Transcript Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee

Food and Drug Administration
Cardiovascular and Renal Drugs
Advisory Committee
Levitra® Tablets (NDA 21-400)
(vardenafil HCl)
May 29, 2003
1
Introduction
Mary E. Taylor, MPH
Bayer Pharmaceuticals Corporation
Vice President, Regulatory Affairs
North America
2
Agenda
Introduction
Mary Taylor, MPH
Vice President
Regulatory Affairs North America
Bayer Pharmaceuticals Corporation
Assessment of the QT/QTc
Effect of Vardenafil
Thomas Segerson, MD
Vice President
Medical and Scientific Affairs
Bayer Canada
QT/QTc Study Design,
Heart Rate Correction &
Risk of Cardiac Arrhythmia
Joel Morganroth, MD
Clinical Professor of Medicine
University of Pennsylvania
Chief Scientist
eResearchTechnology
3
Consultants
Joel Morganroth, MD
Clinical Professor of Medicine
University of Pennsylvania
Chief Scientist
eResearchTechnology
John Camm, MD
Professor of Clinical Cardiology
St. George's Hospital
London
Gerald Faich, MD
Pharmaceutical Safety Assessments, Inc.
Gary Koch, PhD
Professor of Biostatistics
University of North Carolina
Udho Thadani, MD
Professor of Medicine, Cardiovascular Section
University of Oklahoma
4
Levitra® Tablets
(vardenafil HCl)
 Proposed Indication: Levitra is indicated for the
treatment of erectile dysfunction defined as the
consistent or recurrent inability to attain and/or
maintain a penile erection sufficient for sexual
performance.
 Dosage and Administration: 5, 10, 20 mg
(starting dose 10 mg) may be titrated up or down
5
Regulatory History
 NDA submitted September 2001
 Approvable letter received July 23, 2002
 Application is currently under review
 Approved in 34 countries including the UK, Germany,
and 13 other EU countries; Australia; New Zealand;
and several Latin American countries
6
Timeline
3/01 Health
Canada
12/97 EU
Guidance
1998
11/02 FDA Concept
Paper
QT Interval
Regulatory
Activities
2/02 ICH Safety
Pharmacology
1999
2000
2001
2002
2003
Vardenafil
Development
Phase III
7/02 Approvable
Action
9/01 Levitra NDA
Submitted
5/03 Advisory
Committee
3/03 European
Launch
7
Cardiovascular & Renal Drugs
Advisory Committee Topics
 Clinical trial design for the assessment of
QT/QTc prolongation
 Approaches to the correction of the QT interval
for drugs that affect heart rate
 The risk of cardiac arrhythmia associated with
different degrees of QT/QTc prolongation
8
Assessment of the
QT/QTc Effect of
Vardenafil
Thomas P. Segerson, MD
Vice President
Medical and Scientific Affairs
Bayer Canada
9
Agenda
 Background information on vardenafil
 Pharmacology and mechanism of action
 Efficacy and adverse event profile
 Human pharmacokinetics
 Vardenafil data relevant to QT/QTc assessment
 Preclinical effects
 Clinical pharmacology
 Phase III clinical studies
 Study to rigorously evaluate the QT/QTc effect of
vardenafil
10
Vardenafil: Pharmacology and
Mechanism of Action
 Vardenafil is a potent PDE5 (phosphodiesterase type 5)
inhibitor (IC50 ~1 nM).
 Vardenafil is highly specific for the type 5 PDE
isoenzyme, inhibition of which leads to cyclic guanosine
monophosphate (cGMP) accumulation and corpus
cavernosum smooth muscle relaxation.
 Transient effects of vardenafil on BP and HR are
consistent with the distribution of PDEs in vascular
tissue.
11
Mean EF Domain† Score Change
Vardenafil Efficacy Data in General and
‘Resistant to Treatment’ ED Populations
NA Pivotal Study 100249
*
7.4
8
Diabetes Study 100250
*
*
8.2
7.8
8
*
5.9
*
5.2
6
6
4
4
1.8
2
2
0
0
Placebo
5 mg
10 mg
20 mg
1.4
Placebo
10 mg
20 mg
Treatment Group
†International
Index of Erectile Function
*p <0.01 vs placebo
12
Frequent Adverse Events* in PlaceboControlled Phase III Trials
Adverse Event
Any Event
Headache
Flushing
Rhinitis
Dyspepsia
Accidental Injury
Sinusitis
Flu Syndrome
Dizziness
Increased CK
Nausea
Percentage of Patients with Reported
Event
Placebo
Vardenafil
N = 1199
N = 2203
(%)
(%)
33
53
4
15
1
11
3
9
1
4
2
3
1
3
2
3
1
2
1
2
1
2
*  2% and more frequent with vardenafil than placebo
13
Pharmacokinetic Profile of Vardenafil
after Single 20 mg Oral Dose in Men
mean vardenafil concentration (ng/ml)
20
15
Elimination:
• Hepatic 91-95%
• Renal 2-6%
10
Concentration at 24h
1 - 2% Cmax
5
0
0
6
12
Time (hrs)
18
24
Study 10118, n = 24
14
Human Pharmacokinetics of
Vardenafil and Metabolites
M1, M4 and M5 are
deethylation/
demethylation
products of
vardenafil
metabolism
Concentration ng/ml
100
Peak concentration of
metabolites  50% of
vardenafil
10
vardenafil
1
M1-glucuronide
M5
M4
M1
0.1
0
4
8
Time (h)
12
16
14C
study (10079), n=4
15
Pharmacokinetic Interaction of
Vardenafil with Ritonavir
250
max
C
(ng/ml)
C max(g/l)
200
150
100
76
50
Geometric Mean
n=19
30
2.4
0
vardenafil
5mg
vardenafil
5mg &
ritonavir*
vardenafil
80mg
*interaction assessed on
10th day of ritonavir 600
mg BID dosing
Study 100535
16
Preclinical QT Data
 In vitro evaluation showed an IC50 of 30 M for vardenafil, and 47
M for sildenafil for inhibition of hERG potassium channel, at least
1000-fold above free concentration after maximum clinical dose*
 No QTc prolongation found in vivo in Beagle dogs:
 preclinical model as per guideline
 pattern of vardenafil metabolites similar to human
 safety pharmacology studies up to 10 mg/kg in anesthetized
and conscious Beagle dogs
 Tested concentrations 100-fold greater than the human
exposure (Cmax) to vardenafil after 20 mg and 10-fold
greater than exposure to M1 and M4 metabolites
*Sildenafil 100 mg (NDA #20-885 SBA), Vardenafil 20 mg (Study 100196)
17
ECG Evaluation in Vardenafil NDA
Clinical Pharmacology Program
 Paired ECGs were obtained in 6 placebo-controlled
studies as part of standard safety assessment of
doses up to 80 mg
 These studies were not designed specifically to detect
a QT/QTc effect
 Equivocal changes on QT/QTc were observed with no
obvious dose relationship
18
Incidence of Clinical Adverse Events Which May
be a Potential Signal for Ventricular Arrhythmia in
Placebo-Controlled Phase III Studies
Placebo
n=1199 (%)
Vardenafil
n=2203 (%)
Syncope
1 (<0.1)
2 (<0.1)
Dizziness
11 (0.9)
48 (2.2)
Palpitations
3 (0.3)
11 (0.5)
0 (0)
1 (<0.1)
Adverse Event
Seizures
(convulsions)
No events of TdP reported in clinical trials with vardenafil
19
All Cause Mortality in Clinical Trials
• Nine deaths in patients before receiving study treatment
• Seven deaths in completed phase II/III studies*
 1 of 1351 on placebo (0.07%)
 1 of 164 on sildenafil (0.61%)
 4 of 4814 on vardenafil (0.08%)
 1 randomized to vardenafil but did not take drug
• No deaths on vardenafil were assessed as being related to
vardenafil treatment.
*As of January 2003
20
Study 10929/011:
Effect of Vardenafil on QT/QTc Interval
 Goal of study to define effects of vardenafil on QT/QTc
interval:
 At therapeutic doses
 At supratherapeutic doses
 At plasma concentrations following maximal potential
interaction with CYP 3A4 inhibitors
 Study design discussed and agreed with FDA
 Performed by Clinical Pharmacology and Statistics, GSK
Pharmaceuticals
21
Study 10929/011:
Objectives and Design
Primary Objective: Exclude a greater than 10 msec change from
baseline 1-hour post-dose on QTcF interval compared to placebo after
vardenafil 80 mg
Secondary Objectives:
• change from baseline of QT/QTc versus placebo at Tmax
• maximal change from baseline of QT/QTc versus placebo over 4 hr
Design: Six-way crossover, single-dose, placebo-controlled study. Doses
evaluated, period of evaluation, positive control, statistical analysis all
agreed with FDA.
Treatments:
•Vardenafil 80 mg
•Vardenafil 10 mg
•Moxifloxacin 400 mg
•Sildenafil 400 mg
•Sildenafil 50 mg
•Placebo
22
Study 10929/011 Methodology
 59 healthy subjects, age range 45-60 years
 QT interval determined by a validated central laboratory
blinded to treatment; manual digital measurements of 3
beat average in Lead II
 End of T-wave identified by return to baseline (or, if not
possible, tangent method)
 Subjects were non-ambulatory, supine, fasting
23
Study 10929/011 Procedures
Dose
Dose
Time
(h)
-0.5
ECG
x6
-0.25
ECG
x6
0
0.5
1
1.5
2.5
4
PK
PK
PK
PK
PK
PK
ECG
x6
ECG
x6
ECG
x6
ECG
x6
ECG
x6
ECG
x6
6 ECGs at each timepoint one minute apart
Baseline
Baseline
Study 10929/011
24
QTraw , HR, and QTcF Mean Change
from Baseline (SE) 1 hour after
Placebo
Treatment
QTraw
(msec)
HR
(bpm)
QTcF
(msec)
Placebo
6 (1.0)
-3 (0.5)
0 (0.7)
Study 10929/011; n=58
25
Placebo-Subtracted Mean Change from
Baseline (90% CI) for QTraw, HR and
QTcF at 1 Hour
Treatment effect (90% CI)
Treatment
80 mg vardenafil
QTraw
(msec)
-2 (-4, 0)
HR
(bpm)
6 (5, 7)
QTcF
(msec)
10 (8, 11)
10 mg vardenafil
-2 (-4, 0)
5 (4, 6)
8 (6, 9)
400 mg sildenafil
-1 (-3, 1)
5 (4, 6)
9 (8, 11)
50 mg sildenafil
-2 (-4, 0)
4 (3, 5)
6 (5, 8)
400 mg moxifloxacin
3 ( 1, 5)
2 (1, 3)
8 (6, 9)
Study 10929/011; n=58
26
Individually Corrected QT: QTci
 Alternative to fixed approach to heart rate correction
(Fridericia, Bazett)
 Correction based on each subject’s RR-QT relationship
 Based on placebo and baseline data (n = 138 per subject)
 Two approaches
 Linear relationship, QTci = QT + slope(1-RR)
 Non-linear relationship, QTciX = QT/(RR)x
 Same analyses performed as for QTcF
Study 10929/011
27
Placebo-Subtracted Mean Change from Baseline
for QTcF and QTci* at 1 hour
(Point Estimates of Treatment Effect and 90% CI)
80 mg
vardenafil
10 mg
400 mg
sildenafil
50 mg
moxifloxacin 400 mg
0
2
4
6
8
10 12
0
2
QTcF (msec)
Study 10929/011; n=58
4
6
8
10 12
QTci (msec)
*
linear relationship
28
Placebo-Subtracted Mean Change from
Baseline for QTcF and QTci* (msec) at 1
Hour Post-Dose
Treatment effect (90% CI)
Treatment
*linear
QTcF
(msec)
QTci
(msec)
80 mg vardenafil
10 (8, 11)
6 (4, 7)
10 mg vardenafil
8 (6, 9)
4 (3, 6)
400 mg sildenafil
9 (8, 11)
5 (4, 7)
50 mg sildenafil
6 (5, 8)
4 (2, 5)
400 mg moxifloxacin
8 (6, 9)
7 (5, 8)
relationship
Study 10929/011; n=58
29
Placebo-Subtracted Mean Change from
Baseline for QTcF at 1 Hour, Tmax, and
Maximum QTcF
Treatment Effect (90%CI)
Treatment
1 hour
Tmax
Maximum QTcF
80 mg vardenafil
10 (8, 11)
9 (8, 11)
9 (7, 10)
10 mg vardenafil
8 (6, 9)
7 (5, 9)
6 (5, 7)
400 mg sildenafil
9 (8, 11)
6 (4, 7)
8 (7, 9)
50 mg sildenafil
6 (5, 8)
6 (5, 8)
5 (4, 6)
400 mg moxifloxacin
8 (6, 9)
8 (7, 10)
9 (7, 10)
Study 10929/011; n=58
30
QT/QTc Outlier Analysis
 No QTraw value  500 msec
 No QTcF value  450 msec
 No change in QTcF  60 msec
 Only one subject (sildenafil 400 mg) with mean QTcF
change  30 msec at any time point (average of 6 ECGs)
Study 10929/011; n=59
31
Vardenafil
Vardenafil
Observed & Population Predicted QTcF versus
Vardenafil Plasma Concentration
460
Observed
Predicted
QTcF, msec
440
460
Observed
Predicted
440
420
400
380
QTcF, msec
360
420
340
0
5
10
15
20
Vardenafil Plasma Concentration, ng/mL
400
380
360
340
0
50
100
150
200
250
300
Vardenafil Plasma Concentration, ng/mL
32
Summary
 In clinical trials, vardenafil has been shown to be safe
and effective for the treatment of erectile dysfunction in
men.
 Preclinical studies with vardenafil do not predict
QT/QTc prolongation or arrhythmia at clinically relevant
concentrations.
 In the clinical development program, there was no
evidence of TdP.
33
Summary (continued)
 A QT/QTc study of vardenafil 10 and 80 mg conducted in
accordance with current regulatory guidance demonstrated a
4-10 msec mean maximum QTc prolongation.
 Vardenafil shortened uncorrected QT duration compared to
placebo, whereas moxifloxacin lengthened it.
 Vardenafil concentrations achieved cover the range following
strong metabolic inhibition.
 The relationship between corrected QT values and vardenafil
doses/concentrations is very shallow (2 msec increment with
8-fold increase in dose).
 Vardenafil effect on the QT/QTc interval is similar to that of
sildenafil, an approved drug in the same class.
34
QT/QTc Study Design, Heart Rate
Correction & Risk of Cardiac
Arrhythmia
Joel Morganroth, MD
Clinical Professor of Medicine
University of Pennsylvania
Chief Scientist
eResearchTechnology
35
Agenda
 QT/QTc study design issues
 QT correction factor analysis
 Clinical relevance of 5 to 10 msec QTc effect
36
FDA-Health Canada Preliminary
Concept Paper: November 2002
The document recommends:
 Robust and valid determination of cardiac risk
(QT/QTc duration) using a validated ECG
laboratory with specific design recommendations
 All bioactive compounds should undergo a
“definitive” Phase I QT/QTc assessment
37
What are the design issues in a
“definitive” Phase I QT/QTc trial that
should be considered in light of the
marked spontaneous variability in
QTc duration?
38
Managing Sources of QTc Variability
 Sample size: usually need >30 per arm to detect small QTc effect with
adequate power [used 59]
 Frequency of baseline and on-therapy ECGs to cover maximum
concentration of parent and metabolites; diurnal variation [n=18 at
baseline and 30 on each therapy at the same time of day]
 ECG measurement precision: digital process with manual method in a
validated core ECG laboratory [done]
 Population: male and female volunteers
[all men due to therapeutic use; age 45-60 yrs]
 Conditions of the ECG recording (e.g., subjects resting, supine, ECG
taken before blood sampling) [done]
39
Other Aspects of QT/QTc Trial Design
 Dose ranging (at least 2 doses, one of which is an appropriate multiple
of the recommended dose) - no need to study metabolic inhibitors if
supratherapeutic dose meets theoretical maximum exposure
 [1x and 8x recommended starting clinical dose]
 Control groups: placebo (interpret spontaneous variability) and
positive (assay sensitivity)
 [both done]
 Correction of QT (Fridericia, population, individual, Bazett)
 [Fridericia and individual reported]
 Statistical plan: placebo-corrected, central tendency and outlier
analyses
 [all done]
40
Drug-Specific Factors to Consider
in the Design of a QT/QTc Study
Pharmacokinetics
to ensure observation period covers Cmax of parent and
metabolites [4-hour sampling appropriate]
to ensure no carryover effects in a crossover trial [PK of parent
and metabolites appropriate for crossover]
Therapeutic use
single- vs multiple-dose study [single-dose trial appropriate]
Heart rate effects of drug
consider special procedures for heart rate correction when drug
increases heart rate [QTci analysis done]
41
What Correction Formula Should be Used
to Derive QTc from Heart Rate and QT?
“The traditionally used Bazett’s formula for correction of
the measured QT interval for variations in heart rates
(QTc = QT/RR0.50) has limitations for drugs that significantly
increase the heart rate.”
“Although none of the 30 or so formulae available is entirely
satisfactory, the Fridericia correction (QTc =QT/RR0.33), or
preferably a study-specific derived formula (QTc =QT/RRx),
may be more appropriate.”
Shah Fundamental & Clinical Pharmacology (2002) 16: 147–156.
42
Which Correction Formula Should be Used
to Derive QTc from Heart Rate and QT?
 FDA-Health Canada concept paper, November 2002:
 “...heart rate corrections using individual patient data have
been proposed, applying regression analysis techniques to
obtain individual pretherapy QT/RR interval data over a range
of heart rates, then looking for a change in regression line with
treatment.”
 Practical limitations of this approach:
 heart rate range at baseline
 Need for 50-100 ECGs off therapy [combine baselines and placebo
in crossover trials]
43
Placebo-Subtracted Mean Change from Baseline
for QTcF and QTci* at 1 hour
(Point Estimates of Treatment Effect and 90% CI)
80 mg
vardenafil
10 mg
400 mg
sildenafil
50 mg
moxifloxacin 400 mg
0
2
4
6
8
10 12
0
2
QTcF (msec)
Study 10929/011; n=58
4
6
8
10 12
QTci (msec)
*
linear relationship
44
Placebo-Subtracted Mean Change from
Baseline for QTc (msec) at 1 hr Post-Dose
Treatment Effect (90% CI)
Treatment
QTcF
10 mg vardenafil
8 (6,9)
QTci
(linear)
4 (3,6)
QTci
(nonlinear)
4 (3,6)
80 mg vardenafil
10 (8,11)
6 (4,7)
6 (5,8)
50 mg sildenafil
6 (5,8)
4 (2,5)
4 (2,5)
400 mg sildenafil
9 (8,11)
5 (4,7)
6 (4,7)
400 mg moxifloxacin
8 (6,9)
7 (5,8)
7 (5,8)
Study 10929/011;n=58
45
Population QTc vs HR: Bazett’s and Fredericia
Q350 Tc(mse) 40 450
Q350 Tc(mse) 40 450
QT c
Q
B
T
40
60
80
100
40
60
80
100
H R
(bpm
H R
(
)
Note: data plotted is baseline and placebo data only
46
Population QTc vs HR: Fredericia and Individual
Q350 Tc(mse) 40 450
Q350 Tc(mse) 40 450
QT c
Q
F
T
40
60
80
100
40
60
80
100
H R
(bpm
H R
(
)
Note: data plotted is baseline and placebo data only
47
Individual QTc vs HR relationships:
Fridericia and Individual
Q
T
c
(
m
s
e
)
360 380 40 420
Q
T
c
(
m
s
e
)
360 380 40 420
QT c
Q
F
T
40
60
80
100
40
60
80
100
H R
(bpm
H R
(
)
Note: Data represents fitted linear relationship for baseline and placebo data only
48
Individual QTci.2 vs HR Relationships
 Analysis conducted by
FDA biostatistician
Q TQ
ci T
Q360 380Tc(mse) 40 420
Q360 380Tc(mse) 40 420
 Individual correction
(linear) based on baseline
data only (n = 108 vs. 138
ECGs)
 QTci.2/HR relationship:
applied to both baseline
and placebo
data
40
60
80
100
40
60
80
10
H R
 Thus, “The more data used
the better the QTci”
(bpm
H R
N = 59 Patients
49
QTc Statistical Reporting Issues
 Central tendency
 Mean change
 Mean maximal change
 Categorical analysis looking for outliers
 % of patients (not observations) with:
 a change from baseline of 30-60 msec (sensitive)
and  60 msec (specific)
 new value  500 msec
 new abnormal T-U waves
50
Number of ECGs with Changes from Baseline
30-60 msec in QTci
Regimen
Frequency (%)
V10
V80
S50
S400
M
P
QTci  30<60
2
4
1
4
18
1
30
(0.11)
(0.23)
(0.06)
(0.23)
(1.03)
(0.06)
(0.29)
1740
1740
1740
1740
1740
1740
Total
Total
10440
51
Results of the Vardenafil QT/QTc Study
I consider the trial to be valid and the results reliable
 Placebo and the positive control, moxifloxacin, behaved
as anticipated in the study
 placebo = 0 msec; moxifloxacin = 8 msec
 Vardenafil 10 and 80 mg produced 4 -10 msec change
from baseline at 1 hr and at Tmax, using QTcF or QTci
 Shallow dose response (8x starting dose)
52
Results of the Vardenafil QT/QTc Study
(cont’d)
 QT/QTc effects comparable to sildenafil
 Vardenafil and sildenafil shortened uncorrected QT
duration compared to placebo, whereas moxifloxacin
lengthened it
 Outliers
 None  60 msec
 No new > 500 msec
 No subjects on vardenafil and only 1 subject in sildenafil
group with > 30 msec change
53
Clinical Relevance of a Drug-Induced
QT/QTc Effect: Risk Assessment
 Experience with other compounds
 terfenadine, cisapride, ziprasadone . . .
 moxifloxacin
 Post-marketing surveillance data
 moxifloxacin PMS data
 sildenafil PMS data (similar QT/QTc effect and same
therapeutic class)
 Regulatory opinions
 FDA-Health Canada concept paper
 Medicines Control Agency (EMEA/CPMP)
54
Terfenadine
 Mean change in QTc across the 12-hour dosing intervala:
6 msec
 Mean change in QTc at Tmax (mean maximum change)a:
18 msec
 Mean change in the presence of a metabolic inhibitor
(ketoconazole)b:
up to 82 msec
a
Morganroth, et al., Am J Cardiol 72:26B-32B, 1993
b Honig, et al., JAMA 269: 1513-1518, 1993
55
Moxifloxacin
 hERG channel blockade at concentrations approaching
clinical concentrations
 Mean maximum QTc effect = 6-10 msec increase (400
mg PO) and a doubling of the effect with 800 mg PO
 Minimal effect on heart rate
 Prolongs both QT and QTc
56
Moxifloxacin Cardiac Safety:
Post-Marketing Surveillance
Two post-marketing observational studies (n ~ 55,000)
 No cases of Torsades de Pointes
 No signal of cardiac arrhythmia or a QT interval
prolongation-related cardiac rhythm disorder
57
Moxifloxacin Spontaneous Reports of
Torsades de Pointes as of May 7, 2003
• Moxifloxacin (19 million patients; 8-day average prescription;
416,000 patient-years): N=12 TdP
• Oral: 4 US, 4 Europe
• IV: 3 US and 1 Europe
• All 12 cases showed marked confounders except 2 oral (1 with no
clinical data)
• Rate of TdP on oral moxifloxacin in US
• 4 per 7.7 million patients
• Comparable to other antibiotics (Brinker FDA)
58
Sildenafil FDA AERS Data
Torsades de Pointes:
No cases reporteda from launch to December 15,
2002 (data lock)
Usage:b
38.7 million sildenafil prescriptions written worldwide from
April 1998 to December 2002
aSpontaneous
reports from FDA Adverse Event Reporting System database
bUsage data from IMS
59
What Does a 5 to 10 msec QTc
Increase Mean?
 FDA concept paper notes importance of magnitude of
mean maximal QT/QTc effect:
< 5 msec
5 - 10 msec
10 - 20 msec
> 20 msec
no TdP
no clear risk
some concern
substantially increased
likelihood of being proarrhythmic
 QT is a surrogate. There is good evidence (dofetilide,
sotalol, terfenadine) that the size of the effect relates to risk
of TdP, but there could be other properties that mitigate or
enhance risk.
- Robert Temple, January 2003, Shady Grove Meeting
60
Additional Considerations in the
Assessment of the Clinical Relevance of
Vardenafil’s QTc Effect
 The drug is indicated for use in males (risk of druginduced TdP lower in males)
 Single dose, used intermittently
 Shallow dose response for QTc effects
 Vardenafil tends to increase heart rate
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Conclusions: About Vardenafil
 In a definitive QT/QTc trial, vardenafil and sildenafil
showed comparable maximum QTci effects on cardiac
repolarization of about 5 msec over an 8x dose range
 This magnitude is generally considered by regulatory
authorities as not associated with TdP
 No clinically significant outliers with vardenafil
 Post-marketing surveillance data for sildenafil provides no
reports of TdP
 Thus, the QTc effect of vardenafil should not pose a
cardiac safety concern
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