Mechanism of Action
TIKOSYN (dofetilide) shows
Vaughan Williams Class III antiarrhythmic activity. The mechanism of action is
blockade of the cardiac ion channel carrying the rapid component of the delayed
rectifier potassium current, IKr. At concentrations covering several orders of
magnitude, dofetilide blocks only IKr with no relevant block of the other
repolarizing potassium currents (e.g., IKs, IK1). At clinically relevant
concentrations, dofetilide has no effect on sodium channels (associated with
Class I effect), adrenergic alpha-receptors, or adrenergic beta-receptors.
Electrophysiology
TIKOSYN (dofetilide) increases
the monophasic action potential duration in a predictable, concentration-dependent
manner, primarily due to delayed repolarization. This effect, and the related
increase in effective refractory period, is observed in the atria and
ventricles in both resting and paced electrophysiology studies. The increase in
QT interval observed on the surface ECG is a result of prolongation of both
effective and functional refractory periods in the His-Purkinje system and the
ventricles.
Dofetilide did not influence
cardiac conduction velocity and sinus node function in a variety of studies in
patients with or without structural heart disease. This is consistent with a lack
of effect of dofetilide on the PR interval and QRS width in patients with
pre-existing heart block and/or sick sinus syndrome.
In patients, dofetilide
terminates induced re-entrant tachyarrhythmias (e.g., atrial fibrillation/flutter
and ventricular tachycardia) and prevents their re-induction. TIKOSYN does not
increase the electrical energy required to convert electrically-induced
ventricular fibrillation, and it significantly reduces the defibrillation threshold in patients with ventricular tachycardia and ventricular fibrillation
undergoing implantation of a cardioverter-defibrillator device.
Hemodynamic Effects
In hemodynamic studies, TIKOSYN
had no effect on cardiac output, cardiac index, stroke volume index, or
systemic vascular resistance in patients with ventricular tachycardia, mild to moderate
congestive heart failure or angina and either normal or low left ventricular
ejection fraction. There was no evidence of a negative inotropic effect related
to TIKOSYN therapy in patients with atrial fibrillation. There was no increase
in heart failure in patients with significant left ventricular dysfunction (see
Safety in Patients with Structural Heart Disease: DIAMOND Studies). In
the overall clinical program, TIKOSYN did not affect blood pressure. Heart rate
was decreased by 4-6 bpm in studies in patients.
Pharmacokinetics, General
Absorption and Distribution
The oral bioavailability of
dofetilide is > 90%, with maximal plasma concentrations occurring at about
2-3 hours in the fasted state. Oral bioavailability is unaffected by food or
antacid. The terminal half life of TIKOSYN is approximately 10 hours; steady
state plasma concentrations are attained within 2-3 days, with an accumulation
index of 1.5 to 2.0. Plasma concentrations are dose proportional. Plasma
protein binding of dofetilide is 60-70%, is independent of plasma
concentration, and is unaffected by renal impairment. Volume of distribution is
3 L/kg.
Metabolism and Excretion
Approximately 80% of a single
dose of dofetilide is excreted in urine, of which approximately 80% is excreted
as unchanged dofetilide with the remaining 20% consisting of inactive or
minimally active metabolites. Renal elimination involves both glomerular
filtration and active tubular secretion (via the cation transport system, a
process that can be inhibited by cimetidine, trimethoprim, prochlorperazine,
megestrol and ketoconazole). In vitrostudies with human liver
microsomes show that dofetilide can be metabolized by CYP3A4, but it has a low
affinity for this isoenzyme. Metabolites are formed by N-dealkylation and
Noxidation. There are no quantifiable metabolites circulating in plasma, but 5
metabolites have been identified in urine.
Pharmacokinetics in Special
Populations
Renal Impairment
In volunteers with varying
degrees of renal impairment and patients with arrhythmias, the clearance of
dofetilide decreases with decreasing creatinine clearance. As a result, and as
seen in clinical studies, the half-life of dofetilide is longer in patients
with lower creatinine clearances. Because increase in QT interval and the
risk of ventricular arrhythmias are directly related to plasma concentrations
of dofetilide, dosage adjustment based on calculated creatinine clearance is
critically important (see DOSAGE AND ADMINISTRATION). Patients
with severe renal impairment (creatinine clearance < 20 mL/min) were not
included in clinical or pharmacokinetic studies (see CONTRAINDICATIONS).
Hepatic Impairment
There was no clinically
significant alteration in the pharmacokinetics of dofetilide in volunteers with
mild to moderate hepatic impairment (Child-Pugh class A and B) compared to age-
and weight-matched healthy volunteers. Patients with severe hepatic impairment were not studied.
Patients with Heart Disease
Population pharmacokinetic
analyses indicate that the plasma concentration of dofetilide in patients with
supraventricular and ventricular arrhythmias, ischemic heart disease, or
congestive heart failure are similar to those of healthy volunteers, after adjusting
for renal function.
Elderly
After correction for renal
function, clearance of dofetilide is not related to age.
Women
A population pharmacokinetic
analysis showed that women have approximately 12-18% lower dofetilide oral
clearances than men (14-22% greater plasma dofetilide levels), after correction
for weight and creatinine clearance. In females, as in males, renal function
was the single most important factor influencing dofetilide clearance. In
normal female volunteers, hormone replacement therapy (a combination of
conjugated estrogens and medroxyprogesterone) did not increase dofetilide
exposure.
Drug-Drug Interactions
(see PRECAUTIONS)
Dose-Response and Concentration
Response for Increase in QT Interval
Increase in QT interval is
directly related to dofetilide dose and plasma concentration. Figure 1 shows
that the relationship in normal volunteers between dofetilide plasma
concentrations and change in QTc is linear, with a positive slope of
approximately 15-25 msec/(ng/mL) after the first dose and approximately 10-15
msec/(ng/mL) at Day 23 (reflecting a steady state of dosing). A linear
relationship between mean QTc increase and dofetilide dose was also seen in
patients with renal impairment, in patients with ischemic heart disease, and in
patients with supraventricular and ventricular arrhythmias.
Figure 1 : Mean
QTc-Concentration Relationship in Young Volunteers Over 24 Days.
Note: The range of dofetilide
plasma concentrations achieved with the 500 mcg BID dose adjusted for
creatinine clearance is 1-3.5 ng/mL.
The relationship between dose,
efficacy and the increase in QTc from baseline at steady state for the two randomized, placebo-controlled studies (described further below) is shown in
Figure 2. The studies examined the effectiveness of TIKOSYN in conversion to
sinus rhythm and maintenance of normal sinus rhythm after conversion in
patients with atrial fibrillation/flutter of > 1 week duration. As shown,
both the probability of a patient's remaining in sinus rhythm at six months and
the change in QTc from baseline at steady state of dosing increased in an approximately
linear fashion with increasing dose of TIKOSYN. Note that in these studies
doses were modified by results of creatinine clearance measurement and
in-hospital QTc prolongation.
Figure 2: Relationship
Between TIKOSYN Dose, QTc Increase and Maintenance of NSR.
Clinical Studies
Chronic Atrial Fibrillation
and/or Atrial Flutter
Two randomized, parallel, double-blind, placebo controlled, dose-response trials
evaluated the ability of TIKOSYN 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 TIKOSYN 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 anti-arrhythmic 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 24-36 hours.
Table 1: Conversion of Atrial
Fibrillation/Flutter to Normal Sinus Rhythm
| |
TIKOSYN 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 48-72 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
| |
TIKOSYN 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% |
| Please 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 TIKOSYN in maintaining NSR using
Kaplan Meier analysis, which shows patients remaining on treatment.
Table 3: P-Values and Median
Time (days) to Recurrence of AF/AFl
| |
TIKOSYN Dos |
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 |
27 |
| Median time to recurrence (days) |
31 |
179 |
> 365 |
34 |
| Study 2 |
| p-value vs placebo |
P=0.006 |
P < 0.001 |
P < 0.001 |
|
| Median time to recurrence (days) |
182 |
> 365 |
> 365 |
|
| 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. |
Figure 3: Maintenance of Normal Sinus Rhythm, TIKOSYN 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 TIKOSYN 500 mcg BID, 50% and 37% for TIKOSYN 250 mcg BID, and 37%
and 25% respectively on placebo.
Figure 4: Maintenance of Normal Sinus Rhythm, TIKOSYN 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 TIKOSYN 500 mcg BID, 56% and 51% for TIKOSYN 250 mcg BID, and 26%
and 21% respectively on placebo.
In both studies, TIKOSYN
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, TIKOSYN dose, and increase in QTc (see Figure 2
in CLINICAL PHARMACOLOGY: Dose-Response and Concentration Response for QT
Interval).
Analysis of pooled data for
patients randomized to a TIKOSYN 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 TIKOSYN
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 TIKOSYN 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, TIKOSYN 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 TIKOSYN 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 DIAMOND Patients with Atrial Fibrillation).
In both DIAMOND studies,
patients were randomized to 500 mcg BID of TIKOSYN, but this was reduced to 250
mcg BID if calculated creatinine clearance was 40-60 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. 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 1518
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 TIKOSYN (n=762) and 317 deaths in patients
randomized to placebo (n=756). The probability of survival at one year was 73%
(95% CI: 70% - 76%) in the TIKOSYN group and 72% (95% CI: 69% - 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 TIKOSYN.
The majority of cases (76%) occurred within the first 3 days of dosing. In all,
437/762 (57%) of patients on TIKOSYN and 459/756 (61%) on placebo required
hospitalization. Of these, 229/762 (30%) of patients on TIKOSYN and 290/756
(38%) on placebo required hospitalization because of worsening heart failure.
DIAMOND MI studied 1510 patients
hospitalized with recent myocardial infarction (2-7 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 TIKOSYN (n=749) and 243 deaths in patients
randomized to placebo (n=761). The probability of survival at one year was 79%
(95% CI: 76% - 82%) in the TIKOSYN group and 77% (95% CI: 74% - 80%) in the
placebo group. Cardiac and arrhythmic mortality showed a similar result.
Torsade de pointes occurred in 7/749 patients (0.9%) receiving TIKOSYN. 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
TIKOSYN and 419/761 (55%) on placebo required hospitalization. Of these,
200/749 (27%) of patients on TIKOSYN 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 TIKOSYN and 257 randomized to placebo). DIAMOND AF patients randomized
to TIKOSYN 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 TIKOSYN 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 TIKOSYN and 156/257 or 61% for placebo. Of these,
readmission rates for worsening heart failure were 73/249 or 29% on TIKOSYN 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 TIKOSYN 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 TIKOSYN 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 TIKOSYN-treated patients
(see ADVERSE REACTIONS), TIKOSYN, 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.
Last updated on RxList: 4/3/2009