METHODS OF INTRAVENOUSLY ADMINISTERING DOFETILIDE
Methods of administering dofetilide in an amount effective for treating a cardiovascular condition are described. An initial IV dose can be administered over a period of about 10 minutes to a patient/subject admitted to a medical facility providing cardiac monitoring. The patient/subject can be administered one or more oral or IV maintenance doses before or after being discharged from the medical facility. The IV dosage can be administered in a manner such that maximum serum concentration of dofetilide is reached during the administering of the IV loading dose.
1 . A method of intravenously administering dofetilide, comprising:
administering an IV dosage of dofetilide to a subject over a period of about 10 minutes in the range of ±50% of a target oral dose;
wherein the IV dosage is administered while the subject is in a facility capable of providing cardiac resuscitation and electrocardiographic monitoring.
2 . A method of administering dofetilide, comprising:
administering an IV dosage of dofetilide to a subject over a period of about 10 minutes in an amount of about 62.5-1000 μg;
wherein the IV dosage is administered while the subject is in a facility capable of providing cardiac resuscitation and electrocardiographic monitoring; and
after administering the IV dosage, administering an oral dosage of dofetilide to the subject in an amount of 125 μg, 250 μg or 500 μg.
3 . The method of claim 1 , further comprising administering and optionally repeating oral administration of dofetilide at least once at a selected interval.
4 . The method of claim 3 , wherein the oral administration of one or more of the oral dosages of dofetilide is performed before or after the subject is discharged from the facility capable of providing cardiac resuscitation and electrocardiographic monitoring.
5 . The method of claim 1 , wherein the subject has a cardiovascular condition selected from atrial fibrillation, atrial flutter, atrial tachycardia, ventricular tachycardia, hemodynamically stable or unstable ventricular tachycardia, paroxysmal atrial fibrillation, ventricular fibrillation, ventricular arrhythmia, premature ventricular contractions (PVCs), paroxysmal supraventricular tachycardia, supraventricular tachycardia, junctional ectopic tachycardia, junctional tachycardia, heart failure, coronary artery disease, and pulmonary artery hypertension.
6 . The method of claim 5 , wherein the subject is not in sinus rhythm before the administering of the IV dosage.
7 . The method of claim 1 , wherein the subject is in sinus rhythm and/or has been converted to sinus rhythm.
8 . The method of claim 2 , wherein:
the IV dosage is administered in an amount of:
(a) about 62.5-187.5 μg dofetilide and the oral dosage is 125 μg;
(b) about 125-375 μg dofetilide and the oral dosage is 250 μg; or
(c) about 250-1000 μg dofetilide and the oral dosage is 500 μg.
9 . A method of administering dofetilide, comprising:
(A) before administering an IV dosage of dofetilide to a subject, determining a creatinine clearance (CrCl) of the subject, and selecting an amount of dofetilide to administer to the subject based on the creatinine clearance;
(B) administering to the subject the IV dosage comprising the selected amount of dofetilide based on the CrCl, wherein the IV dosage is administered over a period of about 10 minutes and is administered to the subject in a facility capable of providing cardiac resuscitation and continuous electrocardiographic monitoring.
10 . The method of claim 9 , wherein the selected amount of dofetilide to administer to the subject is further based on a target oral dose of dofetilide.
11 . The method of claim 9 , wherein the subject is capable of experiencing a dofetilide C max steady state during the administering of the IV dosage.
12 . The method of claim 9 , wherein the IV dosage of dofetilide is administered:
in a first higher amount for the subject with a CrCl of 20 mL/min to <40 mL/min; and
in a second lower amount for the subject with a CrCl of 40 mL/min or greater.
13 . The method of claim 10 , further comprising administering one or more IV or oral maintenance dose of dofetilide after administering the IV dosage of dofetilide.
14 . The method of claim 11 , wherein:
the IV dosage comprising the selected amount of dofetilide based on the creatinine clearance and the target oral dose of the subject comprises an amount of dofetilide as follows:
Intravenous Dosage of Dofetilide
Maintenance
Subject's CrCl
Subject's CrCl
Subject's CrCl
Dose
>60 mL/min
40-60 mL/min
20 to <40 mL/min
125 μg
50-150 μg
100-250
μg
up to 125 μg
250 μg
100-350 μg
200-500
μg
up to 250 μg
500 μg
300-800 μg
400-1000
μg
up to 500 μg.
15 . The method of claim 1 , wherein the subject is discharged with instructions to self-administer an oral dose and/or one or more subsequent oral doses of dofetilide every 12 to 48 hours.
16 . The method of claim 1 , further comprising:
obtaining a QT or QTc interval of the subject before administration of the IV dosage; and
obtaining a QT or QTc interval of the subject during or after administration of the IV dosage, but before administration of any oral dosage;
wherein the QT or QTc interval during or after administering the IV dosage is less than a 15% increase from the QT or QTc interval before administering the IV dosage.
17 . The method of claim 16 , further comprising:
measuring a QT or QTc interval of the subject after administration of the IV dosage and if an oral dose is administered, then before a first oral dose;
wherein the QT or QTc interval during and after administering the IV dosage is less than a 15% increase from the QT or QTc interval before administering the first oral dose.
18 . The method of claim 17 , further comprising administering the first oral dose and one or more subsequent oral doses of dofetilide.
19 . The method of claim 18 , wherein the amount of one or more of the subsequent oral doses is different from the amount of the first oral dose.
20 . The method of claim 1 , wherein the IV dosage is administered to the subject in an amount such that the dofetilide reaches or is capable of reaching a C max in the subject that is at least about 70% of a steady state C max for an oral dosing protocol of 125 μg, 250 μg, or 500 μg dofetilide.