1

CR-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. Serruys PW, et al. Arterial Revascularization Therapies Study Group. N Engl J Med.N Engl J Med. 2001; 344:1117-1124. 2001; 344:1117-1124.

CR-3

Limitations to Uptitration of Currently Available Antianginal Drugs

Beta blockers• Bradycardia• Hypotension• Fatigue and/or depressionCalcium channel blockers • Bradycardia• Hypotension• LV dysfunctionLong-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-5Consistent 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-6Ranolazine Increases Total Exercise Duration:

Quantitative Effect Comparable to Other Antianginals

Mean increase in placebo-corrected exercise time, sec

Study populationtest procedures

Ranolazine(monotherapy) 500 bid

1000 bid(combined Rx) 1000 bid

243324

• Severely impaired patients• Stringent test criteria

Atenolol100 mg qd100 mg qd

3929

(NDA 18-240, vol 1.2)

• Mod impaired patients• Test at peak drug levels

Diltiazem (SR form)(Cardizem CD) 360 mg qd (Tiazac) 360 mg qd

2227

• Mod impaired patients

Transdermal TNG0.8 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

0102030405060708090

Ranolazine Ranolazine &Ketoconazole

mse

c

Ranolazine Terfenadine QTci QTcB

0102030405060708090

Terfenadine Terfenadine &Ketoconazole

CR-9

-10

0

10

20

30

40

50

0 1000 2000 3000 4000 5000 6000 7000 8000

RAN concentration, ng/mL

Cha

nge

in Q

Tc fr

om

base

line,

mse

c

All Females CHF Age > 65 HR < 60 CAD Pts

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 EADs • Suppress EADs

• Increase dispersion • Reverse 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 RanolazineSummary

• 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