is loaded with dofetilide by intravenous administration prior to the patient being awake after surgery and having an intact emetic reflex and being able to take oral dofetilide.

[0674] 100. A method of terminating a patient's arrhythmic storm to rapidly terminate the arrhythmic storm and prevent its recurrence, comprising:

[0675] a. intravenously administering to a patient in need thereof a loading dose of about 450-500 μg of dofetilide over about 30-60 minutes;

[0676] b. intravenously administering to a patient with a creatinine clearance of 40-< 60 mL / min a maintenance dose ("IV maintenance dose") of about 225-250 μg of dofetilide about 0-4 hours after completion of the loading dose;

[0677] c. administering the IV maintenance dose over about 12 hours;

[0678] d. discontinuing the IV maintenance dose for those patients who have sufficiently recovered from the arrhythmic storm termination; and

[0679] e. orally administering 125 μg of dofetilide to a patient with a creatinine clearance of 20-< 40 ml / min every 12 hours about 2-6 hours after discontinuing the IV maintenance dose;

[0680] wherein the oral dofetilide dose is discontinued for those patients with a QTc that increases by 15% from baseline, those patients with a QTc > 500 msec, or those patients with a ventricular conduction abnormality with a QTc > 550 msec; and

[0681] wherein the loading dose is expected to reach a maximum serum concentration at the end of the infusion; and wherein the patient is monitored to ensure that there is no excessive QT prolongation leading to abnormal cardiac repolarization resulting in life threatening ventricular arrhythmias.

[0682] 101. The method of embodiment 100, which is a method of terminating a patient's arrhythmic storm after implantation of a cardiac defibrillator.

[0683] 102. The method of embodiment 100, further comprising measuring the patient's QTc to establish a baseline QTc prior to intravenous administration of the loading dose of dofetilide, thereafter measuring the QTc every 15-30 minutes during the infusion of the loading dose, and thereafter measuring the QTc about every 60 minutes until the patient is stable.

[0684] 103. The method of embodiment 102, wherein the patient's physician determines when the patient is stable.

[0685] 104. The method of embodiment 103, wherein the patient can be stable after completion of the loading infusion of dofetilide or after administration of the first oral dose.

[0686] 105. The method of embodiment 100, wherein the loading dose is 450-500 μg dofetilide.

[0687] 106. The method of embodiment 100, wherein 1-3 hours after completion of the loading dose, a patient with a creatinine clearance of 60 ml / min or greater is administered a maintenance dose ("IV maintenance dose") of 450-500 μg dofetilide.

[0688] 107. The method of embodiment 100, wherein the IV maintenance dose is 225-250 μg dofetilide.

[0689] 108. The method of embodiment 100, wherein 2-5 hours after discontinuing the IV maintenance dose, a patient with a creatinine clearance of 20-<40 ml / min is administered 125 μg dofetilide orally every 12 hours.

[0690] 109. The method of embodiment 100, further comprising measuring the patient's creatinine clearance as a proxy for glomerular filtration rate (GFR) prior to administration of the IV maintenance dose to determine the amount of dofetilide indicated for the IV maintenance dose.

[0691] 110. The method of embodiment 100, further comprising measuring the patient's creatinine clearance as a proxy for glomerular filtration rate (GFR) prior to oral administration of dofetilide to determine the amount of dofetilide indicated for the oral dose.

[0692] 111. The method of embodiment 100, wherein the patient has sufficiently recovered from the termination of the arrhythmic storm and has an intact gag reflex at the time of oral administration of dofetilide while awake postoperatively.

[0693] 112. The method of embodiment 100, wherein the intravenous loading dose is administered over about 30-60 minutes.

[0694] 113. The method of embodiment 100, wherein the IV maintenance dose is administered over about 12 hours.

[0695] 114. The method of embodiment 100, wherein the dofetilide is fully loaded in less than 3 days.

[0696] 115. The method of embodiment 114, wherein the dofetilide is fully loaded when the dofetilide reaches a steady state concentration in the blood.

[0697] 116. The method of embodiment 100, wherein the intravenous dofetilide is administered as a first loading dose and a continuous IV maintenance dose.

[0698] 117. The method of embodiment 100, wherein the intravenous dofetilide administration prevents possible arrhythmias by avoiding excessive dofetilide blood levels.

[0699] 118. The method of embodiment 100, wherein the patient is loaded with dofetilide by intravenous administration prior to the patient being awake after surgery and having intact emetic reflexes and being able to take dofetilide orally.

[0700] 119. A method of terminating a patient's arrhythmic storm to rapidly terminate the arrhythmic storm and prevent its recurrence, comprising:

[0701] a. intravenously administering to a patient in need thereof a loading dose of about 450-500 μg of dofetilide over about 30-60 minutes;

[0702] b. intravenously administering to a patient with a creatinine clearance of 20-<40 mL / min a maintenance dose ("IV maintenance dose") of about 100-125 μg of dofetilide about 0-4 hours after completion of the loading dose;

[0703] c. administering the IV maintenance dose over about 12 hours;

[0704] d. discontinuing the IV maintenance dose for those patients who have sufficiently recovered from the arrhythmic storm termination; and

[0705] e. orally administering 500 μg of dofetilide every 12 hours to a patient with a creatinine clearance of 60 ml / min or greater about 2-6 hours after discontinuing the IV maintenance dose;

[0706] wherein the oral dofetilide dose is reduced to 250 μg for those patients with a QTc increase of 15% from baseline, those patients with a QTc > 500 msec, or those patients with ventricular conduction abnormalities with a QTc > 550 msec; and wherein the loading dose is expected to reach maximum serum concentration at the end of the infusion; and wherein the patient is monitored to ensure that there is no excessive QT prolongation leading to abnormal cardiac repolarization resulting in life threatening ventricular arrhythmias.

[0707] 120. The method of embodiment 119 which is a method of terminating a patient's arrhythmic storm after implantation of a cardiac defibrillator.

[0708] 121. The method of embodiment 119, further comprising measuring the patient's QTc to establish a baseline QTc prior to the intravenous administration of the loading dose of dofetilide, thereafter measuring the QTc every 15-30 minutes during the infusion of the loading dose, thereafter measuring the QTc about every 60 minutes until the patient is stable.

[0709] 122. The method of embodiment 121, wherein the patient's physician determines when the patient is stable.

[0710] 123. The method of embodiment 122, wherein the patient can be stable after completion of the loading infusion of dofetilide or after administration of the first oral dose.

[0711] 124. The method of embodiment 119, wherein the loading dose is 450-500 μg dofetilide.

[0712] 125. The method of embodiment 119, wherein 1-3 hours after completion of the loading dose, a patient with a creatinine clearance of 60 ml / min or greater is administered a 450-500 μg maintenance dose ("IV maintenance dose") of dofetilide.

[0713] 126. The method of embodiment 119, wherein the loading dose is 450-500 μg dofetilide.

[0714] 127. The method of embodiment 119, wherein the creatinine clearance is 60 mL / min or greater.

[0715] 128. The method of embodiment 119, wherein 3-5 hours after discontinuing the IV maintenance, a patient with a creatinine clearance of 60 ml / min or greater is administered 500 μg dofetilide orally every 12 hours.

[0716] 129. The method of embodiment 119, further comprising measuring the patient's creatinine clearance as an approximation of glomerular filtration rate (GFR) prior to administration of the IV maintenance dose to determine the amount of dofetilide indicated for the IV maintenance dose.

[0717] 130. The method of embodiment 119, further comprising measuring the patient's creatinine clearance as an approximation of glomerular filtration rate (GFR) prior to oral administration of dofetilide to determine the amount of dofetilide indicated for the oral dose.

[0718] 131. The method of embodiment 119, wherein the patient has sufficiently recovered from the termination of the arrhythmic storm and has an intact gag reflex when orally administered dofetilide while awake postoperatively.

[0719] 132. The method of embodiment 119, wherein the intravenous loading dose is administered over about 30-60 minutes.

[0720] 133. The method of embodiment 119, wherein the IV maintenance dose is administered over about 12 hours.

[0721] 134. The method of embodiment 119, wherein the dofetilide is completely loaded in less than 3 days.

[0722] 135. The method of embodiment 134, wherein the dofetilide is completely loaded when the dofetilide reaches a steady state concentration in the blood.

[0723] 136. The method of embodiment 119, wherein the intravenous dofetilide is administered as a first loading dose and a continuous IV maintenance dose.

[0724] 137. The method of embodiment 119, wherein the intravenous dofetilide administration prevents possible arrhythmias by avoiding excessive dofetilide blood levels.

[0725] 138. The method of embodiment 119, wherein the patient is loaded with dofetilide by intravenous administration before the patient is awake after surgery and has intact emetic reflexes and is able to take dofetilide orally.

[0726] 139. A method of terminating a patient's arrhythmic storm to rapidly terminate the arrhythmic storm and prevent its recurrence, comprising:

[0727] a. intravenously administering to a patient in need thereof a loading dose of about 450-500 μg of dofetilide over about 30-60 minutes;

[0728] b. intravenously administering to a patient with a creatinine clearance of 20-<40 mL / min a maintenance dose ("IV maintenance dose") of about 100-125 μg of dofetilide about 0-4 hours after completion of the loading dose;

[0729] c. administering the IV maintenance dose over about 12 hours;

[0730] d. discontinuing the IV maintenance dose for those patients who have sufficiently recovered from the arrhythmic storm termination; and

[0731] e. orally administering 250 μg of dofetilide every 12 hours to a patient with a creatinine clearance of 40-<60 ml / min about 2-6 hours after discontinuing the IV maintenance dose.

[0732] wherein the dose of oral dofetilide is reduced to 125 μg for those patients with a 15% increase in QTc from baseline, those patients with a QTc > 500 msec, or those patients with a ventricular conduction abnormality of QTc > 550 msec; and wherein the expected loading dose achieves a maximum serum concentration at the end of the infusion; and wherein the patient is monitored to ensure no excessive QT prolongation leading to abnormal cardiac repolarization resulting in life threatening ventricular arrhythmias.

[0733] 140. The method of embodiment 139, which is a method of terminating a patient's arrhythmic storm after implantation of a cardiac defibrillator.

[0734] 141. The method of embodiment 139, further comprising measuring the patient's QTc to establish a baseline QTc prior to intravenous administration of a loading dose of dofetilide, thereafter measuring the QTc every 15-30 minutes during the infusion of the loading dose, and thereafter measuring the QTc about every 60 minutes until the patient is stable.

[0735] 142. The method of embodiment 141, wherein the patient's physician determines when the patient is stable.

[0736] 143. The method of embodiment 142, wherein the patient can be stable after completion of the loading infusion of dofetilide or after administration of the first oral dose.

[0737] 144. The method of embodiment 139, wherein the loading dose is 450-500 μg of dofetilide.

[0738] 145. The method of embodiment 139, wherein 1-3 hours after completion of the loading dose, a patient with a creatinine clearance of 60 ml / min or greater is administered a 450-500 μg maintenance dose ("IV maintenance dose") of dofetilide.

[0739] 146. The method of embodiment 139, wherein the loading dose is 450-500 μg of dofetilide.

[0740] 147. The method of embodiment 139, wherein 2-5 hours after discontinuing the IV maintenance dose, a patient with a creatinine clearance of 40-<60 mL / min is administered 250 μg of dofetilide orally every 12 hours.

[0741] 148. The method of embodiment 139, further comprising measuring the patient's creatinine clearance as an approximation of glomerular filtration rate (GFR) prior to administration of the IV maintenance dose to determine the amount of dofetilide indicated for the IV maintenance dose.

[0742] 149. The method of embodiment 139, further comprising measuring the patient's creatinine clearance rate as an approximation of glomerular filtration rate (GFR) prior to orally administering dofetilide to determine the amount of dofetilide indicated for the oral dose.

[0743] 150. The method of embodiment 139, wherein the patient has sufficiently recovered from the termination of the arrhythmic storm and orally administers dofetilide when postoperatively awake with intact vomiting reflex.

[0744] 151. The method of embodiment 139, wherein the intravenous loading dose is administered over about 30-60 minutes.

[0745] 152. The method of embodiment 139, wherein the IV maintenance dose is administered over about 12 hours.

[0746] 153. The method of embodiment 139, wherein the dofetilide is fully loaded in less than 3 days.

[0747] 154. The method of embodiment 153, wherein the dofetilide is fully loaded when the dofetilide reaches a steady state concentration in the blood.

[0748] 155. The method of embodiment 139, wherein the intravenous dofetilide is administered in a first loading dose and a continuous IV maintenance dose.

[0749] 156. The method of embodiment 139, wherein the intravenous dofetilide administration prevents possible arrhythmias by avoiding excessive dofetilide blood levels.

[0750] 157. The method of embodiment 139, wherein the patient can be loaded with dofetilide intravenously prior to the patient being postoperatively awake and having an intact vomiting reflex and being able to orally administer dofetilide.

[0751] 158. A method of terminating an arrhythmic storm in a patient to rapidly terminate the arrhythmic storm and prevent its recurrence, comprising:

[0752] a. intravenously administering to a patient in need thereof a loading dose of about 450-500 μg of dofetilide over about 30-60 minutes;

[0753] b. intravenously administering to a patient with a creatinine clearance rate of 20-<40 mL / min a maintenance dose ("IV maintenance dose") of about 100-125 μg of dofetilide about 0-4 hours after completion of the loading dose;

[0754] c. administering the IV maintenance dose over about 12 hours;

[0755] d. for those patients who are fully recovered from the arrhythmic storm, discontinue the IV maintenance dose; and

[0756] about 2-6 hours after discontinuing the IV maintenance dose, orally administering 125 μg of dofetilide to the patient every 12 hours or every 24 hours for patients with a creatinine clearance of 20-<40 ml / min;

[0757] wherein for those patients with a QTc increase of 15% from baseline, those patients with a QTc > 500 msec, or those patients with a ventricular conduction abnormality with a QTc > 550 msec, the oral dofetilide dose is discontinued; and

[0758] wherein the loading dose is expected to reach a maximum serum concentration at the end of the infusion; and

[0759] wherein the patient is monitored to ensure that there is no excessive QT prolongation leading to abnormal cardiac repolarization leading to life threatening ventricular arrhythmias.

[0760] 159. The method of embodiment 158, which is a method of terminating an arrhythmic storm in a patient after implantation of a cardiac defibrillator.

[0761] 160. The method of embodiment 158, further comprising measuring the QTc of the patient to establish a baseline QTc prior to intravenously administering the loading dose of dofetilide, thereafter measuring the QTc every 15-30 minutes during the infusion of the loading dose, thereafter measuring the QTc about every 60 minutes until the patient is stable.

[0762] 161. The method of embodiment 160, wherein the patient's physician determines when the patient is stable.

[0763] 162. The method of embodiment 161, wherein the patient can be stable after completion of the loading infusion of dofetilide or after administration of the first oral dose.

[0764] 163. The method of embodiment 158, wherein the loading dose is 450-500 μg of dofetilide.

[0765] 164. The method of embodiment 158, wherein 1-3 hours after completion of the loading dose, the patient is administered a maintenance dose ("IV maintenance dose") of 450-500 μg of dofetilide for patients with a creatinine clearance of 60 ml / min or greater.

[0766] 165. The method of embodiment 158, wherein the loading dose is 450-500 μg of dofetilide.

[0767] 166. The method of embodiment 158, wherein the IV maintenance dose is discontinued after 3-5 hours.

[0768] 167. The method of embodiment 158, further comprising measuring the patient's creatinine clearance as an approximation of glomerular filtration rate (GFR) prior to administering the IV maintenance dose to determine the amount of dofetilide indicated for the IV maintenance dose.

[0769] 168. The method of embodiment 158, further comprising measuring the patient's creatinine clearance as an approximation of glomerular filtration rate (GFR) prior to orally administering dofetilide to determine the amount of dofetilide indicated for the oral dose.

[0770] 169. The method of embodiment 158, wherein the patient has sufficiently recovered from termination of the arrhythmic storm and orally administered dofetilide while awake postoperatively with an intact gag reflex.

[0771] 170. The method of embodiment 158, wherein the intravenous loading dose is administered over about 30-60 minutes.

[0772] 171. The method of embodiment 158, wherein the IV maintenance dose is administered over about 12 hours.

[0773] 172. The method of embodiment 158, wherein the dofetilide is fully loaded in less than 3 days.

[0774] 173. The method of embodiment 172, wherein the dofetilide is fully loaded when the dofetilide reaches a steady state concentration in the blood.

[0775] 174. The method of embodiment 158, wherein the intravenous dofetilide is administered as a first loading dose and a continuing IV maintenance dose.

[0776] 175. The method of embodiment 158, wherein intravenous dofetilide administration prevents possible arrhythmias by avoiding excessive dofetilide blood levels.

[0777] 176. The method of embodiment 158, wherein the patient can be loaded with dofetilide intravenously prior to the patient being awake postoperatively and having an intact gag reflex and being able to orally administer dofetilide.

[0778] C. Intravenous dofetilide for conversion of atrial fibrillation / flutter

[0779] All references cited herein are incorporated by reference in their entirety.

[0780] Definitions

[0781] AF is atrial fibrillation.

[0782] AFL is atrial flutter, which is very similar to AF. Typically, patients with AFL have more organized symptoms (e.g., heart rate is less chaotic).

[0783] about is defined as + / - 10% of the numerical value.

[0784] BID or bid or b.i.d. means twice a day or every 12 hours.

[0785] BP is blood pressure.

[0786] HR is heart rate.

[0787] IV means intravenously or intravenously.

[0788] Highly symptomatic AF / AFL refers to the level of symptoms displayed by the patient. AF / AFL can be asymptomatic, symptomatic, or highly symptomatic. Symptomatic can include patients with palpitations, dizziness, reduced exercise capacity, and presyncope. Highly symptomatic refers to patients with symptoms that reflect more severe hemodynamic impairment. Highly symptomatic can include patients with shortness of breath (SOB), dyspnea, chest pain (angina), orthopnea, syncope (short-term loss of consciousness), and diaphoresis.

[0789] Dofetilide

[0790] Previous studies have reported that a single dose of dofetilide produces a peak plasma concentration of 1.74 ng / mL after a 10 minute infusion of 1.5 μg / kg. (Sedgwick et al., Br. J. Clin Pharmacol 1991 : 31 : 515-519 and Rasmussen et al., J. Cardiovascular Pharmacology 20: 1992, S96-101.) An infusion of 3.0 μg / mL resulted in a plasma concentration of 5.35 ng / mL. (Sedgwick et al. and Rasmussen et al.) Coz and colleagues (Clin. Pharmacology & Therapeutics, 1995; 57(5) 533-54) reported that a 500 μg oral dose of dofetilide produced a plasma concentration Cmax of 1.9 ng / mL. Therefore, if a single dose achieves 70% of the predicted steady state, then at steady state, if 500 μg / mL is administered twice daily for at least 5 doses, the Cmax ss can be estimated to be 2.7 ng / mL. If a 1.5 μg / kg IV dose is known to result in a peak level of 1.7 ng / mL, then assuming linear kinetics, a dose of 2.4 μg / kg would achieve a peak concentration of 2.7 ng / mL, exposing the patient to the peak serum concentration predicted at steady state, and thus to the maximum QTc prolongation. This would expose the patient to the potential maximum risk of cardiac arrhythmia for a short period of time when monitored in a hospital setting.

[0791] IV dofetilide kinetics are linear, allowing a direct relationship between the IV dose of dofetilide administered and the serum concentration achieved. By IV administration, the "overshoot" of serum concentration can be avoided, avoiding excessive dofetilide blood levels and thus potential cardiac arrhythmias. The relationship between serum concentration and QTc interval is well known, with a high degree of correlation.

[0792] AF / AFL conversion

[0793] In view of the foregoing, the present invention is directed to a novel method of loading dofetilide that ensures that there is no excessive QT prolongation, which can lead to abnormal cardiac repolarization and thus life-threatening ventricular arrhythmias, by carefully achieving the minimally necessary effective blood concentration of the drug, thus maximizing patient safety.

[0794] Thus, in one aspect, the present invention is directed to a novel method of converting atrial fibrillation (AF) or atrial flutter (AFL) in a highly symptomatic patient comprising intravenous (IV) loading dofetilide.

[0795] In some aspects, the IV dofetilide loading dose converts the patient to a sinus rhythm. In these aspects, the patient is then converted to oral dofetilide (e.g., BID).

[0796] In some aspects, the IV dofetilide loading dose does not convert the patient to a sinus rhythm. In these aspects, electrical cardioversion is performed. In some aspects, patients who have received electrical cardioversion cannot receive oral medications. In these aspects, an IV maintenance dose is administered until the patient can take oral medications. At this time, the patient is then converted to oral dofetilide (e.g., BID).

[0797] In another aspect, the present application relates to a novel method of converting atrial fibrillation (AF) or atrial flutter (AFL) in a patient presenting with highly symptomatic AF or AFL, comprising:

[0798] j intravenously administering a loading dose of dofetilide to a patient presenting with highly symptomatic AF or AFL, wherein:

[0799] (A) the loading dose is about 450-500 μg dofetilide; and,

[0800] (B) the loading dose is administered over about 30-60 minutes;

[0801] k chemical conversion: if the patient has converted to a sinus rhythm, then about 0-4 h after completion of the IV loading dose, dofetilide is administered orally every 12 h, the oral dose given is based on the patient's creatinine clearance (CrCl) as shown in the table below;

[0802]

[0803] i chemical conversion failure: alternatively, if the patient has not converted to a sinus rhythm after completion of the IV loading infusion, the patient is subjected to electrical cardioversion;

[0804] m about 0-1 h after electrical cardioversion, a maintenance infusion of dofetilide is infused over 3-12 h, the maintenance dose given is based on the patient's CrCl as given in the table above based on a 12 hour infusion;

[0805] n once the patient has recovered from electrical cardioversion and is able to take dofetilide orally, the IV maintenance dose is discontinued; and,

[0806] o about 2-6 h after discontinuing the IV maintenance dose, dofetilide is administered orally every 12 h, the oral dose given is based on the patient's CrCl as given in the table above;

[0807] provided that if the patient's QTc increases by 15% from baseline QTc, or if the QTc measurement is > 500 msec or > 550 msec, the oral dose is reduced from 500 μg to 250 μg, from 250 μg to 125 μg, or if initially 125 μg, discontinued if the patient has a ventricular conduction abnormality.

[0808] In some aspects, QTc is measured prior to administration of dofetilide to establish a baseline QTc, and further QTc measurements can be compared to the baseline QTc. In some aspects, QTc is measured during the initial infusion, thereafter about every 15-30 minutes for 60 minutes, and prior to each oral dose and prior to IV maintenance infusion. These measurements can be discontinued once the physician observes that the patient is stable on dofetilide. For example, QTc measurements can be stopped after the completion of the loading infusion of dofetilide. Alternatively, QTc measurements can be stopped after the first oral dose is administered. The physician determines when to discontinue QTc measurements. Examples of a sufficient number of oral doses include 1, 2, 3, 4, 5 to 6 oral doses. After 6 oral doses, steady state is typically achieved, and no further changes in maximum serum dofetilide concentration or QT prolongation are expected.

[0809] In another aspect, the patient is monitored by electrocardiogram to determine the patient's QTc.

[0810] In some aspects, the IV loading dose is about 450-500 μg of dofetilide. Examples include about 450, 455, 460, 465, 470, 475, 480, 485, 490, 495 to 500 μg of dofetilide. Typically, the loading dose selected is an amount that achieves a predicted maximum serum concentration from oral administration of 500 μg of dofetilide.

[0811] In some aspects, the IV loading dose is administered over about 30-60 minutes. Examples include 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 to 60 minutes.

[0812] Patients chemically converted with an IV dofetilide loading dose can typically receive oral dofetilide.

[0813] Patients requiring cardioversion are typically unable to take oral medications immediately after surgery. In these aspects, a IV maintenance infusion of dofetilide is used. Once it is determined that the patient has recovered from cardioversion sufficiently to take oral dofetilide, the dofetilide IV maintenance infusion can be discontinued and then switched to oral dofetilide. It is determined by the patient's physician or designee when the patient can take oral dofetilide. Typically, the patient can take oral medications when the patient is awake and able to swallow with an intact gag reflex. In some aspects, this will be when the patient wakes up after surgery. In other aspects, the patient can need more time after waking up to be able to swallow the pill without aspiration.

[0814] In another aspect, the IV maintenance infusion is started at completion of the loading infusion. In another aspect, the IV maintenance infusion is started about 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5 to 6 h after completion of the loading dose.

[0815] The IV maintenance infusion is typically given for about 12 hours. In another aspect, the maintenance infusion 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 to 24 h. Additional examples include about 1.5, 2, 2.5, 3, 3.5 to 4 days (or sometimes longer).

[0816] The IV maintenance infusion can be discontinued if needed (e.g., due to an increase in QTc). This is an advantage of IV versus oral therapy. If the patient has an adverse effect to dofetilide, the IV maintenance infusion can be stopped quickly.

[0817] The IV maintenance infusion given depends on the patient's CrCl, as shown in the following table.

[0818]

[0819] For patients with CrCl > 60 mL / min, the IV maintenance dose is typically about 450-500 μg dofetilide and is typically given over about 12 h (but can vary as described above). Examples include about 450, 455, 460, 465, 470, 475, 480, 485, 490, 495 to 500 μg dofetilide. This is equivalent to about 0.625-0.694 μg / min dofetilide (450 / 720-500 / 720). In another aspect, the IV maintenance dose is about 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 069 to 0.7 μg / min.

[0820] For patients with CrCl of 40-<60 mL / min, the IV maintenance dose is typically about 225-250 μg of dofetilide, and is typically administered over about 12 h (but can vary as described above). Examples include about 225, 230, 235, 240, 245 to 250 μg of dofetilide. This corresponds to about 0.313-0.347 μg / min of dofetilide (225 / 720 to 250 / 720). In another aspect, the IV maintenance dose is about 0.3, 0.31, 0.32, 0.33, 0.34 to 0.35 μg / min.

[0821] For patients with CrCl of 20-<40 mL / min, the IV maintenance dose is typically about 100-125 μg of dofetilide, and is typically administered over about 12 h (but can vary as described above). Examples include about 100 μg, 105 μg, 110 μg, 115 μg, 120 μg to 125 μg of dofetilide. This corresponds to about 0.139-0.174 μg / min of dofetilide (100 / 720 to 125 / 720). In another aspect, the IV maintenance dose is about 0.13, 0.14, 0.15, 0.16, 0.17 to 0.18 μg / min.

[0822] In another aspect, the oral dose is initiated about 1, 2, 3, 4, 5, 6, 7, 8, 9 to 10 hours after the maintenance dose is discontinued. In another aspect, the oral dose is initiated about 3-6 hours after the maintenance dose is discontinued.

[0823] Oral dofetilide is available in capsule form in three sizes, 125, 250 and 500 μg. In another aspect, the patient is administered dofetilide orally BID (every 12 hours). Examples of these doses include 125 μg, 250 μg, 375 μg (e.g., 3 x 125 capsules or 125 + 250 capsules) and 500 μg.

[0824] The standard dose for patients with creatinine clearance (CrCl) (or calculated GFR (glomerular filtration rate)) of >60 mL / min is 500 μg. However, if the patient has a CRCL of <60 mL / min, the dose is reduced according to the following table.

[0825]

[0826] If the patient's QTc is assured, the oral dose of domperidone is also reduced. For example, if the patient's QTc is increased by 15% from baseline QTc, or if the QTc is measured at > 500 msec or > 550 msec in patients with ventricular conduction abnormalities, the oral dose of domperidone is reduced from 500 μg to 250 μg, or from 250 μg to 125 μg, or if the original dose was 125 μg, the treatment is discontinued.

[0827] For patients with CrCl > For patients with CrCl of 40-< 60 mL / min, the twice daily oral dose of domperidone is 250 μg. In this regard, if the patient's QTc is increased by 15% from baseline QTc, or if the QTc is measured at > 500 msec or > 550 msec in patients with ventricular conduction abnormalities, the oral dose is reduced to 125 μg.

[0828] For patients with CrCl of 40-< 60 mL / min, the twice daily oral dose of domperidone is 250 μg. In this regard, if the patient's QTc is increased by 15% from baseline QTc, or if the QTc is measured at > 500 msec or > 550 msec in patients with ventricular conduction abnormalities, the oral dose is reduced to 125 μg.

[0829] For patients with CrCl of 20-< 40 mL / min, the twice daily oral dose of domperidone is 125 μg. In this regard, if the patient's QTc is increased by 15% from baseline QTc, or if the QTc is measured at > 500 msec or > 550 msec in patients with ventricular conduction abnormalities, the treatment is discontinued.

[0830] In an alternative aspect, patients with CrCl of 20-< 40 mL / min are administered 125 μg of domperidone once daily orally. This once daily regimen is selected based on the judgment of the patient's physician. In this regard, if the patient's QTc is increased by 15% from baseline QTc, or if the QTc is measured at > 500 msec or > 550 msec in patients with ventricular conduction abnormalities, the treatment is discontinued.

[0831] In another aspect, patients with CrCl of > 60 mL / min are administered an IV maintenance dose of about 450-500 μg of domperidone and given over about 12 h, and the twice daily oral dose of domperidone is 500 μg. In this regard, if the patient's QTc is increased by 15% from baseline QTc, or if the QTc is measured at > 500 msec or > 550 msec in patients with ventricular conduction abnormalities, the oral dose is reduced to 250 μg.

[0832] In another aspect, the patient has a CrCl of 40-<60 ml / min, the IV maintenance dose is about 225-250 μg of dofetilide, and is administered over about 12 h, and the twice daily oral dose of dofetilide is 250 μg. In this aspect, if the patient's QTc increases by 15% from baseline QTc, or if the QTc is measured at >500 msec or >550 msec, the oral dose is reduced to 125 μg if the patient has a ventricular conduction abnormality.

[0833] In another aspect, the patient has a CrCl of 20-<40 ml / min, the IV maintenance dose is about 100-125 μg of dofetilide, and is administered over about 12 h, and the twice daily oral dose of dofetilide is 125 μg. In this aspect, if the patient's QTc increases by 15% from baseline QTc, or if the QTc is measured at >500 msec or >550 msec, the treatment is discontinued if the patient has a ventricular conduction abnormality.

[0834] In another aspect, the patient has a CrCl of 20-<40 ml / min, the IV maintenance dose is about 100-125 μg of dofetilide, and is administered over about 12 h, and the once daily oral dose of dofetilide is 125 μg. In this aspect, if the patient's QTc increases by 15% from baseline QTc, or if the QTc is measured at >500 msec or >550 msec, the treatment is discontinued if the patient has a ventricular conduction abnormality.

[0835] Suitable intravenous formulations are described in U.S. Patent No. 11,364,213.

[0836] Examples of useful concentrations of dofetilide in intravenous solutions include about 1 μg / mL, 2 μg / mL, 3 μg / mL, 4 μg / mL, 5 μg / mL, 10 μg / mL, 15 μg / mL, 20 μg / mL, 25 μg / mL, 30 μg / mL, 35 μg / mL, 40 μg / mL, 45 μg / mL, 50 μg / mL, 55 μg / mL, 60 μg / mL, 65 μg / mL, 70 μg / mL, 75 μg / mL, 80 μg / mL, 85 μg / mL, 90 μg / mL, 95 μg / mL to 100 μg / mL.

[0837] The application can be implemented in other specific forms without departing from the spirit or essential attributes of the application. The application encompasses all combinations of aspects of the application described herein. It will be understood that any and all embodiments of the application can be combined with any other one or more embodiments to describe yet additional embodiments. It will be further understood that each individual element of an embodiment is intended to be separately considered a separate independent embodiment. Furthermore, any element of an embodiment is intended to be combined with any and all other elements from any embodiment to describe additional embodiments.

[0838] Other features of the application will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the application and are not intended to be limiting thereof.

[0839] Embodiments

[0840] Example 5

[0841] A 70 kg patient with CrCl > 60 ml / min presents with highly symptomatic atrial fibrillation (AF) and the patient's physician decides that the AF needs to be terminated with an infusion of dofetilide. The patient is admitted to the hospital and ECG is monitored continuously.

[0842] Chemical cardioversion with dofetilide:

[0843] The patient is then treated with dofetilide as follows.

[0844] (G) Hour 0: Intravenous (IV) loading dose: 450 μg infused over 1 hour, measuring QTc, HR, and BP every 15 minutes; and

[0845] (H) Hour 1: Oral dose: If the patient is converted from the IV loading dose, 500 μg is given orally every 12 hours (BID), starting 1 h after the start of the IV loading infusion.

[0846] Electrical cardioversion:

[0847] The patient is then treated with dofetilide as follows.

[0848] (A) Hour 0: Intravenous (IV) loading dose: 450 μg infused over 1 hour, measuring QTc, HR, and BP every 15 minutes;

[0849] (B) Hour 1: Electrical cardioversion. If the patient is not converted from the dofetilide IV loading dose, the patient is subjected to electrical cardioversion to convert to a sinus rhythm.

[0850] (C) Hour 1.5: IV maintenance dose: Optionally, after cardioversion, start 450 μg, 3-6 h infusion. Once the patient is able to take oral medication, discontinue this maintenance dose; and,

[0851] (D) Hours 4-7: Oral dose: 500 μg orally every 12 hours (BID), start once the converted patient can take oral medication - typically about 4-7 h after IV loading is started.

[0852] The following Figure 1 Estimated multiple-dose pharmacokinetics of dofetilide are shown with the above dosing regimen. The figure was obtained by modeling the above dosing regimen. Software package NONMEM™ version 7.4 (ICON, Hanover, MD, USA) and MWpharm (Mediware, Prague, CZ) 6 were used for Bayesian PK modeling. PsN7 (Dept. of Pharmacy, Uppsala University, Uppsala, Sweden) was used for automation of the procedure. R (version 3.5.1, R Foundation for Statistical Computing) was used for data preparation, graphical analysis, linear regression analysis, and statistical summary. R package ‘mrgsolve’ was used for simulation.

[0853] Step (A): The anticipated loading dose (450 μg dofetilide IV infusion over 1 h in this example) reaches an anticipated maximum serum concentration that is expected from chronic oral dosing of 500 μg dofetilide. Oral dosing will reach a peak after 6 doses of dofetilide twice daily. Peak dofetilide concentration will be reached at the end of the infusion.

[0854] QTc is measured every 15 minutes during the infusion.

[0855] Step (B): At the end of the 1 h IV loading, an IV maintenance dose of 450 μg dofetilide over 12 h IV infusion (0.625 μg / min) is started. This dose can be maintained until the patient is awake and able to take oral dofetilide.

[0856] Once the patient can take oral dofetilide, the dofetilide maintenance IV is discontinued. About 3 h after the maintenance IV is discontinued, 500 μg oral doses of dofetilide are administered every 12 h (BID) are started.

[0857] If the QTc increases by 15% from baseline QTc, or if a QTc > 500 msec (550 msec in patients with ventricular conduction abnormalities) is observed, subsequent oral doses will be reduced to 250 μg BID (or lower if the original oral dose required was lower, see below).

[0858] It should be noted that if the patient exhibits a CrCl below normal, the initial target concentration will be the same, but the oral (maintenance) dose administered will be lower; 250 μg or 125 μg BID (based on the figure below).

[0859]

[0860] In addition, in patients who show excessive QTc prolongation under the initial loading (> 500 msec or > 550 msec in patients with ventricular conduction abnormalities), the first oral dose will be reduced to 250 μg (or 125 μg if the starting oral dose was 250 μg, based on the figure above), and the peak concentration is expected within 4 hours, and the QTc is re-evaluated. The longest QTc will be measured at the peak concentration at the end of the loading infusion, and will be the same peak seen with 250 μg chronic oral dosing. This will allow the QTc response to be measured at the projected peak multivitamins concentration that the patient will be chronically exposed to in order to maintain normal sinus rhythm, thus establishing the safety of chronic multivitamins dosing.

[0861] Example 6

[0862] A 75 kg patient with a CrCl of 45 mL / min presents with highly symptomatic atrial fibrillation (AF), and the patient's physician decides that the AF needs to be terminated with an infusion of multivitamins. The patient is admitted to the hospital, and ECGs are monitored continuously.

[0863] Chemical cardioversion with multivitamins:

[0864] The patient is then treated with multivitamins as follows.

[0865] (A) Hour 0: Intravenous (IV) loading dose: 450 μg, infused over 1 hour, measuring QTc, HR, and BP every 15 minutes; and

[0866] (B) Hour 1: Oral dose: If the patient is converted from the IV loading dose, 250 μg is given orally every 12 hours (BID), starting 1 h after the start of the IV loading infusion.

[0867] Electrical cardioversion:

[0868] The patient is then treated with multivitamins as follows.

[0869] (A) Hour 0: Intravenous (IV) loading dose: 450 μg infused over 1 hour, measuring QTc, HR, and BP every 15 minutes;

[0870] (B) Hour 1 : Cardioversion. If the patient does not convert from the dofetilide IV loading dose, the patient is cardioverted to convert to a sinus rhythm.

[0871] (C) Hour 1.5: IV maintenance dose: Optionally, after cardioversion, a 225 μg, 3-6 h infusion is initiated. This maintenance dose is discontinued once the patient can take oral medication; and,

[0872] (D) Hours 4-7: Oral dose: 250 μg, given orally every 12 hours (BID), initiated once the converted patient can take oral medication, typically about 4-7 h after the IV loading is initiated.

[0873] Many modifications and variations of this application are possible in light of the above teachings. It is, therefore, to be understood that within the scope of the appended embodiments, the application can be practiced otherwise than as specifically described.

[0874] Embodiment-C. Intravenous dofetilide to convert atrial fibrillation / flutter

[0875] 1. A method of converting atrial fibrillation (AF) or atrial flutter (AFL) in a patient presenting with highly symptomatic AF or AFL, comprising:

[0876] a intravenously administering a loading dose of dofetilide to a patient presenting with highly symptomatic AF or AFL, wherein:

[0877] (A) the loading dose is about 450-500 μg dofetilide; and,

[0878] (B) the loading dose is administered over about 30-60 minutes;

[0879] b if the patient has converted to a sinus rhythm, orally administering dofetilide every 12 h, the oral dose given based on the patient's creatinine clearance (CrCl) given in the table below, about 0-4 h after the IV loading dose is completed;

[0880]

[0881] c if the patient has not converted to a sinus rhythm after the IV loading infusion is completed, subjecting the patient to cardioversion;

[0882] d intravenously administering a maintenance dose of dofetilide over about 3-12 h, the maintenance dose given based on the patient's CrCl given in the table above based on a 12 h infusion, about 0-1 h after conversion with cardioversion.

[0883] e Once the patient has recovered from cardioversion and is able to take oral dofetilide, the IV maintenance dose is discontinued; and,

[0884] f About 2-6 h after the IV maintenance dose is discontinued, oral dofetilide is administered every 12 h, the oral dose given based on the patient's CrCl given in the table above;

[0885] with the proviso that if the patient's QTc increases by 15% from baseline QTc, or if the QTc is measured as > 500 msec or > 550 msec, the oral dose is reduced from 500 μg to 250 μg, from 250 μg to 125 μg, or if initially 125 μg, is discontinued, if the patient has a ventricular conduction abnormality.

[0886] 2. The method of embodiment 1, further comprising:

[0887] measuring the patient's QTc prior to the IV loading dose of dofetilide to establish a baseline QTc, then measuring the QTc thereafter about every 15-30 minutes for 60 min, and prior to the IV maintenance infusion and prior to each oral dose.

[0888] 3. The method of embodiment 1, wherein the loading dose is about 450 μg.

[0889] 4. The method of embodiment 1, wherein the loading dose is about 460 μg.

[0890] 5. The method of embodiment 1, wherein the loading dose is about 470 μg.

[0891] 6. The method of embodiment 1, wherein the loading dose is about 480 μg.

[0892] 7. The method of embodiment 1, wherein the loading dose is about 490 μg.

[0893] 8. The method of embodiment 1, wherein the loading dose is about 500 μg.

[0894] 9. The method of embodiment 1, wherein the loading dose is administered over about 30 minutes.

[0895] 10. The method of embodiment 1, wherein the loading dose is administered over about 40 minutes.

[0896] 11. The method of embodiment 1, wherein the loading dose is administered over about 50 minutes.

[0897] 12. The method of embodiment 1, wherein the loading dose is administered over about 60 minutes.

[0898] 13. The method of embodiment 1, wherein the maintenance dose is initiated about Oh after completion of the loading dose.

[0899] 14. The method of embodiment 1, wherein the maintenance dose is initiated about Ih after completion of the loading dose.

[0900] 15. The method of embodiment 1, wherein the maintenance dose is initiated about 2h after completion of the loading dose.

[0901] 16. The method of embodiment 1, wherein the maintenance dose is initiated about 3h after completion of the loading dose.

[0902] 17. The method of embodiment 1, wherein the maintenance dose is initiated about 4h after completion of the loading dose.

[0903] 18. The method of embodiment 1, wherein the patient has a CrCl > 60 mL / min, the IV maintenance dose is about 450-500 μg given over about 12h, and the oral dose is 500 μg.

[0904] 19. The method of embodiment 18, wherein the oral dose is reduced to 250 μg if the patient has a ventricular conduction abnormality, due to a QTc increase of 15% from baseline QTc, or a QTc measurement of > 500 msec or > 550 msec.

[0905] 20. The method of embodiment 1, wherein the patient has a CrCl of 40-< 60 mL / min, the IV maintenance dose is about 225-250 μg given over about 12h, and the oral dose is 250 μg.

[0906] 21. The method of embodiment 20, wherein the oral dose is reduced to 125 μg if the patient has a ventricular conduction abnormality, due to a QTc increase of 15% from baseline QTc, or a QTc measurement of > 500 msec or > 550 msec.

[0907] 22. The method of embodiment 1, wherein the patient has a CrCl of 20-< 40 mL / min, the IV maintenance dose is about 100-125 μg given over about 12h, and the oral dose is 125 μg.

[0908] 23. The method of embodiment 22, wherein the oral dose is discontinued if the patient has a ventricular conduction abnormality, due to a QTc increase of 15% from baseline QTc, or if a QTc measurement of > 500 msec is observed, or > 550 msec.

[0909] Further embodiments - Intravenous dofetilide to convert atrial fibrillation / flutter

[0910] 1. A method of treating a patient presenting with highly symptomatic atrial fibrillation (AF) or atrial flutter (AFL) comprising:

[0911] a. intravenously administering to a patient in need thereof a loading dose of about 450 to 500 μg of dofetilide over about 30 to 60 minutes; and

[0912] b. orally administering 500 μg of dofetilide every 12 hours to a patient with a creatinine clearance of 60 ml / min or greater who has converted to a sinus rhythm about 0 to 4 hours after completion of the loading dose;

[0913] wherein the oral dose of dofetilide is reduced to 250 μg for those patients with a 15% increase in QTc from baseline, those patients with a QTc > 500 msec, or those patients with ventricular conduction abnormalities with a QTc > 550 msec; and wherein the loading dose is expected to reach maximum serum concentration at the end of the infusion; and wherein the patient is monitored to ensure no excessive QT prolongation leading to abnormal cardiac repolarization resulting in life threatening ventricular arrhythmias.

[0914] 2. The method of embodiment 1 which is a method of converting atrial fibrillation (AF) or atrial flutter (AFL).

[0915] 3. The method of embodiment 1 wherein the patient with high symptoms has severe hemodynamic impairment whose symptoms can include shortness of breath, dyspnea, chest pain (angina), orthopnea, syncope, and diaphoresis.

[0916] 4. The method of embodiment 1 further comprising measuring the patient's QTc to establish a baseline QTc prior to intravenous administration of the loading dose of dofetilide, thereafter measuring the QTc every 15-30 minutes during the initial infusion, and thereafter measuring the QTc about every 60 minutes until the patient is stabilized.

[0917] 5. The method of embodiment 4 wherein the patient's physician determines when the patient is stabilized.

[0918] 6. The method of embodiment 5 wherein the patient can be stabilized after completion of the loading infusion of dofetilide or after administration of the first oral dose.

[0919] 7. The method of embodiment 1 wherein the loading dose is about 450 to 500 μg of dofetilide to about 500 μg of dofetilide.

[0920] 8. The method of embodiment 1, wherein a 450-500 μg maintenance dose ("IV maintenance dose") of dofetilide is administered to a patient with a creatinine clearance of 60 ml / min or greater 1-3 hours after the completion of the loading dose.

[0921] 9. The method of embodiment 1, wherein the creatinine clearance is 60 mL / min or greater.

[0922] 10. The method of embodiment 1, wherein the intravenous loading dose is administered over about 30-60 minutes.

[0923] 11. The method of embodiment 1, further comprising measuring the patient's creatinine clearance as a proxy for glomerular filtration rate (GFR) prior to oral administration of dofetilide to determine the amount of dofetilide indicated for the oral dose.

[0924] 12. The method of embodiment 1, wherein the dofetilide is fully loaded in less than 3 days.

[0925] 13. The method of embodiment 12, wherein the dofetilide is fully loaded when the dofetilide reaches a steady state concentration in the blood.

[0926] 14. The method of embodiment 1, wherein intravenous dofetilide administration prevents possible cardiac arrhythmias by avoiding excessive dofetilide blood levels.

[0927] 15. A method of treating a patient presenting with highly symptomatic atrial fibrillation (AF) or atrial flutter (AFL), comprising:

[0928] a. intravenously administering to a patient in need thereof a loading dose of about 450-500 μg dofetilide over about 30-60 minutes; and

[0929] b. orally administering to a patient converted to a sinus rhythm with a creatinine clearance of 40-<60 ml / min 250 μg dofetilide every 12 hours about 0-4 hours after completion of the loading dose;

[0930] wherein the oral dofetilide dose is reduced to 125 μg for those patients with a 15% increase in QTc from baseline, those patients with a QTc > 500 msec, or those patients with ventricular conduction abnormalities with a QTc > 550 msec; and

[0931] wherein the loading dose is expected to reach maximum serum concentration at the end of the infusion; and

[0932] wherein the patient is monitored to ensure no excessive QT prolongation leading to abnormal cardiac repolarization resulting in life threatening ventricular arrhythmias.

[0933] 16. The method of embodiment 15, which is a method of converting atrial fibrillation (AF) or atrial flutter (AFL).

[0934] 17. The method of embodiment 15, wherein the patient with high symptoms has severe hemodynamic impairment, symptoms of which can include shortness of breath, dyspnea, chest pain (angina), orthopnea, syncope, and diaphoresis.

[0935] 18. The method of embodiment 15, further comprising measuring the patient's QTc to establish a baseline QTc prior to intravenous administration of a loading dose of dofetilide, thereafter measuring the QTc every 15-30 minutes during the initial infusion, thereafter measuring the QTc about every 60 minutes until the patient is stabilized.

[0936] 19. The method of embodiment 18, wherein the patient's physician determines when the patient is stabilized.

[0937] 20. The method of embodiment 19, wherein the patient can be stabilized after completion of the loading infusion of dofetilide or after administration of the first oral dose.

[0938] 21. The method of embodiment 15, wherein the loading dose is 450-500 μg dofetilide ~ 500 μg dofetilide.

[0939] 22. The method of embodiment 15, wherein 1-3 hours after completion of the loading dose, a patient with a creatinine clearance of 60 ml / min or greater is administered a 450-500 μg maintenance dose ("IV maintenance dose") of dofetilide.

[0940] 23. The method of embodiment 15, wherein the intravenous loading dose is administered over about 30-60 minutes.

[0941] 24. The method of embodiment 15, further comprising measuring the patient's creatinine clearance as an approximation of glomerular filtration rate (GFR) prior to oral administration of dofetilide to determine the amount of dofetilide indicated for the oral dose.

[0942] 25. The method of embodiment 15, wherein the dofetilide is fully loaded in less than 3 days.

[0943] 26. The method of embodiment 25, wherein the dofetilide is fully loaded when the dofetilide reaches a steady state concentration in the blood.

[0944] 27. The method of embodiment 15, wherein intravenous dofetilide administration prevents possible arrhythmias by avoiding excessive dofetilide blood levels.

[0945] 28. A method of treating a patient presenting with highly symptomatic atrial fibrillation (AF) or atrial flutter (AFL) comprising:

[0946] a. intravenously administering to a patient in need thereof a loading dose of about 450 to 500 μg of dofetilide over about 30 to 60 minutes; and

[0947] b. orally administering 125 μg of dofetilide every 12 hours to a patient with a creatinine clearance of 20 to <40 ml / min who has been converted to a sinus rhythm about 0 to 4 hours after completion of the loading dose;

[0948] wherein oral dofetilide doses are discontinued for those patients with a 15% increase in QTc from baseline, those patients with a QTc > 500 msec, or those patients with ventricular conduction abnormalities with a QTc > 550 msec; and

[0949] wherein the loading dose is expected to reach maximum serum concentration at the end of the infusion; and

[0950] wherein the patient is monitored to ensure that there is no excessive QT prolongation leading to abnormal cardiac repolarization resulting in life threatening ventricular arrhythmias.

[0951] 29. The method of embodiment 28 which is a method of converting atrial fibrillation (AF) or atrial flutter (AFL).

[0952] 30. The method of embodiment 28 wherein the patient with highly symptoms has severe hemodynamic impairment whose symptoms can include shortness of breath, dyspnea, chest pain (angina), orthopnea, syncope, and diaphoresis.

[0953] 31. The method of embodiment 28 further comprising measuring the patient's QTc to establish a baseline QTc prior to intravenous administration of the loading dose of dofetilide, thereafter measuring the QTc every 15 to 30 minutes during the initial infusion, and thereafter measuring the QTc about every 60 minutes until the patient is stabilized.

[0954] 32. The method of embodiment 31 wherein the patient's physician determines when the patient is stabilized.

[0955] 33. The method of embodiment 32 wherein the patient can be stabilized after completion of the loading infusion of dofetilide or after administration of the first oral dose.

[0956] 34. The method of embodiment 28 wherein the loading dose is about 450 to 500 μg of dofetilide.

[0957] 35. The method of embodiment 28, wherein a 450 to 500 μg maintenance dose ("IV maintenance dose") of dofetilide is administered to a patient having a creatinine clearance of 60 ml / min or greater about 1 to 3 hours after completion of the loading dose.

[0958] 36. The method of embodiment 28, wherein the intravenous loading dose is administered over about 30 to 60 minutes.

[0959] 37. The method of embodiment 28, further comprising measuring the patient's creatinine clearance as a proxy for glomerular filtration rate (GFR) prior to oral administration of dofetilide to determine the amount of dofetilide indicated for oral dosing.

[0960] 38. The method of embodiment 28, wherein the dofetilide is fully loaded in less than 3 days.

[0961] 39. The method of embodiment 38, wherein the dofetilide is fully loaded when the dofetilide reaches a steady state concentration in the blood.

[0962] 40. The method of embodiment 28, wherein intravenous dofetilide administration prevents possible arrhythmias by avoiding excessive dofetilide blood levels.

[0963] 41. A method of treating a patient presenting with highly symptomatic atrial fibrillation (AF) or atrial flutter (AFL), comprising:

[0964] a. intravenously administering to a patient in need thereof a loading dose of about 450 to 500 μg dofetilide over about 30 to 60 minutes;

[0965] b. performing electrical cardioversion on those patients who do not convert to sinus rhythm after completion of the loading dose;

[0966] c. intravenously administering to a patient having a creatinine clearance of 60 ml / min or greater a maintenance dose ("IV maintenance dose") of 450 to 500 μg dofetilide over about 3 to 12 hours about 0 to 1 hour after conversion with electrical cardioversion;

[0967] d. discontinuing the IV maintenance dose for those patients who have fully recovered from electrical cardioversion; and

[0968] e. orally administering 500 μg dofetilide to a patient having a creatinine clearance of 60 ml / min or greater every 12 hours about 2 to 6 hours after discontinuing the IV maintenance dose.

[0969] wherein the dose of oral dofetilide is reduced to 250 μg for those patients with a 15% increase in QTc from baseline, those patients with a QTc > 500 msec, or those patients with a ventricular conduction abnormality with a QTc > 550 msec; and

[0970] wherein the expected loading dose achieves a maximum serum concentration at the end of the infusion; and

[0971] wherein the patient is monitored to ensure that there is no excessive QT prolongation leading to abnormal cardiac repolarization leading to life threatening ventricular arrhythmias.

[0972] 42. The method of embodiment 41, which is a method of converting atrial fibrillation (AF) or atrial flutter (AFL).

[0973] 43. The method of embodiment 41, wherein the patient with high symptoms has severe hemodynamic impairment whose symptoms can include shortness of breath, dyspnea, chest pain (angina), orthopnea, syncope, and diaphoresis.

[0974] 44. The method of embodiment 41, further comprising measuring the patient's QTc to establish a baseline QTc prior to intravenous administration of a loading dose of dofetilide, thereafter measuring the QTc every 15-30 minutes during the initial infusion, thereafter measuring the QTc about every 60 minutes until the patient is stabilized.

[0975] 45. The method of embodiment 44, wherein the patient's physician determines when the patient is stabilized.

[0976] 46. The method of embodiment 45, wherein the patient can be stabilized after completion of the loading infusion of dofetilide or after administration of the first oral dose.

[0977] 47. The method of embodiment 41, wherein the loading dose is 450-500 μg of dofetilide.

[0978] 48. The method of embodiment 41, wherein 1-3 hours after completion of the loading dose, a patient with a creatinine clearance of 60 ml / min or greater is administered a maintenance dose ("IV maintenance dose") of 450-500 μg of dofetilide.

[0979] 49. The method of embodiment 41, wherein the IV maintenance dose is about 450-500 μg of dofetilide.

[0980] 50. The method of embodiment 41, wherein the creatinine clearance is 60 mL / min or greater.

[0981] 51. The method of embodiment 41, wherein the oral administration of dofetilide is administered 3-5 hours after the IV maintenance dose is administered.

[0982] 52. The method of embodiment 41, further comprising measuring the patient's creatinine clearance as an approximation of glomerular filtration rate (GFR) prior to administering the IV maintenance dose to determine the amount of dofetilide indicated for the IV maintenance dose.

[0983] 53. The method of embodiment 41, further comprising measuring the patient's creatinine clearance as an approximation of glomerular filtration rate (GFR) prior to administering the oral dose to determine the amount of dofetilide indicated for the oral dose.

[0984] 54. The method of embodiment 41, wherein the patient has sufficiently recovered from cardioversion and has intact gag reflex when orally administered dofetilide while awake postoperatively.

[0985] 55. The method of embodiment 41, wherein the intravenous loading dose is administered over about 30-60 minutes.

[0986] 56. The method of embodiment 41, wherein the IV maintenance dose is administered over about 3-12 hours.

[0987] 57. The method of embodiment 41, wherein the dofetilide is fully loaded in less than 3 days.

[0988] 58. The method of embodiment 57, wherein the dofetilide is fully loaded when the dofetilide reaches a steady state concentration in the blood.

[0989] 59. The method of embodiment 41, wherein the intravenous dofetilide is administered in a first loading dose and a continuous IV maintenance dose.

[0990] 60. The method of embodiment 41, wherein the intravenous dofetilide administration prevents possible arrhythmias by avoiding excessive dofetilide blood levels.

[0991] 61. A method of treating a patient presenting with highly symptomatic atrial fibrillation (AF) or atrial flutter (AFL), comprising:

[0992] a. intravenously administering to a patient in need thereof a loading dose of about 450-500 μg dofetilide over about 30-60 minutes;

[0993] b. after completion of the loading dose, performing cardioversion on those patients who have not converted to sinus rhythm;

[0994] c. about 1 hour after conversion with electrical cardioversion, administering to a patient with a creatinine clearance of 60 ml / min or greater, a maintenance dose ("IV maintenance dose") of 450-500 μg of dofetilide intravenously over about 3-12 hours;

[0995] d. discontinuing the IV maintenance dose for patients who have sufficiently recovered from electrical cardioversion; and

[0996] e. about 2-6 hours after discontinuing the IV maintenance dose, administering to a patient with a creatinine clearance of 40-<60 ml / min, 250 μg of dofetilide orally every 12 hours;

[0997] wherein the oral dose of dofetilide is reduced to 125 μg for those patients with a QTc increase of 15% from baseline, those patients with a QTc > 500 msec, or those patients with a ventricular conduction abnormality with a QTc > 550 msec; and

[0998] wherein the loading dose is expected to reach a maximum serum concentration at the end of the infusion; and

[0999] wherein the patient is monitored to ensure that there is no excessive QT prolongation leading to abnormal cardiac repolarization resulting in life threatening ventricular arrhythmias.

[1000] 62. The method of embodiment 61, which is a method of converting atrial fibrillation (AF) or atrial flutter (AFL).

[1001] 63. The method of embodiment 61, wherein a patient with high symptoms has severe hemodynamic impairment whose symptoms can include shortness of breath, dyspnea, chest pain (angina), orthopnea, syncope, and diaphoresis.

[1002] 64. The method of embodiment 61, further comprising measuring the patient's QTc to establish a baseline QTc prior to intravenous administration of the loading dose of dofetilide, thereafter measuring the QTc every 15-30 minutes during the initial infusion, and thereafter measuring the QTc about every 60 minutes until the patient is stable.

[1003] 65. The method of embodiment 64, wherein the patient's physician determines when the patient is stable.

[1004] 66. The method of embodiment 65, wherein the patient can be stable after completion of the loading infusion of dofetilide or after administration of the first oral dose.

[1005] 67. The method of embodiment 61, wherein the loading dose is 450-500 μg of dofetilide.

[1006] 68. The method of embodiment 61, wherein a 450 to 500 μg maintenance dose ("IV maintenance dose") of dofetilide is administered to a patient having a creatinine clearance of 60 ml / min or more 1 to 3 hours after the completion of the loading dose.

[1007] 69. The method of embodiment 61, wherein the IV maintenance dose is about 450 to 500 μg dofetilide.

[1008] 70. The method of embodiment 61, wherein the creatinine clearance is 60 mL / min or more.

[1009] 71. The method of embodiment 61, wherein the IV maintenance dose is discontinued about 2 to 6 hours later.

[1010] 72. The method of embodiment 61, further comprising measuring the patient's creatinine clearance as an approximation of glomerular filtration rate (GFR) prior to administering the IV maintenance dose to determine the amount of dofetilide indicated for the IV maintenance dose.

[1011] 73. The method of embodiment 61, further comprising measuring the patient's creatinine clearance as an approximation of glomerular filtration rate (GFR) prior to orally administering dofetilide to determine the amount of dofetilide indicated for the oral dose.

[1012] 74. The method of embodiment 61, wherein the patient has sufficiently recovered from cardioversion and orally administered dofetilide with an intact gag reflex while awake postoperatively.

[1013] 75. The method of embodiment 61, wherein the intravenous loading dose is administered over about 30 to 60 minutes.

[1014] 76. The method of embodiment 61, wherein the IV maintenance dose is administered over about 3 to 12 hours.

[1015] 77. The method of embodiment 61, wherein the dofetilide is fully loaded in less than 3 days.

[1016] 78. The method of embodiment 77, wherein the dofetilide is fully loaded when the dofetilide reaches a steady state concentration in the blood.

[1017] 79. The method of embodiment 61, wherein the intravenous dofetilide is administered as a first loading dose and a continuing IV maintenance dose.

[1018] 80. The method of embodiment 61, wherein the intravenous dofetilide administration prevents possible arrhythmias by avoiding excessive dofetilide blood levels.

[1019] 81. A method of treating a patient presenting with highly symptomatic atrial fibrillation (AF) or atrial flutter (AFL) comprising:

[1020] a. intravenously administering to a patient in need thereof a loading dose of about 450 to 500 μg of dofetilide over about 30 to 60 minutes;

[1021] b. after completion of the loading dose, performing electrical cardioversion for those patients who have not converted to a sinus rhythm;

[1022] c. about 0 to 1 hours after conversion with electrical cardioversion, intravenously administering to patients with a creatinine clearance of 60 ml / min or greater a maintenance dose ("IV maintenance dose") of 450 to 500 μg of dofetilide over about 3 to 12 hours;

[1023] d. discontinuing the IV maintenance dose for those patients who have fully recovered from electrical cardioversion; and

[1024] e. about 2 to 6 hours after discontinuing the IV maintenance dose, orally administering to patients with 20 to <40 mL / min 125 μg of dofetilide every 12 hours;

[1025] wherein the oral dofetilide dose is discontinued for those patients with a 15% increase in QTc from baseline, those patients with a QTc > 500 msec, or those patients with ventricular conduction abnormalities with a QTc > 550 msec; and

[1026] wherein the loading dose is expected to reach a maximum serum concentration at the end of the infusion; and

[1027] wherein the patient is monitored to ensure that there is no excessive QT prolongation leading to abnormal cardiac repolarization resulting in life threatening ventricular arrhythmias.

[1028] 82. The method of embodiment 81, which is a method of converting atrial fibrillation (AF) or atrial flutter (AFL).

[1029] 83. The method of embodiment 81, wherein the patient with highly symptoms has severe hemodynamic impairment whose symptoms can include shortness of breath, dyspnea, chest pain (angina), orthopnea, syncope, and diaphoresis.

[1030] 84. The method of embodiment 81, further comprising measuring the patient's QTc to establish a baseline QTc prior to intravenously administering the loading dose of dofetilide, thereafter measuring the QTc every 15 to 30 minutes during the initial infusion, and thereafter measuring the QTc about every 60 minutes until the patient is stabilized.

[1031] 85. The method of embodiment 84, wherein the patient's physician determines when the patient is stabilized.

[1032] 86. The method of embodiment 85, wherein the patient can be stable after completion of the loading infusion of dofetilide or after administration of the first oral dose.

[1033] 87. The method of embodiment 81, wherein the loading dose is 450-500 μg dofetilide.

[1034] 88. The method of embodiment 81, wherein 1-3 hours after completion of the loading dose, a patient with a creatinine clearance of 60 ml / min or greater is administered a maintenance dose ("IV maintenance dose") of 450-500 μg dofetilide.

[1035] 89. The method of embodiment 81, wherein the IV maintenance dose is 450-500 μg dofetilide.

[1036] 90. The method of embodiment 81, wherein the creatinine clearance is 60 mL / min or greater.

[1037] 91. The method of embodiment 81, wherein 3-5 hours after discontinuing the IV maintenance dose, a patient with a creatinine clearance of 60 ml / min or greater is administered 500 μg dofetilide orally every 12 hours.

[1038] 92. The method of embodiment 81, further comprising measuring the patient's creatinine clearance as an approximation of glomerular filtration rate (GFR) prior to administration of the IV maintenance dose to determine the amount of dofetilide indicated for the IV maintenance dose.

[1039] 93. The method of embodiment 81, further comprising measuring the patient's creatinine clearance as an approximation of glomerular filtration rate (GFR) prior to oral administration of dofetilide to determine the amount of dofetilide indicated for the oral dose.

[1040] 94. The method of embodiment 81, wherein the patient has sufficiently recovered from cardioversion and has intact gag reflex when orally administered dofetilide while awake postoperatively.

[1041] 95. The method of embodiment 81, wherein the intravenous loading dose is administered over about 30-60 minutes.

[1042] 96. The method of embodiment 81, wherein the IV maintenance dose is administered over about 3-12 hours.

[1043] 97. The method of embodiment 81, wherein the dofetilide is fully loaded in less than 3 days.

[1044] 98. The method of embodiment 97, wherein the dofetilide is fully loaded when the dofetilide reaches a steady state concentration in the blood.

[1045] 99. The method of embodiment 81, wherein the intravenous dofetilide is administered as a first loading dose and a continuous IV maintenance dose.

[1046] 100. The method of embodiment 81, wherein the intravenous dofetilide administration prevents possible arrhythmias by avoiding excessive dofetilide blood levels.

[1047] 101. A method of treating a patient presenting with highly symptomatic atrial fibrillation (AF) or atrial flutter (AFL), comprising:

[1048] a. intravenously administering to a patient in need thereof a loading dose of about 450-500 μg dofetilide over about 30-60 minutes;

[1049] b. after completion of the loading dose, performing electrical cardioversion for those patients who have not converted to sinus rhythm;

[1050] c. about 0-1 hours after conversion with electrical cardioversion, intravenously administering to a patient with a creatinine clearance of 40-<60 ml / min a maintenance dose ("IV maintenance dose") of 225-250 μg dofetilide over about 3-12 hours;

[1051] d. discontinuing the IV maintenance dose for those patients who have fully recovered from electrical cardioversion; and

[1052] e. about 2-6 hours after discontinuing the IV maintenance dose, orally administering to a patient with a creatinine clearance of 60 ml / min or greater 500 μg dofetilide every 12 hours;

[1053] wherein the oral dofetilide dose is reduced to 250 μg for those patients with a 15% increase in QTc from baseline, those patients with a QTc > 500 msec, or those patients with ventricular conduction abnormalities with a QTc > 550 msec; and

[1054] wherein the loading dose is expected to reach a maximum serum concentration at the end of the infusion; and

[1055] wherein the patient is monitored to ensure that there is no excessive QT prolongation leading to abnormal cardiac repolarization resulting in life threatening ventricular arrhythmias.

[1056] 102. The method of embodiment 101, which is a method of converting atrial fibrillation (AF) or atrial flutter (AFL).

[1057] 103. The method of embodiment 101, wherein the patient with high symptoms has severe hemodynamic impairment whose symptoms can include shortness of breath, dyspnea, chest pain (angina), orthopnea, syncope, and diaphoresis.

[1058] 104. The method of embodiment 101, further comprising measuring the patient's QTc to establish a baseline QTc prior to intravenous administration of the loading dose of dofetilide, thereafter measuring the QTc every 15-30 minutes during the initial infusion, thereafter measuring the QTc about every 60 minutes until the patient is stabilized.

[1059] 105. The method of embodiment 104, wherein the patient's physician determines when the patient is stabilized.

[1060] 106. The method of embodiment 105, wherein the patient can be stabilized after completion of the loading infusion of dofetilide or after administration of the first oral dose.

[1061] 107. The method of embodiment 101, wherein the loading dose is 450-500 μg dofetilide.

[1062] 108. The method of embodiment 101, wherein a maintenance dose ("IV maintenance dose") of 450-500 μg dofetilide is administered to a patient with a creatinine clearance of 60 ml / min or greater 1-3 hours after completion of the loading dose.

[1063] 109. The method of embodiment 101, wherein the IV maintenance dose is 225-250 μg dofetilide.

[1064] 110. The method of embodiment 101, wherein the creatinine clearance is 60 mL / min or greater.

[1065] 111. The method of embodiment 101, wherein 500 μg dofetilide is orally administered to a patient with a creatinine clearance of 60 ml / min or greater every 12 hours 3-5 hours after discontinuing the IV maintenance dose.

[1066] 112. The method of embodiment 101, further comprising measuring the patient's creatinine clearance as an approximation of glomerular filtration rate (GFR) prior to administration of the IV maintenance dose to determine the amount of dofetilide indicated for the IV maintenance dose.

[1067] 113. The method of embodiment 101, further comprising measuring the patient's creatinine clearance as an approximation of glomerular filtration rate (GFR) prior to oral administration of dofetilide to determine the amount of dofetilide indicated for the oral dose.

[1068] 114. The method of embodiment 101, wherein the patient has fully recovered from cardioversion and the oral administration of dofetilide is administered while the patient is awake postoperatively with an intact gag reflex.

[1069] 115. The method of embodiment 101, wherein the intravenous loading dose is administered over about 30-60 minutes.

[1070] 116. The method of embodiment 101, wherein the IV maintenance dose is administered over about 3-12 hours.

[1071] 117. The method of embodiment 101, wherein the dofetilide is fully loaded in less than 3 days.

[1072] 118. The method of embodiment 117, wherein the dofetilide is fully loaded when the dofetilide reaches a steady state concentration in the blood.

[1073] 119. The method of embodiment 101, wherein the intravenous dofetilide is administered as a first loading dose and a continuous IV maintenance dose.

[1074] 120. The method of embodiment 101, wherein the intravenous administration of dofetilide prevents possible arrhythmias by avoiding excessive blood levels of dofetilide.

[1075] 121. A method of treating a patient presenting with highly symptomatic atrial fibrillation (AF) or atrial flutter (AFL), comprising:

[1076] a. intravenously administering to a patient in need thereof a loading dose of about 450-500 μg dofetilide over about 30-60 minutes;

[1077] b. after completion of the loading dose, performing cardioversion on those patients who have not converted to sinus rhythm;

[1078] c. about 0-1 hour after conversion with cardioversion, intravenously administering to a patient with a creatinine clearance of 40-< 60 ml / min a maintenance dose ("IV maintenance dose") of 225-250 μg dofetilide over about 3-12 hours;

[1079] d. discontinuing the IV maintenance dose for patients who have fully recovered from cardioversion; and

[1080] e. about 2-6 hours after discontinuing the IV maintenance dose, orally administering to a patient with a creatinine clearance of 40-< 60 ml / min 250 μg dofetilide every 12 hours;

[1081] wherein the dose of oral dofetilide is reduced to 125 μg for those patients with a QTc increase of 15% from baseline, those patients with a QTc > 500 msec, or those patients with a ventricular conduction abnormality with a QTc > 550 msec; and

[1082] wherein the expected loading dose achieves a maximum serum concentration at the end of the infusion; and

[1083] wherein the patient is monitored to ensure that there is no excessive QT prolongation leading to abnormal cardiac repolarization leading to life threatening ventricular arrhythmias.

[1084] 122. The method of embodiment 121, which is a method of converting atrial fibrillation (AF) or atrial flutter (AFL).

[1085] 123. The method of embodiment 121, wherein the patient with high symptoms has severe hemodynamic impairment whose symptoms can include shortness of breath, dyspnea, chest pain (angina), orthopnea, syncope, and diaphoresis.

[1086] 124. The method of embodiment 121, further comprising measuring the patient's QTc to establish a baseline QTc prior to intravenous administration of a loading dose of dofetilide, thereafter measuring the QTc every 15-30 minutes during the initial infusion, and thereafter measuring the QTc about every 60 minutes until the patient is stable.

[1087] 125. The method of embodiment 124, wherein the patient's physician determines when the patient is stable.

[1088] 126. The method of embodiment 125, wherein the patient can be stable after completion of the loading infusion of dofetilide or after administration of the first oral dose.

[1089] 127. The method of embodiment 121, wherein the loading dose is 450-500 μg of dofetilide.

[1090] 128. The method of embodiment 121, wherein 1-3 hours after completion of the loading dose, a patient with a creatinine clearance of 60 ml / min or greater is administered a maintenance dose ("IV maintenance dose") of 450-500 μg of dofetilide.

[1091] 129. The method of embodiment 121, wherein the IV maintenance dose is 225-250 μg of dofetilide.

[1092] 130. The method of embodiment 121, wherein 3-5 hours after discontinuing the IV maintenance dose, a patient with a creatinine clearance of 60 ml / min or greater is administered 500 μg of dofetilide orally every 12 hours.

[1093] 131. The method of embodiment 121, further comprising measuring the patient's creatinine clearance as an approximation of glomerular filtration rate (GFR) prior to administering the IV maintenance dose to determine the amount of dofetilide indicated for the IV maintenance dose.

[1094] 132. The method of embodiment 121, further comprising measuring the patient's creatinine clearance as an approximation of glomerular filtration rate (GFR) prior to orally administering dofetilide to determine the amount of dofetilide indicated for the oral dose.

[1095] 133. The method of embodiment 121, wherein the patient has sufficiently recovered from cardioversion and the oral dofetilide is administered while the patient is awake postoperatively with intact gag reflex.

[1096] 134. The method of embodiment 121, wherein the intravenous loading dose is administered over about 30-60 minutes.

[1097] 135. The method of embodiment 121, wherein the IV maintenance dose is administered over about 3-12 hours.

[1098] 136. The method of embodiment 121, wherein the dofetilide is fully loaded in less than 3 days.

[1099] 137. The method of embodiment 136, wherein the dofetilide is fully loaded when the dofetilide reaches a steady state concentration in the blood.

[1100] 138. The method of embodiment 121, wherein the intravenous dofetilide is administered as a first loading dose and a continuing IV maintenance dose.

[1101] 139. The method of embodiment 121, wherein the intravenous dofetilide administration prevents possible arrhythmias by avoiding excessive dofetilide blood levels.

[1102] 140. A method of treating a patient presenting with highly symptomatic atrial fibrillation (AF) or atrial flutter (AFL), comprising:

[1103] a. intravenously administering to a patient in need thereof a loading dose of about 450-500 μg dofetilide over about 30-60 minutes;

[1104] b. after completion of the loading dose, performing cardioversion on those patients who have not converted to sinus rhythm;

[1105] c. about 1 hour after conversion with electrical cardioversion, administering to a patient with a creatinine clearance of 40-< 60 ml / min a maintenance dose ("IV maintenance dose") of 225-250 μg of dofetilide intravenously over about 3-12 hours;

[1106] d. discontinuing the IV maintenance dose for patients who have sufficiently recovered from electrical cardioversion; and

[1107] e. about 2-6 hours after discontinuing the IV maintenance dose, administering to a patient with a creatinine clearance of 20-< 40 ml / min 125 μg of dofetilide orally every 12 hours;

[1108] wherein the oral dofetilide dose is discontinued for those patients with a QTc increase of 15% from baseline, those patients with a QTc > 500 msec, or those patients with a ventricular conduction abnormality with a QTc > 550 msec; and

[1109] wherein the loading dose is expected to reach a maximum serum concentration at the end of the infusion; and

[1110] wherein the patient is monitored to ensure that there is no excessive QT prolongation leading to abnormal cardiac repolarization resulting in life threatening ventricular arrhythmias.

[1111] 141. The method of embodiment 140, which is a method of converting atrial fibrillation (AF) or atrial flutter (AFL).

[1112] 142. The method of embodiment 140, wherein a patient with high symptoms has severe hemodynamic impairment whose symptoms can include shortness of breath, dyspnea, chest pain (angina), orthopnea, syncope, and diaphoresis.

[1113] 143. The method of embodiment 140, further comprising measuring the QTc of the patient to establish a baseline QTc prior to intravenous administration of the loading dose of dofetilide, thereafter measuring the QTc every 15-30 minutes during the initial infusion, and thereafter measuring the QTc about every 60 minutes until the patient is stable.

[1114] 144. The method of embodiment 143, wherein the patient's physician determines when the patient is stable.

[1115] 145. The method of embodiment 144, wherein the patient can be stable after completion of the loading infusion of dofetilide or after administration of the first oral dose.

[1116] 146. The method of embodiment 140, wherein the loading dose is about 450-500 μg of dofetilide.

[1117] 147. The method of embodiment 140, wherein 450 to 500 μg of a maintenance dose of dofetilide ("IV maintenance dose") is administered to a patient having a creatinine clearance of 60 ml / min or greater 1 to 3 hours after the completion of the loading dose.

[1118] 148. The method of embodiment 140, wherein the IV maintenance dose is 225 to 250 μg of dofetilide.

[1119] 149. The method of embodiment 140, wherein 500 μg of dofetilide is orally administered to a patient having a creatinine clearance of 60 ml / min or greater every 12 hours 3 to 5 hours after discontinuing the IV maintenance dose.

[1120] 150. The method of embodiment 140, further comprising measuring the patient's creatinine clearance as a proxy for glomerular filtration rate (GFR) prior to administering the IV maintenance dose to determine the amount of dofetilide indicated for the IV maintenance dose.

[1121] 151. The method of embodiment 140, further comprising measuring the patient's creatinine clearance as a proxy for glomerular filtration rate (GFR) prior to orally administering dofetilide to determine the amount of dofetilide indicated for the oral dose.

[1122] 152. The method of embodiment 140, wherein the patient has sufficiently recovered from cardioversion and the dofetilide is orally administered while the patient is awake postoperatively with intact gag reflex.

[1123] 153. The method of embodiment 140, wherein the intravenous loading dose is administered over about 30 to 60 minutes.

[1124] 154. The method of embodiment 140, wherein the IV maintenance dose is administered over about 3 to 12 hours.

[1125] 155. The method of embodiment 140, wherein the dofetilide is fully loaded in less than 3 days.

[1126] 156. The method of embodiment 155, wherein the dofetilide is fully loaded when the dofetilide reaches a steady state concentration in the blood.

[1127] 157. The method of embodiment 140, wherein the intravenous dofetilide is administered as a first loading dose and a continuing IV maintenance dose.

[1128] 158. The method of embodiment 140, wherein the administration of intravenous dofetilide prevents possible arrhythmias by avoiding excessive blood levels of dofetilide.

[1129] 159. A method of treating a patient presenting with highly symptomatic atrial fibrillation (AF) or atrial flutter (AFL) comprising:

[1130] a. intravenously administering to a patient in need thereof a loading dose of about 450 to 500 μg of dofetilide over about 30 to 60 minutes;

[1131] b. after completion of the loading dose, performing electrical cardioversion on those patients who have not converted to a sinus rhythm;

[1132] c. about 0 to 1 hours after conversion with electrical cardioversion, intravenously administering to a patient with a creatinine clearance of 20 to <40 ml / min a maintenance dose ("IV maintenance dose") of 100 to 125 μg of dofetilide over about 3 to 12 hours;

[1133] d. discontinuing the IV maintenance dose for those patients who have fully recovered from electrical cardioversion; and

[1134] e. about 2 to 6 hours after discontinuing the IV maintenance dose, orally administering to a patient with a creatinine clearance of 60 ml / min or greater 500 μg of dofetilide every 12 hours;

[1135] wherein the oral dose of dofetilide is reduced to 250 μg for those patients with a QTc increase of 15% from baseline, those patients with a QTc > 500 msec, or those patients with ventricular conduction abnormalities with a QTc > 550 msec; and

[1136] wherein the loading dose is expected to reach a maximum serum concentration at the end of the infusion; and

[1137] wherein the patient is monitored to ensure that there is no excessive QT prolongation leading to abnormal cardiac repolarization resulting in life threatening ventricular arrhythmias.

[1138] 160. The method of embodiment 159, which is a method of converting atrial fibrillation (AF) or atrial flutter (AFL).

[1139] 161. The method of embodiment 159, wherein the highly symptomatic patient has severe hemodynamic impairment whose symptoms can include shortness of breath, dyspnea, chest pain (angina), orthopnea, syncope, and diaphoresis.

[1140] 162. The method of embodiment 159, further comprising measuring the patient's QTc to establish a baseline QTc prior to intravenous administration of the loading dose of dofetilide, thereafter measuring the QTc every 15 to 30 minutes during the initial infusion, and thereafter measuring the QTc about every 60 minutes until the patient is stabilized.

[1141] 163. The method of embodiment 162, wherein the patient's physician determines when the patient is stable.

[1142] 164. The method of embodiment 163, wherein the patient can be stable after completion of the loading infusion of dofetilide or after administration of the first oral dose.

[1143] 165. The method of embodiment 159, wherein the loading dose is 450-500 μg dofetilide.

[1144] 166. The method of embodiment 159, wherein a maintenance dose ("IV maintenance dose") of 450-500 μg dofetilide is administered to a patient with a creatinine clearance of 60 ml / min or greater 1-3 hours after completion of the loading dose.

[1145] 167. The method of embodiment 159, wherein the loading dose is 450 μL.

[1146] 168. The method of embodiment 159, wherein the creatinine clearance is 60 mL / min or greater.

[1147] 169. The method of embodiment 159, wherein the IV maintenance dose is discontinued about 2-6 hours later.

[1148] 170. The method of embodiment 159, further comprising measuring the patient's creatinine clearance as an approximation of glomerular filtration rate (GFR) prior to administration of the IV maintenance dose to determine the amount of dofetilide indicated for the IV maintenance dose.

[1149] 171. The method of embodiment 159, further comprising measuring the patient's creatinine clearance as an approximation of glomerular filtration rate (GFR) prior to oral administration of dofetilide to determine the amount of dofetilide indicated for the oral dose.

[1150] 172. The method of embodiment 159, wherein the patient has sufficiently recovered from cardioversion and oral administration of dofetilide is performed while the patient is awake after surgery with intact gag reflex.

[1151] 173. The method of embodiment 159, wherein the intravenous loading dose is administered over about 30-60 minutes.

[1152] 174. The method of embodiment 159, wherein the IV maintenance dose is administered over about 3-12 hours.

[1153] 175. The method of embodiment 159, wherein the dofetilide is fully loaded in less than 3 days.

[1154] 176. The method of embodiment 175, wherein the dofetilide is fully loaded when the dofetilide reaches a steady state concentration in the blood.

[1155] 177. The method of embodiment 159, wherein the intravenous dofetilide is administered as a first loading dose and a continuous IV maintenance dose.

[1156] 178. The method of embodiment 159, wherein the intravenous dofetilide administration prevents possible arrhythmias by avoiding excessive dofetilide blood levels.

[1157] 179. A method of treating a patient presenting with highly symptomatic atrial fibrillation (AF) or atrial flutter (AFL), comprising:

[1158] a. intravenously administering to a patient in need thereof a loading dose of about 450-500 μg dofetilide over about 30-60 minutes;

[1159] b. after completion of the loading dose, performing electrical cardioversion for those patients who have not converted to a sinus rhythm;

[1160] c. about 0-1 hours after conversion with electrical cardioversion, intravenously administering to a patient with a creatinine clearance of 20-<40 ml / min a maintenance dose ("IV maintenance dose") of 100-125 μg dofetilide over about 3-12 hours;

[1161] d. discontinuing the IV maintenance dose for those patients who have fully recovered from electrical cardioversion; and

[1162] e. about 2-6 hours after discontinuing the IV maintenance dose, orally administering to a patient with a creatinine clearance of 40-<60 ml / min 250 μg dofetilide every 12 hours;

[1163] wherein the oral dofetilide dose is reduced to 125 μg for those patients with a 15% increase in QTc from baseline, those patients with a QTc > 500 msec, or those patients with ventricular conduction abnormalities with a QTc > 550 msec; and

[1164] wherein the loading dose is expected to reach a maximum serum concentration at the end of the infusion; and

[1165] wherein the patient is monitored to ensure that there is no excessive QT prolongation leading to abnormal cardiac repolarization resulting in life threatening ventricular arrhythmias.

[1166] 180. The method of embodiment 179, which is a method of converting atrial fibrillation (AF) or atrial flutter (AFL).

[1167] 181. The method of embodiment 179, wherein the patient with high symptoms has severe hemodynamic impairment whose symptoms can include shortness of breath, dyspnea, chest pain (angina), orthopnea, syncope, and diaphoresis.

[1168] 182. The method of embodiment 179, further comprising measuring the patient's QTc to establish a baseline QTc prior to the intravenous administration of the loading dose of dofetilide, thereafter measuring the QTc every 15-30 minutes during the initial infusion, thereafter measuring the QTc about every 60 minutes until the patient is stable.

[1169] 183. The method of embodiment 182, wherein the patient's physician determines when the patient is stable.

[1170] 184. The method of embodiment 183, wherein the patient can be stable after the completion of the loading infusion of dofetilide or after the administration of the first oral dose.

[1171] 185. The method of embodiment 179, wherein the loading dose is 450-500 μg dofetilide.

[1172] 186. The method of embodiment 179, wherein 1-3 hours after the completion of the loading dose, a patient with a creatinine clearance of 60 ml / min or greater is administered a 450-500 μg maintenance dose ("IV maintenance dose") of dofetilide.

[1173] 187. The method of embodiment 179, wherein the IV maintenance dose is 100-125 μg dofetilide.

[1174] 188. The method of embodiment 179, wherein 3-5 hours after the discontinuation of the IV maintenance dose, a patient with a creatinine clearance of 40-<60 ml / min is orally administered 250 μg dofetilide every 12 hours.

[1175] 189. The method of embodiment 179, further comprising measuring the patient's creatinine clearance as a proxy for glomerular filtration rate (GFR) prior to the administration of the IV maintenance dose to determine the amount of dofetilide indicated for the IV maintenance dose.

[1176] 190. The method of embodiment 179, further comprising measuring the patient's creatinine clearance as a proxy for glomerular filtration rate (GFR) prior to the oral administration of dofetilide to determine the amount of dofetilide indicated for the oral dose.

[1177] 191. The method of embodiment 179, wherein the patient has sufficiently recovered from cardioversion and is orally administered dofetilide while awake after surgery with intact gag reflex.

[1178] 192. The method of embodiment 179, wherein the intravenous loading dose is administered over about 30-60 minutes.

[1179] 193. The method of embodiment 179, wherein the IV maintenance dose is administered over about 3-12 hours.

[1180] 194. The method of embodiment 179, wherein the dofetilide is fully loaded in less than 3 days.

[1181] 195. The method of embodiment 194, wherein the dofetilide is fully loaded when the dofetilide reaches a steady state concentration in the blood.

[1182] 196. The method of embodiment 179, wherein the intravenous dofetilide is administered as a first loading dose and a continuous IV maintenance dose.

[1183] 197. The method of embodiment 179, wherein the intravenous dofetilide administration prevents possible arrhythmias by avoiding excessive dofetilide blood levels.

[1184] 198. A method of treating a patient presenting with highly symptomatic atrial fibrillation (AF) or atrial flutter (AFL), comprising:

[1185] a. intravenously administering to a patient in need thereof a loading dose of about 450-500 μg dofetilide over about 30-60 minutes;

[1186] b. after completion of the loading dose, performing electrical cardioversion for those patients who have not converted to sinus rhythm;

[1187] c. about 0-1 hours after conversion with electrical cardioversion, intravenously administering to a patient with a creatinine clearance of 20-<40 ml / min a maintenance dose ("IV maintenance dose") of 100-125 μg dofetilide over about 3-12 hours;

[1188] d. discontinuing the IV maintenance dose for those patients who have fully recovered from electrical cardioversion; and

[1189] e. about 2-6 hours after discontinuing the IV maintenance dose, orally administering to a patient with a creatinine clearance of 20-<40 ml / min 125 μg dofetilide every 12 hours or every 24 hours;

[1190] wherein the oral dofetilide dose is discontinued for those patients with a 15% increase in QTc from baseline, those patients with a QTc > 500 msec, or those patients with ventricular conduction abnormalities with a QTc > 550 msec; and

[1191] The expected loading dose reaches maximum serum concentration at the end of infusion; and

[1192] The patient is monitored to ensure that there is no excessive QT prolongation leading to abnormal cardiac repolarization, which could result in life-threatening ventricular arrhythmias.

[1193] 199. The method of implementing 198, which is a method for converting atrial fibrillation (AF) or atrial flutter (AFL).

[1194] 200. The method of implementation scheme 198, wherein a patient with severe symptoms has serious hemodynamic impairment, and the symptoms may include shortness of breath, dyspnea, chest pain (angina pectoris), orthopnea, syncope and sweating.

[1195] 201. The method of implementation scheme 198 further includes measuring the patient's QTc to establish a baseline QTc before administering a loading dose of dofetilide intravenously, and then measuring QTc every 15-30 minutes during the initial infusion, and then approximately every 60 minutes thereafter until the patient is stable.

[1196] 202. The method of implementation 201, wherein the physician of the patient determines when the patient is stable.

[1197] 203. The method of implementation scheme 202, wherein the patient may be stable after the loading infusion of dofetilide is completed or after the administration of the first oral dose.

[1198] 204. The method of embodiment 198, wherein the loading dose is 450-500 μg dofetilide.

[1199] 205. The method of implementation plan 198, wherein 450-500 μg of maintenance dose (“IV maintenance dose”) of dofetilide is administered to patients with a creatine clearance of 60 ml / min or higher 1-3 hours after the loading dose is completed.

[1200] 206. The method of implementation scheme 198, wherein the IV maintenance dose is 100-125 μg dofetilide.

[1201] 207. The method of implementation plan 198, wherein 500 μg of dofetilide is orally administered every 12 hours to patients with a creatine clearance of 60 ml / min or higher, 3-5 hours after interruption of the IV maintenance dose.

[1202] 208. The method of embodiment 198 further includes, prior to administration of the IV maintenance dose, measuring the patient’s creatine clearance as an approximation of the glomerular filtration rate (GFR) to determine the amount of dofetilide indicated for the IV maintenance dose.

[1203] 209. The method of embodiment 198, further comprising measuring the patient's creatinine clearance rate as an approximation of glomerular filtration rate (GFR) prior to orally administering dofetilide to determine the amount of dofetilide indicated for oral dosing.

[1204] 210. The method of embodiment 198, wherein the patient has fully recovered from cardioversion and orally administered dofetilide while awake postoperatively with intact gag reflex.

[1205] 211. The method of embodiment 198, wherein the intravenous loading dose is administered over about 30-60 minutes.

[1206] 212. The method of embodiment 198, wherein the IV maintenance dose is administered over about 3-12 hours.

[1207] 213. The method of embodiment 198, wherein the dofetilide is fully loaded in less than 3 days.

[1208] 214. The method of embodiment 213, wherein the dofetilide is fully loaded when the dofetilide reaches a steady state concentration in the blood.

[1209] 215. The method of embodiment 198, wherein intravenous dofetilide is administered in a first loading dose and a continuous IV maintenance dose.

[1210] 216. The method of embodiment 198, wherein intravenous dofetilide administration prevents possible arrhythmias by avoiding excessive dofetilide blood levels.

Claims

1. A combination of dofetilide IV medications for treating patients in need, comprising the following steps: I. Administer a loading dose of dofetilide intravenously to the patient, wherein the loading dose is administered over 30–60 minutes. II. After the IV loading dose is completed, administer a maintenance infusion of dofetilide intravenously for 12 hours, starting 0–4 hours later. III. When the patient is able to take dofetilide orally, discontinue the IV maintenance infusion; and, IV. 2-6 hours after stopping IV maintenance infusion, administer dofetilide orally every 12 hours; V. The maintenance infusions administered are based on the patients' creatinine clearance (CrCl) as given in the table below. VI. Furthermore, baseline QT was established by measuring the patient's QT before the IV maintenance infusion and before each oral dose, and before the IV loading dose of dofetilide. c Then measure QT every 15-30 minutes. c It lasted for 60 minutes; VII. The oral dose is reduced from 500 μg to 250 μg 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, or is discontinued if the initial dose is 125 μg.

2. The dofetilide IV combination of the drug according to claim 1 for the treatment of patients in need, wherein the risk of atrial fibrillation (AF) and / or atrial flutter (AFL) is reduced in patients undergoing coronary artery bypass grafting (CABS).

3. The combination of dofetilide IV medication according to claim 1 for treating patients in need, wherein the patient's arrhythmia storm is terminated after implantable defibrillator administration.

4. The combination of dofetilide IV drugs according to claim 1 for the treatment of patients in need, wherein atrial fibrillation (AF) or atrial flutter (AFL) is converted in patients presenting with highly symptomatic AF or AFL.

5. The dofetilide IV combination of the drug according to claim 1 for the treatment of patients in need, wherein the patients are given a loading dose of 450-500 μg of dofetilide intravenously.

6. The dofetilide IV combination of the drug according to claim 1 for the treatment of patients in need, wherein a maintenance infusion of 100-500 μg dofetilide is administered intravenously to the patient over 12 hours.

7. A combination of dofetilide IV medications according to any one of claims 1 to 6 for treating patients in need, wherein the duration between the Cmax dofetilide concentration obtained after administration of an IV loading dose of dofetilide and the Cmax dofetilide concentration obtained after administration of the first oral dose of dofetilide is between 14 and 18 hours.

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