DOFETILIDE (dofetilide 0.125 mg) Dailymed

Clinical Studies

Chronic Atrial Fibrillation and/or Atrial Flutter

Two randomized, parallel, double-blind, placebo-controlled, dose-response trials evaluated the ability of dofetilide 1) to convert patients with atrial fibrillation or atrial flutter (AF/AFl) of more than 1-week duration to normal sinus rhythm (NSR) and 2) to maintain NSR (delay time to recurrence of AF/AFl) after drug-induced or electrical cardioversion. A total of 996 patients with a one week to two-year history of atrial fibrillation/atrial flutter were enrolled. Both studies randomized patients to placebo or to doses of dofetilide 125 mcg, 250 mcg, 500 mcg, or in one study a comparator drug, given twice a day (these doses were lowered based on calculated creatinine clearance and, in one of the studies, for QT interval or QTc). All patients were started on therapy in a hospital where their ECG was monitored (see DOSAGE AND ADMINISTRATION).

Patients were excluded from participation if they had had syncope within the past 6 months, AV block greater than first degree, MI or unstable angina within 1-month, cardiac surgery within 2 months, history of QT interval prolongation or polymorphic ventricular tachycardia associated with use of antiarrhythmic drugs, QT interval or QTc > 440 msec, serum creatinine > 2.5 mg/mL, significant diseases of other organ systems; used cimetidine; or used drugs known to prolong the QT interval.

Both studies enrolled mostly Caucasians (over 90%), males (over 70%), and patients ≥ 65 years of age (over 50%). Most (> 90%) were NYHA Functional Class I or II. Approximately one‑half had structural heart disease (including ischemic heart disease, cardiomyopathies, and valvular disease) and about one-half were hypertensive. A substantial proportion of patients were on concomitant therapy, including digoxin (over 60%), diuretics (over 20%), and ACE inhibitors (over 30%). About 90% were on anticoagulants.

Acute conversion rates are shown in Table 1 for randomized doses (doses were adjusted for calculated creatinine clearance and, in Study 1, for QT interval or QTc). Of patients who converted pharmacologically, approximately 70% converted within 24 to 36 hours.

Table 1: Conversion of Atrial Fibrillation/Flutter to Normal Sinus Rhythm

		Dofetilide  Dose		Placebo
	125  mcg BID	250  mcg BID	500  mcg BID
Study 1	5/82(6%)	8/82(10%)	23/77(30%)	1/84(1%)
Study 2	8/135(6%)	14/133(11%)	38/129(29%)	2/137(1%)

Patients who did not convert to NSR with randomized therapy within 48 to 72 hours had electrical cardioversion. Those patients remaining in NSR after conversion in hospital were continued on randomized therapy as outpatients (maintenance period) for up to one year unless they experienced a recurrence of atrial fibrillation/atrial flutter or withdrew for other reasons.

Table 2 shows, by randomized dose, the percentage of patients at 6 and 12 months in both studies who remained on treatment in NSR and the percentage of patients who withdrew because of recurrence of AF/AFl or adverse events.

Table 2: Patient Status at 6 and 12 Months Post Randomization

		Dofetilide  Dose		Placebo
	125  mcg  BID	250  mcg  BID	500  mcg  BID
Study 1
Randomized	82	82	77	84
Achieved NSR	60	61	61	68
6 months
Still on treatment in NSR	38%	44%	52%	32%
D/C for recurrence	55%	49%	33%	63%
D/C for AEs	3%	3%	8%	4%
12 months
Still on treatment in NSR	32%	26%	46%	22%
D/C for recurrence	58%	57%	36%	72%
D/C for AEs	7%	11%	8%	6%
Study 2
Randomized	135	133	129	137
Achieved NSR	103	118	100	106
6 months
Still on treatment in NSR	41%	49%	57%	22%
D/C for recurrence	48%	42%	27%	72%
D/C for AEs	9%	6%	10%	4%
12 months
Still on treatment in NSR	25%	42%	49%	16%
D/C for recurrence	59%	47%	32%	76%
D/C for AEs	11%	6%	12%	5%

Note that columns do not add up to 100% due to discontinuations for "other" reasons.

Table 3 and Figures 3 and 4 show, by randomized dose, the effectiveness of dofetilide in maintaining NSR using Kaplan Meier analysis, which shows patients remaining on treatment.

Median time to recurrence of AF/AFl could not be estimated accurately for the 250 mcg BID treatment group in Study 2 and the
500 mcg BID treatment groups in Studies 1 and 2 because TIKOSYN maintained >50% of patients (51%, 58%, and 66%,
respectively) in NSR for the 12 months duration of the studies.
		Dofetilide Dose		Placebo
	125 mcg BID	250 mcg BID	500 mcg BID
Study 1
p-value vs. placebo	P = 0.21	P = 0.10	P < 0.001
Median time to recurrence (days)	31	179	> 365	27
Study 2
p-value vs. placebo	P = 0.006	P<0.001	P< 0.001
Median time to recurrence (days)	182	>365	> 365	34

Figure 3: Maintenance of Normal Sinus Rhythm, dofetilide Regimen vs. Placebo (Study 1)
The point estimates of the probabilities of remaining in NSR at 6 and 12 months were 62% and 58%, respectively, for dofetilide 500 mcg BID; 50% and 37%, respectively, for dofetilide 250 mcg BID; and 37%, and 25%, respectively, for placebo.

Figure 4: Maintenance of Normal Sinus Rhythm, Dofetilide Regimen vs. Placebo (Study 2)
The point estimates of the probabilities of remaining in NSR at 6 and 12 months were 71% and 66%, respectively, for dofetilide 500 mcg BID; 56% and 51%, respectively, for dofetilide 250 mcg BID; and 26% and 21%, respectively, for placebo.

In both studies, dofetilide resulted in a dose-related increase in the number of patients maintained in NSR at all time periods and delayed the time of recurrence of sustained AF. Data pooled from both studies show that there is a positive relationship between the probability of staying in NSR, dofetilide dose, and increase in QTc (see Figure 2 in CLINICAL PHARMACOLOGY, Dose-Response and Concentration Response for Increase in QT Interval).

Analysis of pooled data for patients randomized to a dofetilide dose of 500 mcg twice daily showed that maintenance of NSR was similar in both males and females, in both patients aged < 65 years and patients ≥ 65 years of age, and in both patients with atrial flutter as a primary diagnosis and those with a primary diagnosis of atrial fibrillation.

During the period of in-hospital initiation of dosing, 23% of patients in Studies 1 and 2 had their dose adjusted downward on the basis of their calculated creatinine clearance, and 3% had their dose down-titrated due to increased QT interval or QTc. Increased QT interval or QTc led to discontinuation of therapy in 3% of patients.

Safety in Patients with Structural Heart Disease: DIAMOND Studies (The Danish Investigations of Arrhythmia and Mortality on Dofetilide)

The two DIAMOND studies were 3-year trials comparing the effects of dofetilide and placebo on mortality and morbidity in patients with impaired left ventricular function (ejection fraction ≤ 35%). Patients were treated for at least one year. One study was in patients with moderate to severe (60% NYHA Class III or IV) congestive heart failure (DIAMOND CHF) and the other was in patients with recent myocardial infarction (DIAMOND MI) (of whom 40% had NYHA Class III or IV heart failure). Both groups were at relatively high risk of sudden death. The DIAMOND trials were intended to determine whether dofetilide could reduce that risk. The trials did not demonstrate a reduction in mortality; however, they provide reassurance that, when initiated carefully, in a hospital or equivalent setting, dofetilide did not increase mortality in patients with structural heart disease, an important finding because other antiarrhythmics [notably the Class IC antiarrhythmics studied in the Cardiac Arrhythmia Suppression Trial (CAST) and a pure Class III antiarrhythmic, d-sotalol (SWORD)] have increased mortality in post-infarction populations. The DIAMOND trials therefore provide evidence of a method of safe use of dofetilide in a population susceptible to ventricular arrhythmias. In addition, the subset of patients with AF in the DIAMOND trials provide further evidence of safety in a population of patients with structural heart disease accompanying the AF. Note, however, that this AF population was given a lower (250 mcg BID) dose (see CLINICAL STUDIES, DIAMOND Patients with Atrial Fibrillation).

In both DIAMOND studies, patients were randomized to 500 mcg BID of dofetilide, but this was reduced to 250 mcg BID if calculated creatinine clearance was 40 to 60 mL/min, if patients had AF, or if QT interval prolongation (> 550 msec or > 20% increase from baseline) occurred after dosing. Dose reductions for reduced calculated creatinine clearance occurred in 47% and 45% of DIAMOND CHF and MI patients, respectively. Dose reductions for increased QT interval or QTc occurred in 5% and 7% of DIAMOND CHF and MI patients, respectively. Increased QT interval or QTc (> 550 msec or > 20% increase from baseline) resulted in discontinuation of 1.8% of patients in DIAMOND CHF and 2.5% of patients in DIAMOND MI.

In the DIAMOND studies, all patients were hospitalized for at least 3 days after treatment was initiated and monitored by telemetry. Patients with QTc greater than 460 msec, second or third-degree AV block (unless with pacemaker), resting heart rate < 50 bpm, or prior history of polymorphic ventricular tachycardia were excluded.

DIAMOND CHF studied 1,518 patients hospitalized with severe CHF who had confirmed impaired left ventricular function (ejection fraction ≤ 35%). Patients received a median duration of therapy of greater than one year. There were 311 deaths from all causes in patients randomized to dofetilide (n = 762) and 317 deaths in patients randomized to placebo (n = 756). The probability of survival at one year was 73% (95% CI: 70% to 76%) in the dofetilide group and 72% (95% CI: 69% to 75%) in the placebo group. Similar results were seen for cardiac deaths and arrhythmic deaths. Torsade de Pointes occurred in 25/762 patients (3.3%) receiving dofetilide. The majority of cases (76%) occurred within the first 3 days of dosing. In all, 437/762 (57%) of patients on dofetilide and 459/756 (61%) on placebo required hospitalization. Of these, 229/762 (30%) of patients on dofetilide and 290/756 (38%) on placebo required hospitalization because of worsening heart failure.

DIAMOND MI studied 1,510 patients hospitalized with recent myocardial infarction (2 to 7 days) who had confirmed impaired left ventricular function (ejection fraction ≤ 35%). Patients received a median duration of therapy of greater than one year. There were 230 deaths in patients randomized to dofetilide (n = 749) and 243 deaths in patients randomized to placebo (n = 761). The probability of survival at one year was 79% (95% CI: 76% to 82%) in the dofetilide group and 77% (95% CI: 74% to 80%) in the placebo group. Cardiac and arrhythmic mortality showed a similar result. Torsade de Pointes occurred in 7/749 patients (0.9%) receiving dofetilide. Of these, 4 cases occurred within the first 3 days of dosing and 3 cases occurred between Day 4 and the conclusion of the study. In all, 371/749 (50%) of patients on dofetilide and 419/761 (55%) on placebo required hospitalization. Of these, 200/749 (27%) of patients on dofetilide and 205/761 (27%) on placebo required hospitalization because of worsening heart failure.

DIAMOND Patients with Atrial Fibrillation (the DIAMOND AF subpopulation). There were 506 patients in the two DIAMOND studies who had atrial fibrillation (AF) at entry to the studies (249 randomized to dofetilide and 257 randomized to placebo). DIAMOND AF patients randomized to dofetilide received 250 mcg BID; 65% of these patients had impaired renal function, so that 250 mcg BID represents the dose they would have received in the AF trials, which would give drug exposure similar to a person with normal renal function given 500 mcg BID. In the DIAMOND AF subpopulation, there were 111 deaths (45%) in the 249 patients in the dofetilide group and 116 deaths (45%) in the 257 patients in the placebo group. Hospital readmission rates for any reason were 125/249 or 50% on dofetilide and 156/257 or 61% for placebo. Of these, readmission rates for worsening heart failure were 73/249 or 29% on dofetilide and 102/257 or 40% for placebo.

Of the 506 patients in the DIAMOND studies who had atrial fibrillation or flutter at baseline, 12% of patients in the dofetilide group and 2% of patients in the placebo group had converted to normal sinus rhythm after one month. In those patients converted to normal sinus rhythm, 79% of the dofetilide group and 42% of the placebo group remained in normal sinus rhythm for one year.

In the DIAMOND studies, although Torsade de Pointes occurred more frequently in the dofetilide-treated patients (see ADVERSE REACTIONS ), dofetilide, given with an initial 3‑day hospitalization and with dose modified for reduced creatinine clearance and increased QT interval, was not associated with an excess risk of mortality in these populations with structural heart disease in the individual studies or in an analysis of the combined studies. The presence of atrial fibrillation did not affect outcome.

Ventricular Arrhythmia: Dofetilide can cause serious ventricular arrhythmias, primarily Torsade de Pointes (TdP) type ventricular tachycardia, a polymorphic ventricular tachycardia associated with QT interval prolongation. QT interval prolongation is directly related to dofetilide plasma concentration. Factors such as reduced creatinine clearance or certain dofetilide drug interactions will increase dofetilide plasma concentration. The risk of TdP can be reduced by controlling the plasma concentration through adjustment of the initial dofetilide dose according to creatinine clearance and by monitoring the ECG for excessive increases in the QT interval.

Treatment with dofetilide must therefore be started only in patients placed for a minimum of three days in a facility that can provide electrocardiographic monitoring and in the presence of personnel trained in the management of serious ventricular arrhythmias. Calculation of the creatinine clearance for all patients must precede administration of the first dose of dofetilide. For detailed instructions regarding dose selection, see DOSAGE AND ADMINISTRATION.

The risk of dofetilide induced ventricular arrhythmia was assessed in three ways in clinical studies: 1) by description of the QT interval and its relation to the dose and plasma concentration of dofetilide; 2) by observing the frequency of TdP in dofetilide-treated patients according to dose; 3) by observing the overall mortality rate in patients with atrial fibrillation and in patients with structural heart disease.

Relation of QT Interval to Dose: The QT interval increases linearly with increasing dofetilide dose (see Figures 1 and 2 in CLINICAL PHARMACOLOGY and Dose-Response and Concentration Response for Increase in QT Interval).

Frequency of Torsade de Pointes: In the supraventricular arrhythmia population (patients with AF and other supraventricular arrhythmias), the overall incidence of Torsade de Pointes was 0.8%. The frequency of TdP by dose is shown in Table 4. There were no cases of TdP on placebo.

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Table 4: Summary of Torsade de Pointes in Patients Randomized to Dofetilide by Dose; Patients with Supraventricular Arrhythmias

	Dofetilide  Dose
	<  250  mcg BID	250  mcg BID	>  250  to  500  mcg BID	>  500  mcg BID	All  Doses
Number of Patients	217	388	703	38	1,346
Torsade de Pointes	0	1 (0.3%)	6 (0.9%)	4 (10.5%)	11 (0.8%)

As shown in Table 5, the rate of TdP was reduced when patients were dosed according to their renal function (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations, Renal Impairment and DOSAGE AND ADMINISTRATION ).

Table 5: Incidence of Torsade de Pointes Before and After Introduction of Dosing According to Renal Function

Population :	Total	Before	After
	n / N  %	n / N  %	n / N  %
Supraventricular Arrhythmias	11/1,346 (0.8%)	6/193 (3.1%)	5/1,153 (0.4%)
DIAMOND CHF	25/762 (3.3%)	7/148 (4.7%)	18/614 (2.9%)
DIAMOND MI	7/749 (0.9%)	3/101 (3.0%)	4/648 (0.6%)
DIAMOND AF	4/249 (1.6%)	0/43 (0%)	4/206 (1.9%)

The majority of the episodes of TdP occurred within the first three days of dofetilide therapy (10/11 events in the studies of patients with supraventricular arrhythmias; 19/25 and 4/7 events in DIAMOND CHF and DIAMOND MI, respectively; 2/4 events in the DIAMOND AF subpopulation).

Mortality: In a pooled survival analysis of patients in the supraventricular arrhythmia population (low prevalence of structural heart disease), deaths occurred in 0.9% (12/1,346) of patients receiving dofetilide and 0.4% (3/677) in the placebo group. Adjusted for duration of therapy, primary diagnosis, age, gender, and prevalence of structural heart disease, the point estimate of the hazard ratio for the pooled studies (dofetilide/placebo) was 1.1 (95% CI: 0.3, 4.3). The DIAMOND CHF and MI trials examined mortality in patients with structural heart disease (ejection fraction ≤ 35%). In these large, double-blind studies, deaths occurred in 36% (541/1,511) of dofetilide patients and 37% (560/1,517) of placebo patients. In an analysis of 506 DIAMOND patients with atrial fibrillation/flutter at baseline, one-year mortality on dofetilide was 31% vs. 32% on placebo (see CLINICAL STUDIES ).

Because of the small number of events, an excess mortality due to dofetilide cannot be ruled out with confidence in the pooled survival analysis of placebo-controlled trials in patients with supraventricular arrhythmias. However, it is reassuring that in two large placebo-controlled mortality studies in patients with significant heart disease (DIAMOND CHF/MI), there were no more deaths in dofetilide-treated patients than in patients given placebo (see CLINICAL STUDIES ).

Drug-Drug Interactions (see CONTRAINDICATIONS)

Because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant drugs that interfere with the metabolism or renal elimination of dofetilide may increase the risk of arrhythmia (Torsade de Pointes). Dofetilide is metabolized to a small degree by the CYP3A4 isoenzyme of the cytochrome P450 system and an inhibitor of this system could increase systemic dofetilide exposure. More important, dofetilide is eliminated by cationic renal secretion, and three inhibitors of this process have been shown to increase systemic dofetilide exposure. The magnitude of the effect on renal elimination by cimetidine, trimethoprim, and ketoconazole (all contraindicated concomitant uses with dofetilide) suggests that all renal cation transport inhibitors should be contraindicated.

Hypokalemia and Potassium-Depleting Diuretics

Hypokalemia or hypomagnesemia may occur with administration of potassium-depleting diuretics, increasing the potential for Torsade de Pointes. Potassium levels should be within the normal range prior to administration of dofetilide and maintained in the normal range during administration of dofetilide (see DOSAGE AND ADMINISTRATION ).

Use with Drugs that Prolong QT Interval and Antiarrhythmic Agents

The use of dofetilide in conjunction with other drugs that prolong the QT interval has not been studied and is not recommended. Such drugs include phenothiazines, cisapride, bepridil, tricyclic antidepressants, certain oral macrolides, and certain fluoroquinolones. Class I or Class III antiarrhythmic agents should be withheld for at least three half-lives prior to dosing with dofetilide. In clinical trials, dofetilide was administered to patients previously treated with oral amiodarone only if serum amiodarone levels were below 0.3 mg/L or amiodarone had been withdrawn for at least three months.