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Study No: SK&F-105517/906
Title : An Open-label, Single Dose, Three Session, Partially Randomized, Crossover Study to Assess Morning and
Evening Dosing of Carvedilol Phosphate MR Capsules in Healthy Adult Subjects
Rationale: The availability of a once daily dosage formulation of carvedilol would simplify a patient's dosing regimen
and may improve compliance rates.
Phase: I
Study Period: 10 January 2005 - 28 February 2005
Study Design: This was an open-label, single dose, partially randomized, three-period crossover study in healthy
volunteers.
Centers: The study was conducted at a single center in the United States.
Indication: None
Treatment: In Sessions 1 and 2, subjects were randomly assigned to receive either 80 mg carvedilol CR dosed in the
morning under fed conditions or 80 mg carvedilol CR dosed in the evening under fed conditions. In Session 3, all
subjects received 80 mg carvedilol CR dosed in the morning under fed conditions.
Objectives: The primary objective was to estimate the effect of evening dosing (fed state) on the single dose
pharmacokinetics of the enantiomers of carvedilol (R(+)- and S(-)-carvedilol) relative to morning dosing (fed state) in
healthy adult subjects when administered as 80 mg carvedilol CR. The secondary objectives were to evaluate the
within-subject inter-day variability of the R(+) and S(-) carvedilol pharmacokinetic parameters following replicate
administration of 80 mg carvedilol CR in the morning (fed state) and to assess the tolerability of carvedilol in healthy
volunteers following single dose administration of 80 mg carvedilol CR capsules.
Statistical Methods:
Comparison of Evening to Morning Dosing:
Following loge transformation, AUC(0-), AUC(0-t), AUC(0-t'), Cmax and t of R(+)- and S(-)-carvedilol from Session
1 (Regimen A, first AM administration or Regimen B, PM administration) and Session 2 (Regimen B, PM
administration or Regimen A, first AM administration) were analyzed separately by a mixed effects model, fitting fixed
effects terms for sequence, period and regimen, and fitting subject as a random effect. Point estimates and associated
90% confidence intervals for the difference B-A were constructed using the residual variance. Point and intervals
estimates were then exponentially backtransformed to construct point and interval estimates for the ratio B:A. Tmax
values were analyzed nonparametrically using the Wilcoxons Matched pairs Method. The point estimates and 90%
confidence intervals for the median difference were calculated for the difference B-A for R(+)- and S(-)-carvedilol
separately using the data from Sessions 1 and 2.
Assessment of Inter-Day Variability:
Using only the regimen A data and following loge transformation, AUC(0-), AUC(0-t), AUC(0-t'), Cmax and t of
R(+)- and S(-)-carvedilol were separately analyzed by a mixed effects model, fitted a fixed effect term for dosing
occasion (1 or 2), and fitting subject as a random effect. Point estimates and associated 90% confidence intervals for
the difference Admin2 Admin1 were constructed using the residual variance. Point and intervals estimates were
then exponentially backtransformed to construct point and interval estimates for the ratio Admin2:Admin1.
Study Population: Subjects were healthy adult males and non-pregnant females, between 18 and 55 years of age.
Subjects who had any clinically relevant abnormality identified at screening, or subjects who were poor metabolizers of
CYP2D6 were excluded from the study. Subjects with a documented history of low blood pressure (SBP 110 mmHg
and/or DBP 50 mmHg), blood pressure below these values at screening, or orthostatic hypotension diagnosed at
screening were excluded from the study.
Number of Subjects:
80 mg carvedilol CR dosed in
80 mg carvedilol CR dosed in
the morning
the evening
Planned N
22
22
Dosed N
22
22
Completed n (%)
21 (95)
21(95)
Total Number Subjects Withdrawn N (%)
1 (5)
1 (5)

Withdrawn due to Adverse Events n (%)

0
0
Withdrawn due to Lack of Efficacy n (%)
0
0
Withdrawn for Other Reasons n (%)
1 (5)
1 (5)
Demographics
All Subjects
N (ITT)
22
Females: Males
7:15
Mean Age in Years (sd)
32.2 (11.25)
Mean Weight in Kg (sd)
81.1 (11.4)
White n (%)
19 (86)
Pharmacokinetics (PK) Endpoints:
1. AUC
2. Cmax
3. tmax
4. t
PK Results: Evening administration of carvedilol CR resulted in an approximate 10% decrease in AUC of both R(+)and S(-)-carvedilol and a 15% to 19% decrease in Cmax of both R(+)- and S(-)-carvedilol compared to morning
administration. Additionally, there was a decrease in the rate of absorption of both R(+)- and S(-)-carvedilol with
evening administration (tmax delayed approximately 1.5 hours). The within-subject inter-day variability for AUC and
Cmax for CR carvedilol [both R(+)- and S(-)-carvedilol] was similar to IR carvedilol (compared to historical data).
A summary of selected plasma pharmacokinetic parameters [Geometric mean (CVb%)] is provided in the table below.
Analyte
Regimen
N
AUC(0-t)
AUC(0-t')
Cmax
tmax
(nghr/mL)
(nghr/mL)
(ng/mL)
(hr)1
R(+)A (Admin 1)
22
378 (67.6)
369 (69.3)
43.9 (57.8)
5.00 (1.50-8.00)
carvedilol
A (Admin 2)
20
398 (67.6)
393 (68.7)
47.9 (64.7)
5.00 (3.00-8.00)
B
22
347 (58.6)
343 (60.5)
37.3 (66.5)
7.00 (3.00-10.00)
S(-)-carvedilol A (Admin 1)
22
157 (57.2)
151 (59.0)
16.6 (55.0)
5.00 (1.50-8.00)
A (Admin 2)
20
168 (57.0)
166 (57.4)
18.7 (62.4)
5.00 (3.00-6.00)
B
22
143 (50.8)
140 (54.8)
13.5 (58.6)
7.00 (3.00-10.00)
1. Median (range)
Point estimates and 90% confidence intervals for the comparisons of evening to morning dosing for each
pharmacokinetic parameter are provided in the table below.
Parameter
Comparison of
Point Estimate1
90% CI
CVw%
Interest
R(+)-CARVEDILOL
AUC(0-t)
B:A
0.92
(0.81 ,1.04)
23.8
AUC(0-t')
B:A
0.93
(0.82 ,1.05)
23.8
Cmax
B:A
0.85
(0.72 ,1.00)
31.3
tmax
B-A
1.50 hr2
(1.00, 2.50)
S(-)-CARVEDILOL
AUC(0-t)
B:A
0.91
(0.80 ,1.03)
24.5
AUC(0-t')
B:A
0.92
(0.81 ,1.05)
25.0
Cmax
B:A
0.81
(0.69 ,0.96)
32.0
tmax
B-A
1.50 hr2
(0.56, 2.50)
1. Point estimate represents ratio of adjusted geometric means between regimens.
2. Point estimate represents estimated median difference between regimens.
Point estimates and 90% confidence intervals for assessment of within-subject inter-day variability for each
pharmacokinetic parameter are provided in the table below.

Parameter

Comparison of
Interest

Point Estimate1

90% CI

CVw%

R(+)-carvedilol
1.00
(0.93 ,1.09)
14.7
1.02
(0.94 ,1.11)
14.8
1.07
(0.93 ,1.23)
26.0
0.00 hr3
(-0.50, 0.51)
S(-)-carvedilol
AUC(0-t)
Admin2 : Admin12
1.03
(0.95 ,1.13)
15.9
AUC(0-t')
Admin2 : Admin12
1.05
(0.96 ,1.15)
16.5
Cmax
Admin2 : Admin12
1.11
(0.95 ,1.31)
29.9
tmax
Admin2 - Admin12
0.00 hr3
(-1.00, 0.01)
1. Point estimate represents ratio of adjusted geometric means between regimens.
2. Admin1 and Admin2 represent the first and second dosing occasions, respectively of 80 mg carvedilol phosphate
CR dosed in morning under fed conditions (Regimen A).
3. Point estimate represents estimated median difference between regimens.
Safety results: An on therapy adverse event (AE) or serious adverse event (SAE) was defined as an AE or SAE with
onset after administration of the first dose of study medication but not later than the date of the follow-up visit. All AEs
were mild or moderate in intensity and were resolved by the completion of the study.
Adverse Events:
80 mg carvedilol CR 80 mg carvedilol CR
dosed in the
dosed in the
morning1
evening
N
22
22
No. subjects with AEs n (%)
13
11
Most Frequent AEs:
Headache
6
3
Blood pressure fluctuation
3
4
Nausea
2
5
Dizziness
3
2
Dyspepsia
2
1
Chest discomfort
2
0
Serious Adverse Events, n (%)
0
0
1. Subjects were administered 80 mg carvedilol CR in the morning at two sessions.
AUC(0-t)
AUC(0-t')
Cmax
tmax

Admin2 : Admin12
Admin2 : Admin12
Admin2 : Admin12
Admin2 - Admin12

Publications: No Publication
Date updated: 05-Apr-2007