Dofetilide

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 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 …

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.

ADVERSE REACTIONS The dofetilide capsules clinical program involved approximately 8,600 patients in 130 clinical studies of normal volunteers and patients with supraventricular and ventricular arrhythmias. Dofetilide capsules were administered to 5,194 patients, including two large, placebo-controlled mortality trials (DIAMOND CHF and DIAMOND MI) in which 1,511 patients received dofetilide capsules 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 capsules 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 capsules 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 Dofetilide Capsules Dose Placebo Arrhythmia event: 250–500 mcg BID N=703 >500 mcg BID N=38 N=677 Ventricular arrhythmias Patients with more than one arrhythmia are counted only once in this category. Ventricular arrhythmias and ventricular tachycardia include all cases of Torsade de Pointes. 3.7% 2.6% 3.4% 15.8% 2.7% Ventricular fibrillation 0 0.3% 0.4% 2.6% 0.1% Ventricular tachycardia 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 capsules 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 Capsules Placebo N=249 N=257 Ventricular arrhythmias Patients with more than one arrhythmia are counted only once in this category. Ventricular arrhythmias and ventricular tachycardia include all cases of Torsade de Pointes. 14.5% 13.6% Ventricular fibrillation 4.8% 3.1% Ventricular tachycardia 12.4% 11.3% Torsade de Pointes 1.6% 0 Various forms of block AV block 0.8% 2.7% (Left) bundle branch block 0 0.4% Heart block 1.2% 0.8% Other Adverse Reactions Table 8 presents other adverse events reported with a frequency of >2% on dofetilide capsules and reported numerically more frequently on dofetilide capsules than on placebo in the studies of patients with supraventricular arrhythmias. Table 8: Frequency of Adverse Events Occurring at >2% on Dofetilide Capsule …

Drug-Drug Interactions Cimetidine: (see WARNINGS , CONTRAINDICATIONS ) Concomitant use of cimetidine is contraindicated. Cimetidine at 400 mg BID (the usual prescription dose) co-administered with dofetilide (500 mcg BID) for 7 days has been shown to increase dofetilide plasma levels by 58%. Cimetidine at doses of 100 mg BID (OTC dose) resulted in a 13% increase in dofetilide plasma levels (500 mcg single dose). No studies have been conducted at intermediate doses of cimetidine. If a patient requires dofetilide and anti-ulcer therapy, it is suggested that omeprazole, ranitidine, or antacids (aluminum and magnesium hydroxides) be used as alternatives to cimetidine, as these agents have no effect on the pharmacokinetic profile of dofetilide. Verapamil: (see CONTRAINDICATIONS ) Concomitant use of verapamil is contraindicated. Co-administration of dofetilide with verapamil resulted in increases in dofetilide peak plasma levels of 42%, although overall exposure to dofetilide was not significantly increased. In an analysis of the supraventricular arrhythmia and DIAMOND patient populations, the concomitant administration of verapamil with dofetilide was associated with a higher occurrence of Torsade de Pointes. Ketoconazole: (see WARNINGS , CONTRAINDICATIONS ) Concomitant use of ketoconazole is contraindicated. Ketoconazole at 400 mg daily (the maximum approved prescription dose) co-administered with dofetilide (500 mcg BID) for 7 days has been shown to increase dofetilide C max by 53% in males and 97% in females, and AUC by 41% in males and 69% in females. Trimethoprim Alone or in Combination with Sulfamethoxazole: (see WARNINGS , CONTRAINDICATIONS ) Concomitant use of trimethoprim alone or in combination with sulfamethoxazole is contraindicated. Trimethoprim 160 mg in combination with 800 mg sulfamethoxazole co-administered BID with dofetilide (500 mcg BID) for 4 days has been shown to increase dofetilide AUC by 103% and C max by 93%. Hydrochlorothiazide (HCTZ) Alone or in Combination with Triamterene: (see CONTRAINDICATIONS ) Concomitant use of HCTZ alone or in combination with triamterene is contraindicated. HCTZ 50 mg QD or HCTZ/triamterene 50/100 mg QD was co-administered with dofetilide (500 mcg BID) for 5 days (following 2 days of diuretic use at half dose). In patients receiving HCTZ alone, dofetilide AUC increased by 27% and C max by 21%. However, the pharmacodynamic effect increased by 197% (QTc increase over time) and by 95% (maximum QTc increase). In patients receiving HCTZ in combination with triamterene, dofetilide AUC increased by 30% and C max by 16%. However, the pharmacodynamic effect increased by 190% (QTc increase over time) and by 84% (maximum QTc increase). The pharmacodynamic effects can be explained by a combination of the increase in dofetilide exposure and the reductions in serum potassium. In the DIAMOND trials, 1252 patients were treated with dofetilide and diuretics concomitantly, of whom 493 died compared to 508 deaths among the 1248 patients receiving placebo and diuretics. Of the 229 patients who had potassium depleting diuretics added to their concomitant medications in the DIAMOND trials, the patients on dofetilide had a non-significantly reduced relative risk for death of 0.68 (95% CI: 0.376, 1.230). 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, grapefru …

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.

DESCRIPTION Dofetilide is an antiarrhythmic drug with Class III (cardiac action potential duration prolonging) properties. Its empirical formula is C 19 H 27 N 3 O 5 S 2 and it has a molecular weight of 441.6. The structural formula is The chemical name for dofetilide is: N -[4-[2-[methyl[2-[4-[(methylsulfonyl)amino]phenoxy]ethyl]amino]ethyl]phenyl]methanesulfonamide. Dofetilide is a white to off-white powder. It is very slightly soluble in water and propan-2-ol and is soluble in 0.1M aqueous sodium hydroxide, acetone, and aqueous 0.1M hydrochloric acid. Dofetilide Capsules contain the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, silicon dioxide, magnesium stearate, anhydrous citric acid and copovidone. Dofetilide Capsules are supplied for oral administration in three dosage strengths: 125 mcg (0.125 mg) opaque orange capsules, 250 mcg (0.25 mg) opaque peach and white capsules, and 500 mcg (0.5 mg) opaque peach capsules. The capsule shell contains FD&C Red# 40, D&C Yellow# 10, titanium dioxide, sodium lauryl sulfate, gelatin and edible imprinting ink. The 0.125 mg strength capsule shell also contains D&C Red# 28. The ingredients in the imprinting ink include Ferrosoferric oxide, n-butyl alcohol, propylene glycol, shellac glaze~45% (20% esterified) in ethanol, FD&C Blue #2 Indigo Carmine Aluminum Lake, FD&C Blue #1/ Brilliant Blue FCF Aluminum Lake, FD&C Red #40/ Allura Red AC Aluminum Lake and D&C Yellow #10 Aluminum Lake. Chemical Structure

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

HOW SUPPLIED Dofetilide capsules, USP 125 mcg (0.125 mg) capsules are supplied as No. 4 capsules with a light orange cap and white body, printed with "HCl" in black ink on capsule body and are available in: Dofetilide capsules, USP 250 mcg (0.25 mg) capsules are supplied as No. 4 capsules, peach cap and body, printed with "HC2" in black ink on capsule body and are available in: Dofetilide capsules, USP 500 mcg (0.5 mg) capsules are supplied as No. 2 capsules, peach cap and white body, printed with "HC3" in black ink on capsule body and are available in: 125 mcg (0.125 mg) 250 mcg (0.25 mg) 500 mcg (0.5 mg) Obverse HC l HC 2 HC 3 Bottle of 60 count with a child-resistant closure 16729-490-12 16729-491-12 16729-492-12 Bottle of 180 16729-490-59 16729-491-59 16729-492-59 Store at 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. PROTECT FROM MOISTURE AND HUMIDITY. Dispense in tight (USP), child-resistant containers. Rx only Manufactured For: Accord Healthcare, Inc., 8041 Arco Corporate Drive, Suite 200, Raleigh, NC 27617, USA Manufactured By: Intas Pharmaceuticals Limited, Plot No 5 to 14, Pharmez, Sarkhej-Bavla, National Highway No 8-A, Near Village Matoda, Tal Sanand, Ahmedabad - 382 213, Gujarat, India 51 3377 2 735303 Issued May 2024