This document discusses the pros and cons of different treatment approaches for atrial fibrillation (AFib), including antiarrhythmic drug therapy and rate control. It provides details on FDA-approved antiarrhythmic agents for AFib treatment and their classes. Trial results are presented showing sotalol to be effective in maintaining normal sinus rhythm for AFib/AFL compared to placebo, with a low risk of proarrhythmia.

4. Antiarrhythmic Drug Algorithm to Prevent AFib CAD=coronary artery disease; CHF=congestive heart failure; HBP=high blood pressure. Prystowsky EN. Am J Cardiol. 2000;85(10A):3D-11D. *BETAPACE AF ™ : The only sotalol formulation FDA-approved for treatment of AFib/AFL. Sotalol* Disopyramide CR Amiodarone Disopyramide CR Dofetilide Amiodarone Quinidine Flecainide Sotalol* Lone AFib Heart Disease Propafenone Disopyramide CR Propafenone Amiodarone Amiodarone Dofetilide CAD Sotalol* HBP Initial Secondary CHF Initial Initial Secondary Initial Secondary

5. BETAPACE AF ™ Y Y Y Y Y Y Y N Betapace ® N N N N N N N Y Generic sotalol N N N N N N N Y Issues of enhanced patient safety with BETAPACE AF Approved for AFib Specific dosing for AFib Specific renal function guidelines for AFib Specific QT guidelines for AFib FDA-mandated patient package insert Patient newsletter Formulation substitution inequivalence Physician/pharmacist liability issues if used for AFib Avoidable adverse events due to inappropriate dosing or inadequate patient education and support

6. Atrial Fibrillation Established Persistent (Requires cardioversion) Permanent (NSR is not/cannot be restored) Paroxysmal-(Self-terminating)

7. Drug Algorithm for Rate Control in AFib 1 BB=beta-blocker; BTS=brady-tachy syndrome; CAD=coronary artery disease; CCB=calcium channel blocker; CHF=congestive heart failure; COPD=chronic obstructive pulmonary disease; HTN=hypertension; PVD=peripheral vascular disease. *Varies with ischemic and ventricular functional status and infarct type. Reference: 1. Reiffel JA, Camm AJ, Haffajee CI, et al. CME Report. International Consensus Roundtable on Atrial Fibrillation. Cardiology Review . 2000;17(suppl):1-20 HTN CCB BB Digoxin CHF Digoxin  BB CAD BB Digoxin/ CCB* BTS Pindolol Pacer & alternative drug COPD Verapamil Diltiazem Digoxin PVD CCB Digoxin Lone AFib CCB BB Digoxin 1st- Choice Agents: 2nd- Choice Agents: (Based on Efficacy, Tolerance, and Disease Interactions)

12. d,I-Sotalol vs Placebo for AFib/AFL 1,2 27% outpatient initiation. *In the presence of renal insufficiency (creatinine clearance 40-60 mL/min), patients received the dose QD. † Open-label treatment optional for remainder of 12 months after recurrence. NDA #19-865. 1. Data presented at NASPE Annual Scientific Sessions 5/98. d,l-Sotalol AFib/AFL Multicenter Study Group. Pacing Clin Electrophysiol . 1998;21(Part II):812. Abstract 91. 2. Benditt DG et al. Am J Cardiol . 1999;84:270-277. Outpatient optional for non-SHD Inpatient mandatory for SHD Double-blind treatment for 12 months or until recurrence † Placebo BID* n=69 Sotalol 80 mg BID* n=59 Sotalol 120 mg BID* n=63 Sotalol 160 mg BID* n=62 R Patients with documented AFib/AFL in past 3 months, now in NSR 57% w/SHD

15. d,l-Sotalol vs Placebo for AFib/AFL 1 Category of Cardiovascular Concomitant Medication Received by Subjects During the Initiation Period Diuretics 14 (20) 13 (22) 9 (14) 7 (11) ACE inhibitors 13 (19) 14 (24) 10 (16) 10 (16) Digitalis 29 (42) 23 (39) 23 (36) 20 (32) Calcium channel-blockers 19 (28) 16 (27) 24 (38) 18 (29) Beta-blockers 17 (25) 14 (24) 10 (16) 10 (16) Oral anticoagulation 34 (49) 28 (48) 27 (43) 31 (50) Antiarrhythmics 0 0 1 (12) 0 Any concomitant 59 (86) 51 (86) 52 (82) 46 (74) medication NDA #19-865. 1. Data on file. Berlex Laboratories; 2000. Placebo 80 mg 120 mg 160 mg Category (N=69) (N=59) (N=63) (N=62) d,l-Sotalol Number (%) of Subjects by Treatment Group

16. d,l-Sotalol vs Placebo for AFib/AFL 1 Time to Recurrence of Symptomatic AFib/AFL Since Randomization Data presented at NASPE Annual Scientific Sessions 5/98. 1. Reprinted with permission from Benditt DG et al. Am J Cardiol . 1999;84:270-277. Log-Rank 0.325 0.018 0.029 Gehan 0.111 0.001 0.012 80 mg: 120 mg: 160 mg: P Value (d,l-Sotalol vs Placebo) Treatment: Placebo 80 mg 120 mg 160 mg N at Risk 69 59 63 62 31 35 40 30 29 29 33 24 27 27 31 21 22 23 29 20 21 20 29 18 20 19 27 17 20 15 26 17 19 13 24 16 17 13 22 15 17 13 20 15 16 13 19 15 16 13 19 14 Placebo 80 mg 120 mg 160 mg 0 30 60 90 120 150 180 210 240 270 300 330 360 390 Time (Days) Recurrence-Free Survival 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

17. BETAPACE AF ™ : Efficacy Profile 1 *Statistically significant longer time to recurrence compared with placebo (P=0.018 (120 mg), P=0.029 (160 mg). 1. Benditt DG et al. Am J Cardiol. 1999;84:270-277. AFib Free at 12 months 0 10 20 30 40 50 Placebo Relapse-Free Survival Probability (%) n=21 n=69 Sotalol (mg dose) 59 0 30 60 90 120 150 180 210 240 Placebo 80 120* 160* Days Sotalol (mg dose) Median Time to Recurrence at 12 months 80 n=22 120 n=31 63 160 n=36 62

19. BETAPACE AF ™ : Incidence of Torsade de Pointes Is Dose Related 1 < 160 mg BID >160 mg BID Daily Dose Incidence TdP (%) 0.0% 0.3% 3.2% (n=358) (n=597) (n=62) Placebo *One incidence of torsade de pointes at 80 mg BID occurring at day 1, one incidence of torsade de pointes at 160 mg BID occurring at day 4. 1. BETAPACE AF ™ (sotalol HCI) prescribing information. * 100 5 0