SS-1 Ranexa™ Supportive Slides 18. SS-2 Exercise Duration at Trough at Wk 12 (LOCF) by Background Therapy CARISA (CVT 3033) Treatment by background therapy

SS-1

Ranexa™Supportive Slides

18

SS-2Exercise Duration at Trough at Wk 12 (LOCF) by Background TherapyCARISA (CVT 3033)

Treatment by background therapy p = 0.63Data presented as LS mean ± SE.

0

20

40

60

80

100

120

140

160

Placebo Ranolazine 750 mg bid

Ranolazine 1000 mg bid

Cha

nge

from

bas

elin

e, s

ec

Diltiazem (N = 199)Amlodipine (N = 249)Atenolol (N = 343)

SS-3

ETT by Treatment and PeriodMARISA (CVT 3031)

450

500

550

600

650

0 1 2 3 4 5Period

ET

T,s

ec

Placebo RAN 500 RAN1000 RAN1500

SS-4End-Exercise Heart Rate, Blood Pressure, RPP, and Exercise DurationMARISA (CVT 3031) and CARISA (CVT 3033)

Ranolazine SR dose

LS mean difference from placebop-values ≤ 0.05

500 mg bid† 750 mg bid‡ 1000 mg bid‡ 1000 mg bid† 1500 mg bid†

Trough Peak Trough Peak Trough Peak Trough Peak Trough Peak

Standing end-exerciseHR, bpm

0.6NS

1.7NS

–3.1p = 0.01

–2.3NS

–2.8p = 0.021

–2.1NS

–1.7NS

–0.4NS

–1.5NS

–1.5NS

Standing end-exerciseSBP, mmHg

–1.7NS

–2.2NS

–1.8NS

0.4NS

–3.3p = 0.035

0.1NS

–3.6p = 0.008

–3.5p = 0.006

–5.4p < 0.001

–6.5p < 0.001

RPP at end-exercise, bpm mm Hg

–107.2NS

43.3NS

–617.9p = 0.036

–258.3NS

–822.1p = 0.006

–315.5NS

–737.8p = 0.004

–512.5p = 0.035

–929.0p < 0.001

–1006.5p < 0.001

Exercise duration, sec

23.8p = 0.003

29.3p < 0.001

27.1p = 0.017

34.2p = 0.002

26.8p = 0.020

24.3p = 0.031

33.7 p < 0.001

50.1p < 0.001

45.9p < 0.001

55.5p < 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

SS-5

Rate Pressure Product at Peak—Wk 12CARISA (CVT 3033)

66

8000

12000

16000

20000

24000

Pre-exercise

Stage 0 Stage 0.5 Stage 1 Stage 2 Stage 3 Stage 4

RP

P,

mm

Hg

• b

pm

Placebo RAN 750 mg bid RAN 1000 mg bid

Placebo 244

RAN 750 250

RAN 1000 238

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_

exst

ag

e (2

1N

OV

03 1

4:5

0)

s:\C

VT

-30

3\N

DA

_re

que

sts\

CV

T3

033

\ta

ble

_g

rap

h\v

s_e

xsta

ge_

est

.RT

F

SS-6Overall Summary of Key Efficacy Results in Ranolazine IR, Study RAN1514(All Patients Analysis)

Variable

Placebo

Ranolazine IR

267 mg tid 400 mg bid 400 mg tid All ranolazine doses

TroughN = 306

PeakN = 306

TroughN = 299

PeakN = 296

TroughN = 300

PeakN = 299

TroughN = 304

PeakN = 303

TroughN = 312

PeakN = 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 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 NS NS NS NS NS NS 0.013

Time to onset of angina, sec



(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 < 0.01 NS 0.013 NS 0.012 NS 0.01

Time to 1-mm ST-segment depression, sec



(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 < 0.01 NS 0.02 NS < 0.01 0.047 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.

SS-7

**

Ranolazine Effect on Exercise Duration Maintained Over 12 Wk of TherapyCARISA (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..

RanolazineRanolazineRanolazineRanolazinePlaceboPlacebo

4040

6060

8080

100100

120120

140140

00 22 44 66 88 1010 1212

1000 mg bid1000 mg bid750 mg bid750 mg bid

Ch

ang

e fr

om

bas

elin

eC

han

ge

fro

m b

asel

ine

(tro

ug

h,

sec)

(tro

ug

h,

sec) ******

****

Weeks

SS-8Rebound Assessment—Change From Baseline in Exercise Treadmill Test Duration at Trough CARISA (CVT 3033)

90

100

110

120

130

140

150

Ch

an

ge

fro

m b

as

elin

e, s

ec

Double-blind:

Withdrawal:

Placebo RAN 750 RAN 1000 RAN 750 RAN 1000

Placebo Placebo Placebo RAN 750 RAN 1000

Data presented as LS mean ± SE.

243 128 118 120 118N =

SS-9Exercise 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

0

50

100

150

200

Placebo Ranolazine750 mg bid

Ranolazine1000 mg bid

Ch

an

ge

fro

m b

as

eli

ne

, s

ec Revascularization

No revascularization

n = 70 188 81 191 90 171

43

SS-10Exercise 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

0

50

100

150

200



Ch

ang

e fr

om

bas

elin

e, s

ec

Revascularization


n = 70 186 80 190 85 170

43

SS-11Exercise 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

0

100

200

300

400

500

600

700




Tim

e, s

ec

RevascularizationNo revascularization

n = 84 90 84 90 85 89 82 87

43

SS-12Exercise 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

0

100

200

300

400

500

600

700




Tim

e,

se

c

Revascularization


n = 83 89 84 90 85 89 81 86

43

SS-13Exercise Duration at Trough at Wk 12 (LOCF) by Background TherapyCARISA (CVT 3033)


0

20

40

60

80

100

120

140

160



Cha

nge

from

bas

elin

e, s

ec


SS-14Exercise Duration at Peak at Wk 12 (LOCF) by Background TherapyCARISA (CVT 3033)


0

20

40

60

80

100

120

140



Cha

nge

from

bas

elin

e, s

ec


SS-15Estimated 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%) 23.7 21.9

Ranolazine 1000 mg

63/261 (24.1%) 24.0 22.4

ITT population.†µadj = µ fd r + µ (1-fd), where µ is the mean difference from primary efficacy analysis,fd is the fraction of patients taking diltiazem, and r is the ratio of ranolazine plasmaconcentrations in patients not taking diltiazem to those taking diltiazem.

ND

A T

6-5.

45

SS-16

Projected Diltiazem Plasma Concentration Profiles

5 I

SE

F-6

Diltiazem SR 180 mg qd

240

200

160

120

80

40

0

Pla

sma

con

cen

trat

ion

, n

g/m

L

0 4 8 12 16 20 24Time, hr 2.5h3h

Diltiazem IR 60 mg tid

Diltiazem SR 300 mg qdDiltiazem SR 360 mg qd

NDA 20-092, study RG83606-103 comparing Dilacor XR to dilitiazem IR tablets; NDA 20-939study 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

SS-17

Diltiazem—Plateau in Efficacy Effect

Daily dose, mg

Mean change from placebo at trough, sec

60 120 180 240 300 360 480 540

Cardizem CD† 11 27 - 22 - 40 39 -

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

SS-18Calculated Improvement in ETTConverted to Stage 0 Work ConditionsMARISA (CVT 3031) and CARISA (CVT 3033)

23

Exercise duration, min

Ranolazine 500 mg

Ranolazine 750 mg

Ranolazine 1000 mg

Ranolazine 1500 mg

MARISA

Peak 70.3 NA 132.0 150.3

Trough 57.1 NA 80.8 121.9

CARISA

Peak NA 108.3 81.4 NA

Trough NA 56.9 57.7 NA

SS-19Exercise Duration at Trough—Patients With DiabetesCARISA (CVT 3033)

5 I

SE

T-4

3

0

25

50

75

100

125

150



Ch

ang

e fr

om

bas

elin

e, s

ec

Diabetes No diabetes

n = 55 203 68 204 60 201

NOTE: ITT population. Data presented as LS mean ± SE.Treatment by subgroup interaction p = 0.89

SS-20Exercise Duration at Peak—Patients With DiabetesCARISA (CVT 3033)

5 I

SE

T-4

3

0

25

50

75

100

125

150



Ch

ang

e fr

om

bas

elin

e, s

ec


n = 55 201 67 203 59 196

NOTE: ITT population. Data presented as LS mean ± SE.Treatment by subgroup interaction p = 0.58

SS-21Exercise Duration at Trough—Patients With DiabetesMARISA (CVT 3031)

5 I

SE

T-4

4

300

400

500

600




Tim

e, s

ec


n = 42 132 42 132 42 132

NOTE: All/Near Completers population. Data presented as LS mean ± SE.Treatment by subgroup interaction p = 0.77

40 129

SS-22Exercise Duration at Peak—Patients With DiabetesMARISA (CVT 3031)

5 I

SE

T-4

4

400

500

600




Tim

e, s

ec


n = 41 131 42 132 42 132

NOTE: All/Near Completers population. Data presented as LS mean ± SE. Treatment by subgroup interaction p = 0.95

40 127

SS-23Exercise Performance in Males vs Females Ranolazine IR vs AtenololRAN080

23

Difference from placebo

Variable Male Female

Duration of exercise, sec

Atenolol 100 mg qd 16.2 ± 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



Time to onset of 1-mm ST-segment depression, sec

Atenolol 100 mg qd 57.7 ± 9.3 –20.4 ± 26.9



Data presented as LS mean ± SE.

Tab

le 1

9

SS-24Exercise Duration at Trough at Wk 12 (LOCF) by SubgroupCARISA (CVT 3033)

23

0 50 100 150

Difference from placebo, secIn subgroup Not in subgroupIS

E T

36,

39,

41,

43

n = 184

n = 179

n = 185

n = 185

n = 204

n = 201

n = 246

n = 244

Subgroup(interactiontest p-value)

Ranolazine treatment, mg bid

Borderline VSor AV conduction†

p = 0.75

750 n = 88

1000 n = 82

CHFp = 0.22

750 n = 87

1000 n = 76

Diabetesp = 0.89

750 n = 68

1000 n = 60

RADp = 0.30

750 n = 26

1000 n = 17

Any subgroup 750 n = 193

P = 0.59 1000 N = 164

0 50 100 150

Difference from placebo, sec

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.

SS-25Exercise Duration at Peak at Wk 12 (LOCF) by SubgroupCARISA (CVT 3033)

23

0 50 100 150

Difference from placebo, secIn subgroup Not in subgroupIS

E T

36,

39,

41,

43

n = 182

n = 174

n = 184

n = 179

n = 203

n = 196

n = 244

n = 238

Subgroup(interactiontest p-value)


Borderline VSor AV conduction†

p = 0.51

750 n = 88

1000 n = 81

CHFp = 0.22

750 n = 86

1000 n = 76

Diabetesp = 0.58

750 n = 67

1000 n = 59

RADp = 0.73

750 n = 26

1000 n = 17

Any subgroup 750 n = 192

P = 0.38 1000 N = 162

0 50 100 150


n = 78

n = 93

CHF = Congestive heart failure; RAD = Reactive airway disease.†SBP ≤ 100 mm Hg, HR ≤ 60 bpm, or PR interval ≥ 200 msec.

SS-26

0 50 100 150


Exercise Duration at Trough by SubgroupMARISA (CVT 3031)

0 50 100 150

Difference from placebo, secSubgroup(interactiontest p-value)


Borderline VSor AV conduction†p = 0.54

50010001500

CHF 500p = 0.94 1000

1500

Diabetes 500p = 0.77 1000

1500

RAD 500p = 0.12 1000

1500

Any subgroupp = 0.68

50010001500


23

In subgroup Not in subgroup

n = 29n = 29n = 29

n = 29n = 29n = 28

n = 42n = 42n = 40

n = 10n = 10n = 9

n = 82n = 82n = 79

n = 145n = 145n = 140

n = 145

n = 145n = 141

n = 132n = 132n = 129

n = 164n = 164n = 160

n = 92n = 92n = 90

ISE

T 3

6, 3

9, 4

1, 4

3

SS-27

Exercise Duration at Peak by SubgroupMARISA (CVT 3031)

0 50 100 150Difference from placebo, sec

0 50 100 150Difference from placebo, sec

23

In subgroup Not in subgroupSubgroup(interactiontest p-value)


Borderline VSor AV conduction†p = 0.74

50010001500

CHF 500p = 0.01 1000

1500

Diabetes 500p = 0.95 1000

1500

RAD 500p = 0.89 1000

1500

Any subgroupp = 0.77

50010001500

n = 29n = 29n = 28

n = 29n = 29n = 28

n = 42n = 42n = 40

n = 10n = 10n = 9

n = 82n = 82n = 78

n = 145

n = 145

n = 139

n = 145

n = 145

n = 139

n = 132

n = 132

n = 127

n = 164

n = 164

n = 158

n = 92

n = 92

n = 89

ISE

T 3

6, 3

9, 4

1, 4

3


SS-28Most Common AEs ≥ 2% In CHF PatientsPhase 2/3 SR Controlled Studies

Patients, n %

Placebo Ranolazine

WithCHF

n = 107

WithoutCHF

n = 348

WithCHF

n = 197

WithoutCHF

n = 197Total with any AEs 14 (13.1) 87 (25.0) 41 (20.8) 234 (42.4)Body as a whole

Asthenia 1 (0.9) 9 (2.6) 3 (1.5) 28 (5.1)Cardiovascular system

Angina pectoris 3 (2.8) 18 (5.2) 6 (3.0) 28 (5.1)Digestive system

Constipation 0 2 (0.6) 6 (3.0) 43 (7.8)Nausea 0 3 (0.9) 3 (1.5) 40 (7.2)

Nervous system

Dizziness 0 6 (1.7) 3 (1.5) 58 (10.5)

ISS

T-5

214

SS-29

Relationship Between Plasma Ranolazine Levels and Adverse Effects

Category

VariableNausea/vomiting

Dizziness/vertigo Syncope

Abnormal vision/

diplopiaParesthesia/confusion

Patients/subjects, n 65 86 27 13 6

Ranolazine concentration,ng/mL

Mean 3212 3279 3307 5641 6485

SD 2715 2820 2823 3460 3119

44

SS-30Ranolazine Reduces Incidence of Ischemia/Reperfusion VF in Rat Isolated Working Hearts

0

25

50

75

100

Control 0.1 1 10

Ranolazine, MAT 4474

Inci

den

ce

of

VF

, %

SS-31

Known Risk Factors (Predisposing Conditions) for TdP With QT-Prolonging Drugs

Predisposing Conditions

1. IKr,s blockers

2. Na+- and Ca++-channel “openers”

3. Bradycardia (sinus pauses)

4. Hypokalemia, hypomagnesemia

5. Ion channel mutations (Pharm. Simulation)

IKs (LQT1); IKr (LQT2); INa, late (LQT3)

6. Heart failure

7. Sex (female)

8. Epicardial pacing

Ischemia*

28

Ranolazine

NO

NO

NO

NO

NO

NO

NO

NO

NO

NO=no EADs, no TDR, no EBs, no VT, no VF*

SS-32Ventricular Arrhythmias During Exercise Treadmill Testing at PeakMARISA (CVT 3031)

Patients, n (%)

Ranolazine, mg

Placebon = 176

500n = 177

1000n = 178

1500n = 170

Arrhythmiaduring exercise

44 (25) 36 (20) 40 (22) 28 (16)

Arrhythmiaduring recovery

38 (22) 35 (20) 29 (16) 20 (12)

[RA

NO

010.

AN

ALY

SY

S.T

AB

LELI

B] E

XM

ILL_

P.S

AS

, QU

INT

ILE

S (

US

), 1

3-S

EP

-01

16:1

6

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 Systema

StudiedDrug Action in Canine LV

MyocardiumTdP

Reported in Humans

Prolongs

QTLV Tissue

Induces EADs

Increases TDRMid Epi PF Wedge

Antiarrhythmics Amiodarone Azimilide Quinidine (low concentration) Quinidine (high concentration) Sotalol Verapamil

YYYYYY

YYYYYY

YYYY

YY

Antihistamines Terfenadine Y Y Y

Antibiotics

Erythromycin

Moxifloxacin

Y

Y

Y

Y Y

Y

Miscellaneous Sodium pentobarbital

Cisapride

IKs + adrenergic stimulation

IKs + Blocker

Mibefradil

Ranolazine

Y

Y

Y

Y

Y

Y

Y

Y

Y

Y

Y

Y

Y

Y

Y

Y

Y

Y

Y

Y

SS-33

SS-34Sensitivity and Specificity of Canine Ventricular Tissues in Detecting Agents That Predispose to TdP

Sensitivity 90%* Specificity 100%

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 APD90TD-APDAPD90

M Cell

Epicardium

SS-35

SS-36

Electrocardiographic FindingsMARISA (CVT 3031)

Ranolazine

PlaceboN = 179

500 mg bidN =181

1000 mg bidN = 180

1500 mg bidN = 187

Parameter Trough Peak Trough Peak Trough Peak Trough Peak

PR interval, msec

LS mean 161.6 163.5 164.2 166.4 168.0 168.2 166.1 169.8

p-value vs placebo — — 0.253 0.082 0.004 0.005 0.049 < 0.001

QRS interval, msec

LS mean 93.0 91.9 93.5 92.5 93.6 93.9 94.3 94.9p-value vs placebo — — 0.409 0.404 0.344 0.005 0.051 < 0.001

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

SS-38Incidence of Nausea, Dizziness, and Postural Hypotension At High IV DosesCVT 3111

0

10

20

30

40

50

60

70

80

2000 4000 10,000 15,000

Ranolazine target concentration, ng/mL

Pat

ien

ts w

ith

AE

, %

Nausea/vomiting

Dizziness

Postural hypotension

SS-39Orthostatic Change in SystolicBlood PressureRAN0201

0

1000

2000

3000

4000

5000

6000

7000

8000

0 2 4 6 8 10 12

Time, hr

Mea

n p

lasm

a le

vel,

ng

/mL

-12

-10

-8

-6

-4

-2

0

2

4

Mean

chan

ge in

o

rtho

static SB

P, m

mH

g

1500 mg 2000 mg

1500 mg SR – Placebo 2000 mg SR – Placebo

Plasma levels:SBP changes:

High dose response in orthostatic BP change: healthy volunteers

SS-40

Table 5-8. Listing of Healthy Subjects With Syncope (1)

Study/pt. no.Age/sex Dose/formulation Event date

Days onranolazine

QTc† (change from baseline)

msec/date Medications Narrative

CVT 301-13 / 2612353

33 / M RAN 1000 mg bid / SR

16SEP01 12 413 (6) / 16SEP01

None While standing to urinate, felt lightheaded, and fainted while being assisted.

CVT 3015 / 2223043

74 / M RAN 1500 mg bid / SR

16MAY00 12 428 (25) / 16MAY00

None Syncope lasting for 2 minutes, dizziness persisted for the next 25 minutes.

CVT 3111 / 6053403

37 / M 15,000 ug/mL‡ / iv 16JUN01 11 408 (–9) / 16JUN01

None Syncope while returning from the toilet in a wheelchair.

CVT 3111 / 6053424

28 / M 10,000 ug/mL‡ / iv 23JAN01 5 406 (23) / 23JAN01

None Syncope upon standing.

CVT 3111 / 6053426

42 / F 2000 ug/mL‡ / iv 14DEC00 1 449 (30) / 14DEC00

None Syncope upon standing for the measurement of her erect vital signs.

CVT 3111 / 6053432

34 / F 10,000 ug/mL‡ / iv 30MAR01 7 483 (69) / 30MAR01

None In 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

SS-41

Table 5-8. Listing of Healthy Subjects With Syncope (2)

Study/pt. no.Age/sex Dose/formulation Event date

Days onranolazine

QTc† (change from baseline)

msec/date Medications Narrative

RAN0102 / 607DS004

23 / M RAN 342 mg single dose / IR

26AUG93 1 414 (0) / 26AUG93

None Syncope during the measurement of his erect vital signs.

RAN0112 / 607SA023

29 / M RAN 2000 mg qd / SR

03DEC93 2 391 (5) / 03DEC93

None Reported to have fainted.

RAN063 / 607RM020


27MAY91 1 399 (–7) / 27MAY91

None Syncope during the measurement of his erect vital signs.

RAN068 / 607RK005

22 / M RAN 240 mg tid / IR

11NOV92 7 393 (12) / 11NOV92

Diltiazem Syncope during the measurement of his erect BP.

RAN090 / 607LD010


02NOV92 1 N/A / 02NOV92

None Syncope during performance of a venipuncture.

†Bazett correction; Fridericia not available.‡Target concentration.

54

SS-42Syncope Occurs Early in Treatment in Patients Randomized to Higher DosesPhase 2/3 Controlled Studies

0.00

0.01

0.02

0.03

0.04

0 14 28 42 56 70 84 98 112 126 140

Time to event, days

Syn

cop

e ra

te

Placebo RAN IR RAN 500 bidRAN 750 bid RAN 1000 bid RAN 1500 bid

501

0/2

7/0

3 N

DA

re

qu

ests

/IS

S

SS-43

Renal ImpairmentCVT 3016

0 10 20 30 40 50 60 70 80 90 100 110 120 130Creatinine clearance, mL/min

0

20

40

60

80

100

120

Ora

l ran

ola

zin

e cl

eara

nce

, L/h

r

Severe Moderate Mild Normal

SS-44Distribution of Ranolazine PK Parameters at Steady-State in Healthy Controls and Patients With Hepatic ImpairmentCVT 3018

ND

A It

em 6

, T 6

.14-

219

Hepatic impairment AUC(0–12), ng/mL × hr Cmax, ng/ml

None n 16 16Mean (SD) 9249 (3756) 1155 (558)

Mild n 8 8

Mean (SD) 9618 (2613) 1295 (213)

Moderate n 8 8

Mean (SD) 16,252 (5271) 1747 (512)

SS-45Concomitant Medications in Patients With SyncopePhase 2/3 Controlled and Open Label Studies

Patients n (%)

SyncopalN = 37†

Phase 2/3 controlled studies and open label

N = 1943†

Concomitant medications

Nitrates 30 (81) 1385 (71)Long-acting nitrates 13 (35) 267 (14)

ACEI 18 (49) 503 (26)Calcium channel blockers 21 (57) 411 (21)

Diltiazem 12 (32) 365 (19)Beta blockers 16 (43) 703 (36)Alpha blockers 5 (14) 44 (2)Diuretics 14 (38) 250 (14)

Exposed to ranolazine.

16

SS-46

Summary of Syncope Patients on Vasoactive Medications

Number of vasoactive

medicationsPatients, n (%)

n = 38

0 7 (18)

1 5 (13)

2 13 (34)

3 7 (18)

4 5 (13)

> 4 1 (3)

SS-47

Postural Hypotension and Syncope

Syncope incidence

Postural hypotension incidence

Prazosin 1% NA

Doxazosin 0.5 - 1.0% 0.3%

Atenolol NA 2.0%

Metoprolol 1% NA

Carvedilol 3.4% > 1% and < 2%

Ranolazine† 1.10% 0.40%

16

Physicians’ Desk Reference. 2003.†Phase 2/3 controlled studies.

SS-48

Effect of Ranolazine on CYP2D6 ActivityCVT 301-13

ND

A It

em 6

, T 6

.13-

919

Treatment

Geometric mean (SD)

n = 14 Min Max

Day –1, baseline 0.00674(0.02514)

0.00183 0.0996

Day 4, ranolazine 0.05674(0.9432)

0.00898 3.58

Day 11, ranolazine +paroxetine

0.5944(1.053)

0.262 4.31

SS-49

Effect of Ranolazine on LVSP and LV dP/dt in Awake Dogs

0

30

60

90

120

150

0 5 30 4510 15 20

Ranolazine

0

1000

2000

3000

n = 5 n = 5

Time, min

LV

dP

/dt,

mm

Hg

/s

LV

SP

, mm

Hg

0 5 30 4510 15 20

Ranolazine

Time, min

1 M 3 M 14 M 18 M

SS-50

Effect of Ranolazine on CBF and CVR in Awake Dogs

0

11

22

33

44

55

0 5 30 4510 15 20

Ranolazine

0

1

2

3

4n = 5 n = 5

Time, min

CB

F, m

l/min

CV

R, m

m H

g/m

l/min

0 5 30 4510 15 20

Ranolazine

Time, min

1 M 3 M 14 M 18 M

SS-51

0 500 1000 1500 2000 2500 3000

Concentration, ng/mL

-40

-20

0

20

40

60

80

Ch

ang

e i

n Q

Tc

fro

m b

asel

ine

, m

sec

Moderate Mild

Change in QTc by Plasma Ranolazine Concentration in Mild and Moderate Hepatic ImpairmentCVT 3018

SS-52

QTc Values > 500 msec on Ranolazine Random Variation Plus a Linear Increase

Ranolazine concentration, ng/mL

Ch

ang

e in

QT

c fr

om

bas

elin

e, m

sec

540

520

500

480

460

440

420

400

380

360

340

320320 2000 4000 6000 8000 10,000 12,000 14,000

2.4 msec per 1000 ng/mL (95%prediction interval)

2.4 msec per 1000 ng/mL (95%prediction interval)

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