METHODS OF ADMINISTERING DOFETILIDE
Methods of administering dofetilide in an amount effective for treating a cardiovascular condition are described. An IV dose can be administered over a selected period of time, such as about one hour, followed by a first oral dose. The patient can be discharged from the medical facility providing cardiac monitoring prior to administration of additional oral doses. The IV and first oral doses can be administered in a manner such that maximum serum concentration of dofetilide is reached and the patient can be discharged within about 7-8 hours.
1 . A method of administering dofetilide comprising:
administering to a subject an intravenous (IV) dosage of dofetilide, wherein the subject is in a facility capable of providing cardiac resuscitation and continuous electrocardiographic monitoring, and wherein the IV dosage is administered:
(a) in an amount of about 62.5-187.5 μg;
(b) in an amount of about 125-375 μg; or
(c) in an amount of about 250-750 μg; and
after completion of the administering of the IV dosage, administering a maintenance dose of dofetilide;
optionally administering a subsequent maintenance dose of dofetilide at least once at a selected interval, optionally after the subject is discharged from the facility capable of providing cardiac resuscitation and continuous electrocardiographic monitoring.
2 . The method of claim 1 , wherein the IV dosage of dofetilide and the maintenance dose are administered to the subject in a facility capable of providing cardiac resuscitation and continuous electrocardiographic monitoring, and the subsequent maintenance dose of dofetilide, if administered, is administered after the subject is discharged from the facility capable of providing cardiac resuscitation and continuous electrocardiographic monitoring.
3 . The method of claim 1 , wherein the IV dosage of dofetilide is administered as a single IV dosage over a period of about 1-5 hours, and the maintenance dose of dofetilide is administered at least 1 hour after completion of the administration of the IV dosage of dofetilide.
4 . The method of claim 1 , wherein:
the maintenance dose of dofetilide is an intravenous maintenance dose and/or an oral maintenance dose; and
the subsequent maintenance dose of dofetilide, if administered, is a subsequent intravenous maintenance dose and/or a subsequent oral maintenance dose comprising an amount of dofetilide that is the same or a different amount of dofetilide as in the maintenance dose.
5 . The method of claim 4 , wherein the maintenance dose and/or the subsequent maintenance dose, if administered, comprises an amount of dofetilide that is less than the IV dosage, and/or the subsequent maintenance dose, if administered, comprises an amount of dofetilide that is less than the maintenance dose.
6 . The method of claim 1 , wherein the IV dosage comprises dofetilide in an amount in the range of about 50% to about 110% of the amount of dofetilide in the maintenance dose.
7 . The method of claim 6 , wherein the maintenance dose and/or the subsequent maintenance dose, if administered, is an oral maintenance dose of dofetilide in an amount of 125 μg, 250 μg, or 500 μg.
8 . The method of claim 6 , wherein the maintenance dose and/or the subsequent maintenance dose, if administered, is an intravenous maintenance dose of dofetilide in an amount in the range of about 62.5 μg-750 μg.
9 . 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.
10 . The method of claim 1 , further comprising:
measuring a baseline QT interval and/or determining a baseline QTc interval for the subject before administering the IV dosage;
determining one or more QT interval(s) or QTc interval(s) after administration of the maintenance dose;
if at least one of the one or more QT or QTc intervals determined after the maintenance dose is more than 500 msec or increases greater than 15% from the baseline QT or QTc interval, refraining from administering a subsequent maintenance dose of dofetilide.
11 . The method of claim 1 , wherein the IV dosage of dofetilide is administered:
in a first higher amount for the subject who is renally impaired; and
in a second lower amount for the subject who is non-renally impaired.
12 . The method of claim 1 , wherein the amount of dofetilide for any one or more or all doses is below 1.8 μg/kg.
13 . The method of claim 1 , wherein the amount of dofetilide for any one or more or all doses is above 3 μg/kg.
14 . The method of claim 1 , wherein the amount of dofetilide for any one or more or all doses is an amount in the range of about: 85-100 μg, 90-150 μg, 105-115 μg, 175-200 μg, 190-300 μg, 210-240 μg, 400-450 μg, 425-550 μg, or 440-475 μg.
15 . The method of claim 14 , wherein the IV dosage comprises an amount of dofetilide based on a creatinine clearance of the subject as follows:
Intravenous Dosage of Dofetilide
Subject's
Maintenance
Subject's
Subject's
CrCl 20 mL/min
Dose
CrCl >60 mL/min
CrCl 40-60 mL/min
to <40 mL/min
125 μg
85-100 μg
90-150 μg
105-115 μg
250 μg
175-200 μg
190-300 μg
210-240 μg
500 μg
400-450 μg
425-550 μg
440-475 μg
16 . 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 of dofetilide comprising the selected amount of dofetilide based on the creatinine clearance and comprising an amount of dofetilide in the range of 0.1-12 μg/kg, and
(C) after the administering of the IV dosage, administering a first maintenance dose of dofetilide to the subject;
(D) optionally administering one or more subsequent maintenance doses of dofetilide at selected interval from the first maintenance dose.
17 . The method of claim 16 , wherein the IV dosage and the first maintenance dose of dofetilide are administered to the subject in a facility capable of providing cardiac resuscitation and continuous electrocardiographic monitoring, and the subsequent maintenance dose of dofetilide, if administered, is administered after the subject is discharged from the facility capable of providing cardiac resuscitation and continuous electrocardiographic monitoring.
18 . The method of claim 16 , wherein the first maintenance dose of dofetilide is an intravenous maintenance dose and/or an oral maintenance dose.
19 . The method of claim 18 , wherein:
the first maintenance dose and/or one or more of the subsequent maintenance doses, if administered, of dofetilide is a higher dose than the IV dosage.
20 . The method of claim 18 , wherein:
the first maintenance dose and/or one or more of the subsequent maintenance doses, if administered, of dofetilide is a lower dose than the IV dosage.
21 . The method of claim 16 , wherein the IV dosage comprises an amount of dofetilide in the range of about ±50% of the amount of the first maintenance dose.
22 . The method of claim 16 , wherein the IV dosage is administered over about 60 minutes.
23 . The method of claim 16 , wherein the subject is capable of experiencing a dofetilide C max steady state within about 8 hours of administration of the IV dosage.
24 . The method of claim 23 , wherein the IV dosage is administered to the subject in an amount and over a period of time 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.
25 . The method of claim 16 , 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.