Understanding Atrial Fibrillation/ Atrial Flutter (AF/AFL)

Transcription

1 UNDERSTANDING AF/AFL Understanding Atrial Fibrillation/ Atrial Flutter (AF/AFL) Please see full Prescribing Information, including Boxed Warning, and Medication Guide beginning on page 7. Please see Important Safety Information on page 6.

2 Understanding AF/AFL In this brochure, you ll learn about atrial fibrillation (AF) and atrial flutter (AFL). You ll also learn about the options you have for treatment. [What is arrhythmia?] An arrhythmia is a medical term for an abnormal heartbeat. Your heart can beat too slow, too fast, or in an unusual pattern. There are many kinds of arrhythmias. They can happen in any part of the heart. Here, you ll learn about 2 kinds of arrhythmias that happen in parts of your heart called the atria. The first is called atrial fibrillation. The second is called atrial flutter. Indication TIKOSYN (dofetilide) is a medicine for highly symptomatic atrial fibrillation or atrial flutter (irregular heartbeats). TIKOSYN may help by converting the irregular heartbeats to normal rhythm. It may also help by keeping the normal rhythm for a longer period of time. It has not been shown to work on certain types of irregular heartbeats that may come and go on their own. Warning To decrease the chance of your getting a different type of dangerous abnormal heartbeat, TIKOSYN treatment must be started or re-started while you are in the hospital. The doctor who prescribed TIKOSYN and the hospital must have gone through special TIKOSYN training. Feeling faint, dizziness/lightheadedness, or having fast heartbeats are symptoms of this abnormal heartbeat. Call your doctor or emergency room as soon as possible if you have any of these symptoms. While in the hospital, your kidney function and heart rhythm will be monitored for a minimum of 3 days. This helps the doctor to choose the right TIKOSYN dose for you. Only doctors who have gone through TIKOSYN training will be able to prescribe or refill your TIKOSYN prescription. [What are atrial fibrillation and atrial flutter?] AF and AFL are arrhythmias that happen in parts of your heart called the atria. Your heart has 4 parts, or chambers. The atria are the top 2 chambers. The bottom 2 are called the ventricles. Normally, these chambers tighten and relax to a regular beat. In AF/AFL, the atria beat very quickly. The beats can be disorganized. The timing of their beat with the ventricles can be off, too. Top Chambers Bottom Chambers Right Atrium Right Ventricle Left Atrium Left Ventricle Chambers of your heart Disorganized Signals Disorganized and rapid signals in AF Please see full Prescribing Information, including Boxed Warning, and Medication Guide beginning on page 7. Please see additional Important Safety Information on page 6. 2

3 Understanding AF/AFL [What are the signs of atrial fibrillation and atrial flutter?] Some of the symptoms you might feel are: Irregular and rapid pulse Heart palpitations Dizziness, sweating, and chest pain or pressure Shortness of breath or anxiety Tiring more easily, especially when exercising Fainting The symptoms you feel may come and go. Or they may be constant. If you have any of these symptoms, your doctor can check your heartbeat using an electrocardiogram, or ECG, recording. [What are the causes of atrial fibrillation and atrial flutter?] Doctors are not quite sure what causes AF/AFL. However, there are some conditions that might make them more likely. These include: AF/AFL: Heart disease, such as congestive heart failure, coronary artery disease, and structural heart disease Thyroid disease AF only: Older than 60 years of age Serious illness Chronic lung disease Diabetes Drinking too much alcohol Infection [What are the risks of atrial fibrillation and atrial flutter?] In AF/AFL, your heart doesn t pump blood as well as normal. Blood carries oxygen to your cells. So in AF/AFL, your cells don t get as much oxygen. This can make you feel tired. Also, when your heart doesn t pump normally, you can have low blood pressure. This can make you pass out. There are other serious conditions AF/AFL can lead to if not treated. These include: Chronic fatigue if you re not getting enough blood, you may feel tired Heart failure prolonged AF/AFL can weaken the heart, making heart failure more likely Stroke when your heart doesn t pump blood normally, blood can pool in your heart. This can cause clots to form. If these clots travel to the brain or the lungs, they can stop the flow of blood. This can cause a stroke in the brain. This can also lead to a blood clot stuck in the lungs (pulmonary embolism). Either of these may lead to death Selected Safety Information Do not take TIKOSYN (dofetilide) if you have congenital or acquired long QT syndrome (a disorder of the heartbeat which may be present from birth, or it may be acquired as a result of certain medical conditions or from taking certain medications. People with long QT syndrome may have symptoms including an unusually rapid heartbeat, fainting, and seizures. Sudden cardiac death may also result from long QT syndrome); have serious kidney problems or are on kidney dialysis; or are allergic to dofetilide or other ingredients in TIKOSYN. Please see full Prescribing Information, including Boxed Warning, and Medication Guide beginning on page 7. Please see additional Important Safety Information on page 6. 3

4 Understanding AF/AFL [Types of treatment] Treating underlying conditions and changing lifestyle habits Before your treatment, your doctor might ask you questions about your medical history and lifestyle. There might be a disease or habit causing your AF/AFL. If the disease is treated or the habit changed, the arrhythmia may go away. Preventing stroke No matter what treatment you receive, you ll probably also take anticoagulants or antiplatelets, which help prevent blood clots. This is to reduce your risk of stroke. Treating arrhythmia Depending on your symptoms, your doctor will discuss your treatment options with you. There are 2 main types of treatment with medicines. They are: Rhythm control using drugs to help your heart beat at a normal rhythm Rate control using drugs to control the rate of your heart Your doctor may also consider certain procedures to restore normal rhythm to your heart. Surgical procedures electrical signals in your heart are redirected using surgery Catheter ablation a catheter is used to reach the heart and create scars with radio waves There are a number of reasons your doctor may choose one treatment over another. Your doctor will consider: Your medical history Your type of arrhythmia Other conditions you might have Then your doctor will determine which treatment is right for you. Restoring the rhythm With AF/AFL, your doctor may attempt to restore your heartbeat to a regular and controlled rhythm. This is called normal sinus rhythm. The process of restoring rhythm is called cardioversion. Cardioversion can happen in 2 ways: Rhythm control medicines Direct-current cardioversion when electricity is applied directly to the heart Maintaining the rhythm After cardioversion, your doctor may prescribe drugs. These help maintain your normal rhythm. There are several drugs for doing this. The drug you are prescribed will depend on what kind of arrhythmia you have. It will also depend on the other conditions you have and the possible side effects of the drug. If the first drug doesn t work, your doctor might consider a different medicine. Your doctor may also try a different approach to treatment. Rate control Depending on your condition, your doctor may use rate-controlling drugs to control the rate of your heart. Your doctor may consider cardioversion before starting these drugs. There are many kinds of medicines that can be used for rate control. Your doctor may also combine agents in order to increase their effect. The type of drug you re prescribed will depend on your symptoms, the kind of AF/AFL, and any other conditions you have. Selected Safety Information Do not take TIKOSYN (dofetilide) if are taking certain other medicines, including cimetidine (Tagamet, Tagamet HB ), verapamil (Calan, Calan SR, Covera-HS, Isoptin, Isoptin SR, Verelan, Verelan PM ), ketoconazole (Nizoral ), trimethoprim alone (Proloprim, Trimpex ), the combination of trimethoprim and sulfamethoxazole (Bactrim, Septra ), prochlorperazine (Compazine ), megestrol (Megace ), dolutegravir (Tivicay ) or hydrochlorothiazide alone or in combination with other medicines (such as Esidrix, Ezide, Hydrodiuril, Hydro-Par, Microzide, or Oretic ). Listed trademarks are the property of their respective owners. Please see full Prescribing Information, including Boxed Warning, and Medication Guide beginning on page 7. Please see additional Important Safety Information on page 6. 4

5 Understanding AF/AFL [Types of treatment] (cont d) Procedures AF/AFL can sometimes be treated with certain procedures. One type, done using surgery, is called the maze procedure: The electrical signals in your heart are slowed by a maze This maze is created through small cuts. These cuts are stitched up and allowed to scar over The scars redirect electrical signals, slowing them down Your doctor may also consider catheter ablation. There are a few steps in this process: A catheter is used to reach the heart to block and correct electrical signals Radio waves are sent through the catheter These waves create small scars in specific places on heart tissue This blocks electrical signals to help ensure they travel the right way Catheter ablation can be used in 2 ways: Hot spot ablation scars are made on areas along the vein that carries blood to your lungs Atrioventricular (AV) node ablation the AV node sends electrical signals from the atria to the ventricles. In AV node ablation, scars are made on the node. A pacemaker, a device used to control your heartbeat, may then be inserted [More information] To learn more about AF, AFL, arrhythmias, or heart disease, contact these groups: American Heart Association 7272 Greenville Ave Dallas, TX (800) AHA-USA-1 CardioSmart Resource Center American College of Cardiology 2400 N Street NW Washington, DC Heart Rhythm Society 1400 K Street NW Suite 500 Washington, DC (202) Selected Safety Information The most common side effects of TIKOSYN (dofetilide) are headache, chest pain, and dizziness. TIKOSYN can also cause other side effects. If you are concerned about these or any other side effects, ask your doctor. Please see full Prescribing Information, including Boxed Warning, and Medication Guide beginning on page 7. Please see additional Important Safety Information on page 6. 5

6 Indication TIKOSYN (dofetilide) is a medicine for highly symptomatic atrial fibrillation or atrial flutter (irregular heartbeats). TIKOSYN may help by converting the irregular heartbeats to normal rhythm. It may also help by keeping the normal rhythm for a longer period of time. It has not been shown to work on certain types of irregular heartbeats that may come and go on their own. Important Safety Information To decrease the chance of your getting a different type of dangerous abnormal heartbeat, TIKOSYN treatment must be started or re-started while you are in the hospital. The doctor who prescribed TIKOSYN and the hospital must have gone through special TIKOSYN training. Feeling faint, dizziness/lightheadedness, or having fast heartbeats are symptoms of this abnormal heartbeat. Call your doctor or emergency room as soon as possible if you have any of these symptoms. While in the hospital, your kidney function and heart rhythm will be monitored for a minimum of 3 days. This helps the doctor to choose the right TIKOSYN dose for you. Only doctors who have gone through TIKOSYN training will be able to prescribe or refill your TIKOSYN prescription. Do not take TIKOSYN if you have congenital or acquired long QT syndrome (a disorder of the heartbeat which may be present from birth, or it may be acquired as a result of certain medical conditions or from taking certain medications. People with long QT syndrome may have symptoms including an unusually rapid heartbeat, fainting, and seizures. Sudden cardiac death may also result from long QT syndrome); have serious kidney problems or are on kidney dialysis; are taking certain other medicines, including cimetidine (Tagamet, Tagamet HB ), verapamil (Calan, Calan SR, Covera-HS, Isoptin, Isoptin SR, Verelan, Verelan PM ), ketoconazole (Nizoral ), trimethoprim alone (Proloprim, Trimpex ), the combination of trimethoprim and sulfamethoxazole (Bactrim, Septra ), prochlorperazine (Compazine ), megestrol (Megace ), dolutegravir (Tivicay ) or hydrochlorothiazide alone or in combination with other medicines (such as Esidrix, Ezide, Hydrodiuril, Hydro-Par, Microzide, or Oretic ); or are allergic to dofetilide or other ingredients in TIKOSYN. The most common side effects of TIKOSYN are headache, chest pain, and dizziness. TIKOSYN can also cause other side effects. If you are concerned about these or any other side effects, ask your doctor. Listed trademarks are the property of their respective owners. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit or call FDA Please see full Prescribing Information, including Boxed Warning, and Medication Guide beginning on page 7. For more information, please visit TKU Pfizer Inc. All rights reserved. January 2014

7 TIKOSYN (dofetilide) Capsules To To minimize the the risk of of induced arrhythmia, patients initiated or or re-initiated on on TIKOSYN should be be placed for for a a minimum of of 33 days in in a a facility that can provide calculations of of creatinine clearance, continuous electrocardiographic monitoring, and cardiac resuscitation. For detailed instructions regarding dose selection, see DOSAGE AND ADMINISTRATION. TIKOSYN is is available only to to hospitals and prescribers who have received appropriate TIKOSYN dosing and treatment initiation education; see DOSAGE AND ADMINISTRATION. DESCRIPTION TIKOSYN (dofetilide) is is an an antiarrhythmic drug with Class III III (cardiac action potential duration prolonging) properties. Its Its empirical formula is is C H N 3 3 O 5 S 5 S 2 2 and it it has a a molecular weight of of The structural formula is is NHSOCHCH NN CH CHSO SOHNHN HHC C OO The chemical name for for dofetilide is: is: N-[4-[2-[methyl[2-[4-[(methylsulfonyl)amino]phenoxy]ethyl]amino]ethyl]phenyl]- methanesulfonamide. Dofetilide is is a a white to to off-white powder. It It is is very slightly soluble in in water and propan-2-ol and is is soluble in in 0.1M aqueous sodium hydroxide, acetone, and aqueous 0.1M hydrochloric acid. TIKOSYN capsules contain the the following inactive ingredients: microcrystalline cellulose, corn starch, colloidal silicon dioxide and magnesium stearate. TIKOSYN is is supplied for for oral administration in 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. CLINICAL PHARMACOLOGY Mechanism of of Action TIKOSYN (dofetilide) shows Vaughan Williams Class III III antiarrhythmic activity. The mechanism of of action is is blockade of of the the cardiac ion channel carrying the the rapid component of of the the delayed rectifier potassium current, I Kr I Kr. At. At concentrations covering several orders of of magnitude, dofetilide blocks only I Kr I Kr with no no relevant block of of the the other repolarizing potassium currents (e.g., I Ks I Ks, I, K1 I K1 ). ). At At clinically relevant concentrations, dofetilide has no no effect on on sodium channels (associated with Class I I effect), adrenergic alpha-receptors, or or adrenergic beta-receptors. Electrophysiology TIKOSYN (dofetilide) increases the the monophasic action potential duration in in a a predictable, concentration-dependent manner, primarily due to to delayed repolarization. This effect, and the the related increase in in effective refractory period, is is observed in in the the atria and ventricles in in both resting and paced electrophysiology studies. The increase in in QT interval observed on on the the surface ECG is is a a result of of prolongation of of both effective and functional refractory periods in in the the His- Purkinje system and the the ventricles. Dofetilide did not influence cardiac conduction velocity and sinus node function in in a a variety of of studies in in patients with or or without structural heart disease. This is is consistent with a a lack of of effect of of dofetilide on on the the PR PR interval and QRS width in in patients with pre-existing heart block and/or sick sinus syndrome. In In patients, dofetilide terminates induced re-entrant tachyarrhythmias (e.g., atrial fibrillation/flutter and ventricular tachycardia) and prevents their re-induction. TIKOSYN does not increase the the electrical energy required to to convert electrically induced ventricular fibrillation, and it it significantly reduces the the defibrillation threshold in in patients with ventricular tachycardia and ventricular fibrillation undergoing implantation of of a a cardioverter-defibrillator device. Hemodynamic Effects In In hemodynamic studies, TIKOSYN had no no effect on on cardiac output, cardiac index, stroke volume index, or or systemic vascular resistance in in patients with ventricular tachycardia, mild to to moderate congestive heart failure or or angina, and either normal or or low left ventricular ejection fraction. There was no no evidence of of a a negative inotropic effect related to to TIKOSYN therapy in in patients with atrial fibrillation. There was no no increase in in heart failure in in patients with significant left ventricular dysfunction (see CLINICAL STUDIES, Safety in in Patients with Structural Heart Disease, DIAMOND Studies). In In the the overall clinical program, TIKOSYN did not affect blood pressure. Heart rate was decreased by by 4 6 bpm in in studies in in patients. Pharmacokinetics, General Absorption and Distribution: The oral bioavailability of of dofetilide is is >90%, with maximal plasma concentrations occurring at at about 2 3 hours in in the the fasted state. Oral bioavailability is is unaffected by by food or or antacid. The terminal half-life of of TIKOSYN is is approximately hours; steady state plasma concentrations are are attained within 2 3 days, with an an accumulation index of of to to 2.0. Plasma concentrations are are dose proportional. Plasma protein binding of of dofetilide is is 60 70%, is is independent of of plasma concentration, and is is unaffected by by renal impairment. Volume of of distribution is is 33 L/kg. Metabolism and Excretion: Approximately 80% of of a a single dose of of dofetilide is is excreted in in urine, of of which approximately 80% is is excreted as as unchanged dofetilide with the the remaining 20% consisting of of inactive or or minimally active metabolites. Renal elimination involves both glomerular filtration and active tubular secretion (via the the cation transport system, a a process that can be be inhibited by by cimetidine, trimethoprim, prochlorperazine, megestrol, ketoconazole and dolutegravir). In In vitro studies with human liver microsomes show that dofetilide can be be metabolized by by CYP3A4, but it it has a a low affinity for for this isoenzyme. Metabolites are are formed by by 7

8 N-dealkylation and N-oxidation. There are are no no quantifiable metabolites circulating in in plasma, but 55 metabolites have been identified in in urine. Pharmacokinetics in in Special Populations Renal Impairment: In In volunteers with varying degrees of of renal impairment and patients with arrhythmias, the the clearance of of dofetilide decreases with decreasing creatinine clearance. As As a a result, and as as seen in in clinical studies, the the half-life of of dofetilide is is longer in in patients with lower creatinine clearances. Because increase in in QT interval and the risk of of ventricular arrhythmias are directly related to to plasma concentrations of of dofetilide, dosage adjustment based on on calculated creatinine clearance is is critically important (see DOSAGE AND ADMINISTRATION). Patients with severe renal impairment (creatinine clearance <20 ml/min) were not included in in clinical or or pharmacokinetic studies (see CONTRAINDICATIONS). Hepatic Impairment: There was no no clinically significant alteration in in the the pharmacokinetics of of dofetilide in in volunteers with mild to to moderate hepatic impairment (Child-Pugh Class A and B) B) compared to to age- and weight-matched healthy volunteers. Patients with severe hepatic impairment were not studied. Patients with Heart Disease: Population pharmacokinetic analyses indicate that the the plasma concentration of of dofetilide in in patients with supraventricular and ventricular arrhythmias, ischemic heart disease, or or congestive heart failure are are similar to to those of of healthy volunteers, after adjusting for for renal function. Elderly: After correction for for renal function, clearance of of dofetilide is is not related to to age. Women: A population pharmacokinetic analysis showed that women have approximately 12 18% lower dofetilide oral clearances than men (14 22% greater plasma dofetilide levels), after correction for for weight and creatinine clearance. In In females, as as in in males, renal function was the the single most important factor influencing dofetilide clearance. In In normal female volunteers, hormone replacement therapy (a (a combination of of conjugated estrogens and medroxyprogesterone) did not increase dofetilide exposure. Figure 1: 1: Mean QTc-Concentration Relationship in in Young Volunteers Over Days Mean Change from Baseline QTc Mean Change from Baseline QTc (msec) (msec) Day 11 Day (Steady State) Mean Plasma Dofetilide Concentration (ng/ml) Note: The range of of dofetilide plasma concentrations achieved with the the 500 mcg dose adjusted for for creatinine clearance is is ng/ml. The relationship between dose, efficacy, and the the increase in in QTc from baseline at at steady state for for the the two randomized, placebo-controlled studies (described further below) is is shown in in Figure The studies examined the the effectiveness of of TIKOSYN in in conversion to to sinus rhythm and maintenance of of normal sinus rhythm after conversion in in patients with atrial fibrillation/flutter of of >1 >1 week duration. As As shown, both the the probability of of a a patient s remaining in in sinus rhythm at at six six months and the the change in in QTc from baseline at at steady state of of dosing increased in in an an approximately linear fashion with increasing dose of of TIKOSYN. Note that in in these studies, doses were modified by by results of of creatinine clearance measurement and in-hospital QTc prolongation. Drug-Drug Interactions (see PRECAUTIONS) Dose-Response and Concentration Response for Increase in in QT Interval Increase in in QT interval is is directly related to to dofetilide dose and plasma concentration. Figure 11 shows that the the relationship in in normal volunteers between dofetilide plasma concentrations and change in in QTc is is linear, with a a positive slope of of approximately msec/(ng/ml) after the the first dose and approximately msec/(ng/ml) at at Day (reflecting a a steady state of of dosing). A linear relationship between mean QTc increase and dofetilide dose was also seen in in patients with renal impairment, in in patients with ischemic heart disease, and in in patients with supraventricular and ventricular arrhythmias. 8

9 Figure 2: 2: Relationship Between TIKOSYN Dose, QTc Increase and Maintenance of of NSR QTc Change from Baseline QTc Change from Baseline at Steady State (msec) at Steady State (msec) QTc (95% CI) CI) = Probability of of NSR (95% CI) CI) = Probability of Remaining in NSR Probability at of months Remaining (%) in NSR at 6 months (%) Dofetilide Dofetilide Dofetilide Placebo 125mcg 250mcg 500mcg Number of of patients evaluated for for maintenance of of NSR: TIKOSYN, placebo. Number of of patients evaluated for for QTc change: TIKOSYN, placebo. CLINICAL STUDIES Chronic Atrial Fibrillation and/or Atrial Flutter Two randomized, parallel, double-blind, placebo-controlled, dose-response trials evaluated the the ability of of TIKOSYN 1) 1) to to convert patients with atrial fibrillation or or atrial flutter (AF/AFl) of of more than 11 week duration to to normal sinus rhythm (NSR) and 2) 2) to to maintain NSR (delay time to to recurrence of of AF/AFl) after drug-induced or or electrical cardioversion. A total of of 996 patients with a a one week to to two year history of of atrial fibrillation/atrial flutter were enrolled. Both studies randomized patients to to placebo or or to to doses of of TIKOSYN 125 mcg, 250 mcg, 500 mcg, or or in in one study a a comparator drug, given twice a a day (these doses were lowered based on on calculated creatinine clearance and, in in one of of the the studies, for for QT interval or or QTc). All patients were started on on therapy in in a a hospital where their ECG was monitored (see DOSAGE AND ADMINISTRATION). Patients were excluded from participation if if they had had syncope within the the past 66 months, AV block greater than first degree, MI MI or or unstable angina within 11 month, cardiac surgery within 22 months, history of of QT interval prolongation or or polymorphic ventricular tachycardia associated with use of of antiarrhythmic drugs, QT interval or or QTc >440 msec, serum creatinine >2.5 mg/ml, significant diseases of of other organ systems; used cimetidine; or or used drugs known to to prolong the the QT interval. Both studies enrolled mostly Caucasians (over 90%), males (over 70%), and patients 65 years of of age (over 50%). Most (>90%) were NYHA Functional ClassI I or or II. II. Approximately one-half had structural heart disease (including ischemic heart disease, cardiomyopathies, and valvular disease) and about one-half were hypertensive. A substantial proportion of of patients were on on concomitant therapy, including digoxin (over 60%), diuretics (over 20%), and ACE inhibitors (over 30%). About 90% were on on anticoagulants. Acute conversion rates are are shown in in Table 11 for for randomized doses (doses were adjusted for for calculated creatinine clearance and, in in Study 1, 1, for for QT interval or or QTc). Of Of patients who converted pharmacologically, approximately 70% converted within hours. Table 1: 1: Conversion of of Atrial Fibrillation/Flutter to to Normal Sinus Rhythm TIKOSYN Dose mcg mcg mcg Placebo Study 11 5/82(6%) 8/82(10%) 23/77(30%) 1/84(1%) Study 22 8/135(6%) 14/133(11%) 38/129(29%) 2/137(1%) Patients who did not convert to to NSR with randomized therapy within hours had electrical cardioversion. Those patients remaining in in NSR after conversion in in hospital were continued on on randomized therapy as as outpatients (maintenance period) for for up up to to one year unless they experienced a a recurrence of of atrial fibrillation/atrial flutter or or withdrew for for other reasons. Table 22 shows, by by randomized dose, the the percentage of of patients at at 66 and months in in both studies who remained on on treatment in in NSR and the the percentage of of patients who withdrew because of of recurrence of of AF/AFl or or adverse events. Table 2: 2: Patient Status at at 66 and Months Post Randomization TIKOSYN Dose mcg mcg mcg Placebo Study 1 1 Randomized Achieved NSR months Still Still on on treatment in in NSR 38% 44% 52% 32% D/C D/C for for recurrence 55% 49% 33% 63% D/C D/C for for AEs 3% 3% 3% 3% 8% 8% 4% 4% months Still Still on on treatment in in NSR 32% 26% 46% 22% D/C D/C for for recurrence 58% 57% 36% 72% D/C D/C for for AEs 7% 7% 11% 8% 8% 6% 6% Study 2 2 Randomized Achieved NSR months Still Still on on treatment in in NSR 41% 49% 57% 22% D/C D/C for for recurrence 48% 42% 27% 72% D/C D/C for for AEs 9% 9% 6% 6% 10% 4% 4% months Still Still on on treatment in in NSR 25% 42% 49% 16% D/C D/C for for recurrence 59% 47% 32% 76% D/C D/C for for AEs 11% 6% 6% 12% 5% 5% Note that that columns do do not not add add up up to to 100% due due to to discontinuations for for other reasons. 9

10 Table 33 and Figures 33 and 44 show, by by randomized dose, the the effectiveness of of TIKOSYN in in maintaining NSR using Kaplan Meier analysis, which shows patients remaining on on treatment. Table3: 3: P-Values and Median Time (days) to to Recurrence of of AF/AFl TIKOSYN Dose mcg mcg mcg Placebo Study 1 1 p-value vs. vs. placebo P=0.21 P=0.10 P<0.001 Median time to to recurrence (days) > Study 2 2 p-value vs. vs. placebo P=0.006 P<0.001 P<0.001 Median time to to recurrence (days) >365 > Median time to to recurrence of of AF/AFl could not not be be estimated accurately for for the the mcg treatment group in in Study 2 2 and and the the mcg treatment groups in in Studies 1 1 and and 2 2 because TIKOSYN maintained >50% of of patients (51%, 58%, and and 66%, respectively) in in NSR for for the the months duration of of the the studies. Figure 3: 3: Maintenance of of Normal Sinus Rhythm, TIKOSYN Regimen vs. vs. Placebo (Study 1) 1) Probability of Remaining in NSR Probability of Remaining in NSR p-value Log Rank Test mcg p= mcg p= mcg p< mcg Dofetilide 250mcg Dofetilide 125mcg Dofetilide Placebo Time (Months) The point estimates of of the the probabilities of of remaining in in NSR at at 66 and months were 62% and 58%, respectively, for for TIKOSYN 500 mcg ; 50% and 37%, respectively, for for TIKOSYN 250 mcg ; and 37%, and 25%, respectively, for for placebo. Figure 4: 4: Maintenance of of Normal Sinus Rhythm, TIKOSYN Regimen vs. vs. Placebo (Study 2) 2) Probability of Remaining in NSR Probability of Remaining in NSR mcg Dofetilide 250mcg Dofetilide 125mcg Dofetilide p-value Log Rank Test Placebo mcg p= mcg p< mcg p< Time (Months) The point estimates of of the the probabilities of of remaining in in NSR at at 66 and months were 71% and 66%, respectively, for for TIKOSYN 500 mcg ; 56% and 51%, respectively, for for TIKOSYN 250 mcg ; and 26% and 21%, respectively, for for placebo. In In both studies, TIKOSYN resulted in in a a dose-related increase in in the the number of of patients maintained in in NSR at at all all time periods and delayed the the time of of recurrence of of sustained AF. Data pooled from both studies show that there is is a a positive relationship between the the probability of of staying in in NSR, TIKOSYN dose, and increase in in QTc (see Figure 22 in in CLINICAL PHARMACOLOGY, Dose-Response and Concentration Response for Increase in in QT Interval). Analysis of of pooled data for for patients randomized to to a a TIKOSYN dose of of 500 mcg twice daily showed that maintenance of of NSR was similar in in both males and females, in in both patients aged <65 years and patients 65 years of of age, and in in both patients with atrial flutter as as a a primary diagnosis and those with a a primary diagnosis of of atrial fibrillation. During the the period of of in-hospital initiation of of dosing, 23% of of patients in in Studies 11 and 22 had their dose adjusted downward on on the the basis of of their calculated creatinine clearance, and 3% had their dose down-titrated dueto to increased QT interval or or QTc. Increased QT interval or or QTc led led to to discontinuation of of therapy in in 3% of of patients. Safety in in Patients with Structural Heart Disease: DIAMOND Studies (The Danish Investigations of of Arrhythmia and Mortality on on Dofetilide) The two DIAMOND studies were 3-year trials comparing the the effects of of TIKOSYN and placebo on on mortality and morbidity in in patients with impaired left ventricular function (ejection fraction 35%). Patients were treated for for at at least one year. One study was in in patients with moderate to to severe (60% NYHA Class III III or or IV) congestive heart failure (DIAMOND CHF) and the the other 10

11 was in in patients with recent myocardial infarction (DIAMOND MI) (of (of whom 40% had NYHA Class III III or or IV IV heart failure). Both groups were at at relatively high risk of of sudden death. The DIAMOND trials were intended to to determine whether TIKOSYN could reduce that risk. The trials did not demonstrate a a reduction in in mortality; however, they provide reassurance that, when initiated carefully, in in a a hospital or or equivalent setting, TIKOSYN did not increase mortality in in patients with structural heart disease, an an important finding because other antiarrhythmics [notably the the Class IC IC antiarrhythmics studied in in the the Cardiac Arrhythmia Suppression Trial (CAST) and a a pure Class III III antiarrhythmic, d-sotalol (SWORD)] have increased mortality in in post-infarction populations. The DIAMOND trials therefore provide evidence of of a a method of of safe use of of TIKOSYN in in a a population susceptible to to ventricular arrhythmias. In In addition, the the subset of of patients with AF in in the the DIAMOND trials provide further evidence of of safety in in a a population of of patients with structural heart disease accompanying the the AF. Note, however, that this AF population was given a a lower (250 mcg ) dose (see CLINICAL STUDIES, DIAMOND Patients with Atrial Fibrillation). In In both DIAMOND studies, patients were randomized to to 500 mcg of of TIKOSYN, but this was reduced to to 250 mcg if if calculated creatinine clearance was ml/min, if if patients had AF, or or if if QT interval prolongation (>550 msec or or >20% increase from baseline) occurred after dosing. Dose reductions for for reduced calculated creatinine clearance occurred in in 47% and 45% of of DIAMOND CHF and MI MI patients, respectively. Dose reductions for for increased QT interval or or QTc occurred in in 5% and 7% of of DIAMOND CHF and MI MI patients, respectively. Increased QT interval or or QTc (>550 msec or or >20% increase from baseline) resulted in in discontinuation of of 1.8% of of patients in in DIAMOND CHF and 2.5% of of patients in in DIAMOND MI. In In the DIAMOND studies, all all patients were hospitalized for at at least 33 days after treatment was initiated and monitored by by telemetry. Patients with QTc greater than 460 msec, second or or third degree AV block (unless with pacemaker), resting heart rate <50 bpm, or or prior history of of polymorphic ventricular tachycardia were excluded. DIAMOND CHF studied 1518 patients hospitalized with severe CHF who had confirmed impaired left ventricular function (ejection fraction 35%). Patients received a a median duration of of therapy of of greater than one year. There were 311 deaths from all all causes in in patients randomized to to TIKOSYN (n=762) and 317 deaths in in patients randomized to to placebo (n=756). The probability of of survival at at one year was 73% (95% CI: CI: 70% 76%) in in the the TIKOSYN group and 72% (95% CI: CI: 69% 75%) in in the the placebo group. Similar results were seen for for cardiac deaths and arrhythmic deaths. Torsade de de Pointes occurred in in 25/762 patients (3.3%) receiving TIKOSYN. The majority of of cases (76%) occurred within the the first 33 days of of dosing. In In all, all, 437/762 (57%) of of patients on on TIKOSYN and 459/756 (61%) on on placebo required hospitalization. Of Of these, 229/762 (30%) of of patients on on TIKOSYN and 290/756 (38%) on on placebo required hospitalization because of of worsening heart failure. DIAMOND MI MI studied 1510 patients hospitalized with recent myocardial infarction (2 7 days) who had confirmed impaired left ventricular function (ejection fraction 35%). Patients received a a median duration of of therapy of of greater than one year. There were 230 deaths in in patients randomized to to TIKOSYN (n=749) and 243 deaths in in patients randomized to to placebo (n=761). The probability of of survival at at one year was 79% (95% CI: CI: 76% 82%) in in the the TIKOSYN group and 77% (95% CI: CI: 74% 80%) in in the the placebo group. Cardiac and arrhythmic mortality showed a a similar result. Torsade de de Pointes occurred in in 7/749 patients (0.9%) receiving TIKOSYN. Of Of these, 44 cases occurred within the the first 33 days of of dosing and 33 cases occurred between Day 44 and the the conclusion of of the the study. In In all, all, 371/749 (50%) of of patients on on TIKOSYN and 419/761 (55%) on on placebo required hospitalization. Of Of these, 200/749 (27%) of of patients on on TIKOSYN and 205/761 (27%) on on placebo required hospitalization because of of worsening heart failure. DIAMOND Patients with Atrial Fibrillation (the DIAMOND AF subpopulation). There were 506 patients in in the the two DIAMOND studies who had atrial fibrillation (AF) at at entry to to the the studies (249 randomized to to TIKOSYN and 257 randomized to to placebo). DIAMOND AF patients randomized to to TIKOSYN received 250 mcg ; 65% of of these patients had impaired renal function, so so that 250 mcg represents the the dose they would have received in in the the AF trials, which would give drug exposure similar to to a a person with normal renal function given 500 mcg. In In the the DIAMOND AF subpopulation, there were 111 deaths (45%) in in the the 249 patients in in the the TIKOSYN group and 116 deaths (45%) in in the the 257 patients in in the the placebo group. Hospital readmission rates for for any reason were 125/249 or or 50% on on TIKOSYN and 156/257 or or 61% for for placebo. Of Of these, readmission rates for for worsening heart failure were 73/249 or or 29% on on TIKOSYN and 102/257 or or 40% for for placebo. Of Of the the 506 patients in in the the DIAMOND studies who had atrial fibrillation or or flutter at at baseline, 12% of of patients in in the the TIKOSYN group and 2% of of patients in in the the placebo group had converted to to normal sinus rhythm after one month. In In those patients converted to to normal sinus rhythm, 79% of of the the TIKOSYN group and 42% of of the the placebo group remained in in normal sinus rhythm for for one year. In In the the DIAMOND studies, although Torsade de de Pointes occurred more frequently in in the the TIKOSYN-treated patients (see ADVERSE REACTIONS), TIKOSYN, given with an an initial 3-day hospitalization and with dose modified for for reduced creatinine clearance and increased QT interval, was not associated with an an excess risk of of mortality in in these populations with structural heart disease in in the the individual studies or or in in an an analysis of of the the combined studies. The presence of of atrial fibrillation did not affect outcome. INDICATIONS AND USAGE Maintenance of of Normal Sinus Rhythm (Delay in in AF/AFl Recurrence) TIKOSYN is is indicated for for the the maintenance of of normal sinus rhythm (delay in in time to to recurrence of of atrial fibrillation/atrial flutter [AF/AFl]) in in patients with atrial fibrillation/atrial flutter of of greater than one week duration who have been converted to to normal sinus rhythm. Because TIKOSYN can cause life threatening ventricular arrhythmias, it it should be be reserved for for patients in in whom atrial fibrillation/atrial flutter is is highly symptomatic. In In general, antiarrhythmic therapy for for atrial fibrillation/atrial flutter aims to to prolong the the time in in normal sinus rhythm. Recurrence is is expected in in some patients (see CLINICAL STUDIES). Conversion of of Atrial Fibrillation/Flutter TIKOSYN is is indicated for for the the conversion of of atrial fibrillation and atrial flutter to to normal sinus rhythm. TIKOSYN has not been shown to to be be effective in in patients with paroxysmal atrial fibrillation. 11

12 CONTRAINDICATIONS TIKOSYN is is contraindicated in in patients with congenital or or acquired long QT syndromes. TIKOSYN should not be be used in in patients with a a baseline QT interval or or QTc >440 msec (500 msec in in patients with ventricular conduction abnormalities). TIKOSYN is is also contraindicated in in patients with severe renal impairment (calculated creatinine clearance <20 ml/min). The concomitant use of of verapamil or or the the cation transport system inhibitors cimetidine, trimethoprim (alone or or in in combination with sulfamethoxazole), or or ketoconazole with TIKOSYN is is contraindicated (see WARNINGS and PRECAUTIONS, Drug-Drug Interactions), as as each of of these drugs cause a a substantial increase in in dofetilide plasma concentrations. In In addition, other known inhibitors of of the the renal cation transport system such as as prochlorperazine, dolutegravir and megestrol should not be be used in in patients on on TIKOSYN. The concomitant use of of hydrochlorothiazide (alone or or in in combinations such as as with triamterene) with TIKOSYN is is contraindicated (see PRECAUTIONS, Drug-Drug Interactions) because this has been shown to to significantly increase dofetilide plasma concentrations and QT interval prolongation. TIKOSYN is is also contraindicated in in patients with a a known hypersensitivity to to the the drug. WARNINGS Ventricular Arrhythmia: TIKOSYN (dofetilide) can cause serious ventricular arrhythmias, primarily Torsade de de Pointes (TdP) type ventricular tachycardia, a a polymorphic ventricular tachycardia associated with QT interval prolongation. QT interval prolongation is is directly related to to dofetilide plasma concentration. Factors such as as reduced creatinine clearance or or certain dofetilide drug interactions will increase dofetilide plasma concentration. The risk of of TdP can be be reduced by by controlling the plasma concentration through adjustment of of the initial dofetilide dose according to to creatinine clearance and by by monitoring the ECG for excessive increases in in the QT interval. Treatment with dofetilide must therefore be be started only in in patients placed for a a minimum of of three days in in a a facility that can provide electrocardiographic monitoring and in in the presence of of personnel trained in in the management of of serious ventricular arrhythmias. Calculation of of the creatinine clearance for all all patients must precede administration of of the first dose of of dofetilide. For detailed instructions regarding dose selection, see DOSAGE AND ADMINISTRATION. The risk of of dofetilide induced ventricular arrhythmia was assessed in in three ways in in clinical studies: 1) 1) by by description of of the the QT interval and its its relation to to the the dose and plasma concentration of of dofetilide; 2) 2) by by observing the the frequency of of TdP in in TIKOSYN-treated patients according to to dose; 3) 3) by by observing the the overall mortality rate in in patients with atrial fibrillation and in in patients with structural heart disease. Relation of of QT Interval to to Dose: The QT interval increases linearly with increasing TIKOSYN dose (see Figures 11 and 22 in in CLINICAL PHARMACOLOGY and Dose-Response and Concentration Response for Increase in in QT Interval). Frequency of of Torsade de de Pointes: In In the the supraventricular arrhythmia population (patients with AF and other supraventricular arrhythmias), the the overall incidence of of Torsade de de Pointes was 0.8%. The frequency of of TdP by by dose is is shown in in Table There were no no cases of of TdP on on placebo. Table 4: 4: Summary of of Torsade de de Pointes in in Patients Randomized to to Dofetilide by by Dose; Patients with Supraventricular Arrhythmias TIKOSYN Dose <250 mcg mcg > mcg >500 mcg All All Doses Number of of Patients Torsade de de Pointes (0.3%) 6 6 (0.9%) 4 4 (10.5%) (0.8%) As As shown in in Table 5, 5, the the rate of of TdP was reduced when patients were dosed according to to their renal function (see CLINICAL PHARMACOLOGY, Pharmacokinetics in in Special Populations, Renal Impairment and DOSAGE AND ADMINISTRATION). Table 5: 5: Incidence of of Torsade de de Pointes Before and After Introduction of of Dosing According to to Renal Function Total Before After Population: n/n n/n %% n/n n/n %% n/n n/n %% Supraventricular Arrhythmias 11/1346 (0.8%) 6/193 (3.1%) 5/1153 (0.4%) DIAMOND CHF 25/762 (3.3%) 7/148 (4.7%) 18/614 (2.9%) DIAMOND MI MI 7/749 (0.9%) 3/101 (3.0%) 4/648 (0.6%) DIAMOND AF AF 4/249 (1.6%) 0/43 (0%) 4/206 (1.9%) The majority of of the the episodes of of TdP occurred within the the first three days of of TIKOSYN therapy (10/11 events in in the the studies of of patients with supraventricular arrhythmias; 19/25 and 4/7 events in in DIAMOND CHF and DIAMOND MI, respectively; 2/4 events in in the the DIAMOND AF subpopulation). Mortality: In In a a pooled survival analysis of of patients in in the the supraventricular arrhythmia population (low prevalence of of structural heart disease), deaths occurred in in 0.9% (12/1346) of of patients receiving TIKOSYN and 0.4% (3/677) in in the the placebo group. Adjusted for for duration of of therapy, primary diagnosis, age, gender, and prevalence of of structural heart disease, the the point estimate of of the the hazard ratio for for the the pooled studies (TIKOSYN/placebo) was (95% CI: CI: 0.3, 4.3). The DIAMOND CHF and MI MI trials examined mortality in in patients with structural heart disease (ejection fraction 35%). In In these large, double-blind studies, deaths occurred in in 36% (541/1511) of of TIKOSYN patients and 37% (560/1517) of of placebo patients. In In an an analysis of of 506 DIAMOND patients with atrial fibrillation/flutter at at baseline, one year mortalityon on TIKOSYN was 31% vs. vs. 32% on on placebo (see CLINICAL STUDIES). Because of of the the small number of of events, an an excess mortality due to to TIKOSYN cannot be be ruled out with confidence in in the the pooled survival analysis of of placebo-controlled trials in in patients with supraventricular arrhythmias. However, it it is is reassuring that in in two large placebo-controlled mortality studies in in patients with significant heart disease (DIAMOND CHF/MI), there were no no 12

13 more deaths in in TIKOSYN-treated patients than in in patients given placebo (see CLINICAL STUDIES). Drug-Drug Interactions (see CONTRAINDICATIONS) Because there is is a a linear relationship between dofetilide plasma concentration and QTc, concomitant drugs that interfere with the the metabolism or or renal elimination of of dofetilide may increasethe the risk of of arrhythmia (Torsade de de Pointes). TIKOSYN is is metabolized to to a a small degree by by the the CYP3A4 isoenzyme of of the the cytochrome P450 system and an an inhibitor of of this system could increase systemic dofetilide exposure. More important, dofetilide is is eliminated by by cationic renal secretion, and three inhibitors of of this process have been shown to to increase systemic dofetilide exposure. The magnitude of of the the effect on on renal elimination by by cimetidine, trimethoprim, and ketoconazole (all contraindicated concomitant uses with dofetilide) suggests that all all renal cation transport inhibitors should be be contraindicated. Hypokalemia and Potassium-Depleting Diuretics Hypokalemia or or hypomagnesemia may occur with administration of of potassium-depleting diuretics, increasing the the potential for for Torsade de de Pointes. Potassium levels should be be within the the normal range prior to to administration of of TIKOSYN and maintained in in the the normal range during administration of of TIKOSYN (see DOSAGE AND ADMINISTRATION). Use with Drugs that Prolong QT Interval and Antiarrhythmic Agents The use of of TIKOSYN in in conjunction with other drugs that prolong the the QT interval has not been studied and is is not recommended. Such drugs include phenothiazines, cisapride, bepridil, tricyclic antidepressants, certain oral macrolides, and certain fluoroquinolones. Class I I or or Class III III antiarrhythmic agents should be be withheld for for at at least three half-lives prior to to dosing with TIKOSYN. In In clinical trials, TIKOSYN was administered to to patients previously treated with oral amiodarone only if if serum amiodarone levels were below mg/l or or amiodarone had been withdrawn for for at at least three months. PRECAUTIONS Renal Impairment The overall systemic clearance of of dofetilide is is decreased and plasma concentration increased with decreasing creatinine clearance. The dose of of TIKOSYN must be be adjusted based on on creatinine clearance (see DOSAGE AND ADMINISTRATION). Patients undergoing dialysis were not included in in clinical studies, and appropriate dosing recommendations for for these patients are are unknown. There is is no no information about the the effectiveness of of hemodialysis in in removing dofetilide from plasma. Hepatic Impairment After adjustment for for creatinine clearance, no no additional dose adjustment is is required for for patients with mild or or moderate hepatic impairment. Patients with severe hepatic impairment have not been studied. TIKOSYN should be be used with particular caution in in these patients. Cardiac Conduction Disturbances Animal and human studies have not shown any adverse effects of of dofetilide on on conduction velocity. No No effect on on AV nodal conduction following TIKOSYN treatment was noted in in normal volunteers and in in patients with 1 st 1 st degree heart block. Patients with sick sinus syndrome or or with 2 nd 2 nd or or 3 rd 3 rd degree heart block were not included in in the the Phase 33 clinical trials unless a a functioning pacemaker was present. TIKOSYN has been used safely in in conjunction with pacemakers (53 patients in in DIAMOND studies, 136 in in trials in in patients with ventricular and supraventricular arrhythmias). Information for Patients Please refer patient to to the Medication Guide. Prior to to initiation of of TIKOSYN therapy, the patient should be be advised to to read the Medication Guide and reread it it each time therapy is is renewed in in case the patient s status has changed. The patient should be be fully instructed on on the need for compliance with the recommended dosing of of TIKOSYN and the potential for drug interactions, and the need for periodic monitoring of of QTc and renal function to to minimize the risk of of serious abnormal rhythms. Medications and Supplements: Assessment of of patients medication history should include all all over-the-counter, prescription, and herbal/natural preparations with emphasis on on preparations that may affect the the pharmacokinetics of of TIKOSYN such as as cimetidine (see CONTRAINDICATIONS), trimethoprim alone or or in 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 or in in combinations such as as with triamterene) (see CONTRAINDICATIONS), other cardiovascular drugs (especially verapamil see CONTRAINDICATIONS), phenothiazines, and tricyclic antidepressants (see WARNINGS). If If aa patient is is taking TIKOSYN and requires anti-ulcer therapy, omeprazole, ranitidine, or or antacids (aluminum and magnesium hydroxides) should be be used as as alternatives to to cimetidine, as as these agents have no no effect on on the the pharmacokinetics of of TIKOSYN. Patients should be be instructed to to notify their health care providers of of any change in in over-the-counter, prescription, or or supplement use. If If a a patient is is hospitalized or or is is prescribed a a new medication for for any condition, the the patient must inform the the health care provider of of ongoing TIKOSYN therapy. Patients should also check with their health care provider and/or pharmacist prior to to taking a a new over-thecounter preparation. Electrolyte Imbalance: If If patients experience symptoms that may be be associated with altered electrolyte balance, such as as excessive or or prolonged diarrhea, sweating, or or vomiting or or loss of of appetite or or thirst, these conditions should immediately be be reported to to their health care provider. Dosing Schedule: Patients should be be instructed NOT to to double the the next dose if if a a dose is is missed. The next dose should be be taken at at the the usual time. Drug/Laboratory Test Interactions None known. 13

14 Drug-Drug Interactions Cimetidine: (see WARNINGS, CONTRAINDICATIONS) Concomitant use of of cimetidine is is contraindicated. Cimetidine at at 400 mg (the usual prescription dose) co-administered with TIKOSYN (500 mcg ) for for 77 days has been shown to to increase dofetilide plasma levels by by 58%. Cimetidine at at doses of of 100 mg (OTC dose) resulted in in a a 13% increase in in dofetilide plasma levels (500 mcg single dose). No No studies have been conducted at at intermediate doses of of cimetidine. If If a a patient requires TIKOSYN and anti-ulcer therapy, it it is is suggested that omeprazole, ranitidine, or or antacids (aluminum and magnesium hydroxides) be be used as as alternatives to to cimetidine, as as these agents have no no effect on on the the pharmacokinetic profile of of TIKOSYN. Verapamil: (see CONTRAINDICATIONS) Concomitant use of of verapamil is is contraindicated. Co-administration of of TIKOSYN with verapamil resulted in in increases in in dofetilide peak plasma levels of of 42%, although overall exposure to to dofetilide was not significantly increased. In In an an analysis of of the the supraventricular arrhythmia and DIAMOND patient populations, the the concomitant administration of of verapamil with dofetilide was associated with a a higher occurrence of of Torsade de de Pointes. Ketoconazole: (see WARNINGS, CONTRAINDICATIONS) Concomitant use of of ketoconazole is is contraindicated. Ketoconazole at at 400 mg daily (the maximum approved prescription dose) co-administered with TIKOSYN (500 mcg ) for for 77 days has been shown to to increase dofetilide C max max by by 53% in in males and 97% in in females, and AUC by by 41% in in males and 69% in in females. Trimethoprim Alone or or in in Combination with Sulfamethoxazole: (see WARNINGS, CONTRAINDICATIONS) Concomitant use of of trimethoprim alone or or in in combination with sulfamethoxazole is is contraindicated. Trimethoprim 160 mg in in combination with 800 mg sulfamethoxazole co-administered with TIKOSYN (500 mcg ) for for 44 days has been shown to to increase dofetilide AUC by by 103% and C max max by by 93%. Hydrochlorothiazide (HCTZ) Alone or or in in Combination with Triamterene: (see CONTRAINDICATIONS) Concomitant use of of HCTZ alone or or in in combination with triamterene is is contraindicated. HCTZ mg QD or or HCTZ/triamterene 50/100 mg QD was co-administered with TIKOSYN (500 mcg ) for for 55 days (following 22 days of of diuretic use at at half dose). In In patients receiving HCTZ alone, dofetilide AUC increased by by 27% and C max max by by 21%. However, the the pharmacodynamic effect increased by by 197% (QTc increase over time) and by by 95% (maximum QTc increase). In In patients receiving HCTZ in in combination with triamterene, dofetilide AUC increased by by 30% and C max max by by 16%. However, the the pharmacodynamic effect increased by by 190% (QTc increase over time) and by by 84% (maximum QTc increase). The pharmacodynamic effects can be be explained by by a a combination of of the the increase in in dofetilide exposure and the the reductions in in serum potassium. In In the the DIAMOND trials, 1252 patients were treated with TIKOSYN and diuretics concomitantly, of of whom 493 died compared to to 508 deaths among the the 1248 patients receiving placebo and diuretics. Of Of the the 229 patients who had potassium depleting diuretics added to to their concomitant medications in in the the DIAMOND trials, the the patients on on TIKOSYN had a a non-significantly reduced relative risk for for death of of 0.68 (95% CI: 0.376, 1.230). Potential Drug Interactions Dofetilide is is eliminated in in the the kidney by by cationic secretion. Inhibitors of of renal cationic secretion are are contraindicated with TIKOSYN. In In addition, drugs that are are actively secreted via via this route (e.g., triamterene, metformin, and amiloride) should be be co-administered with care as as they might increase dofetilide levels. Dofetilide is is metabolized to to a a small extent by by the the CYP3A4 isoenzyme of of the the cytochrome P450 system. Inhibitors of of the the CYP3A4 isoenzyme could increase systemic dofetilide exposure. Inhibitors of 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 be cautiously co-administered with TIKOSYN as as they can potentially increase dofetilide levels. Dofetilide is is not an an inhibitor of of CYP3A4 nor of of other cytochrome P450 isoenzymes (e.g., CYP2C9, CYP2D6) and is is not expected to to increase levels of of drugs metabolized by by CYP3A4. Other Drug Interaction Information Digoxin: Studies in in healthy volunteers have shown that TIKOSYN does not affect the the pharmacokinetics of of digoxin. In In patients, the the concomitant administration of of digoxin with dofetilide was associated with a a higher occurrence of of Torsade de de Pointes. It It is is not clear whether this represents an an interaction with TIKOSYN or or the the presence of of more severe structural heart disease in in patients on on digoxin; structural heart disease is is a a known risk factor for for arrhythmia. No No increase in in mortality was observed in in patients taking digoxin as as concomitant medication. Other Drugs: In In healthy volunteers, amlodipine, phenytoin, glyburide, ranitidine, omeprazole, hormone replacement therapy (a (a combination of of conjugated estrogens and medroxyprogesterone), antacid (aluminum and magnesium hydroxides), and theophylline did not affect the the pharmacokinetics of of TIKOSYN. In In addition, studies in in healthy volunteers have shown that TIKOSYN does not affect the the pharmacokinetics or or pharmacodynamics of of warfarin, or or the the pharmacokinetics of of propranolol (40 mg twice daily), phenytoin, theophylline, or or oral contraceptives. Population pharmacokinetic analyses were conducted on on plasma concentration data from 1445 patients in in clinical trials to to examine the the effects of of concomitant medications on on clearance or or volume of of distribution of of dofetilide. Concomitant medications were grouped as as ACE inhibitors, oral anticoagulants, calcium channel blockers, beta blockers, cardiac glycosides, inducers of of CYP3A4, substrates and inhibitors of of CYP3A4, substrates and inhibitors of of P-glycoprotein, nitrates, sulphonylureas, loop diuretics, potassium sparing diuretics, thiazide diuretics, substrates and inhibitors of of tubular organic cation transport, and QTc-prolonging drugs. Differences in in clearance between patients on on these medications (at (at any occasion in in the the study) and those off off medications varied between -16% and +3%. The mean clearances of of dofetilide were 16% and 15% lowerin in patients on on thiazide diuretics and inhibitors of of tubular organic cation transport, respectively. Carcinogenesis, Mutagenesis, Impairment of of Fertility Dofetilide had no no genotoxic effects, with or or without metabolic activation, based on on the the bacterial mutation assay and tests of of cytogenetic aberrations in in vivoin in mouse bone marrow and in in vitroin in human lymphocytes. Rats and mice treated with dofetilide in in the the diet for for two years showed no no evidence of of an an increased incidence of of tumors compared to to controls. The highest dofetilide dose 14

15 administered for for months was mg/kg/day to to rats and mg/kg/day to to mice. Mean dofetilide AUCs (0 24hr) at at these doses were about and times, respectively, the the maximum likely human AUC. There was no no effect on on mating or or fertility when dofetilide was administered to to male and female rats at at doses as as high as as mg/kg/day, a a dose that would be be expected to to provide a a mean dofetilide AUC (0 24hr) about 33 times the the maximum likely human AUC. Increased incidences of of testicular atrophy and epididymal oligospermia and a a reduction in in testicular weight were, however, observed in in other studies in in rats. Reduced testicular weight and increased incidence of of testicular atrophy were also consistent findings in in dogs and mice. The no no effect doses for for these findings in in chronic administration studies in in these 33 species (3, (3, 0.1, and 66 mg/kg/day) were associated with mean dofetilide AUCs that were about 4, 4, 1.3, and 33 times the the maximum likely human AUC, respectively. Pregnancy Category C Dofetilide has been shown to to adversely affect in in utero growth and survival of of rats and mice when orally administered during organogenesis at at doses of of 22 or or more mg/kg/day. Other than an an increased incidence of of non-ossified 5 th 5 th metacarpal, and the the occurrence of of hydroureter and hydronephroses at at doses as as low as as 11 mg/kg/day in in the the rat, structural anomalies associated with drug treatment were not observed in in either species at at doses below 22 mg/kg/day. The clearest drug-effect associations were for for sternebral and vertebral anomalies in in both species; cleft palate, adactyly, levocardia, dilation of of cerebral ventricles, hydroureter, hydronephroses, and unossified metacarpal in in the the rat; and increased incidence of of unossified calcaneum in in the the mouse. The no observed adverse effect dose in in both species was mg/kg/day. The mean dofetilide AUCs (0 (0 24hr) at at this dose in in the the rat rat and mouse are are estimated to to be be about equal to to the the maximum likely human AUC and about half the the likely human AUC, respectively. There are are no no adequate and well controlled studies in in pregnant women. Therefore, dofetilide should only be be administered to to pregnant women where the the benefit to to the the patient justifies the the potential risk to to the the fetus. Nursing Mothers There is is no no information on on the the presence of of dofetilide in in breast milk. Patients should be be advised not to to breast-feed an an infant if if they are are taking TIKOSYN. Geriatric Use Of Of the the total number of of patients in in clinical studies of of TIKOSYN, 46% were to to years old. No No overall differences in in safety, effect on on QTc, or or effectiveness were observed between elderly and younger patients. Because elderly patients are are more likely to to have decreased renal function with a a reduced creatinine clearance, care must be be taken in in dose selection (see DOSAGE AND ADMINISTRATION). specifically investigated this risk, in in post-hoc analyses, no no increased mortality was observed in in females on on TIKOSYN compared to to females on on placebo. Pediatric Use The safety and effectiveness of of TIKOSYN in in children (<18 years old) has not been established. ADVERSE REACTIONS The TIKOSYN clinical program involved approximately 8,600 patients in in 130 clinical studies of of normal volunteers and patients with supraventricular and ventricular arrhythmias. TIKOSYN was administered to to 5,194 patients, including two large, placebo-controlled mortality trials (DIAMOND CHF and DIAMOND MI) in in which 1,511 patients received TIKOSYN for for up up to to three years. In In the the following section, adverse reaction data for for cardiac arrhythmias and non-cardiac adverse reactions are are presented separately for for patients included in in the the supraventricular arrhythmia development program and for for patients included in in the the DIAMOND CHF and MI MI mortality trials (see CLINICAL STUDIES, Safety in in Patients with Structural Heart Disease, DIAMOND Studies, for for a a description of of these trials). In In studies of of patients with supraventricular arrhythmias, a a total of of 1,346 and 677 patients were exposed to to TIKOSYN and placebo for for 551 and 207 patient years, respectively. A total of of 8.7% of of patients in in the the dofetilide groups were discontinued from clinical trials due to to adverse events compared to to 8.0% in in the the placebo groups. The most frequent reason for for discontinuation (>1%) was ventricular tachycardia (2.0% on on dofetilide vs. vs. 1.3% on on placebo). The most frequent adverse events were headache, chest pain, and dizziness. Serious Arrhythmias and Conduction Disturbances: Torsade de de Pointes is is the the only arrhythmia that showed a a dose-response relationship to to TIKOSYN treatment. It It did not occur in in placebo treated patients. The incidence of of Torsade de de Pointes in in patients with supraventricular arrhythmias was 0.8% (11/1346) (see WARNINGS). The incidence of of Torsade de de Pointes in in patients who were dosed according to to the the recommended dosing regimen (see DOSAGE AND ADMINISTRATION) was 0.8% (4/525). Table 66 shows the the frequency by by randomized dose of of serious arrhythmias and conduction disturbances reported as as adverse events in in patients with supraventricular arrhythmias. Use in in Women Female patients constituted 32% of of the the patients in in the the placebo-controlled trials of of TIKOSYN. As As with other drugs that cause Torsade de de Pointes, TIKOSYN was associated with a a greater risk of of Torsade de de Pointes in in female patients than in in male patients. During the the TIKOSYN clinical development program, the the risk of of Torsade de de Pointes in in females was approximately 33 times the the risk in in males. Unlike Torsade de de Pointes, the the incidence of of other ventricular arrhythmias was similar in in female patients receiving TIKOSYN and patients receiving placebo. Although no no study 15

16 Table 6: 6: Incidence of of Serious Arrhythmias and Conduction Disturbances in in Patients with Supraventricular Arrhythmias TIKOSYN Dose Placebo Arrhythmia event: <250 mcg mcg > mcg >500 mcg N=217 N=388 N=703 N=38 N=677 Ventricular arrhythmias* ^ ^ 3.7% 2.6% 3.4% 15.8% 2.7% Ventricular fibrillation % 0.4% 2.6% 0.1% Ventricular tachycardia^ 3.7% 2.6% 3.3% 13.2% 2.5% Torsade de de Pointes % 0.9% 10.5% 0 0 Various forms of of block AV AV block 0.9% 1.5% 0.4% % Bundle branch block % 0.1% % Heart block % 0.1% % * * Patients with more than one one arrhythmia are are counted only once in in this this category. ^ ^ Ventricular arrhythmias and and ventricular tachycardia include all all cases of of Torsade de de Pointes. In In the the DIAMOND trials, a a total of of 1,511 patients were exposed to to TIKOSYN for for 1757 patient years. The incidence of of Torsade de de Pointes was 3.3% in in CHF patients and 0.9% in in patients with a a recent MI. Table 77 shows the the incidence of of serious arrhythmias and conduction disturbances reported as as adverse events in in the the DIAMOND subpopulation that had AF at at entry to to these trials. Table 7: 7: Incidence of of Serious Arrhythmias and Conduction Disturbances in in Patients with AF at at Entry to to the DIAMOND Studies TIKOSYN 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 de Pointes 1.6% 0 0 Various forms of of block AV AV block 0.8% 2.7% (Left) bundle branch block % Heart block 1.2% 0.8% * * Patients with more than one one arrhythmia are are counted only once in in this this category. ^ ^ Ventricular arrhythmias and and ventricular tachycardia include all all cases of of Torsade de de Pointes. Other Adverse Reactions: Table 88 presents other adverse events reported with a a frequency of of >2% on on TIKOSYN and reported numerically more frequently on on TIKOSYN than on on placebo in in the the studies of of patients with supraventricular arrhythmias. Table 8: 8: Frequency of of Adverse Events Occurring at at >2% on on TIKOSYN, and Numerically More Frequently on on TIKOSYN than Placebo in in Patients with Supraventricular Arrhythmias TIKOSYN Placebo Adverse Event %% %% headache chest pain dizziness respiratory tract infection dyspnea nausea flu flu syndrome insomnia accidental injury back pain procedure (medical/surgical/health service) diarrhea rash rash abdominal pain Adverse events reported at at a a rate >2% but no no more frequently on on TIKOSYN than on on placebo were: angina pectoris, anxiety, arthralgia, asthenia, atrial fibrillation, complications (application, injection, incision, insertion, or or device), hypertension, pain, palpitation, peripheral edema, supraventricular tachycardia, sweating, urinary tract infection, ventricular tachycardia. The following adverse events have been reported with a a frequency of of <2% and numerically more frequently with TIKOSYN than placebo in in patients with supraventricular arrhythmias: angioedema, bradycardia, cerebral ischemia, cerebrovascular accident, edema, facial paralysis, flaccid paralysis, heart arrest, increased cough, liver damage, migraine, myocardial infarct, paralysis, paresthesia, sudden death, and syncope. The incidences of of clinically significant laboratory test abnormalities in in patients with supraventricular arrhythmias were similar for for patients on on TIKOSYN and those on on placebo. No No clinically relevant effects were noted in in serum alkaline phosphatase, serum GGT, LDH, AST, ALT, total bilirubin, total protein, blood urea nitrogen, creatinine, serum electrolytes (calcium, chloride, glucose, magnesium, potassium, sodium), or or creatine kinase. Similarly, no no clinically relevant effects were observed in in hematologic parameters. In In the the DIAMOND population, adverse events other than those related to to the the post-infarction and heart failure patient population were generally similar to to those seen in in the the supraventricular arrhythmia groups. OVERDOSAGE There is is no no known antidote to to TIKOSYN; treatment of of overdose should therefore be be symptomatic and supportive. The most prominent manifestation of of overdosage is is likely to to be be excessive prolongation of of the the QT interval. 16

17 In In cases of of overdose, cardiac monitoring should be be initiated. Charcoal slurry may be be given soon after overdosing but has been useful only when given within minutes of of TIKOSYN administration. Treatment of of Torsade de de Pointes or or overdose may include administration of of isoproterenol infusion, with or or without cardiac pacing. Administration of of intravenous magnesium sulfate may be be effective in in the the management of of Torsade de de Pointes. Close medical monitoring and supervision should continue until the the QT interval returns to to normal levels. Isoproterenol infusion into anesthetized dogs with cardiac pacing rapidly attenuates the the dofetilide-induced prolongation of of atrial and ventricular effective refractory periods in in a a dosedependent manner. Magnesium sulfate, administered prophylactically either intravenously or or orally in in a a dog model, was effective in in the the prevention of of dofetilide-induced Torsade de de Pointes ventricular tachycardia. Similarly, in in man, intravenous magnesium sulfate may terminate Torsade de de Pointes, irrespective of of cause. TIKOSYN overdose was rare in in clinical studies; there were two reported cases of of TIKOSYN overdose in in the the oral clinical program. One patient received very high multiples of of the the recommended dose (28 capsules), was treated with gastric aspiration minutes later, and experienced no no events. One patient inadvertently received two 500 mcg doses one hour apart and experienced ventricular fibrillation and cardiac arrest 22 hours after the the second dose. In In the the supraventricular arrhythmia population, only patients received doses greater than 500 mcg, all all of of whom received 750 mcg irrespective of of creatinine clearance. In In this very small patient population, the the incidence of of Torsade de de Pointes was 10.5% (4/38 patients), and the the incidence of of new ventricular fibrillation was 2.6% (1/38 patients). DOSAGE AND ADMINISTRATION Patients with atrial fibrillation should be be anticoagulated according to to usual medical practice prior to to electrical or or pharmacological cardioversion. Anticoagulant therapy may be be continued after cardioversion according to to usual medical practice for for the the treatment of of people with AF. Hypokalemia should be be corrected before initiation of of TIKOSYN therapy (see WARNINGS, Ventricular Arrhythmia). Patients to to be be discharged on on TIKOSYN therapy from an an inpatient setting as as described above must have an an adequate supply of of TIKOSYN, at at the the patient s individualized dose, to to allow uninterrupted dosing until the the patient receives the the first outpatient supply. TIKOSYN is is distributed only to to those hospitals and other appropriate institutions confirmed to to have received applicable dosing and treatment initiation education programs. Inpatient and subsequent outpatient discharge and refill prescriptions are are filled only upon confirmation that the the prescribing physician has received applicable dosing and treatment initiation education programs. For this purpose, a a list list for for use by by pharmacists is is maintained containing hospitals and physicians who have received one of of the the education programs. Instructions for Individualized Dose Initiation Initiation of of TIKOSYN Therapy Step Electrocardiographic assessment: Prior to to administration of of the the first dose, the the QTc must be be determined using an an average of of 5 10 beats. If If the the QTc is is greater than 440 msec (500 msec in in patients with ventricular conduction abnormalities), TIKOSYN is is contraindicated. If If heart rate is is less than beats per minute, QT interval should be be used. Patients with heart rates <50 beats per minute have not been studied. Therapy with TIKOSYN must be be initiated (and, if if necessary, re-initiated) in in a a setting that provides continuous electrocardiographic (ECG) monitoring and in in the the presence of of personnel trained in in the the management of of serious ventricular arrhythmias. Patients should continue to to be be monitored in in this way for for a a minimum of of three days. Additionally, patients should not be be discharged within hours of of electrical or or pharmacological conversion to to normal sinus rhythm. The dose of of TIKOSYN must be be individualized according to to calculated creatinine clearance and QTc. (QT interval should be be used if if the heart rate is is <60 beats per minute. There are no no data on on use of of TIKOSYN when the heart rate is is <50 beats per minute.) The usual recommended dose of of TIKOSYN is is 500 mcg, as as modified by by the the dosing algorithm described below. For consideration of of a a lower dose, see Special Considerations below. Serum potassium should be be maintained within the the normal range before TIKOSYN treatment is is initiated and should be be maintained within the the normal range while the the patient remains on on TIKOSYN therapy. (See WARNINGS, Hypokalemia and Potassium-Depleting Diuretics). In In clinical trials, potassium levels were generally maintained above meq/l. Step Calculation of of creatinine clearance: Prior to to the the administration of of the the first dose, the the patient s creatinine clearance must be be calculated using the the following formula: creatinine clearance (male) = = (140-age) x x actual body weight in in kg kg x x serum creatinine (mg/dl) creatinine clearance (female) = = (140-age) x x actual body weight in in kg kg x x x x serum creatinine (mg/dl) When serum creatinine is is given in in mol/l, divide the the value by by 88.4 (1 (1 mg/dl = = 88.4 mol/l). Step Starting Dose: The starting dose of of TIKOSYN is is determined as as follows: Calculated Creatinine Clearance TIKOSYN Dose 60 ml/min 500 mcg twice daily ml/min 250 mcg twice daily <40 ml/min 125 mcg twice daily 20 ml/min Dofetilide is is contraindicated in in these patients Step Administer the the adjusted TIKOSYN dose and begin continuous ECG monitoring. 17

18 Step At At 2 3 hours after administering the the first dose of of TIKOSYN, determine the the QTc. If If the the QTc has increased by by greater than 15% compared to to the the baseline established in in Step 11 ORif if the the QTc is is greater than 500 msec (550 msec in in patients with ventricular conduction abnormalities), subsequent dosing should be be adjusted as as follows: If If the the Starting Dose Based on on Then the the Adjusted Dose Creatinine Clearance is: is: (for QTc Prolongation) is: is: 500 mcg twice daily 250 mcg twice daily 250 mcg twice daily 125 mcg twice daily 125 mcg twice daily 125 mcg once a a day Step At At 2 3 hours after each subsequent dose of of TIKOSYN, determine the the QTc (for in- inhospital doses 2 5). No No further down titration of of TIKOSYN based on on QTc is is recommended. NOTE: If If at at any time after the the second dose of of TIKOSYN is is given the the QTc is is greater than 500 msec (550 msec in in patients with ventricular conduction abnormalities), TIKOSYN should be be discontinued. Step Patients are are to to be be continuously monitored by by ECG for for a a minimum of of three days, or or for for a a minimum of of hours after electrical or or pharmacological conversion to to normal sinus rhythm, whichever is is greater. Place Patient on on Telemetry Check Baseline QTc If If QTc >440 msec,, DO NOT Use dofetilide If If QTc 440 msec,, Proceed Calculated Creatinine Clearance ( ( Clcr ) ) Male Clcr = = (140-age) x x actual body weight in in kg kg x x serum creatinine (mg/dl) Female Clcr = = 0.85 x x male If If Clcris is <20 ml/min, dofetilideis is CONTRAINDICATED The steps described above are are summarized in in the the following diagram: If If Clcris is >60 ml/min, give 500 mcg dofetilide If If Clcris is ml/min, give 250 mcg dofetilide If If Clcris is 20-<40 ml/min, give 125 mcg dofetilide Post Dose Adjustment: 2-3 hours after dose Check QTc (first dose only) If If Increase in in QTcis is 15%, Continue Current Dose (first dose only) If If Increase in in QTcis is >15%, or or >500 msec,, Decrease Dose (see text) If If at at any time after the second dose QTc increases >500 msec dofetilide should be be discontinued 18

19 Maintenance of of TIKOSYN Therapy Renal function and QTc should be be re-evaluated every three months or or as as medically warranted. If If QTc exceeds 500 milliseconds (550 msec in in patients with ventricular conduction abnormalities), TIKOSYN therapy should be be discontinued and patients should be be carefully monitored until QTc returns to to baseline levels. If If renal function deteriorates, adjust dose as as described in in Initiation of of TIKOSYN Therapy, Step Special Considerations Consideration of of a a Dose Lower than that Determined by by the Algorithm: The dosing algorithm shown above should be be used to to determine the the individualized dose of of TIKOSYN. In In clinical trials (see CLINICAL STUDIES), the the highest dose of of 500 mcg of of TIKOSYN as as modified by by the the dosing algorithm led led to to greater effectiveness than lower doses of of 125 or or 250 mcg as as modified by by the the dosing algorithm. The risk of of Torsade de de Pointes, however, is is related to to dose as as well as as to to patient characteristics (see WARNINGS). Physicians, in in consultation with their patients, may therefore in in some cases choose doses lower than determined by by the the algorithm. It It is is critically important that if if at at any time this lower dose is is increased, the the patient needs to to be be rehospitalized for for three days. Previous toleration of of higher doses does not eliminate the the need for for rehospitalization. The maximum recommended dose in in patients with a a calculated creatinine clearance greater than ml/min is is 500 mcg ; doses greater than 500 mcg have been associated with an an increased incidence of of Torsade de de Pointes. TIKOSYN 250 mcg (0.25 mg) capsules are are supplied as as No. 44 capsules, peach cap and body, printed with TKN 250 PFIZER, and are are available in: in: TIKOSYN 500 mcg (0.5 mg) capsules are are supplied as as No. 22 capsules, peach cap and white body, printed with TKN 500 PFIZER, and are are available in: in: 125 mcg (0.125 mg) 250 mcg (0.25 mg) 500 mcg (0.5 mg) Obverse TKN 125 TKN 250 TKN 500 Reverse PFIZER PFIZER PFIZER Bottle of of Bottle of of Unit dose / / Store at at controlled room temperature, 15 to to 30 C (59 to to 86 F). PROTECT FROM MOISTURE AND HUMIDITY. Dispense in in tight containers (USP). Rx Rx only A patient who misses a a dose should NOT double the the next dose. The next dose should be be taken at at the the usual time. Cardioversion: If If patients do do not convert to to normal sinus rhythm within hours of of initiation of of TIKOSYN therapy, electrical conversion should be be considered. Patients continuing on on TIKOSYN after successful electrical cardioversion should continue to to be be monitored by by electrocardiography for for hours post cardioversion, or or a a minimum of of 33 days after initiation of of TIKOSYN therapy, whichever is is greater. LAB Revised December 2013 Switch to to TIKOSYN from Class I I or or other Class III III Antiarrhythmic Therapy Before initiating TIKOSYN therapy, previous antiarrhythmic therapy should be be withdrawn under careful monitoring for for a a minimum of of three (3) (3) plasma half-lives. Because of of the the unpredictable pharmacokinetics of of amiodarone, TIKOSYN should not be be initiated following amiodarone therapy until amiodarone plasma levels are are below mcg/ml or or until amiodarone has been withdrawn for for at at least three months. Stopping TIKOSYN Prior to to Administration of of Potentially Interacting Drugs If If TIKOSYN needs to to be be discontinued to to allow dosing of of other potentially interacting drug(s), a a washout period of of at at least two days should be be followed before starting the the other drug(s). HOW SUPPLIED TIKOSYN 125 mcg (0.125 mg) capsules are are supplied as as No. 44 capsules with a a light orange cap and white body, printed with TKN 125 PFIZER, and are are available in: in: 19

20 MEDICATION GUIDE TIKOSYN (Tee ko ko sin) (dofetilide) Capsules Read the Medication Guide before you start taking TIKOSYN and each time you get a a refill. This information does not take the place of of talking with your doctor about your condition or or treatment. What is is the most important information I I should know about TIKOSYN? TIKOSYN can cause serious side effects, including a a type of of abnormal heartbeat called Torsade de de Pointes, which can lead to to death. To To establish the right dose of of TIKOSYN, treatment with TIKOSYN must be be started in in a a hospital where your heart rate and kidney function will be be checked for for the first 33 days of of treatment. It It is is important that when you go go home, you take the exact dose of of TIKOSYN that your doctor prescribed for for you. While you take TIKOSYN, always watch for for signs of of abnormal heartbeat. Call your doctor and go go to to the hospital right away if if you: feel faint become dizzy, or or have a a fast heartbeat What is is TIKOSYN? TIKOSYN is is a a prescription medicine that is is used to to treat an an irregular heartbeat (atrial fibrillation or or atrial flutter). It It is is not known if if TIKOSYN is is safe and effective in in children under years of of age. Who should not take TIKOSYN? Do Do not take TIKOSYN if if you: have an an irregular heartbeat called long QT syndrome have kidney problems or or are on on kidney dialysis take any of of these medicines: cimetidine (TAGAMET, TAGAMET HB)* verapamil (CALAN, CALAN SR, COVERA-HS, ISOPTIN, ISOPTIN SR, VERELAN, VERELAN PM, TARKA)* ketoconazole (NIZORAL, XOLEGEL, EXTINA)* trimethoprim alone (PROLOPRIM, TRIMPEX)* or or the combination of of trimethoprim and sulfamethoxazole (BACTRIM, SEPTRA SULFATRIM)* prochlorperazine (COMPAZINE, COMPO)* megestrol (MEGACE)* dolutegravir (TIVICAY)* hydrochlorothiazide alone or or in in combination with other medicines (such as as ESIDRIX, EZIDE, HYDRODIURIL, HYDRO-PAR, MICROZIDE, or or ORETIC)* Ask your doctor if if you are not sure if if any of of your medicines are the kind listed above. are allergic to to dofetilide in in TIKOSYN. See the end of of this leaflet for for a a complete list list of of ingredients in in TIKOSYN. What should I I tell my doctor before taking TIKOSYN? Before taking TIKOSYN, tell tell your doctor about all all of of your medical conditions including if if you: have heart problems have kidney or or liver problems are pregnant or or plan to to become pregnant. It It is is not known if if TIKOSYN will harm your unborn baby. are breast-feeding or or plan to to breast-feed. It It is is not known if if TIKOSYN passes into your breast milk. You and your doctor should decide if if you will take TIKOSYN or or breast-feed. You should not do do both. Especially tell tell your doctor if if you take medicines to to treat: heart problems high blood pressure depression or or other mental problems asthma allergies, or or hay fever skin problems infections Ask your doctor if if you are not sure about the medicines you take. Tell your doctor about all all prescription and non-prescription medicines, vitamins, dietary supplements, and any natural or or herbal remedies. TIKOSYN and other medicines may affect each other, causing serious side effects. If If you take TIKOSYN with certain medicines, you will be be more likely to to have a a different type of of abnormal heartbeat. See Who should not take TIKOSYN? Know the medicines you take. Keep a a list list of of your medicines and show it it to to your doctor and pharmacist when you get a a new medicine. How should I I take TIKOSYN? Take TIKOSYN exactly as as your doctor tells you. Do Do not change your TIKOSYN dose unless your doctor tells you to. to. Your doctor will do do tests before you start and while you take TIKOSYN. Do Do not stop taking TIKOSYN until your doctor tells you to to stop. If If you miss a a dose, just take the next dose at at your regular time. Do Do not take 22 doses of of TIKOSYNat at the same time. TIKOSYN can be be taken with or or without food. If If you take too much TIKOSYN, call your doctor or or go go to to the nearest hospital emergency room right away. Take your TIKOSYN capsules with you to to show to to the doctor. What are the possible side effects of of TIKOSYN? TIKOSYN can cause serious side effects, including a a type of of abnormal heartbeat called Torsade de de Pointes, which can lead to to death. See What is is the most important information I I should know about TIKOSYN? 20