Principal Display Panel - 0.500 Mg Capsule Bottle Label

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 beats per minute. There are no data on use of dofetilide capsules when the heart rate is < 50 beats per minute.) The usual recommended dose of dofetilide capsules 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 capsules treatment is initiated and should be maintained within the normal range while the patient remains on dofetilide capsules therapy. (See WARNINGS, Hypokalemia and Potassium-Depleting Diuretics ). In clinical trials, potassium levels were generally maintained above 3.6-4.0 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 capsules therapy (see WARNINGS, Ventricular Arrhythmia ). Patients to be discharged on dofetilide capsules therapy from an inpatient setting as described above must have an adequate supply of dofetilide capsules, at the patient's individualized dose, to allow uninterrupted dosing until the patient can fill a dofetilide capsules prescription.

Dofetilide capsules, 125 mcg (0.125 mg) are supplied as No. 4 capsules with a dark caramel cap and white body, imprinted with ML 125 in black ink, and are available in: Dofetilide capsules, 250 mcg (0.25 mg) are supplied as No. 4 capsules with a light orange cap and light orange body, imprinted with ML 250 in black ink, and are available in: Dofetilide capsules, 500 mcg (0.5 mg) are supplied as No. 2 capsules with a light orange cap and white body, imprinted with ML 500 in black ink, and are available in: 125 mcg (0.125 mg) 250 mcg (0.25 mg) 500 mcg (0.5 mg) Body 125 250 500 Cap ML ML ML Bottle of 60 51862-125-60 51862-025-60 51862-005-60

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 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 capsules. The concomitant use of hydrochlorothiazide (alone or in combinations such as with triamterene) with dofetilide capsules is 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.

Dofetilide capsules are 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, corn starch, colloidal silicon dioxide and magnesium stearate. The capsule shells contain gelatin, titanium dioxide, red iron oxide, yellow iron oxide, and black ink. The imprint ink contains iron oxide black, shellac, ethanol, n-butyl alcohol, isopropyl alcohol, propylene glycol, and ammonium hydroxide. Dofetilide capsules are supplied for oral administration in three dosage strengths: 125 mcg (0.125 mg) dark caramel and white capsules, 250 mcg (0.25 mg) light orange capsules, and 500 mcg (0.5 mg) light orange and white capsules.

(see PRECAUTIONS )

None known.

Please refer patient to the Medication Guide. Prior to initiation of dofetilide capsules 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 capsules 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.

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 capsules.

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

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

Dofetilide had no genotoxic effects, with or without metabolic activation, based on the bacterial mutation assay and tests of cytogenetic aberrations in vivo in mouse bone marrow and in vitro in 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.

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.

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).

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.

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 .

Dofetilide Capsules (doe-FEH-till-ide) 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 are Dofetilide Capsules? Dofetilide capsules 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) Listed trademarks are the property of their respective owners. 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 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 much 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 between 59° to 86°F (15° to 30°C). 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 1-844-825-8500. What are the ingredients in Dofetilide Capsules? Active ingredient : dofetilide, USP Inactive ingredients : Capsule fill : microcrystalline cellulose, corn starch, colloidal silicon dioxide, and magnesium stearate Capsule shell : gelatin, titanium dioxide, red iron oxide and yellow iron oxide Imprinting ink : iron oxide black, shellac, ethanol, n-butyl alcohol, isopropyl alcohol, propylene glycol, and ammonium hydroxide R x only

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.

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] PROTECT FROM MOISTURE AND HUMIDITY. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

NDC 51862- 125 -60 Dofetilide Capsules 125 mcg (0.125 mg ) PHARMACIST: Dispense the accompanying medication guide to each patient. Rx Only 60 Capsules mayne pharma

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 beats per minute. There are no data on use of dofetilide capsules when the heart rate is < 50 beats per minute.) The usual recommended dose of dofetilide capsules 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 capsules treatment is initiated and should be maintained within the normal range while the patient remains on dofetilide capsules therapy. (See WARNINGS, Hypokalemia and Potassium-Depleting Diuretics ). In clinical trials, potassium levels were generally maintained above 3.6-4.0 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 capsules therapy (see WARNINGS, Ventricular Arrhythmia ). Patients to be discharged on dofetilide capsules therapy from an inpatient setting as described above must have an adequate supply of dofetilide capsules, at the patient's individualized dose, to allow uninterrupted dosing until the patient can fill a dofetilide capsules prescription.

Dofetilide capsules, 125 mcg (0.125 mg) are supplied as No. 4 capsules with a dark caramel cap and white body, imprinted with ML 125 in black ink, and are available in: Dofetilide capsules, 250 mcg (0.25 mg) are supplied as No. 4 capsules with a light orange cap and light orange body, imprinted with ML 250 in black ink, and are available in: Dofetilide capsules, 500 mcg (0.5 mg) are supplied as No. 2 capsules with a light orange cap and white body, imprinted with ML 500 in black ink, and are available in: 125 mcg (0.125 mg) 250 mcg (0.25 mg) 500 mcg (0.5 mg) Body 125 250 500 Cap ML ML ML Bottle of 60 51862-125-60 51862-025-60 51862-005-60

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 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 capsules. The concomitant use of hydrochlorothiazide (alone or in combinations such as with triamterene) with dofetilide capsules is 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.

(see PRECAUTIONS )

None known.

Please refer patient to the Medication Guide. Prior to initiation of dofetilide capsules 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 capsules 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.

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 capsules.

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

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

Dofetilide had no genotoxic effects, with or without metabolic activation, based on the bacterial mutation assay and tests of cytogenetic aberrations in vivo in mouse bone marrow and in vitro in 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.

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.

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).

Dofetilide capsules are 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, corn starch, colloidal silicon dioxide and magnesium stearate. The capsule shells contain gelatin, titanium dioxide, red iron oxide, yellow iron oxide, and black ink. The imprint ink contains iron oxide black, shellac, ethanol, n-butyl alcohol, isopropyl alcohol, propylene glycol, and ammonium hydroxide. Dofetilide capsules are supplied for oral administration in three dosage strengths: 125 mcg (0.125 mg) dark caramel and white capsules, 250 mcg (0.25 mg) light orange capsules, and 500 mcg (0.5 mg) light orange and white capsules.

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.

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 .

Dofetilide Capsules (doe-FEH-till-ide) 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 are Dofetilide Capsules? Dofetilide capsules 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) Listed trademarks are the property of their respective owners. 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 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 much 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 between 59° to 86°F (15° to 30°C). 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 1-844-825-8500. What are the ingredients in Dofetilide Capsules? Active ingredient : dofetilide, USP Inactive ingredients : Capsule fill : microcrystalline cellulose, corn starch, colloidal silicon dioxide, and magnesium stearate Capsule shell : gelatin, titanium dioxide, red iron oxide and yellow iron oxide Imprinting ink : iron oxide black, shellac, ethanol, n-butyl alcohol, isopropyl alcohol, propylene glycol, and ammonium hydroxide R x only

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.

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] PROTECT FROM MOISTURE AND HUMIDITY. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

NDC 51862- 125 -60 Dofetilide Capsules 125 mcg (0.125 mg ) PHARMACIST: Dispense the accompanying medication guide to each patient. Rx Only 60 Capsules mayne pharma