Generic Name: DOFETILIDE
Brand Name: Tikosyn
- Substance Name(s):
Ventricular Arrhythmia TIKOSYN (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 TIKOSYN-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 TIKOSYN 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.
Table 4: Summary of Torsade de Pointes in Patients Randomized to Dofetilide by Dose; Patients with Supraventricular Arrhythmias TIKOSYN Dose 250–500 mcg BID >500 mcg BID All Doses Number of Patients 217 388 703 38 1346 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 Total Before After Population: n/N % n/N % n/N % Supraventricular Arrhythmias 11/1346 (0.8%) 6/193 (3.1%) 5/1153 (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 TIKOSYN 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% (12/1346) of patients receiving TIKOSYN 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 (TIKOSYN/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% (541/1511) of TIKOSYN patients and 37% (560/1517) of placebo patients.
In an analysis of 506 DIAMOND patients with atrial fibrillation/flutter at baseline, one year mortality on TIKOSYN was 31% vs.
32% on placebo (see CLINICAL STUDIES ).
Because of the small number of events, an excess mortality due to TIKOSYN 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 TIKOSYN-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 TIKOSYN and maintained in the normal range during administration of TIKOSYN (see DOSAGE AND ADMINISTRATION ).
Use with Drugs that Prolong QT Interval and Antiarrhythmic Agents The use of TIKOSYN 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 TIKOSYN.
In clinical trials, TIKOSYN 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.
There is no known antidote to TIKOSYN; treatment of overdose should therefore be symptomatic and supportive.
The most prominent manifestation of overdosage is likely to be excessive prolongation of the QT interval.
In cases of overdose, cardiac monitoring should be initiated.
Charcoal slurry may be given soon after overdosing but has been useful only when given within 15 minutes of TIKOSYN administration.
Treatment of Torsade de Pointes or overdose may include administration of isoproterenol infusion, with or without cardiac pacing.
Administration of intravenous magnesium sulfate may be effective in the management of Torsade de Pointes.
Close medical monitoring and supervision should continue until the QT interval returns to normal levels.
Isoproterenol infusion into anesthetized dogs with cardiac pacing rapidly attenuates the dofetilide-induced prolongation of atrial and ventricular effective refractory periods in a dose-dependent manner.
Magnesium sulfate, administered prophylactically either intravenously or orally in a dog model, was effective in the prevention of dofetilide-induced Torsade de Pointes ventricular tachycardia.
Similarly, in man, intravenous magnesium sulfate may terminate Torsade de Pointes, irrespective of cause.
TIKOSYN overdose was rare in clinical studies; there were two reported cases of TIKOSYN overdose in the oral clinical program.
One patient received very high multiples of the recommended dose (28 capsules), was treated with gastric aspiration 30 minutes later, and experienced no events.
One patient inadvertently received two 500 mcg doses one hour apart and experienced ventricular fibrillation and cardiac arrest 2 hours after the second dose.
In the supraventricular arrhythmia population, only 38 patients received doses greater than 500 mcg BID, all of whom received 750 mcg BID irrespective of creatinine clearance.
In this very small patient population, the incidence of Torsade de Pointes was 10.5% (4/38 patients), and the incidence of new ventricular fibrillation was 2.6% (1/38 patients).
TIKOSYN ® (dofetilide) is an antiarrhythmic drug with Class III (cardiac action potential duration prolonging) properties.
Its empirical formula is C 19 H 27 N 3 O 5 S 2 and it has a molecular weight of 441.6.
The structural formula is The chemical name for dofetilide is: N -[4-[2-[methyl[2-[4-[(methylsulfonyl)amino]phenoxy]ethyl]amino]ethyl]phenyl]-methanesulfonamide.
Dofetilide is a white to off-white powder.
It is very slightly soluble in water and propan-2-ol and is soluble in 0.1M aqueous sodium hydroxide, acetone, and aqueous 0.1M hydrochloric acid.
TIKOSYN capsules contain the following inactive ingredients: microcrystalline cellulose, corn starch, colloidal silicon dioxide and magnesium stearate.
TIKOSYN is supplied for oral administration in three dosage strengths: 125 mcg (0.125 mg) orange and white capsules, 250 mcg (0.25 mg) peach capsules, and 500 mcg (0.5 mg) peach and white capsules.
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 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 24–36 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 125 mcg BID 250 mcg BID 500 mcg BID Placebo Note that columns do not add up to 100% due to discontinuations for “other” reasons.
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% 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 Dose 125 mcg BID 250 mcg BID 500 mcg BID Placebo 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.
Study 1 p-value vs.
placebo P=0.21 P=0.10 P365 27 Study 2 p-value vs.
placebo P=0.006 P<0.001 P365 >365 34 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%, respectively, for TIKOSYN 250 mcg BID; and 37%, and 25%, respectively, for 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%, respectively, for TIKOSYN 250 mcg BID; and 26% and 21%, respectively, for 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 Increase in 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.
figure 3 figure 4 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, 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 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.
TIKOSYN 125 mcg (0.125 mg) capsules are supplied as No.
4 capsules with a light orange cap and white body, printed with TKN 125 PFIZER, and are available in: TIKOSYN 250 mcg (0.25 mg) capsules are supplied as No.
4 capsules, peach cap and body, printed with TKN 250 PFIZER, and are available in: TIKOSYN 500 mcg (0.5 mg) capsules are supplied as No.
2 capsules, peach cap and white body, printed with TKN 500 PFIZER, and are available in: 125 mcg (0.125 mg) 250 mcg (0.25 mg) 500 mcg (0.5 mg) Obverse TKN 125 TKN 250 TKN 500 Reverse PFIZER PFIZER PFIZER Bottle of 14 0069-5800-61 0069-5810-61 0069-5820-61 Bottle of 60 0069-5800-60 0069-5810-60 0069-5820-60 Unit dose / 40 0069-5800-43 0069-5810-43 0069-5820-43 Store at controlled room temperature, 15° to 30°C (59° to 86°F).
PROTECT FROM MOISTURE AND HUMIDITY.
Dispense in tight containers (USP).
Geriatric Use Of the total number of patients in clinical studies of TIKOSYN, 46% were 65 to 89 years old.
No overall differences in safety, effect on QTc, or effectiveness were observed between elderly and younger patients.
Because elderly patients are more likely to have decreased renal function with a reduced creatinine clearance, care must be taken in dose selection (see DOSAGE AND ADMINISTRATION ).
MECHANISM OF ACTION
Mechanism of Action 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, I Kr .
At concentrations covering several orders of magnitude, dofetilide blocks only I Kr with no relevant block of the other repolarizing potassium currents (e.g., I Ks , I K1 ).
At clinically relevant concentrations, dofetilide has no effect on sodium channels (associated with Class I effect), adrenergic alpha-receptors, or adrenergic beta-receptors.
INDICATIONS AND USAGE
Maintenance of Normal Sinus Rhythm (Delay in AF/AFl Recurrence) TIKOSYN is indicated for the maintenance of normal sinus rhythm (delay in time to recurrence of atrial fibrillation/atrial flutter [AF/AFl]) in patients with atrial fibrillation/atrial flutter of greater than one week duration who have been converted to normal sinus rhythm.
Because TIKOSYN can cause life threatening ventricular arrhythmias, it should be reserved for patients in whom atrial fibrillation/atrial flutter is highly symptomatic.
In general, antiarrhythmic therapy for atrial fibrillation/atrial flutter aims to prolong the time in normal sinus rhythm.
Recurrence is expected in some patients (see CLINICAL STUDIES ).
Conversion of Atrial Fibrillation/Flutter TIKOSYN is indicated for the conversion of atrial fibrillation and atrial flutter to normal sinus rhythm.
TIKOSYN has not been shown to be effective in patients with paroxysmal atrial fibrillation.
Pediatric Use The safety and effectiveness of TIKOSYN in children (<18 years old) has not been established.
Pregnancy Dofetilide has been shown to adversely affect in utero growth and survival of rats and mice when orally administered during organogenesis at doses of 2 or more mg/kg/day.
Other than an increased incidence of non-ossified 5 th metacarpal, and the occurrence of hydroureter and hydronephroses at doses as low as 1 mg/kg/day in the rat, structural anomalies associated with drug treatment were not observed in either species at doses below 2 mg/kg/day.
The clearest drug-effect associations were for sternebral and vertebral anomalies in both species; cleft palate, adactyly, levocardia, dilation of cerebral ventricles, hydroureter, hydronephroses, and unossified metacarpal in the rat; and increased incidence of unossified calcaneum in the mouse.
The “no observed adverse effect dose” in both species was 0.5 mg/kg/day.
The mean dofetilide AUCs (0–24hr) at this dose in the rat and mouse are estimated to be about equal to the maximum likely human AUC and about half the likely human AUC, respectively.
There are no adequate and well controlled studies in pregnant women.
Therefore, dofetilide should only be administered to pregnant women where the benefit to the patient justifies the potential risk to the fetus.
Nursing Mothers There is no information on the presence of dofetilide in breast milk.
Patients should be advised not to breast-feed an infant if they are taking TIKOSYN.
To minimize the risk of induced arrhythmia, patients initiated or re-initiated on TIKOSYN should be placed for a minimum of 3 days in a facility that can provide calculations of creatinine clearance, continuous electrocardiographic monitoring, and cardiac resuscitation.
For detailed instructions regarding dose selection, see DOSAGE AND ADMINISTRATION .
INFORMATION FOR PATIENTS
Information for Patients Please refer patient to the Medication Guide.
Prior to initiation of TIKOSYN therapy, the patient should be advised to read the Medication Guide and reread it each time therapy is renewed in case the patient’s status has changed.
The patient should be fully instructed on the need for compliance with the recommended dosing of TIKOSYN and the potential for drug interactions, and the need for periodic monitoring of QTc and renal function to minimize the risk of serious abnormal rhythms.
Medications and Supplements Assessment of patients’ medication history should include all over-the-counter, prescription, and herbal/natural preparations with emphasis on preparations that may affect the pharmacokinetics of TIKOSYN such as cimetidine (see CONTRAINDICATIONS ), trimethoprim alone or in combination with sulfamethoxazole (see WARNINGS , CONTRAINDICATIONS ), prochlorperazine (see WARNINGS , CONTRAINDICATIONS ), megestrol (see WARNINGS , CONTRAINDICATIONS ), ketoconazole (see WARNINGS , CONTRAINDICATIONS ), dolutegravir (see CONTRAINDICATIONS ), hydrochlorothiazide (alone or in combinations such as with triamterene) (see CONTRAINDICATIONS ), other cardiovascular drugs (especially verapamil – see CONTRAINDICATIONS ), phenothiazines, and tricyclic antidepressants (see WARNINGS ).
If a patient is taking TIKOSYN and requires anti-ulcer therapy, omeprazole, ranitidine, or antacids (aluminum and magnesium hydroxides) should be used as alternatives to cimetidine, as these agents have no effect on the pharmacokinetics of TIKOSYN.
Patients should be instructed to notify their health care providers of any change in over-the-counter, prescription, or supplement use.
If a patient is hospitalized or is prescribed a new medication for any condition, the patient must inform the health care provider of ongoing TIKOSYN therapy.
Patients should also check with their health care provider and/or pharmacist prior to taking a new over-the-counter preparation.
Electrolyte Imbalance If patients experience symptoms that may be associated with altered electrolyte balance, such as excessive or prolonged diarrhea, sweating, or vomiting or loss of appetite or thirst, these conditions should immediately be reported to their health care provider.
Dosing Schedule Patients should be instructed NOT to double the next dose if a dose is missed.
The next dose should be taken at the usual time.
DOSAGE AND ADMINISTRATION
Therapy with TIKOSYN must be initiated (and, if necessary, re-initiated) in a setting that provides continuous electrocardiographic (ECG) monitoring and in the presence of personnel trained in the management of serious ventricular arrhythmias.
Patients should continue to be monitored in this way for a minimum of three days.
Additionally, patients should not be discharged within 12 hours of electrical or pharmacological conversion to normal sinus rhythm.
The dose of TIKOSYN must be individualized according to calculated creatinine clearance and QTc.
(QT interval should be used if the heart rate is <60 beats per minute.
There are no data on use of TIKOSYN when the heart rate is <50 beats per minute.) The usual recommended dose of TIKOSYN is 500 mcg BID, as modified by the dosing algorithm described below.
For consideration of a lower dose, see Special Considerations below.
Serum potassium should be maintained within the normal range before TIKOSYN treatment is initiated and should be maintained within the normal range while the patient remains on TIKOSYN therapy.
(See WARNINGS, Hypokalemia and Potassium-Depleting Diuretics ).
In clinical trials, potassium levels were generally maintained above 3.6–4.0 mEq/L.
Patients with atrial fibrillation should be anticoagulated according to usual medical practice prior to electrical or pharmacological cardioversion.
Anticoagulant therapy may be continued after cardioversion according to usual medical practice for the treatment of people with AF.
Hypokalemia should be corrected before initiation of TIKOSYN therapy (see WARNINGS, Ventricular Arrhythmia ).
Patients to be discharged on TIKOSYN therapy from an inpatient setting as described above must have an adequate supply of TIKOSYN, at the patient’s individualized dose, to allow uninterrupted dosing until the patient can fill a TIKOSYN prescription.
Instructions for Individualized Dose Initiation Initiation of TIKOSYN Therapy Step 1.
Electrocardiographic assessment: Prior to administration of the first dose, the QTc or QT must be checked using an average of 5–10 beats.
If the QTc or QT is greater than 440 msec (500 msec in patients with ventricular conduction abnormalities), TIKOSYN is contraindicated.
If heart rate is less than 60 beats per minute, QT interval should be used.
Proceed to Step 2 if the QTc or QT is 440 msec.
Patients with heart rates <50 beats per minute have not been studied.
Calculation of creatinine clearance: Prior to the administration of the first dose, the patient’s creatinine clearance must be calculated using the following formula: creatinine clearance (male) = (140-age) × actual body weight in kg 72 × serum creatinine (mg/dL) creatinine clearance (female) = (140-age) × actual body weight in kg × 0.85 72 × serum creatinine (mg/dL) When serum creatinine is given in µmol/L, divide the value by 88.4 (1 mg/dL = 88.4 µmol/L).
Starting Dose: The starting dose of TIKOSYN is determined as follows: Calculated Creatinine Clearance TIKOSYN Dose >60 mL/min 500 mcg twice daily 40 to 60 mL/min 250 mcg twice daily 20 to <40 mL/min 125 mcg twice daily <20 mL/min Tikosyn is contraindicated in these patients Step 4.
Administer the adjusted TIKOSYN dose and begin continuous ECG monitoring.
At 2–3 hours after administering the first dose of Tikosyn, determine the QTc or QT (if heart rate is less than 60 beats per minute).
If the QTc or QT has increased by greater than 15% compared to the baseline established in Step 1 OR if the QTc or QT is greater than 500 msec (550 msec in patients with ventricular conduction abnormalities), subsequent dosing should be adjusted as follows: If the Starting Dose Based on Creatinine Clearance is: Then the Adjusted Dose (for QTc or QT Prolongation) is: 500 mcg twice daily 250 mcg twice daily 250 mcg twice daily 125 mcg twice daily 125 mcg twice daily 125 mcg once a day Step 6.
At 2–3 hours after each subsequent dose of Tikosyn, determine the QTc or QT (if heart rate is less than 60 beats per minute) (for in-hospital doses 2–5).
No further down titration of Tikosyn based on QTc or QT is recommended.
NOTE: If at any time after the second dose of Tikosyn is given the QTc or QT is greater than 500 msec (550 msec in patients with ventricular conduction abnormalities), Tikosyn should be discontinued.
Patients are to be continuously monitored by ECG for a minimum of three days, or for a minimum of 12 hours after electrical or pharmacological conversion to normal sinus rhythm, whichever is greater.
The steps described above are summarized in the following diagram: flow chart Maintenance of TIKOSYN Therapy Renal function and QTc or QT (if heart rate is less than 60 beats per minute) should be re-evaluated every three months or as medically warranted.
If QTc or QT exceeds 500 milliseconds (550 msec in patients with ventricular conduction abnormalities), TIKOSYN therapy should be discontinued and patients should be carefully monitored until QTc or QT returns to baseline levels.
If renal function deteriorates, adjust dose as described in Initiation of TIKOSYN Therapy , Step 3 .
Special Considerations Consideration of a Dose Lower than that Determined by the Algorithm The dosing algorithm shown above should be used to determine the individualized dose of TIKOSYN.
In clinical trials (see CLINICAL STUDIES ), the highest dose of 500 mcg BID of TIKOSYN as modified by the dosing algorithm led to greater effectiveness than lower doses of 125 or 250 mcg BID as modified by the dosing algorithm.
The risk of Torsade de Pointes, however, is related to dose as well as to patient characteristics (see WARNINGS ).
Physicians, in consultation with their patients, may therefore in some cases choose doses lower than determined by the algorithm.
It is critically important that if at any time this lower dose is increased, the patient needs to be rehospitalized for three days.
Previous toleration of higher doses does not eliminate the need for rehospitalization.
The maximum recommended dose in patients with a calculated creatinine clearance greater than 60 mL/min is 500 mcg BID; doses greater than 500 mcg BID have been associated with an increased incidence of Torsade de Pointes.
A patient who misses a dose should NOT double the next dose.
The next dose should be taken at the usual time.
Cardioversion If patients do not convert to normal sinus rhythm within 24 hours of initiation of TIKOSYN therapy, electrical conversion should be considered.
Patients continuing on TIKOSYN after successful electrical cardioversion should continue to be monitored by electrocardiography for 12 hours post cardioversion, or a minimum of 3 days after initiation of TIKOSYN therapy, whichever is greater.
Switch to TIKOSYN from Class I or other Class III Antiarrhythmic Therapy Before initiating TIKOSYN therapy, previous antiarrhythmic therapy should be withdrawn under careful monitoring for a minimum of three (3) plasma half-lives.
Because of the unpredictable pharmacokinetics of amiodarone, TIKOSYN should not be initiated following amiodarone therapy until amiodarone plasma levels are below 0.3 mcg/mL or until amiodarone has been withdrawn for at least three months.
Stopping TIKOSYN Prior to Administration of Potentially Interacting Drugs If TIKOSYN needs to be discontinued to allow dosing of other potentially interacting drug(s), a washout period of at least two days should be followed before starting the other drug(s).