Dofetilide Capsules

BOXED WARNING SECTION

BOXED WARNING SECTION

To minimize the risk of induced arrhythmia, patients initiated or re-initiated on dofetilide capsules 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 .

DESCRIPTION

DESCRIPTION SECTION

Dofetilide is an antiarrhythmic drug with Class III (cardiac action potential duration prolonging) properties. Its molecular 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 USP 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. Dofetilide capsules contain the following inactive ingredients: silicified microcrystalline cellulose, corn starch and magnesium stearate. The components of the hard gelatin capsule shell include gelatin, FD&C Yellow 6 and titanium dioxide. Black imprinting ink contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, black iron oxide, potassium hydroxide and purified water. Dofetilide capsule is supplied for oral administration in three dosage strengths: 125 mcg (0.125 mg) light orange and white capsules, 250 mcg (0.25 mg) peach capsules, and 500 mcg (0.5 mg) peach and white capsules.

CLINICAL PHARMACOLOGY

CLINICAL PHARMACOLOGY SECTION

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 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.

CLINICAL STUDIES

CLINICAL STUDIES SECTION

Chronic Atrial Fibrillation and/or Atrial Flutter Two randomized, parallel, double-blind, placebo-controlled, dose-response trials evaluated the ability of dofetilide 1) to convert patients with atrial fibrillation or atrial flutter (AF/AFl) of more than 1 week duration to normal sinus rhythm (NSR) and 2) to maintain NSR (delay time to recurrence of AF/AFl) after drug-induced or electrical cardioversion. A total of 996 patients with a one week to two year history of atrial fibrillation/atrial flutter were enrolled. Both studies randomized patients to placebo or to doses of dofetilide 125 mcg, 250 mcg, 500 mcg, or in one study a comparator drug, given twice a day (these doses were lowered based on calculated creatinine clearance and, in one of the studies, for QT interval or QTc). All patients were started on therapy in a hospital where their ECG was monitored (see DOSAGE AND ADMINISTRATION). Patients were excluded from participation if they had had syncope within the past 6 months, AV block greater than first degree, MI or unstable angina within 1 month, cardiac surgery within 2 months, history of QT interval prolongation or polymorphic ventricular tachycardia associated with use of antiarrhythmic drugs, QT interval or QTc >440 msec, serum creatinine >2.5 mg/mL, significant diseases of other organ systems; used cimetidine; or used drugs known to prolong the QT interval. Both studies enrolled mostly Caucasians (over 90%), males (over 70%), and patients ≥65 years of age (over 50%). Most (>90%) were NYHA Functional Class I or II. Approximately one-half had structural heart disease (including ischemic heart disease, cardiomyopathies, and valvular disease) and about one-half were hypertensive. A substantial proportion of patients were on concomitant therapy, including digoxin (over 60%), diuretics (over 20%), and ACE inhibitors (over 30%). About 90% were on anticoagulants. Acute conversion rates are shown in Table 1 for randomized doses (doses were adjusted for calculated creatinine clearance and, in Study 1, for QT interval or QTc). Of patients who converted pharmacologically, approximately 70% converted within 24 to 36 hours. Table 1: Conversion of Atrial Fibrillation/Flutter to Normal Sinus Rhythm Dofetilide Dose 125 mcg BID 250 mcg BID 500 mcg BID Placebo Study 1 5/82(6%) 8/82(10%) 23/77(30%) 1/84(1%) Study 2 8/135(6%) 14/133(11%) 38/129(29%) 2/137(1%) Patients who did not convert to NSR with randomized therapy within 48 to 72 hours had electrical cardioversion. Those patients remaining in NSR after conversion in hospital were continued on randomized therapy as outpatients (maintenance period) for up to one year unless they experienced a recurrence of atrial fibrillation/atrial flutter or withdrew for other reasons. Table 2 shows, by randomized dose, the percentage of patients at 6 and 12 months in both studies who remained on treatment in NSR and the percentage of patients who withdrew because of recurrence of AF/AFl or adverse events. Table 2: Patient Status at 6 and 12 Months Post Randomization Dofetilide Dose Placebo 125 mcg BID 250 mcg BID 500 mcg BID Study 1 Randomized 82 82 77 84 Achieved NSR 60 61 61 68 6 months Still on treatment in NSR 38% 44% 52% 32% D/C for recurrence 55% 49% 33% 63% D/C for AEs 3% 3% 8% 4% 12 months Still on treatment in NSR 32% 26% 46% 22% D/C for recurrence 58% 57% 36% 72% D/C for AEs 7% 11% 8% 6% Study 2 Randomized 135 133 129 137 Achieved NSR 103 118 100 106 6 months Still on treatment in NSR 41% 49% 57% 22% D/C for recurrence 48% 42% 27% 72% D/C for AEs 9% 6% 10% 4% 12 months Still on treatment in NSR 25% 42% 49% 16% D/C for recurrence 59% 47% 32% 76% D/C for AEs 11% 6% 12% 5% Note that columns do not add up to 100% due to discontinuations for “other” reasons. Table 3 and Figures 3 and 4 show, by randomized dose, the effectiveness of dofetilide in maintaining NSR using Kaplan Meier analysis, which shows patients remaining on treatment. Table 3: P-Values and Median Time (days) to Recurrence of AF/AFl Dofetilide Dose Placebo 125 mcg BID 250 mcg BID 500 mcg BID Study 1 p-value vs. placebo P=0.21 P=0.10 P365 27 Study 2 p-value vs. placebo P=0.006 P365 34 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 dofetilide 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, Dofetilide Regimen vs. Placebo (Study 1) The point estimates of the probabilities of remaining in NSR at 6 and 12 months were 62% and 58%, respectively, for dofetilide 500 mcg BID; 50% and 37%, respectively, for dofetilide 250 mcg BID; and 37%, and 25%, respectively, for placebo. Figure 4: Maintenance of Normal Sinus Rhythm, Dofetilide Regimen vs. Placebo (Study 2) The point estimates of the probabilities of remaining in NSR at 6 and 12 months were 71% and 66%, respectively, for dofetilide 500 mcg BID; 56% and 51%, respectively, for dofetilide 250 mcg BID; and 26% and 21%, respectively, for placebo. In both studies, dofetilide resulted in a dose-related increase in the number of patients maintained in NSR at all time periods and delayed the time of recurrence of sustained AF. Data pooled from both studies show that there is a positive relationship between the probability of staying in NSR, dofetilide dose, and increase in QTc (see Figure 2 in CLINICAL PHARMACOLOGY, Dose-Response and Concentration Response for Increase in QT Interval ). Analysis of pooled data for patients randomized to a dofetilide dose of 500 mcg twice daily showed that maintenance of NSR was similar in both males and females, in both patients aged 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

INDICATIONS AND USAGE

INDICATIONS & USAGE SECTION

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

CONTRAINDICATIONS

CONTRAINDICATIONS SECTION

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

WARNINGS

WARNINGS SECTION

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-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 to 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 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 and 0.4% (3/677) in the placebo group. Adjusted for duration of therapy, primary diagnosis, age, gender, and prevalence of structural heart disease, the point estimate of the hazard ratio for the pooled studies (dofetilide/placebo) was 1.1 (95% CI: 0.3, 4.3). The DIAMOND CHF and MI trials examined mortality in patients with structural heart disease (ejection fraction ≤35%). In these large, double-blind studies, deaths occurred in 36% (541/1511) of dofetilide 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 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.

PRECAUTIONS

PRECAUTIONS SECTION

ADVERSE REACTIONS

ADVERSE REACTIONS SECTION

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% (11/1346) (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 * 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. Dofetilide Dose Placebo Arrhythmia event: 250 to 500 mcg BID N=703 >500 mcg BID N=38 N=677 Ventricular arrhythmias *^ 3.7% 2.6% 3.4% 15.8% 2.7% Ventricular fibrillation 0 0.3% 0.4% 2.6% 0.1% Ventricular tachycardia^ 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% 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 1757 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*^ 14.5% 13.6% Ventricular fibrillation 4.8% 3.1% Ventricular tachycardia^ 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% * 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. 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 < 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.

OVERDOSAGE

OVERDOSAGE SECTION

There is no known antidote to dofetilide; 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 dofetilide capsule 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. Dofetilide capsule overdose was rare in clinical studies; there were two reported cases of dofetilide capsule 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).

DOSAGE AND ADMINISTRATION

DOSAGE & ADMINISTRATION SECTION

Therapy with dofetilide 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 must be individualized according to calculated creatinine clearance and QTc. (QT interval should be used if the heart rate is

HOW SUPPLIED

HOW SUPPLIED SECTION

Dofetilide capsules 125 mcg (0.125 mg) are supplied as hard gelatin capsule, size "4", light orange colored cap and white colored body, imprinted with '598' on cap and body in black ink, and are available in: Bottles of 60 NDC 72603-130-01 Dofetilide capsules 250 mcg (0.25 mg) are supplied as hard gelatin capsule, size "4", peach colored cap and body, imprinted with '505' on cap and body in black ink, and are available in: Bottles of 60 NDC 72603-131-01 Dofetilide capsules 500 mcg (0.5 mg) are supplied as hard gelatin capsule, size "2", peach colored cap and white colored body, imprinted with '504' on cap and body in black ink, and are available in: Bottles of 60 NDC 72603-132-01 Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [see USP Controlled Room Temperature]. PROTECT FROM MOISTURE AND HUMIDITY. Dispense in tight containers (USP). Medication guides available at www.northstarrxllc.com/products or call 1-800-206-7821

MEDICATION GUIDE

SPL MEDGUIDE SECTION

Dofetilide (doe-FET-i-lide) Capsules Read the Medication Guide before you start taking dofetilide capsules and each time you get a refill. This information does not take the place of talking with your doctor about your condition or treatment. What is the most important information I should know about dofetilide capsules? Dofetilide capsules can cause serious side effects, including a type of abnormal heartbeat called Torsade de Pointes, which can lead to death. To establish the right dose of dofetilide capsules, treatment with dofetilide capsules must be started in a hospital where your heart rate and kidney function will be checked for the first 3 days of treatment. It is important that when you go home, you take the exact dose of dofetilide capsules that your doctor prescribed for you. While you take dofetilide capsules, always watch for signs of abnormal heartbeat. Call your doctor and go to the hospital right away if you: feel faint become dizzy, or have a fast heartbeat What is dofetilide capsule? Dofetilide capsule is a prescription medicine that is used to treat an irregular heartbeat (atrial fibrillation or atrial flutter). It is not known if dofetilide capsules are safe and effective in children under 18 years of age. Who should not take dofetilide capsules? Do not take dofetilide capsules if you: have an irregular heartbeat called long QT syndrome have kidney problems or are on kidney dialysis take any of these medicines: cimetidine (TAGAMET, TAGAMET HB)* verapamil (CALAN, CALAN SR, COVERA-HS, ISOPTIN, ISOPTIN SR, VERELAN, VERELAN PM, TARKA)* ketoconazole (NIZORAL, XOLEGEL, EXTINA)* trimethoprim alone (PROLOPRIM, TRIMPEX)* or the combination of trimethoprim and sulfamethoxazole (BACTRIM, SEPTRA SULFATRIM)* prochlorperazine (COMPAZINE, COMPO)* megestrol (MEGACE)* dolutegravir (TIVICAY)* hydrochlorothiazide alone or in combination with other medicines (such as ESIDRIX, EZIDE, HYDRODIURIL, HYDRO-PAR, MICROZIDE, or ORETIC)* Ask your doctor if you are not sure if any of your medicines are the kind listed above. are allergic to dofetilide in dofetilide capsules. See the end of this leaflet for a complete list of ingredients in dofetilide capsules. What should I tell my doctor before taking dofetilide capsules? Before taking dofetilide capsules, tell your doctor about all of your medical conditions including if you: have heart problems have kidney or liver problems are pregnant or plan to become pregnant. It is not known if dofetilide capsules will harm your unborn baby. are breast-feeding or plan to breast-feed. It is not known if dofetilide passes into your breast milk. You and your doctor should decide if you will take dofetilide capsules or breast-feed. You should not do both. Especially tell your doctor if you take medicines to treat: heart problems high blood pressure depression or other mental problems asthma allergies, or hay fever skin problems infections Ask your doctor if you are not sure about the medicines you take. Tell your doctor about all prescription and non-prescription medicines, vitamins, dietary supplements, and any natural or herbal remedies. Dofetilide capsules and other medicines may affect each other, causing serious side effects. If you take dofetilide capsules with certain medicines, you will be more likely to have a different type of abnormal heartbeat. See “Who should not take dofetilide capsules?” Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine. How should I take dofetilide capsules? Take dofetilide capsules exactly as your doctor tells you. Do not change your dofetilide capsules dose unless your doctor tells you to. Your doctor will do tests before you start and while you take dofetilide capsules. Do not stop taking dofetilide capsules until your doctor tells you to stop. If you miss a dose, just take the next dose at your regular time. Do not take 2 doses of dofetilide capsules at the same time. Dofetilide capsules can be taken with or without food. If you take too many dofetilide capsules, call your doctor or go to the nearest hospital emergency room right away. Take your dofetilide capsules with you to show to the doctor. What are the possible side effects of dofetilide capsules? Dofetilide capsules can cause serious side effects, including a type of abnormal heartbeat called Torsade de Pointes, which can lead to death. See “What is the most important information I should know about dofetilide capsules?” The most common side effects of dofetilide capsules include: headache chest pain dizziness Call your doctor right away if you have signs of electrolyte imbalance: severe diarrhea unusual sweating vomiting not hungry (loss of appetite) increased thirst (drinking more than normal) Tell your doctor if you have any side effects that bother you or do not go away. These are not all the possible side effects of dofetilide capsules. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store dofetilide capsules? Store dofetilide capsules at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F). Keep dofetilide capsules away from moisture and humidity. Keep dofetilide capsules in a tightly closed container. Keep dofetilide capsules and all medicines out of the reach of children. General information about dofetilide capsules Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use dofetilide capsules for a condition for which it was not prescribed. Do not give dofetilide capsules to other people, even if they have the same symptoms you have. It may harm them. This Medication Guide summarizes the most important information about dofetilide capsules. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about dofetilide capsules that is written for health professionals. For more about dofetilide capsules, call NorthStar Rx LLC at 1-800-206-7821 What are the ingredients in dofetilide capsules? Active ingredient : dofetilide Inactive ingredients: Capsule fill: silicified microcrystalline cellulose, corn starch and magnesium stearate. Capsule shell: gelatin, FD&C Yellow 6 and titanium dioxide Imprinting ink: shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, black iron oxide, potassium hydroxide and purified water Medication guides available at www.northstarrxllc.com/products or call 1-800-206-7821 * Listed trademarks are the property of their respective owners. Manufactured for: NorthStar Rx LLC Memphis, TN 38141. Manufactured by: Sun Pharmaceutical Industries Ltd. Survey No. 1012, Dadra-396 193, U.T. of D & NH and Daman & Diu, India. 5246128 ISS: 10/2023 This Medication Guide has been approved by the U.S. Food and Drug Administration.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 0.125 mg label

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

Rx only NDC 72603-130-01 Dofetilide Capsules 125 mcg (0.125 mg) PHARMACIST: Dispense with Medication Guide provided separately to each patient. 60 Capsules

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 0.25 mg label

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

Rx only NDC 72603-131-01 Dofetilide Capsules 250 mcg (0.25 mg) PHARMACIST: Dispense with Medication Guide provided separately to each patient. 60 Capsules

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 0.5 mg label

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

Rx only NDC 72603-132-01 Dofetilide Capsules 500 mcg (0.5 mg) PHARMACIST: Dispense with Medication Guide provided separately to each patient. 60 Capsules