DOFETILIDE 0.125MG

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: colloidal silicon dioxide, corn starch, gelatin, magnesium stearate, microcrystalline cellulose and titanium dioxide. The 125 mcg capsules contain FD & C Yellow # 6 and D & C yellow # 10. The 250 mcg and 500 mcg capsules contain FD & C Yellow # 6 and FD& C Red # 40. Dofetilide is 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. In addition, capsule printing ink contains ammonium hydroxide, black iron oxide, propylene glycol, and shellac glaze. dofetilide-structure-jpg

Maintenance of Normal Sinus Rhythm (Delay in AF/AFl Recurrence) Dofetilide capsule is 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 capsule 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 capsule is indicated for the conversion of atrial fibrillation and atrial flutter to normal sinus rhythm. Dofetilide capsule has not been shown to be effective in patients with paroxysmal atrial fibrillation.

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 Considerations below. 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 to 4 mEq/L. Patients with atrial fibrillation should be anticoagulated according to usual medical practice prior to electrical or pharmacological cardioversion. Anticoagulant therapy may be continued after cardioversion according to usual medical practice for the treatment of people with AF. Hypokalemia should be corrected before initiation of dofetilide 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. Instructions for Individualized Dose Initiation 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 to10 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: creatinine clearance (male) = (140-age) x actual body weight in kg 72 x serum creatinine (mg/dL) creatinine clearance (female) = (140-age) x actual body weight in kg x 0.85 72 x serum creatinine (mg/dL) When serum creatinine is given in μmol/L, divide the value by 88.4 (1 mg/dL = 88.4 μmol/L). Step 3. Starting Dose: The starting dose of dofetilide is determined as follows: Calculated Creatinine Clearance Dofetilide Dose >60 mL/min 500 mcg twice daily 40 to 60 mL/min 250 mcg twice daily 20 to <40 mL/min 125 mcg twice daily <20 mL/min Dofetilide is contraindicated in these patients Step 4. Administer the adjusted dofetilide dose and begin continuous ECG monitoring. Step 5 . At 2 to 3 hours after administering the first dose 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 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 Then the Adjusted Dose Creatinine Clearance is: (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 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: 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. 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. In clinical trials (see CLINICAL STUDIES ), the highest dose of 500 mcg BID of dofetilide as modified by the dosing algorithm led to greater effectiveness than lower doses of 125 or 250 mcg BID as modified by the dosing algorithm. The risk of Torsade de Pointes, however, is related to dose as well as to patient characteristics (see WARNINGS ). Physicians, in consultation with their patients, may therefore in some cases choose doses lower than determined by the algorithm. It is critically important that if at any time this lower dose is increased, the patient needs to be rehospitalized for three days. Previous toleration of higher doses does not eliminate the need for rehospitalization. The maximum recommended dose in patients with a calculated creatinine clearance greater than 60 mL/min is 500 mcg BID; doses greater than 500 mcg BID have been associated with an increased incidence of Torsade de Pointes. A patient who misses a dose should NOT double the next dose. The next dose should be taken at the usual time. Cardioversion: If patients do not convert to normal sinus rhythm within 24 hours of initiation of dofetilide therapy, electrical conversion should be considered. Patients continuing on dofetilide after successful electrical cardioversion should continue to be monitored by electrocardiography for 12 hours post cardioversion, or a minimum of 3 days after initiation of dofetilide therapy, whichever is greater. 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). dofetilide-flow-chart-jpg

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.

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% in the placebo groups. The most frequent reason for discontinuation (>1%) was ventricular tachycardia (2% 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 Dofetilide Dose Placebo Arrhythmia event: <250 mcg BID N=217 250 mcg BID N=388 >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% * 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. In the DIAMOND trials, a total of 1,511 patients were exposed to dofetilide for 1,757 patient years. The incidence of Torsade de Pointes was 3.3% in CHF patients and 0.9% in patients with a recent MI. Table 7 shows the incidence of serious arrhythmias and conduction disturbances reported as adverse events in the DIAMOND subpopulation that had AF at entry to these trials. Table 7: Incidence of Serious Arrhythmias and Conduction Disturbances in Patients with AF at Entry to the DIAMOND Studies Dofetilide Placebo N=249 N=257 Ventricular arrhythmias*^ 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.