Dofetilide

Dofetilide may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• headache
• chest pain
• shortness of breath
• nausea
• flu-like symptoms
• stomach pain
• back pain
• difficulty falling asleep or staying asleep

If you experience any of the following symptoms, call your doctor immediately:

• fast, pounding, or irregular heartbeat
• rash
• severe diarrhea
• dizziness or fainting
• unusual sweating
• vomiting
• loss of appetite
• increased thirst (drinking more than normal)

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

TIKOSYN 125 mcg (0.125 mg) capsules are supplied as No. 4 capsules with a light orange cap and white body, printed with TKN 125 PFIZER, and are available in:

TIKOSYN 250 mcg (0.25 mg) capsules are supplied as No. 4 capsules, peach cap and body, printed with TKN 250 PFIZER, and are available in:

TIKOSYN 500 mcg (0.5 mg) capsules are supplied as No. 2 capsules, peach cap and white body, printed with TKN 500 PFIZER, and are available in:

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

PROTECT FROM MOISTURE AND HUMIDITY.

Dispense in tight containers (USP).

Distributed by: Pfizer Labs, Division of Pfizer Inc, NY, NY 10017. Revised: Jan 2014

Ventricular Arrhythmia

TIKOSYN (dofetilide) can cause serious ventricular arrhythmias, primarily Torsade de Pointes (TdP) type ventricular tachycardia, a polymorphic ventricular tachycardia associated with QT interval prolongation. QT interval prolongation is directly related to dofetilide plasma concentration. Factors such as reduced creatinine clearance or certain dofetilide drug interactions will increase dofetilide plasma concentration. The risk of TdP can be reduced by controlling the plasma concentration through adjustment of the initial dofetilide dose according to creatinine clearance and by monitoring the ECG for excessive increases in the QT interval.

Treatment with dofetilide must therefore bestarted only in patients placed for a minimum of three days in a facility that can provide electrocardiographic monitoring and in the presence of personnel trained in the management of serious ventricular arrhythmias. Calculation of the creatinine clearance for all patients must precede administration of the first dose of dofetilide. For detailed instructions regarding doses election, see DOSAGE AND ADMINISTRATION.

The risk of dofetilide induced ventricular arrhythmia was assessed in three ways in clinical studies: 1) by description of the QT interval and its relation to the dose and plasma concentration of dofetilide; 2) by observing the frequency of TdP in TIKOSYN-treated patients according to dose; 3) by observing the overall mortality rate in patients with atrial fibrillation and in patients with structural heart disease.

The QT interval increases linearly with increasing TIKOSYN dose (see Figures 1 and 2 in CLINICAL PHARMACOLOGY And Dose-Response And Concentration Response For Increase In QT Interval).

In the supraventricular arrhythmia population (patients with AF and other supraventricular arrhythmias), the overall incidence of Torsade de Pointes was 0.8%. The frequency of TdP by dose is shown in Table 4. There were no cases of TdP on placebo.

Table 4: Summary of Torsade de Pointes in Patients Randomized to Dofetilide by Dose; Patients with Supraventricular Arrhythmias

As shown in Table 5, the rate of TdP was reduced when patients were dosed according to their renal function (see CLINICAL PHARMACOLOGY, Pharmacokinetics In Special Populations, Renal Impairment and DOSAGE AND ADMINISTRATION).

Table 5: Incidence of Torsade de Pointes Before and After Introduction of Dosing According to Renal Function

The majority of the episodes of TdP occurred within the first three days of TIKOSYN therapy (10/11 events in the studies of patients with supraventricular arrhythmias; 19/25 and 4/7 events in DIAMOND CHF and DIAMOND MI, respectively; 2/4 events in the DIAMOND AF subpopulation).

In a pooled survival analysis of patients in the supraventricular arrhythmia population (low prevalence of structural heart disease), deaths occurred in 0.9% (12/1346) of patients receiving TIKOSYN and 0.4% (3/677) in the placebo group. Adjusted for duration of therapy, primary diagnosis, age, gender, and prevalence of structural heart disease, the point estimate of the hazard ratio for the pooled studies (TIKOSYN/placebo) was 1.1 (95% CI: 0.3, 4.3). The DIAMOND CHF and MI trials examined mortality in patients with structural heart disease (ejection fraction ≤35%). In these large, double-blind studies, deaths occurred in 36% (541/1511) of TIKOSYN patients and 37% (560/1517) of placebo patients. In an analysis of 506 DIAMOND patients with atrial fibrillation/flutter at baseline, one year mortality on TIKOSYN was 31% vs. 32% on placebo (see Clinical Studies).

Because of the small number of events, an excess mortality due to TIKOSYN cannot be ruled out with confidence in the pooled survival analysis of placebo-controlled trials in patients with supraventricular arrhythmias. However, it is reassuring that in two large placebo-controlled mortality studies in patients with significant heart disease (DIAMOND CHF/MI), there were no more deaths in TIKOSYN-treated patients than in patients given placebo (see Clinical Studies).

Drug-Drug Interactions

(see CONTRAINDICATIONS)

Because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant drugs that interfere with the metabolism or renal elimination of dofetilide may increase the risk of arrhythmia (Torsade de Pointes). TIKOSYN is metabolized to a small degree by the CYP3A4 isoenzyme of the cytochrome P450 system and an inhibitor of this system could increase systemic dofetilide exposure. More important, dofetilide is eliminated by cationic renal secretion, and three inhibitors of this process have been shown to increase systemic dofetilide exposure. The magnitude of the effect on renal elimination by cimetidine, trimethoprim, and ketoconazole (all contraindicated concomitant uses with dofetilide) suggests that all renal cation transport inhibitors should be contraindicated.

Hypokalemia And Potassium-Depleting Diuretics

Hypokalemia or hypomagnesemia may occur with administration of potassium-depleting diuretics, increasing the potential for Torsade de Pointes. Potassium levels should be within the normal range prior to administration of TIKOSYN and maintained in the normal range during administration of TIKOSYN (see DOSAGE AND ADMINISTRATION).

Use With Drugs That Prolong QT Interval And Antiarrhythmic Agents

The use of TIKOSYN in conjunction with other drugs that prolong the QT interval has not been studied and is not recommended. Such drugs include phenothiazines, cisapride, bepridil, tricyclic antidepressants, certain oral macrolides, and certain fluoroquinolones. Class I or Class III antiarrhythmic agents should be withheld for at least three half-lives prior to dosing with TIKOSYN. In clinical trials, TIKOSYN was administered to patients previously treated with oral amiodarone only if serum amiodarone levels were below 0.3 mg/L or amiodarone had been withdrawn for at least three months.

Take dofetilide exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The usual recommended dose range of dofetilide is 125 to 500 mcg once or twice daily. This dose will be based on your kidney and heart rhythm activity.

If you take too much dofetilide, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

If dofetilide is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention

Dofetilide is available only from a hospital or specialty pharmacy.

You should not take dofetilide if you are allergic to it, or if you have severe kidney disease (or you are on dialysis) or a history of Long QT syndrome.

Before you receive dofetilide, tell your doctor if you have heart disease, high blood pressure, kidney disease, severe liver disease, depression, mental illness, or an electrolyte imbalance (such as low levels of potassium or magnesium in your blood).

There are many other drugs that should not be used together with dofetilide. Tell your doctor about all other medicines you use.

You will need to spend at least 3 days in a hospital setting when you first start taking dofetilide. This is so your heart rhythm and kidney function can be monitored in case the medication causes serious side effects.

Tell your doctor if you have a prolonged illness that causes severe diarrhea, vomiting, heavy sweating, increased thirst, or loss of appetite. These conditions can cause an electrolyte imbalance (such as low potassium levels), making it dangerous for you to use dofetilide.

Your blood pressure will need to be checked often. Visit your doctor regularly.

You should not take dofetilide if you are allergic to it, or if you have:

• severe kidney disease (or if you are on dialysis); or

• a history of Long QT syndrome.

Some medicines can cause unwanted or dangerous effects when used with dofetilide, and should not be used at the same time. Your doctor may need to change your treatment plan if you use any of the following drugs:

• cimetidine;

• dolutegravir;

• ketoconazole;

• megestrol;

• prochlorperazine;

• trimethoprim (Proloprim, Trimpex, Bactrim, Septra);

• verapamil; or

• a diuretic (water pill) that contains hydrochlorothiazide (HCTZ), such as Accuretic, Aldactazide, Atacand HCT, Benicar HCT, Diovan HCT, Dyazide, Exforge HCT, Hyzaar, Lopressor HCT, Maxzide, Micardis HCT, Monopril HCT, Prinzide, Tekturna HCT, Vaseretic, and others.

To make sure dofetilide is safe for you, tell your doctor if you have:

• heart disease, high blood pressure;

• liver or kidney disease;

• depression, mental illness;

• asthma or allergies;

• any active infection;

• skin problems; or

• an electrolyte imbalance (such as low levels of potassium or magnesium in your blood).

It is not known whether this medicine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medicine.

It is not known whether dofetilide passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using dofetilide.

Skip the missed dose and take your next dose at the usual time to stay on schedule. Do not take extra medicine to make up the missed dose.

Supraventricular Tachyarrhythmias

Maintenance of normal sinus rhythm in patients with previous atrial fibrillation/atrial flutter of >1 week’s duration.1 2 4 5 11 Reserve for patients in whom atrial fibrillation/atrial flutter was highly symptomatic.1 2 4

Conversion of atrial fibrillation and atrial flutter to normal sinus rhythm.1 2 4 5 11 Has not been shown to be effective in patients with paroxysmal atrial fibrillation.1 2

Contraindications

• Congenital or acquired long QT syndromes; baseline QT or QTc interval >440 msec (500 msec in patients with ventricular conduction abnormalities).1 2

• Severe renal impairment (calculated Clcr <20 mL/minute).1 2

• Concomitant use of verapamil or cation transport system inhibitors (e.g., cimetidine, ketoconazole, megestrol, prochlorperazine, or trimethoprim [alone or in combination with sulfamethoxazole]).1 2 b (See Specific Drugs under Interactions.)

• Concomitant use of hydrochlorothiazide alone or in combination with triamterene.1

• Known hypersensitivity to dofetilide.1 2 12

Warnings/Precautions

Warnings

May cause serious ventricular arrhythmias, principally polymorphic ventricular tachycardia associated with QT interval prolongation (i.e., torsades de pointes).1 2 3 4 5 6 7 8 11 Generally occurs within the first 3 days of initiation of therapy.1 2 The risk is threefold greater in women than in men.1 2 (See Boxed Warnings.)

Reduce risk of torsades de pointes by controlling the plasma concentration (e.g., adjustment of initial dofetilide dosage according to Clcr, avoiding certain drug interactions) and monitoring the ECG for excessive increases in the QT interval.1 2

Limited evidence suggests a possible excess mortality as a result of dofetilide use.1

General Precautions

No apparent adverse effects on conduction velocity.1 2 AV nodal conduction unaffected in normal volunteers or in patients with first degree heart block.1 2 Used safely in conjunction with pacemakers.1 2

Hypokalemia or hypomagnesemia may increase the risk of torsades de pointes.1 2 Closely monitor patients experiencing prolonged or excessive diarrhea, sweating, vomiting, loss of appetite, or thirst.1 2 Closely monitor patients receiving concomitant therapy with drugs that may increase the risk of such electrolyte imbalance (e.g., diuretics).1 2 (See Specific Drugs under Interactions.)

Specific Populations

Category C.1 2

Not known whether dofetilide is distributed into milk.1 2 Use not recommended.1 2

Safety and efficacy not established.1 2

No substantial differences in safety and efficacy relative to younger adults.1 2 Select dosage with caution because of age-related decreases in renal function.1 2 12

If clearance is decreased, dosage adjustments are necessary depending on degree of renal impairment.1 b Safety and efficacy not established in patients with Clcr <20 mL/minute.1 2 (See Table 1 under Dosage and Administration for dosage adjustment based on Clcr.)

Not studied in patients with severe hepatic impairment; use with particular caution in these patients.1 2 (See Hepatic Impairment under Dosage and Administration.)

Common Adverse Effects

Headache, chest pain, dizziness.1

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Dizziness
• fainting
• fast heartbeat

• Chest pain
• confusion
• facial or flaccid paralysis
• numbness or tingling of the hands, feet, or face
• paralysis
• pounding, slow heartbeat
• slurred speech
• swelling of the ankles, arms, face, feet, fingers, legs, lips, tongue, or throat
• troubled breathing
• unexplained shortness of breath
• unusual tiredness or weakness
• weight gain
• yellow eyes or skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Abdominal or stomach pain
• accidental injury
• back pain
• chills
• cough
• diarrhea
• fever
• flu-like symptoms
• general feeling of discomfort or illness
• headache
• joint pain
• loss of appetite
• migraine
• muscle aches and pains
• nausea
• rash
• runny nose
• shivering
• sneezing
• sore throat
• sweating
• trouble sleeping
• vomiting

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Dofetilide capsules are an antiarrhythmic drug with Class III (cardiac action potential duration prolonging) properties. Its empirical formula is C19H27N3O5S2 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.

Renal Impairment

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

Hepatic Impairment

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

Cardiac Conduction Disturbances

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

Information for Patients

Please refer patient to the Medication Guide.

Prior to initiation of Dofetilide 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.

Assessment of patients' medication history should include all over-the-counter, prescription, and herbal/natural preparations with emphasis on preparations that may affect the pharmacokinetics of Dofetilide capsules such as cimetidine (see CONTRAINDICATIONS), trimethoprim alone or in combination with sulfamethoxazole (see WARNINGS, CONTRAINDICATIONS), prochlorperazine (see WARNINGS, CONTRAINDICATIONS), megestrol (see WARNINGS, CONTRAINDICATIONS), ketoconazole (see WARNINGS, CONTRAINDICATIONS), dolutegravir (see CONTRAINDICATIONS), hydrochlorothiazide (alone or in combinations such as with triamterene) (see CONTRAINDICATIONS), other cardiovascular drugs (especially verapamil – see CONTRAINDICATIONS), phenothiazines, and tricyclic antidepressants (see WARNINGS). If a patient is taking Dofetilide capsules and requires anti-ulcer therapy, omeprazole, ranitidine, or antacids (aluminum and magnesium hydroxides) should be used as alternatives to cimetidine, as these agents have no effect on the pharmacokinetics of Dofetilide capsules. Patients should be instructed to notify their health care providers of any change in over-the-counter, prescription, or supplement use. If a patient is hospitalized or is prescribed a new medication for any condition, the patient must inform the health care provider of ongoing Dofetilide capsules therapy. Patients should also check with their health care provider and/or pharmacist prior to taking a new over-the-counter preparation.

If patients experience symptoms that may be associated with altered electrolyte balance, such as excessive or prolonged diarrhea, sweating, or vomiting or loss of appetite or thirst, these conditions should immediately be reported to their health care provider.

Patients should be instructed NOT to double the next dose if a dose is missed. The next dose should be taken at the usual time.

Drug/Laboratory Test Interactions

None known.

Drug-Drug Interactions

(see WARNINGS, CONTRAINDICATIONS) Concomitant use of cimetidine is contraindicated. Cimetidine at 400 mg BID (the usual prescription dose) co-administered with Dofetilide capsules (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 capsules 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 capsules.

(see CONTRAINDICATIONS) Concomitant use of verapamil is contraindicated. Co-administration of Dofetilide capsules 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.

(see WARNINGS, CONTRAINDICATIONS) Concomitant use of ketoconazole is contraindicated. Ketoconazole at 400 mg daily (the maximum approved prescription dose) co-administered with Dofetilide capsules (500 mcg BID) for 7 days has been shown to increase Dofetilide Cmax by 53% in males and 97% in females, and AUC by 41% in males and 69% in females.

(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 capsules (500 mcg BID) for 4 days has been shown to increase Dofetilide AUC by 103% and Cmax by 93%.

(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 capsules (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 Cmax 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 Cmax 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 capsules 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 capsules 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 capsules. In addition, drugs that are actively secreted via this route (e.g., triamterene, metformin, and amiloride) should be co-administered with care as they might increase Dofetilide levels.

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

Other Drug Interaction Information

Studies in healthy volunteers have shown that Dofetilide capsules do not affect the pharmacokinetics of digoxin. In patients, the concomitant administration of digoxin with Dofetilide was associated with a higher occurrence of Torsade de Pointes. It is not clear whether this represents an interaction with Dofetilide capsules or the presence of more severe structural heart disease in patients on digoxin; structural heart disease is a known risk factor for arrhythmia. No increase in mortality was observed in patients taking digoxin as concomitant medication.

In healthy volunteers, amlodipine, phenytoin, glyburide, ranitidine, omeprazole, hormone replacement therapy (a combination of conjugated estrogens and medroxyprogesterone), antacid (aluminum and magnesium hydroxides), and theophylline did not affect the pharmacokinetics of Dofetilide capsules. In addition, studies in healthy volunteers have shown that Dofetilide capsules do not affect the pharmacokinetics or pharmacodynamics of warfarin, or the pharmacokinetics of propranolol (40 mg twice daily), phenytoin, theophylline, or oral contraceptives.

Population pharmacokinetic analyses were conducted on plasma concentration data from 1445 patients in clinical trials to examine the effects of concomitant medications on clearance or volume of distribution of Dofetilide. Concomitant medications were grouped as ACE inhibitors, oral anticoagulants, calcium channel blockers, beta blockers, cardiac glycosides, inducers of CYP3A4, substrates and inhibitors of CYP3A4, substrates and inhibitors of P-glycoprotein, nitrates, sulphonylureas, loop diuretics, potassium sparing diuretics, thiazide diuretics, substrates and inhibitors of tubular organic cation transport, and QTc-prolonging drugs. Differences in clearance between patients on these medications (at any occasion in the study) and those off medications varied between -16% and +3%. The mean clearances of Dofetilide were 16% and 15% lower in patients on thiazide diuretics and inhibitors of tubular organic cation transport, respectively.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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

Pregnancy Category C

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 5th 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 breastfeed an infant if they are taking Dofetilide capsules.

Geriatric Use

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).

Use in Women

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

Pediatric Use

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

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)1
  • verapamil (CALAN, CALAN SR, COVERA-HS, ISOPTIN, ISOPTIN SR, VERELAN, VERELAN PM, TARKA)1
  • ketoconazole (NIZORAL, XOLEGEL, EXTINA)1
  • trimethoprim alone (PROLOPRIM, TRIMPEX)1 or the combination of trimethoprim and sulfamethoxazole (BACTRIM, SEPTRA SULFATRIM)1
  • prochlorperazine (COMPAZINE, COMPO)1
  • megestrol (MEGACE)1
  • dolutegravir (TIVICAY)1
  • hydrochlorothiazide alone or in combination with other medicines (such as ESIDRIX, EZIDE, HYDRODIURIL, HYDRO-PAR, MICROZIDE, or ORETIC)1

• 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 breastfeeding or plan to breastfeed. It is not known if Dofetilide passes into your breast milk. You and your doctor should decide if you will take Dofetilide capsules or breastfeed. 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:

Rx only

Manufactured by:
Mayne Pharma
Greenville, NC 27834
Revised: January 2017
61013

This Medication Guide has been approved by the U.S. Food and Drug Administration.

• Tikosyn

• Antiarrhythmic Agent, Class III

Atrial fibrillation/atrial flutter: Maintenance of normal sinus rhythm in patients with chronic atrial fibrillation/atrial flutter of longer than 1-week duration who have been converted to normal sinus rhythm; conversion of atrial fibrillation and atrial flutter to normal sinus rhythm.

Store at 15°C to 30°C (59°F to 86°F). Protect from moisture and humidity.

Adverse events have been observed in animal reproduction studies.