Generic: DOFETILIDE
Antiarrhythmic [EPC]
INDICATIONS AND USAGE Maintenance of Normal Sinus Rhythm (Delay in AF/AFl Recurrence) Dofetilide capsules are 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 dofetilide can cause life threatening ventricular arrhythmias, it should be reserved for patients in whom atrial fibri...
INDICATIONS AND USAGE Maintenance of Normal Sinus Rhythm (Delay in AF/AFl Recurrence) Dofetilide capsules are 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 dofetilide 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 Dofetilide capsules are indicated for the conversion of atrial fibrillation and atrial flutter to normal sinus rhythm. Dofetilide has not been shown to be effective in patients with paroxysmal atrial fibrillation.
WARNINGS 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 plasm...
WARNINGS 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. 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 Total Before After Population 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 โค 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.
ADVERSE REACTIONS The dofetilide clinical program involved approximately 8,600 patients in 130 clinical studies of normal volunteers and patients with supraventricular and ventricular arrhythmias. Dofetilide was administered to 5,194 patients, including two large, placebo-controlled mortality trials (DIAMOND CHF and DIAMOND MI) in which 1,511 patients received dofetilide for up to three years. In the following section, adverse reaction data for cardiac arrhythmias and non-cardiac adverse reactio...
ADVERSE REACTIONS The dofetilide clinical program involved approximately 8,600 patients in 130 clinical studies of normal volunteers and patients with supraventricular and ventricular arrhythmias. Dofetilide was administered to 5,194 patients, including two large, placebo-controlled mortality trials (DIAMOND CHF and DIAMOND MI) in which 1,511 patients received dofetilide for up to three years. In the following section, adverse reaction data for cardiac arrhythmias and non-cardiac adverse reactions are presented separately for patients included in the supraventricular arrhythmia development program and for patients included in the DIAMOND CHF and MI mortality trials (see CLINICAL STUDIES, Safety in Patients with Structural Heart Disease, DIAMOND Studies , for a description of these trials). In studies of patients with supraventricular arrhythmias, a total of 1,346 and 677 patients were exposed to dofetilide and placebo for 551 and 207 patient years, respectively. A total of 8.7% of patients in the dofetilide groups were discontinued from clinical trials due to adverse events compared to 8.0% in the placebo groups. The most frequent reason for discontinuation (> 1%) was ventricular tachycardia (2.0% on dofetilide vs. 1.3% on placebo). The most frequent adverse events were headache, chest pain, and dizziness. Serious Arrhythmias and Conduction Disturbances : Torsade de Pointes is the only arrhythmia that showed a dose-response relationship to dofetilide treatment. It did not occur in placebo treated patients. The incidence of Torsade de Pointes in patients with supraventricular arrhythmias was 0.8% (11/1,346) (see WARNINGS ). The incidence of Torsade de Pointes in patients who were dosed according to the recommended dosing regimen (see DOSAGE AND ADMINISTRATION ) was 0.8% (4/525). Table 6 shows the frequency by randomized dose of serious arrhythmias and conduction disturbances reported as adverse events in patients with supraventricular arrhythmias. Table 6: Incidence of Serious Arrhythmias and Conduction Disturbances in Patients with Supraventricular Arrhythmias Dofetilide Dose Placebo Arrhythmia event: < 250 mcg BID N = 217 250 mcg BID N = 388 > 250-500 mcg BID N = 703 > 500 mcg BID N = 38 N = 677 Ventricular Arrhythmias Patients with more than one arrhythmia are counted only once in this category. Ventricular arrhythmias and ventricular tachycardia include all cases of Torsade de Pointes. 3.7 % 2.6 % 3.4 % 15.8 % 2.7 % Ventricular fibrillation 0 0.3 % 0.4 % 2.6 % 0.1 % Ventricular tachycardia โ 3.7 % 2.6 % 3.3 % 13.2 % 2.5 % Torsade de Pointes 0 0.3 % 0.9 % 10.5 % 0 Various forms of block AV block 0.9 % 1.5 % 0.4 % 0 0.3 % (Left) bundle branch block 0 0.5 % 0.1 % 0 0.1 % Heart block 0 0.5 % 0.1 % 0 0.1 % In the DIAMOND trials, a total of 1,511 patients were exposed to dofetilide for 1,757 patient years. The incidence of Torsade de Pointes was 3.3% in CHF patients and 0.9% in patients with a recent MI. Table 7 shows the incidence of serious arrhythmias and conduction disturbances reported as adverse events in the DIAMOND subpopulation that had AF at entry to these trials. Table 7: Incidence of Serious Arrhythmias and Conduction Disturbances in Patients with AF at Entry to the DIAMOND Studies Dofetilide Placebo N = 249 N = 257 Ventricular arrhythmias Patients with more than one arrhythmia are counted only once in this category. Ventricular arrhythmias and ventricular tachycardia include all cases of Torsade de Pointes. 14.5 % 13.6 % Ventricular fibrillation 4.8 % 3.1 % Ventricular tachycardia โ 12.4 % 11.3 % Torsade de Pointes 1.6 % 0 Various forms of block AV block 0.8 % 2.7 % (Left) bundle branch block 0 0.4 % Heart block 1.2 % 0.8 % Other Adverse Reactions: Table 8 presents other adverse events reported with a frequency of > 2% on dofetilide and reported numerically more frequently on dofetilide than on placebo in the studies of patients with supraventricular arrhythmias. Table 8: Frequency of Adverse Events Occurring at > 2% on Dofetilide, and Numerically More Frequently on Dofetilide than Placebo in Patients with Supraventricular Arrhythmias Dofetilide Placebo Adverse Event % % headache 11 9 chest pain 10 7 dizziness 8 6 respiratory tract infection 7 5 dyspnea 6 5 nausea 5 4 flu syndrome 4 2 insomnia 4 3 accidental injury 3 1 back pain 3 2 procedure (medical/surgical/health service) 3 2 diarrhea 3 2 rash 3 2 abdominal pain 3 2 Adverse events reported at a rate > 2% but no more frequently on dofetilide than on placebo were: angina pectoris, anxiety, arthralgia, asthenia, atrial fibrillation, complications (application, injection, incision, insertion, or device), hypertension, pain, palpitation, peripheral edema, supraventricular tachycardia, sweating, urinary tract infection, ventricular tachycardia. The following adverse events have been reported with a frequency of โค 2% and numerically more frequently with dofetilide than placebo in patients with supraventricular arrhythmias: angioedema, bradycardia, cerebral ischemia, cerebrovascular accident, edema, facial paralysis, flaccid paralysis, heart arrest, increased cough, liver damage, migraine, myocardial infarct, paralysis, paresthesia, sudden death, and syncope. The incidences of clinically significant laboratory test abnormalities in patients with supraventricular arrhythmias were similar for patients on dofetilide and those on placebo. No clinically relevant effects were noted in serum alkaline phosphatase, serum GGT, LDH, AST, ALT, total bilirubin, total protein, blood urea nitrogen, creatinine, serum electrolytes (calcium, chloride, glucose, magnesium, potassium, sodium), or creatine kinase. Similarly, no clinically relevant effects were observed in hematologic parameters. In the DIAMOND population, adverse events other than those related to the post-infarction and heart failure patient population were generally similar to those seen in the supraventricular arrhythmia groups.
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