CR-1 1 Ranolazine Benefit/Risk Jeremy N. Ruskin, MD, FACC

CR-2 Current Management of Patients With Angina Pectoris Many patients face recurrent episodes of angina pectoris that limit physical activity and impair quality of life Epidemiologic data suggest that a significant minority of patients with angina are inadequately treated with available therapies and would benefit from additional pharmacological alternatives 1 year after angioplasty or surgery for relief of ischemia 10 to 20% of patients still have angina and 60 to 80% are still taking antianginal medications †Serruys PW, et al. Arterial Revascularization Therapies Study Group. N Engl J Med. 2001; 344:

CR-3 Limitations to Uptitration of Currently Available Antianginal Drugs Beta blockers Bradycardia Hypotension Fatigue and/or depression Calcium channel blockers Bradycardia Hypotension LV dysfunction Long-acting nitrates Headache Hypotension Need for drug free interval

CR-4 Advantages of Ranolazine Novel agent Pharmacodynamically distinct from other antianginals Hemodynamically neutral at therapeutic doses Safe and effective alone or combination with other antianginal drugs

CR-5 Consistent Benefit of Ranolazine in Patients With Comorbidities and in Combination With Other Drugs CHF Diabetes COPD Prior myocardial infarction Previous revascularization Patients with low heart rates or blood pressures Other antianginal medications

CR-6 Ranolazine Increases Total Exercise Duration: Quantitative Effect Comparable to Other Antianginals Mean increase in placebo-corrected exercise time, sec Study population test procedures Ranolazine (monotherapy) 500 bid 1000 bid (combined Rx) 1000 bid Severely impaired patients Stringent test criteria Atenolol 100 mg qd 100 mg qd (NDA , vol 1.2) Mod impaired patients Test at peak drug levels Diltiazem (SR form) (Cardizem CD) 360 mg qd (Tiazac) 360 mg qd Mod impaired patients Transdermal TNG 0.8 mg/hr 28 (Circ. 91:1368, 1995) Mod Impaired patients

CR-7 Ranolazine: Overall Safety Outcomes AEs mild to moderate No serious organ toxicity Discontinuations infrequent Drug-drug interactions well characterized Effect on the QTc interval (dose-dependent)

CR-8 Mean Change in QTc RanolazineTerfenadine QTci QTcB

CR-9 Similar QTc Effects in High-Risk Patient Subgroups Compared to Overall Population

CR-10 Electrophysiological Events Associated With Drug Induced Torsade de Pointes Prolongation of ventricular action potential (QTc) Increase in dispersion of refractoriness (  APD) Induction of early afterdepolarizations (EADs)

CR-11 Ranolazine Preclinical Profile Ranolazine does not...Ranolazine does... Induce EADsSuppress EADs Increase dispersionReverse dispersion caused by known QT prolonging drugs Cause arrhythmias in any experimental model Reverse arrhythmias caused by known QT prolonging drugs

CR-12 QT Effects of Ranolazine Summary Well-characterized and linearly related to plasma concentration Side effects limit exposure to concentrations < 8,000 ng/mL Syncope occurs but with no evidence of arrhythmic mechanism No case of TdP observed (> 1700 patient-yr) Ventricular arrhythmias not more frequent than placebo Extensive nonclinical studies demonstrate a unique EP profile and no evidence for proarrhythmia

CR-13 Ranolazine Benefit/Risk Summary Effective and well tolerated antianginal Unique clinical profile (hemodynamically neutral) Unique preclinical profile (no proarrhythmia) Theoretical risk associated with QTc prolongation Risk management strategies Dose titration Labeling Physician and patient education Post marketing studies