The study listed may include approved and non-approved uses, formulations or treatment regimens. The results
reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any
product mentioned in this Register, healthcare professionals should consult prescribing information for the product
approved in their country.
Study No.: INT-CAR-06
Title: Carvedilol-nifedipine S.R. interaction study.
Rationale: This study was conducted to investigate the acute and short-term safety of the addition of carvedilol to preexistent nifedipine sustained release (SR) therapy, as well as on the addition of nifedipine SR to pre-existent carvedilol
therapy in the treatment of essential hypertension when treatment with either nifedipine SR or carvedilol alone did not
adequately control blood pressure (BP).
Phase: IIIB
Study Period: 26 January 1989 to 21 June 1989.
Study Design: A 2-phase, randomised, double-blind study.
Centres: One centre, the Netherlands.
Indication: Essential hypertension.
Treatment: During the 2-week monotherapy phase, subjects were randomised to either:
Treatment 1: Carvedilol 12.5mg once daily (od) plus placebo matching nifedipine bid for the first 2 days, then carvedilol
25mg od plus placebo matching nifedipine bid, or;
Treatment 2: Nifedipine SR 20mg twice daily (bid) plus placebo matching carvedilol 12.5 mg od.
After 2 weeks of monotherapy, subjects, who had a mean supine diastolic BP of 91 to 115 mmHg recorded after both 1
and 2 weeks of monotherapy, received combination therapy for 10 days:
Treatment 1: Carvedilol 25mg od plus nifedipine SR 20mg bid,
Treatment 2: Nifedipine SR 20mg bid plus carvedilol 12.5mg od for the first 2 days, then carvedilol 25mg od.
Objectives: The objective of this study was to investigate the acute and short-term safety of the addition of carvedilol
to pre-existent nifedipine SR therapy, as well as on the addition of nifedipine SR to pre-existent carvedilol therapy in
the treatment of essential hypertension when treatment with either nifedipine SR or carvedilol alone did not adequately
control BP.
Primary Outcome/Efficacy Variable: SAFETY.
Secondary Outcome/Efficacy Variable(s): Blood Pressure and heart rate.
Statistical Methods: Only descriptive statistics were presented. A formal statistical analysis was not planned
because the study was designed primarily to assess safety. All subjects were included in the analyses of efficacy and
safety.
Study Population: Non-black male or nonpregnant female subjects were eligible if they were aged at least 18 years
and had established essential hypertension (mean supine diastolic blood pressure of 100 to 115 mmHg). Subjects
were excluded from participation in the study if they met any of the following criteria: pregnancy or lactation,
hypertension secondary to another primary disease, WHO Stage III hypertension, mean supine diastolic blood
pressure >115 mm Hg, mean supine systolic blood pressure >200 mm Hg, bradycardia (,50 bpm), second or third
degree heart block, sick sinus syndrome, history of angina pectoris, evidence of myocardial infarction within 3 months
of Visit 1, cerebrovascular accident within 6 months of Visit 1, congestive heart failure, obstructive pulmonary disease,
serum creatinine >2.0 mg/dL, or abnormal liver function tests (SGOT/ASAT and SGPT/ALAT >2 times upper limit of
normal, bilirubin >1.5 times upper limit of normal). Additional reasons for exclusion from participation in the study were
concomitant treatment with any other drug that might alter blood pressure, known hypersensitivity to carvedilol or
nifedipine sr, or use of an investigational drug within 30 days of entry into the study.
Treatment 1
Treatment 2
Number of Subjects:
Planned, N
6
6
Randomised, N
7
7
Completed, n (%)
6 (86)
7 (100)
Total Number Subjects Withdrawn, n (%)
1 (14.3)
0
Withdrawn due to Adverse Events, n (%)
1 (14.3)
0
Withdrawn due to Lack of Efficacy, n (%)
0
0
Withdrawn for Other Reasons, n (%)
0
0
Demographics
N (All subjects)
7
7
Females: Males
4: 3
2: 5
1
Mean Age, years (standard error [SE])
Caucasian, n (%)
Primary Efficacy Results: See Safety Results below.
Secondary Outcome Variable(s): (All subjects)
59 (6)
7 (100)
56 (2)
7 (100)
Treatment 1
(N=7)
Treatment 2
(N=7)
Blood pressure (mmHg)
Supine, mean pre-dose
Initial screen
171/105
170/106
After 1 week of monotherapy
171/104
165/104
After 2 weeks of monotherapy
173/106
166/102
After 2 days of combination therapy
167/99
167/101
After 10 days of combination therapy
172/103
160/97
Supine, mean post-dose (mean peak change from pre-dose)
After 1 week of monotherapy
149/93 (-21/-11)
145/87 (-20/-16)
After 1st dose of combination therapy
136/84 (-37/-23)
138/88 (-29/-14)
After 2 days of combination therapy
129/79 (-39/-20)
133/82 (-35/-19)
After 10 days of combination therapy
132/83 (-40/-20)
134/83 (-26/-14)
Standing, mean pre-dose
Initial screen
171/107
171/106
After 1 week of monotherapy
172/106
159/105
After 2 weeks of monotherapy
173/105
167/104
After 2 days of combination therapy
169/102
167/103
After 10 days of combination therapy
166/102
155/100
Standing, mean post-dose (mean peak change from pre-dose)
After 1 week of monotherapy
142/91 (-29/-16)
149/89 (-10/-16)
After 1st dose of combination therapy
137/84 (-36/-21)
138/87 (-29/-16)
After 2 days of combination therapy
128/79 (-41/-23)
128/83 (-39/-20)
After 10 days of combination therapy
124/82 (-42/-19)
132/85 (-23/-14)
Heart rate (beats per minute)
Supine, mean pre-dose
Initial screen
70
73
After 1 week of monotherapy
71
76
After 2 weeks of monotherapy
70
75
After 2 days of combination therapy
71
72
After 10 days of combination therapy
73
71
Supine, mean post-dose (mean peak change from pre-dose)
After 1 week of monotherapy
68 (-4)
74 (-2)
After 1st dose of combination therapy
65 (-5)
71 (-4)
After 2 days of combination therapy
68 (-4)
68 (-4)
After 10 days of combination therapy
68 (-4)
66 (-5)
Standing, mean pre-dose
Initial screen
73
76
After 1 week of monotherapy
73
79
After 2 weeks of monotherapy
74
77
After 2 days of combination therapy
75
76
After 10 days of combination therapy
75
75
Standing, mean post-dose (mean peak change from pre-dose)
After 1 week of monotherapy
71 (-2)
79 (0)
After 1st dose of combination therapy
67 (-6)
74 (-3)
After 2 days of combination therapy
70 (-5)
71 (-5)
After 10 days of combination therapy
69 (-7)
71 (-4)
Safety Results: (All subjects) - Adverse events (AEs) were recorded throughout the study until Visit 5 (end of
combination therapy), and serious adverse events (SAEs) were recorded during the study until 30 days after receiving
the last dose of study medication.
2
Treatment 1
(N=7)
n (%)
4 (57)
2 (29)
2 (29)
Most Frequent Adverse Events – On-Therapy
Subjects with any AE(s), n (%)
Dizziness
Faintness
Serious Adverse Events - On-Therapy
n (%) [n considered by the investigator to be related to study medication]
Treatment 1
(N=7)
Subjects with any SAEs, n (%)
0
Treatment 2
(N=7)
n (%)
1 (14)
0
0
Treatment 2
(N=7)
0
Conclusion:
See publication below.
Publications:
Juttmann JR, Robles P, Venuti RP. Safety of the coadministration of carvedilol and nifedipine sustained-release in the
treatment of essential hypertension. J Cardiovasc Pharmacol 1992; 19(Suppl 1): S134-S137.
Date Updated: 13-Sep-2005
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