FDA Label for Dofetilide

Boxed Warning

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

Dofetilide is an antiarrhythmic drug with Class III (cardiac action potential duration prolonging) properties. Its empirical formula is C ₁₉H ₂₇N ₃O ₅S ₂and it has a molecular weight of 441.6. The structural formula is

structural formula - chemstructure00001

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.

Dofetilide capsules contain the following inactive ingredients: microcrystalline cellulose, corn starch, colloidal silicon dioxide and magnesium stearate. The capsule shells contain gelatin, titanium dioxide, FD&C yellow 6 and black imprint ink. The black imprint ink contains shellac, alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, ammonia solution, black iron oxide and potassium hydroxide. Dofetilide capsules are 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.

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 _Krwith 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 bpm to 6 bpm in studies in patients.

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 msec/(ng/mL) to 25 msec/(ng/mL) after the first dose and approximately 10 msec/(ng/mL) 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

Figure 1 - graph001

Note: The range of dofetilide plasma concentrations achieved with the 500 mcg BID dose adjusted for creatinine clearance is 1 ng/mL 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.

Chronic Atrial Fibrillation And/Or Atrial Flutter

Two randomized, parallel, double-blind, placebo-controlled, dose-response trials evaluated the ability of dofetilide 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 hours to 36 hours.

Patients who did not convert to NSR with randomized therapy within 48 hours 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 months 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 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.

Figure 3: Maintenance of Normal Sinus Rhythm, Dofetilide Regimen vs. Placebo (Study 1)

Figure 3 - graph0003

The point estimates of the probabilities of remaining in NSR at 6 months 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 months 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 < 65 years and patients ≥ 65 years of age, and in both patients with atrial flutter as a primary diagnosis and those with a primary diagnosis of atrial fibrillation.

During the period of in-hospital initiation of dosing, 23% of patients in Studies 1 and 2 had their dose adjusted downward on the basis of their calculated creatinine clearance, and 3% had their dose down-titrated due to increased QT interval or QTc. Increased QT interval or QTc led to discontinuation of therapy in 3% of patients.

Safety In Patients With Structural Heart Disease: Diamond Studies (The Danish Investigations Of Arrhythmia And Mortality On Dofetilide)

The two DIAMOND studies were 3-year trials comparing the effects of dofetilide 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 dofetilide 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, dofetilide 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 dofetilide 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 CLINICAL STUDIES, DIAMOND Patients with Atrial Fibrillation).

In both DIAMOND studies, patients were randomized to 500 mcg BID of dofetilide, but this was reduced to 250 mcg BID if calculated creatinine clearance was 40 mL/min to 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.

DIAMONDCHFstudied 1,518 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 dofetilide (n = 762) and 317 deaths in patients randomized to placebo (n = 756). The probability of survival at one year was 73% (95% CI: 70% to 76%) in the dofetilide group and 72% (95% CI: 69% to 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 dofetilide. The majority of cases (76%) occurred within the first 3 days of dosing. In all, 437/762 (57%) of patients on dofetilide and 459/756 (61%) on placebo required hospitalization. Of these, 229/762 (30%) of patients on dofetilide and 290/756 (38%) on placebo required hospitalization because of worsening heart failure.

DIAMOND MIstudied 1,510 patients hospitalized with recent myocardial infarction (2 days to 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 dofetilide (n = 749) and 243 deaths in patients randomized to placebo (n = 761). The probability of survival at one year was 79% (95% CI: 76% to 82%) in the dofetilide group and 77% (95% CI: 74% to 80%) in the placebo group. Cardiac and arrhythmic mortality showed a similar result. Torsade de Pointes occurred in 7/749 patients (0.9%) receiving dofetilide. 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 dofetilide and 419/761 (55%) on placebo required hospitalization. Of these, 200/749 (27%) of patients on dofetilide 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 dofetilide and 257 randomized to placebo). DIAMOND AF patients randomized to dofetilide 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 dofetilide 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 dofetilide and 156/257 or 61% for placebo. Of these, readmission rates for worsening heart failure were 73/249 or 29% on dofetilide 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 dofetilide 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 dofetilide 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 dofetilide-treated patients (see ADVERSE REACTIONS), dofetilide, 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.

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.

Contraindications

Dofetilide is contraindicated in patients with congenital or acquired long QT syndromes. Dofetilide should not be used in patients with a baseline QT interval or QTc > 440 msec (500 msec in patients with ventricular conduction abnormalities). Dofetilide is 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 is 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.

The concomitant use of hydrochlorothiazide (alone or in combinations such as with triamterene) with dofetilide is contraindicated (see PRECAUTIONS, Drug-Drug Interactions) because this has been shown to significantly increase dofetilide plasma concentrations and QT interval prolongation.

Dofetilide is also contraindicated in patients with a known hypersensitivity to the drug.

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.

Renal Impairment

The overall systemic clearance of dofetilide is decreased and plasma concentration increased with decreasing creatinine clearance. The dose of dofetilide must be adjusted based on creatinine clearance (see DOSAGE AND ADMINISTRATION). Patients undergoing dialysis were not included in clinical studies, and appropriate dosing recommendations for these patients are unknown. There is no information about the effectiveness of hemodialysis in removing dofetilide from plasma.

Hepatic Impairment

After adjustment for creatinine clearance, no additional dose adjustment is required for patients with mild or moderate hepatic impairment. Patients with severe hepatic impairment have not been studied. Dofetilide should be used with particular caution in these patients.

Cardiac Conduction Disturbances

Animal and human studies have not shown any adverse effects of dofetilide on conduction velocity. No effect on AV nodal conduction following dofetilide-treatment was noted in normal volunteers and in patients with 1 ^stdegree heart block. Patients with sick sinus syndrome or with 2 ^ndor 3 ^rddegree heart block were not included in the Phase 3 clinical trials unless a functioning pacemaker was present. Dofetilide has been used safely in conjunction with pacemakers (53 patients in DIAMOND studies, 136 in trials in patients with ventricular and supraventricular arrhythmias).

Information For Patients

Please refer patient to the Medication Guide.

Prior to initiation of dofetilide 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 dofetilide 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.

Drug/Laboratory Test Interactions

None known.

Potential Drug Interactions

Dofetilide is eliminated in the kidney by cationic secretion. Inhibitors of renal cationic secretion are contraindicated with dofetilide. In addition, drugs that are actively secreted via this route (e.g., triamterene, metformin, and amiloride) should be co-administered with care as they might increase dofetilide levels.

Dofetilide is metabolized to a small extent by the CYP3A4 isoenzyme of the cytochrome P450 system. Inhibitors of the CYP3A4 isoenzyme could increase systemic dofetilide exposure. Inhibitors of this isoenzyme (e.g., macrolide antibiotics, azole antifungal agents, protease inhibitors, serotonin reuptake inhibitors, amiodarone, cannabinoids, diltiazem, grapefruit juice, nefazadone, norfloxacin, quinine, zafirlukast) should be cautiously co-administered with dofetilide as they can potentially increase dofetilide levels. Dofetilide is not an inhibitor of CYP3A4 nor of other cytochrome P450 isoenzymes (e.g., CYP2C9, CYP2D6) and is not expected to increase levels of drugs metabolized by CYP3A4.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Dofetilide had no genotoxic effects, with or without metabolic activation, based on the bacterial mutation assay and tests of cytogenetic aberrations in vivoin mouse bone marrow and in vitroin human lymphocytes. Rats and mice treated with dofetilide in the diet for two years showed no evidence of an increased incidence of tumors compared to controls. The highest dofetilide dose administered for 24 months was 10 mg/kg/day to rats and 20 mg/kg/day to mice. Mean dofetilide AUCs  _(0–24hr)at these doses were about 26 and 10 times, respectively, the maximum likely human AUC.

There was no effect on mating or fertility when dofetilide was administered to male and female rats at doses as high as 1.0 mg/kg/day, a dose that would be expected to provide a mean dofetilide AUC _(0–24hr)about 3 times the maximum likely human AUC. Increased incidences of testicular atrophy and epididymal oligospermia and a reduction in testicular weight were, however, observed in other studies in rats. Reduced testicular weight and increased incidence of testicular atrophy were also consistent findings in dogs and mice. The no effect doses for these findings in chronic administration studies in these 3 species (3, 0.1, and 6 mg/kg/day) were associated with mean dofetilide AUCs that were about 4, 1.3, and 3 times the maximum likely human AUC, respectively.

Pregnancy

Dofetilide has been shown to adversely affect in uterogrowth 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 ^thmetacarpal, 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 dofetilide.

Geriatric Use

Of the total number of patients in clinical studies of dofetilide, 46% were 65 years old 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).

Use In Women

Female patients constituted 32% of the patients in the placebo-controlled trials of dofetilide. As with other drugs that cause Torsade de Pointes, dofetilide was associated with a greater risk of Torsade de Pointes in female patients than in male patients. During the dofetilide clinical development program, the risk of Torsade de Pointes in females was approximately 3 times the risk in males. Unlike Torsade de Pointes, the incidence of other ventricular arrhythmias was similar in female patients receiving dofetilide and patients receiving placebo. Although no study specifically investigated this risk, in post-hoc analyses, no increased mortality was observed in females on dofetilide compared to females on placebo.

Pediatric Use

The safety and effectiveness of dofetilide in children (< 18 years old) has not been established.

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.

Overdosage

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 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 overdose was rare in clinical studies; there were two reported cases of dofetilide 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

• 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 < 60 beats per minute. There are no data on use of dofetilide when the heart rate is < 50 beats per minute.)The usual recommended dose of dofetilide is 500 mcg BID, as modified by the dosing algorithm described below. For consideration of a lower dose, see Special Considerationsbelow.
• Serum potassium should be maintained within the normal range before dofetilide treatment is initiated and should be maintained within the normal range while the patient remains on dofetilide therapy. (See WARNINGS, Hypokalemia and Potassium‑Depleting Diuretics). In clinical trials, potassium levels were generally maintained above 3.6 m Eq/L to 4.0 m Eq/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 therapy (see WARNINGS, Ventricular Arrhythmia).
• Patients to be discharged on dofetilide therapy from an inpatient setting as described above must have an adequate supply of dofetilide, at the patient’s individualized dose, to allow uninterrupted dosing until the patient can fill a dofetilide prescription.

Initiation Of Dofetilide Therapy

Step 1. Electrocardiographic assessment: Prior to administration of the first dose, the QTc or QT must be checked using an average of 5 beats to 10 beats. If the QTc or QT is greater than 440 msec (500 msec in patients with ventricular conduction abnormalities), dofetilide 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.

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:

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 is determined as follows:

Step 4.Administer the adjusted dofetilide dose and begin continuous ECG monitoring.

Step 5. At 2 hours to 3 hours after administering the firstdose of dofetilide, 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 ORif the QTc or QT is greater than 500 msec (550 msec in patients with ventricular conduction abnormalities), subsequent dosing should be adjusted as follows:

Step 6. At 2 hours to 3 hours after each subsequent dose of dofetilide, determine the QTc or QT (if heart rate is less than 60 beats per minute) (for in-hospital doses 2 to 5). No further down titration of dofetilide based on QTc or QT is recommended.

NOTE: If at any time after the second dose of dofetilide is given the QTc or QT is greater than 500 msec (550 msec in patients with ventricular conduction abnormalities), dofetilide 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:

Diagram - graph00005

Maintenance Of Dofetilide 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 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 Therapy, Step 3.

Switch To Dofetilide From Class I Or Other Class Iii Antiarrhythmic Therapy

Before initiating dofetilide 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 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 Prior To Administration Of Potentially Interacting Drugs

If dofetilide 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).

How Supplied

Dofetilide 125 mcg (0.125 mg) capsules are supplied as No. 4 capsules with opaque light orange cap and opaque white body, printed with '125 mcg' in black ink on body and "710" in black ink on cap and are available in:

Dofetilide 250 mcg (0.25 mg) capsules are supplied as No. 4 capsules with opaque peach cap and opaque peach body, printed with '250 mcg' in black ink on body and "711" in black ink on cap and are available in:

Dofetilide 500 mcg (0.5 mg) capsules are supplied as No. 2 capsules with opaque peach cap and opaque white body, printed with '500 mcg' in black ink on body and "712" in black ink on cap and are available in:

Store at controlled room temperature, 15° to 30°C (59° to 86°F).

PROTECT FROM MOISTURE AND HUMIDITY.

Dispense in tight containers (USP).

Rx Only

Distributed by: Bionpharma, Inc.
Princeton, NJ 08540

Made in India

948026787

Revised: 1/2023

Marketed by:

GSMS, Inc.

Camarillo, CA 93012 USA

Medication Guide

Package Label.Principal Display Panel

Package Label - Principal Display Panel – 125 mcg (0.125 mg) 60's Label

NDC 51407-541-60

Dofetilide Capsules

125 mcg (0.125 mg)

PHARMACIST: Dispense the enclosed Medication Guide to each patient.

Rx Only

60 Capsules

51407-541-60.jpg - 51407 541 60

Package Label - Principal Display Panel – 250 mcg (0.25 mg) 60's Label

NDC 51407-542-60

Dofetilide Capsules

250 mcg (0.25 mg)

PHARMACIST: Dispense the enclosed Medication Guide to each patient.

Rx Only

60 Capsules

Package Label - Principal Display Panel – 500 mcg (0.5 mg) 60's Label

NDC 51407-543-60

Dofetilide Capsules

500 mcg (0.5 mg)

PHARMACIST: Dispense the enclosed Medication Guide to each patient.

Rx Only

60 Capsules