Tikosyn

INDICATIONS AND USAGE Maintenance of Normal Sinus Rhythm (Delay in AF/AFl Recurrence) TIKOSYN is indicated for the maintenance of normal sinus rhythm (delay in time to recurrence of atrial fibrillation/atrial flutter [AF/AFl]) in patients with atrial fibrillation/atrial flutter of greater than one week duration who have been converted to normal sinus rhythm. Because TIKOSYN can cause life threatening ventricular arrhythmias, it should be reserved for patients in whom atrial fibrillation/atrial flutter is highly symptomatic. In general, antiarrhythmic therapy for atrial fibrillation/atrial flutter aims to prolong the time in normal sinus rhythm. Recurrence is expected in some patients (see CLINICAL STUDIES ). Conversion of Atrial Fibrillation/Flutter TIKOSYN is indicated for the conversion of atrial fibrillation and atrial flutter to normal sinus rhythm. TIKOSYN has not been shown to be effective in patients with paroxysmal atrial fibrillation.

DOSAGE AND ADMINISTRATION • Therapy with TIKOSYN must be initiated (and, if necessary, re-initiated) in a setting that provides continuous electrocardiographic (ECG) monitoring and in the presence of personnel trained in the management of serious ventricular arrhythmias. Patients should continue to be monitored in this way for a minimum of three days. Additionally, patients should not be discharged within 12 hours of electrical or pharmacological conversion to normal sinus rhythm. • The dose of TIKOSYN must be individualized according to calculated creatinine clearance and QTc. (QT interval should be used if the heart rate is <60 beats per minute. There are no data on use of TIKOSYN when the heart rate is <50 beats per minute.) The usual recommended dose of TIKOSYN is 500 mcg BID, as modified by the dosing algorithm described below. For consideration of a lower dose, see Special Considerations below. • Serum potassium should be maintained within the normal range before TIKOSYN treatment is initiated and should be maintained within the normal range while the patient remains on TIKOSYN therapy. (See WARNINGS, Hypokalemia and Potassium-Depleting Diuretics ). In clinical trials, potassium levels were generally maintained above 3.6–4.0 mEq/L. • Patients with atrial fibrillation should be anticoagulated according to usual medical practice prior to electrical or pharmacological cardioversion. Anticoagulant therapy may be continued after cardioversion according to usual medical practice for the treatment of people with AF. Hypokalemia should be corrected before initiation of TIKOSYN therapy (see WARNINGS, Ventricular Arrhythmia ). • Patients to be discharged on TIKOSYN therapy from an inpatient setting as described above must have an adequate supply of TIKOSYN, at the patient's individualized dose, to allow uninterrupted dosing until the patient can fill a TIKOSYN prescription. Instructions for Individualized Dose Initiation Initiation of TIKOSYN Therapy Step 1. Electrocardiographic assessment: Prior to administration of the first dose, the QTc or QT must be checked using an average of 5–10 beats. If the QTc or QT is greater than 440 msec (500 msec in patients with ventricular conduction abnormalities), TIKOSYN is contraindicated. If heart rate is less than 60 beats per minute, QT interval should be used. Proceed to Step 2 if the QTc or QT is 440 msec. Patients with heart rates <50 beats per minute have not been studied. Step 2. Calculation of creatinine clearance: Prior to the administration of the first dose, the patient's creatinine clearance must be calculated using the following formula: creatinine clearance (male) = (140-age) × actual body weight in kg 72 × serum creatinine (mg/dL) creatinine clearance (female) = (140-age) × actual body weight in kg × 0.85 72 × serum creatinine (mg/dL) When serum creatinine is given in µmol/L, divide the value by 88.4 (1 mg/dL = 88.4 µmol/L). Step 3. Starting Dose: The starting dose of TIKOSYN is determined as follows: Calculated Creatinine Clearance TIKOSYN Dose >60 mL/min 500 mcg twice daily 40 to 60 mL/min 250 mcg twice daily 20 to <40 mL/min 125 mcg twice daily <20 mL/min Tikosyn is contraindicated in these patients Step 4. Administer the adjusted TIKOSYN dose and begin continuous ECG monitoring. Step 5. At 2–3 hours after administering the first dose of Tikosyn, determine the QTc or QT (if heart rate is less than 60 beats per minute). If the QTc or QT has increased by greater than 15% compared to the baseline established in Step 1 OR if the QTc or QT is greater than 500 msec (550 msec in patients with ventricular conduction abnormalities), subsequent dosing should be adjusted as follows: If the Starting Dose Based on Creatinine Clearance is: Then the Adjusted Dose (for QTc or QT Prolongation) is: 500 mcg twice daily 250 mcg twice daily 250 mcg twice daily 125 mcg twice daily 125 mcg twice daily 125 mcg once a day Step 6. At 2–3 hours after each subsequent dose of Tikosyn, determine the QTc or QT (if heart rate is less than 60 beats per minute) (for in-hospital doses 2–5). No further down titration of Tikosyn based on QTc or QT is recommended. NOTE: If at any time after the second dose of Tikosyn is given the QTc or QT is greater than 500 msec (550 msec in patients with ventricular conduction abnormalities), Tikosyn should be discontinued. Step 7. Patients are to be continuously monitored by ECG for a minimum of three days, or for a minimum of 12 hours after electrical or pharmacological conversion to normal sinus rhythm, whichever is greater. The steps described above are summarized in the following diagram: flow chart Maintenance of TIKOSYN Therapy Renal function and QTc or QT (if heart rate is less than 60 beats per minute) should be re-evaluated every three months or as medically warranted. If QTc or QT exceeds 500 milliseconds (550 msec in patients with ventricular conduction abnormalities), TIKOSYN therapy should be discontinued and patients should be carefully monitored until QTc or QT returns to baseline levels. If renal function deteriorates, adjust dose as described in Initiation of TIKOSYN Therapy, Step 3. Special Considerations Consideration of a Dose Lower than that Determined by the Algorithm: The dosing algorithm shown above should be used to determine the individualized dose of TIKOSYN. In clinical trials (see CLINICAL STUDIES ), the highest dose of 500 mcg BID of TIKOSYN as modified by the dosing algorithm led to greater effectiveness than lower doses of 125 or 250 mcg BID as modified by the dosing algorithm. The risk of Torsade de Pointes, however, is related to dose as well as to patient characteristics (see WARNINGS ). Physicians, in consultation with their patients, may therefore in some cases choose doses lower than determined by the algorithm. It is critically important that if at any time this lower dose is increased, the patient needs to be rehospitalized for three days. Previous toleration of higher doses does not eliminate the need for rehospitalization. The maximum recommended dose in patients with a calculated creatinine clearance greater than 60 mL/min is 500 mcg BID; doses greater than 500 mcg BID have been associated with an increased incidence of Torsade de Pointes. A patient who misses a dose should NOT double the next dose. The next dose should be taken at the usual time. Cardioversion: If patients do not convert to normal sinus rhythm within 24 hours of initiation of TIKOSYN therapy, electrical conversion should be considered. Patients continuing on TIKOSYN after successful electrical cardioversion should continue to be monitored by electrocardiography for 12 hours post cardioversion, or a minimum of 3 days after initiation of TIKOSYN therapy, whichever is greater. Switch to TIKOSYN from Class I or other Class III Antiarrhythmic Therapy Before initiating TIKOSYN therapy, previous antiarrhythmic therapy should be withdrawn under careful monitoring for a minimum of three (3) plasma half-lives. Because of the unpredictable pharmacokinetics of amiodarone, TIKOSYN should not be initiated following amiodarone therapy until amiodarone plasma levels are below 0.3 mcg/mL or until amiodarone has been withdrawn for at least three months. Stopping TIKOSYN Prior to Administration of Potentially Interacting Drugs If TIKOSYN needs to be discontinued to allow dosing of other potentially interacting drug(s), a washout period of at least two days should be followed before starting the other drug(s).

CONTRAINDICATIONS TIKOSYN is contraindicated in patients with congenital or acquired long QT syndromes. TIKOSYN should not be used in patients with a baseline QT interval or QTc >440 msec (500 msec in patients with ventricular conduction abnormalities). TIKOSYN is also contraindicated in patients with severe renal impairment (calculated creatinine clearance <20 mL/min). The concomitant use of verapamil or the cation transport system inhibitors cimetidine, trimethoprim (alone or in combination with sulfamethoxazole), or ketoconazole with TIKOSYN is contraindicated (see WARNINGS and PRECAUTIONS, Drug-Drug Interactions ), as each of these drugs cause a substantial increase in dofetilide plasma concentrations. In addition, other known inhibitors of the renal cation transport system such as prochlorperazine, dolutegravir and megestrol should not be used in patients on TIKOSYN. The concomitant use of hydrochlorothiazide (alone or in combinations such as with triamterene) with TIKOSYN is contraindicated (see PRECAUTIONS, Drug-Drug Interactions ) because this has been shown to significantly increase dofetilide plasma concentrations and QT interval prolongation. TIKOSYN is also contraindicated in patients with a known hypersensitivity to the drug.

WARNINGS 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 be started 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 dose selection, 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. Relation of QT Interval to Dose: 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 ). Frequency of Torsade de Pointes: 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 TIKOSYN Dose <250 mcg BID 250 mcg BID >250–500 mcg BID >500 mcg BID All Doses Number of Patients 217 388 703 38 1346 Torsade de Pointes 0 1 (0.3%) 6 (0.9%) 4 (10.5%) 11 (0.8%) 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 Population: Total Before After 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 7/749 (0.9%) 3/101 (3.0%) 4/648 (0.6%) DIAMOND AF 4/249 (1.6%) 0/43 (0%) 4/206 (1.9%) 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). Mortality: 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). Dofetilide 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.

ADVERSE REACTIONS The TIKOSYN clinical program involved approximately 8,600 patients in 130 clinical studies of normal volunteers and patients with supraventricular and ventricular arrhythmias. TIKOSYN was administered to 5,194 patients, including two large, placebo-controlled mortality trials (DIAMOND CHF and DIAMOND MI) in which 1,511 patients received TIKOSYN for up to three years. In the following section, adverse reaction data for cardiac arrhythmias and non-cardiac adverse reactions are presented separately for patients included in the supraventricular arrhythmia development program and for patients included in the DIAMOND CHF and MI mortality trials (see CLINICAL STUDIES, Safety in Patients with Structural Heart Disease, DIAMOND Studies , for a description of these trials). In studies of patients with supraventricular arrhythmias, a total of 1,346 and 677 patients were exposed to TIKOSYN and placebo for 551 and 207 patient years, respectively. A total of 8.7% of patients in the dofetilide groups were discontinued from clinical trials due to adverse events compared to 8.0% in the placebo groups. The most frequent reason for discontinuation (>1%) was ventricular tachycardia (2.0% on dofetilide vs. 1.3% on placebo). The most frequent adverse events were headache, chest pain, and dizziness. Serious Arrhythmias and Conduction Disturbances: Torsade de Pointes is the only arrhythmia that showed a dose-response relationship to TIKOSYN treatment. It did not occur in placebo treated patients. The incidence of Torsade de Pointes in patients with supraventricular arrhythmias was 0.8% (11/1346) (see WARNINGS ). The incidence of Torsade de Pointes in patients who were dosed according to the recommended dosing regimen (see DOSAGE AND ADMINISTRATION ) was 0.8% (4/525). Table 6 shows the frequency by randomized dose of serious arrhythmias and conduction disturbances reported as adverse events in patients with supraventricular arrhythmias. Table 6: Incidence of Serious Arrhythmias and Conduction Disturbances in Patients with Supraventricular Arrhythmias TIKOSYN Dose Placebo Arrhythmia event: <250 mcg BID N=217 250 mcg BID N=388 >250–500 mcg BID N=703 >500 mcg BID N=38 N=677 Ventricular arrhythmias Patients with more than one arrhythmia are counted only once in this category. Ventricular arrhythmias and ventricular tachycardia include all cases of Torsade de Pointes. 3.7% 2.6% 3.4% 15.8% 2.7% Ventricular fibrillation 0 0.3% 0.4% 2.6% 0.1% Ventricular tachycardia 3.7% 2.6% 3.3% 13.2% 2.5% Torsade de Pointes 0 0.3% 0.9% 10.5% 0 Various forms of block AV block 0.9% 1.5% 0.4% 0 0.3% Bundle branch block 0 0.5% 0.1% 0 0.1% Heart block 0 0.5% 0.1% 0 0.1% In the DIAMOND trials, a total of 1,511 patients were exposed to TIKOSYN for 1757 patient years. The incidence of Torsade de Pointes was 3.3% in CHF patients and 0.9% in patients with a recent MI. Table 7 shows the incidence of serious arrhythmias and conduction disturbances reported as adverse events in the DIAMOND subpopulation that had AF at entry to these trials. Table 7: Incidence of Serious Arrhythmias and Conduction Disturbances in Patients with AF at Entry to the DIAMOND Studies TIKOSYN Placebo N=249 N=257 Ventricular arrhythmias Patients with more than one arrhythmia are counted only once in this category. Ventricular arrhythmias and ventricular tachycardia include all cases of Torsade de Pointes. 14.5% 13.6% Ventricular fibrillation 4.8% 3.1% Ventricular tachycardia 12.4% 11.3% Torsade de Pointes 1.6% 0 Various forms of block AV block 0.8% 2.7% (Left) bundle branch block 0 0.4% Heart block 1.2% 0.8% Other Adverse Reactions: Table 8 presents other adverse events reported with a frequency of >2% on TIKOSYN and reported numerically more frequently on TIKOSYN than on placebo in the studies of patients with supraventricular arrhythmias. Table 8: Frequency of Adverse Events Occurring at >2% on TIKOSYN, and Numerically More Frequently on TIKOSYN than Placebo in Patients with Supraventricular Arrhythmias TIKOSYN Placebo Adverse Event % % headache 11 9 chest pain 10 7 dizziness 8 6 respiratory tract infection 7 5 dyspnea 6 5 nausea 5 4 flu syndrome 4 2 insomnia 4 3 accidental injury 3 1 back pain 3 2 procedure (medical/surgical/health service) 3 2 diarrhea 3 2 rash 3 2 abdominal pain 3 2 Adverse events reported at a rate >2% but no more frequently on TIKOSYN than on placebo were: angina pectoris, anxiety, arthralgia, asthenia, atrial fibrillation, complications (application, injection, incision, insertion, or device), hypertension, pain, palpitation, peripheral edema, supraventricular tachycardia, sweating, urinary tract infection, ventricular tachycardia. The following adverse events have been reported with a frequency of ≤2% and numerically more frequently with TIKOSYN than placebo in patients with supraventricular arrhythmias: angioedema, bradycardia, cerebral ischemia, cerebrovascular accident, edema, facial paralysis, flaccid paralysis, heart arrest, increased cough, liver damage, migraine, myocardial infarct, paralysis, paresthesia, sudden death, and syncope. The incidences of clinically significant laboratory test abnormalities in patients with supraventricular arrhythmias were similar for patients on TIKOSYN and those on placebo. No clinically relevant effects were noted in serum alkaline phosphatase, serum GGT, LDH, AST, ALT, total bilirubin, total protein, blood urea nitrogen, creatinine, serum electrolytes (calcium, chloride, glucose, magnesium, potassium, sodium), or creatine kinase. Similarly, no clinically relevant effects were observed in hematologic parameters. In the DIAMOND population, adverse events other than those related to the post-infarction and heart failure patient population were generally similar to those seen in the supraventricular arrhythmia groups.

Pregnancy Dofetilide has been shown to adversely affect in utero growth and survival of rats and mice when orally administered during organogenesis at doses of 2 or more mg/kg/day. Other than an increased incidence of non-ossified 5 th metacarpal, and the occurrence of hydroureter and hydronephroses at doses as low as 1 mg/kg/day in the rat, structural anomalies associated with drug treatment were not observed in either species at doses below 2 mg/kg/day. The clearest drug-effect associations were for sternebral and vertebral anomalies in both species; cleft palate, adactyly, levocardia, dilation of cerebral ventricles, hydroureter, hydronephroses, and unossified metacarpal in the rat; and increased incidence of unossified calcaneum in the mouse. The "no observed adverse effect dose" in both species was 0.5 mg/kg/day. The mean dofetilide AUCs (0–24hr) at this dose in the rat and mouse are estimated to be about equal to the maximum likely human AUC and about half the likely human AUC, respectively. There are no adequate and well controlled studies in pregnant women. Therefore, dofetilide should only be administered to pregnant women where the benefit to the patient justifies the potential risk to the fetus.