ss-1 ranexa™ supportive slides 18. ss-2 exercise duration at trough at wk 12 (locf) by background...
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SS-1
Ranexa™Supportive Slides
18
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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)
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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
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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.
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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
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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
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 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 < 0.01 NS 0.013 NS 0.012 NS 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 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 < 0.01 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.
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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
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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 =
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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
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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
Placebo Ranolazine750 mg bid
Ranolazine1000 mg bid
Ch
ang
e fr
om
bas
elin
e, s
ec
Revascularization
No revascularization
n = 70 186 80 190 85 170
43
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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
Placebo Ranolazine500 mg bid
Ranolazine1000 mg bid
Ranolazine1500 mg bid
Tim
e, s
ec
RevascularizationNo revascularization
n = 84 90 84 90 85 89 82 87
43
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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
Placebo Ranolazine500 mg bid
Ranolazine1000 mg bid
Ranolazine1500 mg bid
Tim
e,
se
c
Revascularization
No revascularization
n = 83 89 84 90 85 89 81 86
43
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SS-13Exercise 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)
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SS-14Exercise Duration at Peak 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
Placebo Ranolazine 750 mg bid
Ranolazine 1000 mg bid
Cha
nge
from
bas
elin
e, s
ec
Diltiazem (N = 195)Amlodipine (N = 247)Atenolol (N = 339)
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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
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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
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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
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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
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SS-19Exercise Duration at Trough—Patients With DiabetesCARISA (CVT 3033)
5 I
SE
T-4
3
0
25
50
75
100
125
150
Placebo Ranolazine750 mg bid
Ranolazine1000 mg bid
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
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SS-20Exercise Duration at Peak—Patients With DiabetesCARISA (CVT 3033)
5 I
SE
T-4
3
0
25
50
75
100
125
150
Placebo Ranolazine750 mg bid
Ranolazine1000 mg bid
Ch
ang
e fr
om
bas
elin
e, s
ec
Diabetes No diabetes
n = 55 201 67 203 59 196
NOTE: ITT population. Data presented as LS mean ± SE.Treatment by subgroup interaction p = 0.58
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SS-21Exercise Duration at Trough—Patients With DiabetesMARISA (CVT 3031)
5 I
SE
T-4
4
300
400
500
600
Placebo Ranolazine500 mg bid
Ranolazine1000 mg bid
Ranolazine 1500 mg bid
Tim
e, s
ec
Diabetes No diabetes
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
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SS-22Exercise Duration at Peak—Patients With DiabetesMARISA (CVT 3031)
5 I
SE
T-4
4
400
500
600
Placebo Ranolazine500 mg bid
Ranolazine1000 mg bid
Ranolazine 1500 mg bid
Tim
e, s
ec
Diabetes No diabetes
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
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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
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.
Tab
le 1
9
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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.
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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)
Ranolazine treatment, mg bid
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
Difference from placebo, sec
n = 78
n = 93
CHF = Congestive heart failure; RAD = Reactive airway disease.†SBP ≤ 100 mm Hg, HR ≤ 60 bpm, or PR interval ≥ 200 msec.
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SS-26
0 50 100 150
Difference from placebo, sec
Exercise Duration at Trough by SubgroupMARISA (CVT 3031)
0 50 100 150
Difference from placebo, secSubgroup(interactiontest p-value)
Ranolazine treatment, mg bid
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
CHF = Congestive heart failure; RAD = Reactive airway disease.†SBP ≤ 100 mm Hg, HR ≤ 60 bpm, or PR interval ≥ 200 msec.
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
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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)
Ranolazine treatment, mg bid
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
CHF = Congestive heart failure; RAD = Reactive airway disease.†SBP ≤ 100 mm Hg, HR ≤ 60 bpm, or PR interval ≥ 200 msec.
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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
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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
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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
, %
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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*
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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
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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
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SS-34Sensitivity and Specificity of Canine Ventricular Tissues in Detecting Agents That Predispose to TdP
Sensitivity 90%* Specificity 100%
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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
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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
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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
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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
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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
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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
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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
20 / M RAN 320 mg single dose / IR
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
19 / M RAN 200 mg single dose / IR
02NOV92 1 N/A / 02NOV92
None Syncope during performance of a venipuncture.
†Bazett correction; Fridericia not available.‡Target concentration.
54
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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
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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
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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)
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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
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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)
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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.
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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
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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
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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
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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
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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)