Dofetilide 0.125Mg

Description

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: 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

What Is Dofetilide 0.125Mg Used For?

INDICATIONS AND USAGE 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.

Dosage and Administration

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 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...

Side Effects (Adverse Reactions)

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% 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...

Contraindications

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.

Pregnancy and Breastfeeding

Pregnancy Dofetilide has been shown to adversely affect in utero growth 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 th metacarpal, 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.

Overdosage

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...

How Supplied

HOW SUPPLIED Dofetilide capsules are supplied as: 125 mcg (0.125 mg): Hard gelatin capsule, orange opaque cap printed with "G125" and white opaque body printed with "024" contains white to off-white powder. Bottles of 60 Capsules NDC 70010-024-06 250 mcg (0.25 mg): Hard gelatin capsule, peach opaque cap printed with "G250" and peach opaque body printed with "025" contains white to off-white powder. Bottles of 60 Capsules NDC 70010-025-06 500 mcg (0.5 mg): Hard gelatin capsule, peach opaque cap printed with "G500" and white opaque body printed with "026" contains white to off-white powder. Bottles of 60 Capsules NDC 70010-026-06 Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. PROTECT FROM MOISTURE AND HUMIDITY. Dispense in a tight child-resistant container as defined in the USP. Print Medication Guides at: https://granulespharma.com/product/dofetilide-cap/ Rx only Manufactured by: Granules Pharmaceuticals Inc., Chantilly, VA 20151 Rev. 05/2023