1. SS-1 Ranexa™ Supportive Slides 18

2. SS-2 Exercise Duration at Trough at Wk 12 (LOCF) by Background Therapy CARISA (CVT 3033) Treatment by background therapy p = 0.63 Data presented as LS mean ± SE.

3. SS-3 ETT by Treatment and Period MARISA (CVT 3031)

4. SS-4 End-Exercise Heart Rate, Blood Pressure, RPP, and Exercise Duration MARISA (CVT 3031) and CARISA (CVT 3033) Ranolazine SR dose LS mean difference from placebo p -values ≤ 0.05 500 mg bid † 750 mg bid ‡ 1000 mg bid ‡ 1000 mg bid † 1500 mg bid † TroughPeakTroughPeakTroughPeakTroughPeakTroughPeak Standing end- exercise HR, bpm 0.6 NS 1.7 NS –3.1 p = 0.01 –2.3 NS –2.8 p = 0.021 –2.1 NS –1.7 NS –0.4 NS –1.5 NS Standing end- exercise SBP, mmHg –1.7 NS –2.2 NS –1.8 NS 0.4 NS –3.3 p = 0.035 0.1 NS –3.6 p = 0.008 –3.5 p = 0.006 –5.4 p < 0.001 –6.5 p < 0.001 RPP at end- exercise, bpm mm Hg –107.2 NS 43.3 NS –617.9 p = 0.036 –258.3 NS –822.1 p = 0.006 –315.5 NS –737.8 p = 0.004 –512.5 p = 0.035 –929.0 p < 0.001 –1006.5 p < 0.001 Exercise duration, sec 23.8 p = 0.003 29.3 p < 0.001 27.1 p = 0.017 34.2 p = 0.002 26.8 p = 0.020 24.3 p = 0.031 33.7 p < 0.001 50.1 p < 0.001 45.9 p < 0.001 55.5 p < 0.001 †MARISA: Efficacy data presented are from the All/Near Completers population (N = 175); i.e., the primary efficacy analysis. HR/BP and RPP data are from all randomized patients with at least one measurement of end-exercise RPP (N = 179). Differences from placebo are from ANOVA model with effects for pooled site, patients within pooled site, period and treatment. ‡CARISA: HR/BP and RPP data presented are from all randomized patients at Week 12 (N = 737). Note that the primary efficacy analysis was performed on Intent-to-Treat at Week 12 using LOCF (N = 791); an RPP analysis was not performed on this population. Differences from placebo are from an analysis of covariance (ANCOVA) model with effects for baseline, pooled site, background therapy and treatment. 54

5. SS-5 Rate Pressure Product at Peak—Wk 12 CARISA (CVT 3033) 66 Placebo 244 RAN 750250 RAN 1000238 NOTE: LS means and p-values from repeated-measure analysis of variance model with effects for treatment, exercise stage, and treatment by stage interaction. Data presented as LS mean ± SE. *p < 0.05 vs placebo * * * * vs_exstage (21NOV03 14:50) s:\CVT-303\NDA_requests\CVT3033\table_graph\vs_exstage_est.RTF

6. SS-6 Overall Summary of Key Efficacy Results in Ranolazine IR, Study RAN1514 (All Patients Analysis) Variable Placebo Ranolazine IR 267 mg tid400 mg bid400 mg tidAll ranolazine doses Trough N = 306 Peak N = 306 Trough N = 299 Peak N = 296 Trough N = 300 Peak N = 299 Trough N = 304 Peak N = 303 Trough N = 312 Peak N = 312 Exercise duration, sec LS mean (SE)630.0 (NA)640.2 (NA)633.6 (NA)652.2 (NA)633.0 (NA)649.8 (NA)636.0 (NA)650.4 (NA)NA Mean difference from placebo (SE) ——3.6 (5.4)12.0 (5.4)3.0 (5.4)10.2 (5.4)6.0 (5.4)10.2 (5.4)4.2 (4.2)10.8 (4.2) p -value ——NS 0.013 Time to onset of angina, sec LS mean (SE)514.8 (NA)540.6 (NA)526.8 (NA)564.0 (NA)526.2 (NA)559.8 (NA)519.0 (NA)559.8 (NA)NA Mean difference from placebo (SE) ——11.4 (7.2)23.4 (7.8)10.8 (7.2)19.2 (7.8)4.2 (7.2)19.2 (7.8)9.0 (6.0)20.4 (6.0) p -value ——NS< 0.01NS0.013NS0.012NS  0.01 Time to 1-mm ST-segment depression, sec LS mean (SE)542.4 (NA)574.8 (NA)553.2 (NA)599.4 (NA)553.2 (NA)591.6 (NA)558.6 (NA)596.4 (NA)NA Mean difference from placebo (SE) ——10.8 (7.8)24.6 (7.2)11.4 (7.8)16.8 (7.2)16.2 (7.8)21.6 (7.2)12.6 (6.0)21.0 (6.0) p -value ——NS< 0.01NS0.02NS< 0.010.047  0.01 54 NOTE: LS means and p-values from analysis of variance with effects for site, patient within site, period, treatment, previous treatment and interactions of site with treatment, and site with previous treatment.

7. SS-7* Ranolazine Effect on Exercise Duration Maintained Over 12 Wk of Therapy CARISA (CVT 3033) N = 791, ITT/LOCF; LS mean ± SE *p < 0.05, **p  0.01, and ***p  0.001 for both ranolazine doses vs placebo.. RanolazineRanolazinePlacebo 40 60 80 100 120 140 024681012 1000 mg bid 750 mg bid Change from baseline (trough, sec) *** ** Weeks

8. SS-8 Rebound Assessment—Change From Baseline in Exercise Treadmill Test Duration at Trough CARISA (CVT 3033) Double-blind: Withdrawal: PlaceboRAN 750RAN 1000RAN 750RAN 1000 Placebo RAN 750RAN 1000 Data presented as LS mean ± SE. 243128118120118N =

9. SS-9 Exercise Duration at Trough in Patients by Revascularization † CARISA (CVT 3033) ITT population. Data presented as LS mean ± SE. †PTCA, CABG, or TMR. Treatment by subgroup interaction p = 0.22 n =701888119190171 43

10. SS-10 Exercise Duration at Peak in Patients by Revascularization † CARISA (CVT 3033) ITT population. Data presented as LS mean ± SE. †PTCA, CABG, or TMR. Treatment by subgroup interaction p = 0.60 n =701868019085170 43

11. SS-11 Exercise Duration at Trough in Patients by Revascularization MARISA (CVT 3031) NOTE: All/Near Completers population. Data presented as LS mean ± SE. Treatment by subgroup interaction p =.95 n =8490849085898287 43

12. SS-12 Exercise Duration at Peak in Patients by Revascularization MARISA (CVT 3031) NOTE: All/Near Completers population. Data presented as LS mean ± SE. Treatment by subgroup interaction p =.84 n =8389849085898186 43

13. SS-13 Exercise Duration at Trough at Wk 12 (LOCF) by Background Therapy CARISA (CVT 3033) Treatment by background therapy p = 0.63 Data presented as LS mean ± SE.

14. SS-14 Exercise Duration at Peak at Wk 12 (LOCF) by Background Therapy CARISA (CVT 3033) Treatment by background therapy p = 0.63 Data presented as LS mean ± SE.

15. SS-15 Estimated Mean Difference From Placebo in Exercise Tolerance Time Adjusting For Increase in Ranolazine Concentrations Due to Diltiazem † CARISA (CVT 3033) Treatment group Fraction of patients taking diltiazem Mean difference from placebo in ETT(s) Adjusted mean difference from placebo in ETT(s) Ranolazine 750 mg 70/272 (25.7%)23.721.9 Ranolazine 1000 mg 63/261 (24.1%)24.022.4 ITT population. † µ adj = µ f d r + µ (1-f d ), where µ is the mean difference from primary efficacy analysis, f d is the fraction of patients taking diltiazem, and r is the ratio of ranolazine plasma concentrations in patients not taking diltiazem to those taking diltiazem. NDA T6-5. 45

16. SS-16 Projected Diltiazem Plasma Concentration Profiles 5 ISE F-6 Diltiazem SR 180 mg qd 240 200 160 120 80 40 0 Plasma concentration, ng/mL 04812162024 Time, hr 2.5h3h Diltiazem IR 60 mg tid Diltiazem SR 300 mg qd Diltiazem SR 360 mg qd NDA 20-092, study RG83606-103 comparing Dilacor XR to dilitiazem IR tablets; NDA 20-939 study P97-062-Steady-state pharmacokinetics. 2.5 to 3 hours after dosing with diltiazem IR 60 mg tid, plasma diltiazem levels are in the same range as with diltiazem 300 mg qd SR at trough

17. SS-17 Diltiazem—Plateau in Efficacy Effect Daily dose, mg Mean change from placebo at trough, sec 60120180240300360480540 Cardizem CD † 1127-22-4039- Tiazac ‡ -12-27-19-18 †Cardizem ® CD tablets (diltiazem hydrochloride) US Package Insert. Marion Merrell Dow, Inc. May 1999. ‡Tiazac ® tablets (diltiazem hydrochloride) US Package Insert. Marion Merrell Dow, Inc. Revised June 2000.  Diltiazem IR dose of 60 mg tid results in the same predicted plasma diltiazem level at 2.5 to 3 hr after dosing as diltiazem 300 mg daily at steady state trough

18. SS-18 Calculated Improvement in ETT Converted to Stage 0 Work Conditions MARISA (CVT 3031) and CARISA (CVT 3033) 23 Exercise duration, min Ranolazine 500 mg Ranolazine 750 mg Ranolazine 1000 mg Ranolazine 1500 mg MARISA Peak70.3NA132.0150.3 Trough57.1NA80.8121.9 CARISA Peak NA 108.381.4 NA Trough NA 56.957.7 NA

19. SS-19 Exercise Duration at Trough— Patients With Diabetes CARISA (CVT 3033) 5 ISE T-43 n =552036820460201 NOTE: ITT population. Data presented as LS mean ± SE. Treatment by subgroup interaction p = 0.89

20. SS-20 Exercise Duration at Peak— Patients With Diabetes CARISA (CVT 3033) 5 ISE T-43 n =552016720359196 NOTE: ITT population. Data presented as LS mean ± SE. Treatment by subgroup interaction p = 0.58

21. SS-21 Exercise Duration at Trough— Patients With Diabetes MARISA (CVT 3031) 5 ISE T-44 n = 42132 4213242132 NOTE: All/Near Completers population. Data presented as LS mean ± SE. Treatment by subgroup interaction p = 0.77 40129

22. SS-22 Exercise Duration at Peak— Patients With Diabetes MARISA (CVT 3031) 5 ISE T-44 n =411314213242132 NOTE: All/Near Completers population. Data presented as LS mean ± SE. Treatment by subgroup interaction p = 0.95 40127

23. SS-23 Exercise Performance in Males vs Females Ranolazine IR vs Atenolol RAN080 23 Difference from placebo Variable MaleFemale Duration of exercise, sec Atenolol 100 mg qd16.2 ± 7.9 8.5 ± 22.7 Ranolazine 400 mg tid 37.2 ± 7.9 37.0 ± 22.6 Treatment by subgroup interaction p-value = 0.93 Time to onset of angina, sec Atenolol 100 mg qd 42.8 ± 8.8 –1.4 ± 25.4 Ranolazine 400 mg tid 54.8 ± 8.8 13.3 ± 25.2 Treatment by subgroup interaction p-value = 0.17 Time to onset of 1-mm ST-segment depression, sec Atenolol 100 mg qd 57.7 ± 9.3–20.4 ± 26.9 Ranolazine 400 mg tid 56.5 ± 9.3 13.3 ± 26.7 Treatment by subgroup interaction p-value = 0.02 Data presented as LS mean ± SE. Table 19

24. SS-24 Exercise Duration at Trough at Wk 12 (LOCF) by Subgroup CARISA (CVT 3033) 23 In subgroupNot in subgroup ISE T 36, 39, 41, 43 n = 184 n = 179 n = 185 n = 204 n = 201 n = 246 n = 244 Subgroup (interaction test p-value) Ranolazine treatment, mg bid Borderline VS or AV conduction† p = 0.75 750n = 88 1000n = 82 CHF p = 0.22 750n = 87 1000n = 76 Diabetes p = 0.89 750n = 68 1000n = 60 RAD p = 0.30 750n = 26 1000n = 17 Any subgroup 750n = 193 P = 0.591000N = 164 n = 79 n = 97 NOTE: Data presented as LS mean ± SE. CHF = Congestive heart failure; RAD = Reactive airway disease. †SBP ≤ 100 mm Hg, HR ≤ 60 bpm, or PR interval ≥ 200 msec.

25. SS-25 Exercise Duration at Peak at Wk 12 (LOCF) by Subgroup CARISA (CVT 3033) 23 In subgroupNot in subgroup ISE T 36, 39, 41, 43 n = 182 n = 174 n = 184 n = 179 n = 203 n = 196 n = 244 n = 238 Subgroup (interaction test p-value) Ranolazine treatment, mg bid Borderline VS or AV conduction† p = 0.51 750n = 88 1000n = 81 CHF p = 0.22 750n = 86 1000n = 76 Diabetes p = 0.58 750n = 67 1000n = 59 RAD p = 0.73 750n = 26 1000n = 17 Any subgroup 750n = 192 P = 0.381000N = 162 n = 78 n = 93 CHF = Congestive heart failure; RAD = Reactive airway disease. †SBP ≤ 100 mm Hg, HR ≤ 60 bpm, or PR interval ≥ 200 msec.

26. SS-26 Exercise Duration at Trough by Subgroup MARISA (CVT 3031) Subgroup (interaction test p-value) Ranolazine treatment, mg bid Borderline VS or AV conduction† p = 0.54 500 1000 1500 CHF 500 p = 0.941000 1500 Diabetes 500 p = 0.771000 1500 RAD 500 p = 0.121000 1500 Any subgroup p = 0.68 500 1000 1500 CHF = Congestive heart failure; RAD = Reactive airway disease. †SBP ≤ 100 mm Hg, HR ≤ 60 bpm, or PR interval ≥ 200 msec. 23 In subgroupNot in subgroup n = 29 n = 28 n = 42 n = 40 n = 10 n = 9 n = 82 n = 79 n = 145 n = 140 n = 145 n = 141 n = 132 n = 129 n = 164 n = 160 n = 92 n = 90 ISE T 36, 39, 41, 43

27. SS-27 Exercise Duration at Peak by Subgroup MARISA (CVT 3031) 23 In subgroupNot in subgroup Subgroup (interaction test p-value) Ranolazine treatment, mg bid Borderline VS or AV conduction† p = 0.74 500 1000 1500 CHF 500 p = 0.011000 1500 Diabetes 500 p = 0.951000 1500 RAD 500 p = 0.891000 1500 Any subgroup p = 0.77 500 1000 1500 n = 29 n = 28 n = 29 n = 28 n = 42 n = 40 n = 10 n = 9 n = 82 n = 78 n = 145 n = 139 n = 145 n = 139 n = 132 n = 127 n = 164 n = 158 n = 92 n = 89 ISE T 36, 39, 41, 43 CHF = Congestive heart failure; RAD = Reactive airway disease. †SBP ≤ 100 mm Hg, HR ≤ 60 bpm, or PR interval ≥ 200 msec.

28. SS-28 Most Common AEs ≥ 2% In CHF Patients Phase 2/3 SR Controlled Studies Patients, n % PlaceboRanolazine With CHF n = 107 Without CHF n = 348 With CHF n = 197 Without CHF n = 197 Total with any AEs14 (13.1)87 (25.0)41 (20.8)234 (42.4) Body as a whole Asthenia1 (0.9)9 (2.6)3 (1.5)28 (5.1) Cardiovascular system Angina pectoris3 (2.8)18 (5.2) 6 (3.0)28 (5.1) Digestive system Constipation02 (0.6)6 (3.0)43 (7.8) Nausea03 (0.9)3 (1.5)40 (7.2) Nervous system Dizziness06 (1.7)3 (1.5)58 (10.5) ISS T-52 14

29. SS-29 Relationship Between Plasma Ranolazine Levels and Adverse Effects Category Variable Nausea/ vomiting Dizziness/ vertigoSyncope Abnormal vision/ diplopia Paresthesia/ confusion Patients/subjects, n658627136 Ranolazine concentration, ng/mL Mean32123279330756416485 SD27152820282334603119 44

30. SS-30 Ranolazine Reduces Incidence of Ischemia/Reperfusion VF in Rat Isolated Working Hearts Ranolazine,  M AT 4474 Incidence of VF, %

31. SS-31 Known Risk Factors (Predisposing Conditions) for TdP With QT-Prolonging Drugs Predisposing Conditions 1.I Kr,s blockers 2.Na + - and Ca ++ -channel “openers” 3.Bradycardia (sinus pauses) 4.Hypokalemia, hypomagnesemia 5.Ion channel mutations (Pharm. Simulation)  I Ks (LQT 1 );  I Kr (LQT 2 );  I Na, late (LQT 3 ) 6.Heart failure 7.Sex (female) 8.Epicardial pacing Ischemia* 28 Ranolazine NO NO=no EADs, no  TDR, no EBs, no VT, no VF*

32. SS-32 Ventricular Arrhythmias During Exercise Treadmill Testing at Peak MARISA (CVT 3031) Patients, n (%) Ranolazine, mg Placebo n = 176 500 n = 177 1000 n = 178 1500 n = 170 Arrhythmia during exercise 44 (25)36 (20)40 (22)28 (16) Arrhythmia during recovery 38 (22)35 (20)29 (16)20 (12) [RANO010.ANALYSYS.TABLELIB] EXMILL_P.SAS, QUINTILES (US), 13-SEP-01 16:16

33. Association of Increased Transmural Dispersion of Repolarization and Early Afterdepolarizations in Canine Left Ventricular Myocardium with Occurrence of Torsade de Pointes in Humans Drug Evaluated Canine Model System a Studied Drug Action in Canine LV Myocardium TdP Reported in Humans Prolongs QT LV Tissue Induces EADs Increases TDR MidEpiPFWedge Antiarrhythmics Amiodarone Azimilide Quinidine (low concentration) Quinidine (high concentration) Sotalol Verapamil YYYYYYYYYYYY YYYYYYYYYYYY YYYYYYYY YYYY         Antihistamines Terfenadine YYY  Antibiotics Erythromycin Moxifloxacin YYYY YYYYY Y     Miscellaneous Sodium pentobarbital Cisapride IKs +  adrenergic stimulation IKs +  Blocker Mibefradil Ranolazine YYYYYYYYYY YYYYYYYYYY YYYYYYYY YYYYYYYYYYYY     SS-33

34. SS-34 Sensitivity and Specificity of Canine Ventricular Tissues in Detecting Agents That Predispose to TdP  Sensitivity 90%*  Specificity 100%

35. Moxilfoxacin Produces a Dramatic Dose-Dependent Increase in Transmural Dispersion of APD and EADs [moxifloxacin] vs M APD90 [moxifloxacin] vs Epi APD90 [moxifloxacin] vs TD-APD90 APD90 TD-APD APD 90 M Cell Epicardium SS-35

36. SS-36 Electrocardiographic Findings MARISA (CVT 3031) Ranolazine Placebo N = 179 500 mg bid N =181 1000 mg bid N = 180 1500 mg bid N = 187 ParameterTroughPeakTroughPeakTroughPeakTroughPeak PR interval, msec LS mean161.6163.5164.2166.4168.0168.2166.1169.8 p-value vs placebo——0.2530.0820.0040.0050.049< 0.001 QRS interval, msec LS mean93.091.993.592.593.693.994.394.9 p-value vs placebo——0.4090.4040.3440.0050.051< 0.001

37. SS-37 The Heart in Cirrhosis  Blunted systolic and diastolic contractile responses to stimuli  ↑ QTc (~40% – 50%)  No increased risk of torsade de pointes  Possible mechanisms: lipid biochemical changes and plasma-membrane bound receptor dysfunction in cardiac sarcolemmal membranes

38. SS-38 Incidence of Nausea, Dizziness, and Postural Hypotension At High IV Doses CVT 3111

39. SS-39 Orthostatic Change in Systolic Blood Pressure RAN0201 1500 mg2000 mg 1500 mg SR – Placebo2000 mg SR – Placebo Plasma levels: SBP changes: High dose response in orthostatic BP change: healthy volunteers

40. SS-40 Table 5-8. Listing of Healthy Subjects With Syncope (1) Study/pt. no. Age/ sexDose/formulationEvent date Days on ranolazine QTc † (change from baseline) msec/dateMedicationsNarrative CVT 301-13 / 2612353 33 / MRAN 1000 mg bid / SR 16SEP0112413 (6) / 16SEP01 NoneWhile standing to urinate, felt lightheaded, and fainted while being assisted. CVT 3015 / 2223043 74 / MRAN 1500 mg bid / SR 16MAY0012428 (25) / 16MAY00 NoneSyncope lasting for 2 minutes, dizziness persisted for the next 25 minutes. CVT 3111 / 6053403 37 / M15,000 ug/mL ‡ / iv16JUN0111408 (–9) / 16JUN01 NoneSyncope while returning from the toilet in a wheelchair. CVT 3111 / 6053424 28 / M10,000 ug/mL ‡ / iv23JAN015406 (23) / 23JAN01 NoneSyncope upon standing. CVT 3111 / 6053426 42 / F2000 ug/mL ‡ / iv14DEC001449 (30) / 14DEC00 NoneSyncope upon standing for the measurement of her erect vital signs. CVT 3111 / 6053432 34 / F10,000 ug/mL ‡ / iv30MAR017483 (69) / 30MAR01 NoneIn the lavatory, fell and hit her head, was not responsive but was moving all four limbs (not in a manner suggesting seizure). Regained consciousness. No significant head injury. †Bazett correction; Fridericia not available. ‡Target concentration. 54

41. SS-41 Table 5-8. Listing of Healthy Subjects With Syncope (2) Study/pt. no. Age/ sexDose/formulationEvent date Days on ranolazine QTc † (change from baseline) msec/dateMedicationsNarrative RAN0102 / 607DS004 23 / MRAN 342 mg single dose / IR 26AUG931414 (0) / 26AUG93 NoneSyncope during the measurement of his erect vital signs. RAN0112 / 607SA023 29 / MRAN 2000 mg qd / SR 03DEC932391 (5) / 03DEC93 NoneReported to have fainted. RAN063 / 607RM020 20 / MRAN 320 mg single dose / IR 27MAY911399 (–7) / 27MAY91 NoneSyncope during the measurement of his erect vital signs. RAN068 / 607RK005 22 / MRAN 240 mg tid / IR 11NOV927393 (12) / 11NOV92 DiltiazemSyncope during the measurement of his erect BP. RAN090 / 607LD010 19 / MRAN 200 mg single dose / IR 02NOV921N/A / 02NOV92 NoneSyncope during performance of a venipuncture. †Bazett correction; Fridericia not available. ‡Target concentration. 54

42. SS-42 Syncope Occurs Early in Treatment in Patients Randomized to Higher Doses Phase 2/3 Controlled Studies 50 10/27/03 NDA requests/ISS

43. SS-43 Renal Impairment CVT 3016 0102030405060708090100110120130 Creatinine clearance, mL/min 0 20 40 60 80 100 120 Oral ranolazine clearance, L/hr Severe ModerateMild Normal

44. SS-44 Distribution of Ranolazine PK Parameters at Steady-State in Healthy Controls and Patients With Hepatic Impairment CVT 3018 NDA Item 6, T 6.14-2 19 Hepatic impairment AUC (0–12), ng/mL × hr C max, ng/ml Nonen16 Mean (SD)9249 (3756)1155 (558) Mildn88 Mean (SD)9618 (2613)1295 (213) Moderaten88 Mean (SD)16,252 (5271)1747 (512)

45. SS-45 Concomitant Medications in Patients With Syncope Phase 2/3 Controlled and Open Label Studies Patients n (%) Syncopal N = 37 † Phase 2/3 controlled studies and open label N = 1943 † Concomitant medications Nitrates30 (81)1385 (71) Long-acting nitrates13 (35)267 (14) ACEI18 (49)503 (26) Calcium channel blockers21 (57)411 (21) Diltiazem12 (32)365 (19) Beta blockers16 (43)703 (36) Alpha blockers5 (14)44 (2) Diuretics14 (38)250 (14) Exposed to ranolazine. 16

46. SS-46 Summary of Syncope Patients on Vasoactive Medications Number of vasoactive medications Patients, n (%) n = 38 07 (18) 15 (13) 213 (34) 37 (18) 45 (13) > 41 (3)

47. SS-47 Postural Hypotension and Syncope Syncope incidence Postural hypotension incidence Prazosin1%NA Doxazosin0.5 - 1.0%0.3% AtenololNA2.0% Metoprolol1%NA Carvedilol3.4%> 1% and < 2% Ranolazine † 1.10%0.40% 16 Physicians’ Desk Reference. 2003. †Phase 2/3 controlled studies.

48. SS-48 Effect of Ranolazine on CYP2D6 Activity CVT 301-13 NDA Item 6, T 6.13-9 19 Treatment Geometric mean (SD) n = 14MinMax Day –1, baseline0.00674 (0.02514) 0.001830.0996 Day 4, ranolazine0.05674 (0.9432) 0.008983.58 Day 11, ranolazine + paroxetine 0.5944 (1.053) 0.2624.31

49. SS-49 Effect of Ranolazine on LVSP and LV dP/dt in Awake Dogs 0 30 60 90 120 150 053045101520 Ranolazine 0 1000 2000 3000 n = 5 Time, min LVdP/dt, mm Hg/s LVSP, mm Hg 053045101520 Ranolazine Time, min 1  M3  M14  M 18  M

50. SS-50 Effect of Ranolazine on CBF and CVR in Awake Dogs 0 11 22 33 44 55 053045101520 Ranolazine 0 1 2 3 4 n = 5 Time, min CBF, ml/min CVR, mm Hg/ml/min 053045101520 Ranolazine Time, min 1  M3  M14  M 18  M

51. SS-51 050010001500200025003000 Concentration, ng/mL -40 -20 0 20 40 60 80 Change in QTc from baseline, msec Moderate Mild Change in QTc by Plasma Ranolazine Concentration in Mild and Moderate Hepatic Impairment CVT 3018

52. SS-52 QTc Values > 500 msec on Ranolazine Random Variation Plus a Linear Increase Ranolazine concentration, ng/mL Change in QTc from baseline, msec 540 520 500 480 460 440 420 400 380 360 340 320 200040006000800010,00012,00014,000 2.4 msec per 1000 ng/mL (95%prediction interval)