dofetilide 0.5 MG Oral Capsule [Tikosyn]

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 capsules 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 capsules have not been shown to be effective in patients with paroxysmal atrial fibrillation.

DOSAGE AND ADMINISTRATION • Therapy with dofetilide capsules 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 dofetilide capsules 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 dofetilide capsules when the heart rate is <50 beats per minute.) The usual recommended dose of dofetilide capsules 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 dofetilide capsules treatment is initiated and should be maintained within the normal range while the patient remains on dofetilide capsules 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 dofetilide capsules therapy (see WARNINGS, Ventricular Arrhythmia ). • Patients to be discharged on dofetilide capsules therapy from an inpatient setting as described above must have an adequate supply of dofetilide capsules, at the patient's individualized dose, to allow uninterrupted dosing until the patient can fill a dofetilide capsules prescription. Instructions for Individualized Dose Initiation Initiation of Dofetilide Capsules 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), dofetilide capsules are 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. Step 2. 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). Step 3. Starting Dose: The starting dose of dofetilide capsules is determined as follows: Calculated Creatinine Clearance Dofetilide Capsules 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 Dofetilide capsules are contraindicated in these patients Step 4. Administer the adjusted dofetilide capsules dose and begin continuous ECG monitoring. Step 5. At 2-3 hours after administering the first dose of dofetilide capsules, 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 dofetilide capsules, 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 dofetilide capsules based on QTc or QT is recommended. NOTE: If at any time after the second dose of dofetilide capsules is given the QTc or QT is greater than 500 msec (550 msec in patients with ventricular conduction abnormalities), dofetilide capsules should be discontinued. Step 7. 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: Figure Maintenance of Dofetilide Capsules 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), dofetilide capsules 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 Dofetilide Capsules 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 dofetilide capsules. In clinical trials (see CLINICAL STUDIES ), the highest dose of 500 mcg BID of dofetilide capsules 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 dofetilide capsules therapy, electrical conversion should be considered. Patients continuing on dofetilide capsules 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 dofetilide capsules therapy, whichever is greater. Switch to Dofetilide Capsules from Class I or other Class III Antiarrhythmic Therapy Before initiating dofetilide capsules 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, dofetilide capsules 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 Dofetilide Capsules Prior to Administration of Potentially Interacting Drugs If dofetilide capsules need 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).

WARNINGS Ventricular Arrhythmia Dofetilide capsules 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 capsules-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 capsules 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 Capsules Dose <250 mcg BID 250 mcg BID >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 Population: Total Before After 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 dofetilide capsules 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 dofetilide capsules 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 capsules/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 dofetilide capsules 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 dofetilide capsules was 31% vs. 32% on placebo (see CLINICAL STUDIES ). Because of the small number of events, an excess mortality due to dofetilide capsules 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 capsules-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 capsules and maintained in the normal range during administration of dofetilide capsules (see DOSAGE AND ADMINISTRATION ). Use with Drugs that Prolong QT Interval and Antiarrhythmic Agents The use of dofetilide capsules 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 capsules. In clinical trials, dofetilide capsules were 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.

CONTRAINDICATIONS Dofetilide capsules are contraindicated in patients with congenital or acquired long QT syndromes. Dofetilide capsules should not be used in patients with a baseline QT interval or QTc >440 msec (500 msec in patients with ventricular conduction abnormalities). Dofetilide capsules are also contraindicated in patients with severe renal impairment (calculated creatinine clearance <20 mL/min). The concomitant use of verapamil or the cation transport system inhibitors cimetidine, trimethoprim (alone or in combination with sulfamethoxazole), or ketoconazole with dofetilide capsules are contraindicated (see WARNINGS and PRECAUTIONS , Drug-Drug Interactions ), as each of these drugs cause a substantial increase in dofetilide plasma concentrations. In addition, other known inhibitors of the renal cation transport system such as prochlorperazine, dolutegravir and megestrol should not be used in patients on dofetilide capsules. The concomitant use of hydrochlorothiazide (alone or in combinations such as with triamterene) with dofetilide capsules are contraindicated (see PRECAUTIONS , Drug-Drug Interactions ) because this has been shown to significantly increase dofetilide plasma concentrations and QT interval prolongation. Dofetilide capsules are also contraindicated in patients with a known hypersensitivity to the drug.

CLINICAL PHARMACOLOGY 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. Electrophysiology 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. Dofetilide 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, dofetilide 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 dofetilide therapy in patients with atrial fibrillation. There was no increase in heart failure in patients with significant left ventricular dysfunction (see CLINICAL STUDIES, Safety in Patients with Structural Heart Disease, DIAMOND Studies ). In the overall clinical program, dofetilide did not affect blood pressure. Heart rate was decreased by 4 to 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 to 3 hours in the fasted state. Oral bioavailability is unaffected by food or antacid. The terminal half-life of dofetilide is approximately 10 hours; steady state plasma concentrations are attained within 2 to 3 days, with an accumulation index of 1.5 to 2.0. Plasma concentrations are dose proportional. Plasma protein binding of dofetilide is 60 to 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, ketoconazole and dolutegravir). In vitro studies 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 N-oxidation. 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 to 18% lower dofetilide oral clearances than men (14 to 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 to 25 msec/(ng/mL) after the first dose and approximately 10 to 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 to 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 dofetilide 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 dofetilide. Note that in these studies, doses were modified by results of creatinine clearance measurement and in-hospital QTc prolongation. Figure 2: Relationship Between Dofetilide Dose, QTc Increase and Maintenance of NSR Number of patients evaluated for maintenance of NSR: 503 dofetilide, 174 placebo. Number of patients evaluated for QTc change: 478 dofetilide, 167 placebo. dof