The safety of amlodipine

The safety profile of amlodipine was assessed from the pooled data base of clinical research
studies. This data base included 4227 subjects, 2495 of whom received amlodipine (including
2189 who received multiple-dose amlodipine); the remainder received comparative agents
(placebo 1213; active comparatives 519). Amlodipine treatment was associated with a slightly
higher incidence of side effects compared with placebo, but most of this difference was the
result of edema, which was usually well tolerated. When compared with the &blockers atenolol
and nadolol, amlodipine had a favorable safety profile. In particular, the incidence of severe side
effects in patients receiving amlodipine was approximately half that reported for patients
receiving /I-blockers. The data base comparing different calcium antagonists was small; in a
study versus verapamil, edema was more common in patients receiving amlodipine, but
constipation was more common in patients receiving verapamil. In a study versus diltiazem, both
amlodipine and diltiarem were similarly well tolerated. Amlodipine was not associated with the
deleterious effects of serum creatinine, urate, and fasting glucose, which was caused by
hydrochlorothiazide, and in contrast to hydrochlorothiazide and nadolol, amlodipine was not
associated with unfavorable changes in serum cholesterol and serum triglyceride levels.
Amlodipine was well tolerated by elderly patients and is not contraindicated in patients with
conduction abnormalities. Dosage modifications are unnecessary in renal impairment, but the
dosage regimen for patients with hepatic impairment is not yet established. Amlodipine is an
antihypertensive and antiischemic agent that has the combined advantages of a good safety
profile with once-daily dosage and a smooth onset and long duration of action. (AM HEART J
1989;118:1114.)

Ian Osterloh, BSc, MSc, MBBS, MRCP, Kent, England

By virtue of their efficacy and good toleration, dipine has a unique pharmacokinetic profile. After
calcium antagonists have emerged as an important oral administration, amlodipine is slowly absorbed
group of drugs in the treatment of patients with hy- (with a time to peak plasma concentrations of 6 to 12
pertension and/or myocardial ischemia. Although hours), and the plasma elimination half-life is rela-
calcium antagonists are well tolerated, the most fre- tively long (approximately 35 to 50 hours). The
quently encountered side effects probably result once-daily treatment regimen has been found to pro-
from the pharmacodynamic actions of the drug. duce a smooth, gradual onset of antihypertensive ac-
For nifedipine, the first representative of the dihy- tion with prolonged duration.4 These features sug-
dropyridine class of calcium antagonists, the kinetics gest that amlodipine may have a favorable safety
have been shown to correlate directly with the onset, profile and a reduced propensity to cause some of the
intensity, and duration of drug effect.’ Thus fast and more commonly encountered side effects associated
excessive peripheral vasodilatation is probably re- with calcium antagonists, such as flushing, headache,
sponsible for the relatively high incidence of side ef- and dizziness. This article evaluates the safety of
fects, such as flushing, headache, and dizziness; and amlodipine using pooled data from the program of
vasodilatation-induced reflex tachycardia may limit clinical research studies conducted in the United
the antihypertensive potential and can also be a States, Canada, and Europe.
cause of paradoxic angina.2, 3
METHODS
Amlodipine is a new calcium antagonist of the di-
hydropyridine class that can be administered in A total of 4227 subjects were evaluable for this study of
amlodipine’s safety. Of these, 2495 received amlodipine
once-daily doses of 5 or 10 mg to patients with
(including 2189 who received multiple-dose amlodipine),
hypertension and/or myocardial ischemia. Amlo- and the remainder received comparative agents (placebo
1213; active comparatives 519). As late as March 1, 1988,
From Pfizer UK Ltd. the multiple-dose safety data base totalled 774 patient-
Reprint requests: Ian Osterloh, Pfizer UK Ltd., Ramsgate Road, Sandwich, years of clinical exposure, and 247 patients had received
Kent CT13 9NJ, England. amlodipine for 1 year or more. Five hundred eighty-one
4/0/1!5306 patients treated with amlodipine were 65 years of age or

1114
Volume 118
Number 5, Part 2 Safety of amlodipine 1115

older; 194 of these patients received amlodipine for at least Table I. Incidence of side effects in comparative studies of
6 months. Most patients received daily doses of 5 to 10 mg amlodipine versus double-blind placebo
of amlodipine. Amlodipine Placebo
In all clinical trials the investigators were asked to
determine the occurrence of side effects by indirect ques- No. of patients n (%,J n (5%) p value’
tioning. The severity of the side effects (mild, moderate, or
severe) and the course (disappeared with continued treat- Evaluable 1775 1213
ment, tolerated with continued treatment, required symp- With side effects? 529 (29.8) 268 (22.1) <O.OOl
tomatic therapy, required dose reduction or temporary Edema 174 (9.8) 28 (2.3) <O.OOl
Headache 143 (8.1) 98 (8.1) NS
discontinuation, or required permanent discontinuation of
Dizziness 54 (3.0) 41 (3.4) NS
study drug) were recorded on the case record forms. The <O.OOl
(0.5)
investigators were also asked to classify the relationship of Nausea
Flushing 49
42 (2.4
(2.8) 2: (1.9) NS
the side effects to the study drug as definitely related, un- Fatigue 81 (4.6) 35 (2.9) <0.05
certain causality, or not related. Withdrawn because of 19 (1.1) 8 (0.7) NS
In the upcoming sections, all side effects of definite or side effects
possible relationship to the study drug and all side effects
Data pooled from 40 studies.
for which no cause was assigned are presented and dis- *The p values based on x2 test comparing the incidence of side effects in the
cussed. Some studies allowed for the addition of concom- two treatment groups; NS indicates p 2 0.10.
itant antihypertensive or antianginal agents, if the optimal tIncludes all side effects of definite or unknown relationship to study drug
therapeutic effect had not been achieved with the maxi- with incidence ~2% in either treatment group.
mum dose of the study drug. In these studies only side ef-
fects that occurred while the patient received monotherapy
are presented and discussed. All side effects were coded to ment groups. However, most occurrences of edema
the nearest preferred term in the World Health Organiza- were of mild or moderate severity, and <l % of these
tion Dictionary. subjects discontinued amlodipine treatment because
Laboratory safety tests were recorded at screening, at of edema.
regular intervals during study drug administration, and Of the other side effects commonly ascribed to cal-
after the end of trial therapy. All clinically significant lab- cium antagonists, flushing occurred with a slightly
oratory test abnormalities were reviewed on an individual higher frequency in amlodipine-treated subjects
patient basis under blind conditions. Unless there were
(2.4%) than in placebo-treated subjects (0.5%), but
positive indications of other causality (e.g., concomitant
the incidence of headache and dizziness was no
therapy or intercurrent illness), the abnormality was clas-
sified as possibly caused by the study drugs. In addition to higher in amlodipine-treated subjects compared with
the routinely monitored laboratory safety tests, total serum placebo-treated subjects. Although the incidence of
triglyceride and total cholesterol levels were measured. fatigue was statistically significantly higher in the
In addition to safety data from therapeutic trials, the re- amlodipine treatment group when compared with
sults of an electrophysiologic study in patients with angina the placebo treatment group, the magnitude of this
and those of formal pharmacokinetic studies in subjects difference (4.6% vs 2.9%) was small.
with renal or hepatic impairment and of interaction studies Data from the double-blind, dose-response studies
with cimetidine and digoxin are reviewed. suggest that the incidence of some side effects, par-
ticularly edema and flushing, may be dose related;
RESULTS the overall incidence of side effects was higher in
Side effects. A summary of the results from 1775 subjects receiving 10 mg daily (31.3%) compared
amlodipine-treated subjects (and 1213 placebo- with subjects receiving lower doses (19.5%). The
treated subjects) who participated in double-blind, overall incidence of discontinuation of treatment be-
placebo-controlled trials is presented in Table I. The cause of side effects was similar in amlodipine-
figures for percentage incidence include all recorded treated subjects (1.1% ) and placebo-treated subjects
side effects except those classified by the investigator (0.7% ).
as definitely not related to study drug, and the six Since edema was the most frequently reported side
most commonly occurring side effects in either treat- effect in subjects receiving amlodipine in placebo-
ment group are presented. controlled studies and in studies versus comparative
The overall incidence of side effects was 29.8 % and agents described below, it is worth making further
22.1% in amlodipine- and placebo-treated subjects, observations on this side effect. The 9.8% incidence
respectively. The most frequently occurring side ef- in placebo-controlled studies included all subjects in
fect in amlodipine-treated subjects was edema whom edema was of definite or uncertain origin. Only
(9.8 % ), which accounted for most of the difference in 4.3% of these subjects had edema that was consid-
overall percentage incidence between the two treat- ered by the investigator to be definitely related to
 November 1989
1116 Osterloh American Heart Journal

Table II. Incidence of side effects in comparative studies of Table IV. Incidence of side effects in a comparative study
amlodipine versus atenolol of amlodipine versus verapamil
Amlodipine Atenolol Amlodipinp Verapamil
-~
No. of patients n (%i II (9,) p o&e* No. of patients 11 i’,i n i’$) p LdN’

Evaluable 210 188 Evaluable 53 54

With side effects? 56 (20.7) 42 (22.3) NS With side effectst 22 (41.5) 19 (35.2) NS
Edema 18 (6.7) 2 (1.1) <O.Ol Edema 14 (26.4) 3 (5.6) 10.01
Headache 15 (5.6) 6 (3.2) NS Constipation 0 (0.0) 8 (14.8) a.01
Fatigue 3 (1.1) 9 (4.8) <0.05 Headache 0 (0.0) 5 (9.3) <o. IO
Flushing 11 (4.1) 0 (0.0) <O.Ol Flushing 3 (5.7) 1 (1.9) NS
Dizziness 2 (0.7) 7 (3.7) <0.05 Fatigue 1 (1.9) 3 (5.6) NS
Insomnia 3 (1.1) 6 (3.2) NS Muscle cramps 2 19.8) 1 (1.9) NS
Peripheral ischemia 0 (0.0) 5 (2.7) <0.05 Vertigo I (1.9) 2 (3.7) NS
Asthenia 2 (0.7) 4 (2.1) NS Dizziness 1 (1.9, 2 (3.7) NS
Withdrawn because of 5 (1.9) 6 (3.2) NS Abnormal dreams 0 (0.0) 2 (3.7) NS
side effects Withdrawn because of 2 (3.8) 1 (1.9) NS
side effects
Data from patients receiving monotherapy in studies 106,307,308,337. and
338. Data from study 336.
*The p values are based on x2 test comparing the incidence of side effects *The p values are based on x2 test comparing the incidence of side effects
in the two treatment groups; NS indicates p 2 0.10. in the two treatment groups; NS indicates p >O.lO.
tIncludes all side effects of definite or unknown relationship to study drug tlncludes all side effects of definite or unknown relationship to study drug
with incidence ~2% in either treatment group. with incidence 22’; in either treatment group.

Table Ill. Incidence of side effects in comparative studies of or possible or unknown relationship to treatment)
amlodipine versus nadolol was 15.0% during the first 6 months of treatment;
Amlodipine Nadolol however, only 4.9 % of the patients developed edema
during the second 6 months of treatment. In those
No. of patients n (%) n (7%) p value” patients who continued to take amlodipine for more
than 1 year, edema was not reported. Thus it can be
Evaluable 247 140
With side effectst 129 (52.2) 85 (60.7) NS concluded that although edema is a relatively com-
Fatigue 26 (10.5) 21 (19.3) <0.05 mon side effect, it is usually well tolerated and is
Edema 45 (18.2) 8 (5.7) <O.Ol rarely troublesome to the patient.
Dizziness 28 (11.3) 21 (15.0) NS ,&Blockers have been the most commonly used
Bradycardia 3 (1.2) 18 (12.9) <O.OOl comparative agents in trials of amlodipine. Table II
Dyspnea 19 (7.7) 17 (12.1) <O.lO
Headache 28 (11.3) 13 NS presents the overall incidence of side effects in com-
(9.3)
Withdrawn because of 15 (6.1) 16 (11.4) <O.lO parative studies of amlodipine versus atenolol and
side effects lists the eight most commonly occurring side effects
Data from patients receiving monotherapy in studies 152, 155. 155A, 159,
for each treatment group. The mean duration of
and 304. treatment was slightly longer for amlodipine-treated
*The p values are based on x2 test comparing the incidence of side effects patients (187 days) than for atenolol-treated patients
in the two treatment groups: NS indicates p 2 0.10.
TIncludes all side effects of definite or unknown relationship to study drug
(156 days). The overall incidence of side effects was
with incidence ~10~~ in either treatment group. similar for the amlodipine (20.7 %) and atenolol
treatment groups (22.3 % ). Amlodipine-treated pa-
tients had a higher incidence of edema and flushing,
amlodipine (compared with a 0.4 % incidence in sub- whereas the incidence of fatigue, dizziness, and
jects receiving placebo). It has already been stated peripheral ischemia was higher in atenolol-treated
that most occurrences of edema were of mild or mod- patients. There were also treatment-related differ-
erate severity and were rarely a cause for premature ences in the incidence of headache (higher for those
discontinuation of treatment. Further support for receivingamlodipine), insomnia, and asthenia (higher
this fact comes from an analysis of the data from the for those receiving atenolol), although these changes
247 patients who completed at least 1 year of contin- did not reach statistical significance. In atenolol-
uous treatment with amlodipine. In this cohort of treated subjects the percentage of side effects classi-
patients the cumulative incidence of edema (definite fied as severe (12.3%) and of patients with side
Volume 118
Number 5, Part 2 Safety of amlodipine 1117

effects causing discontinuation (3.2 % ) was higher Table V. Incidence of side effects in a comparative study of
than for amlodipine-treated subjects (6.1% and 1.9 % , amlodipine versus diltiazem
respectively). Amlodipine Diltiazem
Table III summarizes side effects data from com-
parative studies of amlodipine versus nadolol. The No. of patients n f%) n (%I) p value*
mean durations of amlodipine and nadolol treat- 39 41
Evaluable
ments were 270 days and 212 days, respectively. Al- With side effects? 16 (41.0) 16 (39.0) NS
though the rate of reporting of side effects was rather Headache 6 (15.4) 4 (9.8) NS
high for this group of studies, a clear difference in the Somnolence 4 (10.3) 0 (0.0) NS
Dizziness 2 (5.1) 4 (9.8) NS
side effect profile of these two drugs emerges. The
Edema 3 (7.7) 3 (7.3) NS
incidence of edema was higher in amlodipine-treated Nausea 3 (7.7) 3 (7.3) NS
patients. The incidence of fatigue and bradycardia Palpitations 2 (5.1) 2 (4.9) NS
was much higher (>8% difference) in patients re- Paresthesia 2 (5.1) 1 (2.4) NS
ceiving nadolol. In nadolol-treated subjects the per- Fatigue 2 (5.1) 0 (0.0) <O.lO
Flushing 1 (2.6) 2 (4.9) NS
centage of side effects classified as severe (17.1%)
Pruritus 0 (0.0) 2 (4.9) NS
and of patients with side effects causing discontinu- (0.0) 1
Withdrawn because of 0 (2.4) NS
ation of therapy (11.4%) was higher than for amlo- side effects
dipine-treated subjects (9.3% and 6.1%) respec-
Data from study 305.
tively) . *The p values are based on x2 test comparing the incidence of side effects
The incidence of side effects in studies of amlo- in the two treatment groups; NS indicates p 2 0.10.
dipine versus verapamil and amlodipine versus dilt- tIncludes all side effects of definite or unknown relationship to study drug
with incidence 24% in either treatment group.
iazem is summarized in Tables IV and V, respec-
tively. In these studies the overall incidence of side
effects was slightly higher in amlodipine-treated pa-
tients. However, the data base is too small to allow Table VI. Incidence of side effects in comparative studies
many differences in the side effect profile of the cal- of amlodipine versus HCTZ
cium antagonists to become apparent. Although Amlodipine HCTZ
there was a notable difference in the incidence of
No. of patients N (%) N (%) p value*
edema between amlodipine-treated patients (26.4 % )
and verapamil-treated patients (5.6%) (Table IV), Evaluable 189 96
there was little difference in the incidence of edema With side effects? 92 (48.7) 42 (43.8) NS
between the amlodipine (7.7 % ) and diltiazem (7.3 % ) Edema 39 (20.6) 4 (4.2) <O.OOl
Headache 23 (12.2) 12 (12.5) NS
treatment groups. Another notable finding was the
Fatigue 16 (8.5) 5 (5.2) NS
difference in the incidence of constipation between Dizziness 11 (5.8) 5 (5.2) NS
amlodipine-treated patients (0 % ) and verapamil- Sexual dysfunction (men) 4 (3.4)t: 4 (7.3)t: NS
treated patients (14.8% ). In the verapamil and dilt- Withdrawn because 10 (5.3) 6 (6.3) NS
iazem treatment groups, the proportions of side side effects

effects classified as severe (3.7% and 7.3 % , respec-
tively) were similar to the corresponding amlodipine
treatment groups (3.8% and 5.1% , respectively).
Side effect data are also available from compara-
tive trials of amlodipine versus hydrochlorothiazide
(HCTZ) in the treatment of hypertension. A sum-
mary of the results is presented in Table VI. The
overall incidence of side effects was slightly higher for
the amlodipine treatment group (48.7 % ) than for the
HCTZ group (43.8%), but a higher proportion of pa-
tients discontinued HCTZ (6.3%) compared with
amlodipine (5.3 % ). There was a marked difference in
the incidence of edema between the two treatment
groups (20.6 % , amlodipine; 4.2 % , HCTZ), but there
were no other statistically significant findings.
The amlodipine safety data base has also been used
Data from studies 103 and 105.
*The p values are based on x2 test comparing the incidence of side effects
in the two treatment groups; NS indicates p 2 0.10.
tIncludes all side effects of definite or unknown relationship to study drug
with incidence 24% in either treatment group.
IPercentage incidence calculated using the number of men in each treat-
ment group.
to evaluate whether any particular subgroups of pa-
tients are more susceptible to adverse events. The
incidence and profile of side effects were similar in
patients with hypertension and angina. Five hundred
eighty-one patients, ages 65 years or older, have re-
ceived multiple-dose amlodipine. In subjects receiv-
ing monotherapy the incidence of side effects in the
elderly (38% ) was similar to that in the younger
 November 1989
1118 Osterloh American Heart Journal

Table VII. Incidence of clinically significant laboratory test Other aspects of safety. In an electrophysiologic
abnormalities; comparative studies of amlodipine versus study,5 in which 15 patients with stable exertional
HCTZ angina each received intravenous doses of amlo-.
Amlodipine HC’TZ dipine (10 mg), there were no effects on sinus node
No. of Direction function or atrioventricular conduction.
patients of change n (‘1) I2 (‘k) p value* Formal interaction studies with digoxin” (21 sub-
Evaluable 185 95 jects) and cimetidine: (12 subjects) have been per-
formed. There was no evidence of any pharmacoki-
With laboratory test abnormalities? netic interaction of amlodipine with these drugs.
CPK Increase 16 (8.6) 6 (6.3) NS In a pharmacokinetic study8 of amlodipine in six
ALT Increase 8 (4.3) 6 (6.3) NS
healthy volunteers and 22 subjects with renal im-
GGT Increase 11 (5.9) 8 (8.4) NS
Creatinine Increase 3 (1.6) 7 (7.4) <0.05 pairment, plasma half-lives were similar in the dif-
Uric acid Increase 4 (2.2) 29 (30.5) <O.OOl ferent treatment groups. Only two of the subjects
Potassium Decrease 3 (1.6) 26 (27.4) <O.OOl with renal impairment experienced side effects.
Glucose (fasting) Increase 121 (6.5) 9 (9.5) NS A pharmacokinetic study9 of amlodipine in hepatic
Data from studies 103 and 105. impairment has recently been completed. In the 12
CM, Creatine phosphokinase, AL’I’, alanine aminotransferase; GG7’, subjects with hepatic impairment, the plasma elim-
y-glutamyltransferase.
*The p values are based on x2 test comparing the incidence of laboratory
ination half-life was prolonged, but none of the sub-
test abnormalities in the two treatment groups; NS indicates p 2 0.10. jects reported side effects. This finding is not unex-
tlncludes all clinically significant laboratory test abnormalities with inci- pected, since the dominant route of elimination is
dence of ~5”~ in either treatment group.
IOnly 184 patients evaluable for changes in fasting glucose.
excretion of metabolites into the bile ducts and urine.
However, it is likely that the dose required to achieve
efficacy in subjects with hepatic impairment will be
lower than for other patients.
group (33 % ), although edema (16.4 % ) and dizziness
(7.4%) occurred more frequently in elderly patient DISCUSSION
groups compared with younger patients (11.6% and The studies reviewed indicate that once-daily dos-
3.5%) respectively). age of amlodipine is well tolerated. It is suggested
Some trials recruited patients who were already that the incidence of side effects reported herein
taking antihypertensive or antianginal therapy. The represents a significant overestimation of the true
combinations of amlodipine with atenolol, captopril, incidence of drug-related adverse events, because all
or HCTZ were well tolerated. side effects of definite or uncertain or unknown rela-
Laboratory test abnormalities. The incidence of lab- tionship to treatment have been recorded, and the
oratory test abnormalities in subjects receiving am- incidence of side effects in amlodipine-treated sub-
lodipine was low. The pattern and frequency of lab- jects was only slightly higher than that in subjects
oratory test abnormalities were similar in the amlo- receiving double-blind placebo.
dipine and placebo treatment groups. The most frequently occurring side effect in amlo-
In comparative studies of amlodipine versus HCTZ, dipine-treated subjects was edema. However, this
there was a higher incidence of abnormalities in se- was of mild or moderate severity in the vast majority
rum potassium (decreased) and serum creatinine of patients and caused discontinuation in only 1% of
(increased), fasting glucose (increased), and uric acid all patients (pooled data base). Edema is not an un-
(increased) in patients receiving diuretic (Table VII). expected side effect of a dihydropyridine calcium
Although there was a much higher incidence of antagonist. However, other commonly encountered
hypokalemia in patients receiving diuretics, review of side effects of vasodilators (e.g., headache, flushing,
the total data base suggests that amlodipine treat- and dizziness) may be partly related to the rapidity
ment may be associated with small decreases in of onset of vasodilatation. In double-blind trials the
serum potassium (of the order of 0.1 to 0.2 mEq/L). incidence of headache was identical in subjects re-
Total cholesterol and total triglyceride measure- ceiving amlodipine and placebo. The incidence of
ments are illustrated in Table VIII. Similar changes flushing and dizziness was generally low and was only
were observed in the amlodipine group compared associated with discontinuation of amlodipine in
with the placebo group, but subjects treated with 0.12% and 0.16% of subjects, respectively (pooled
HCTZ or nadolol showed an undesirable pattern with data base). Thus the low incidence of these side ef-
increases in total triglycerides and total cholesterol. fects may be related to the smooth onset of action of
Volume 118
Number 5, Part 2 Safety of amlodipine 1119

Table VIII. Change in mean lipid levels (mg/dl) from baseline to end of treatment in amlodipine monotherapy studies
Amlodipine Placebo HCTZ Atenolol Nadolol

Lipid parameter n % change* n % change* n % change* n % change* n % change*

Total cholesterol 847 -2.2 276 -2.4 93 +4.4 116 to.2 44 +2.5
Total triglycerides 815 -1.9 252 -1.9 93 +6.7 116 +o.o 44 +15.1

Data from studies 002, 004, 101, 102, 105, 106, 110, 151/151A, 152, 154, 155/155A, 156/156A, 159, and 337.
*Percent of change = (geometric mean of final value - geometric mean of baseline value)/geometric mean of baseline value.

amlodipine. The lack of variability in plasma levels combination with the once-daily dosage regimen and
throughout a 24-hour dosage interval may also con- smooth onset of action suggest that amlodipine will
tribute to the tolerability of the drug. be a valuable addition to the range of drugs used to
Unfortunately, no data are currently available treat patients with hypertension and/or myocardial
from comparative trials of amlodipine versus other ischemia.
dihydropyridine calcium antagonists, and the data
base from comparative studies versus verapamil and REFERENCES
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finitive conclusions to be reached. relationship between pharmacokinetics and pharmacodynam-
its. Clin Pharmacokinet 1987;12:12-29.
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safety profile of amlodipine has many advantages pain by nifedipine. Br Med J 1978;1:1181-2.
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1978;1:1619.
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severe side effects was approximately half that ob- namic and electrophysiologic effects of amlodipine, a new
served for P-blocker drugs. Amlodipine treatment long-acting calcium antagonist. AM HEART J 1989;118:1104-5.
was not associated with the deleterious effects on se- 6. Schwartz JB. Effects of amlodipine on steady-state digoxin
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rum creatinine, urate, and fasting glucose, which was Pharmacol 1988;12:1-5.
caused by HCTZ, and in contrast to HCTZ and the Data on file, Pfizer UK, Ltd. Study report 216. A two-way
&blockers, amlodipine was not associated with un- crossover study to evaluate the pharmacodynamic and safety
profile of a single oral dose of amlodipine when coadministered
favorable changes in serum cholesterol and serum with single-blind placebo or cimetidine to healthy volunteer
triglyceride levels. subjects.
In contrast to verapamil and diltiazem, amlodipine Laher MS, Kelly JG, Doyle GD, et al. Pharmacokinetics of
amlodipine in renal impairment. J Cardiovasc Pharmacol
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ular conduction. This suggests that contraindications Data on file, Pfizer UK, Ltd. Study report 369. An open study
may not be necessary in patients with impaired car- to assess the safety and pharmacokinetic profile of oral amlo-
dipine in patients with stable chronic hepatic insufficiency
diac function or conduction abnormalities. compared with a group of convalescent subjects without
Also, in contrast to most calcium antagonists, am- hepatic impairment.
lodipine has no pharmacokinetic interaction with ci-
metidine or digoxin. The kinetic profile and good
toleration in elderly patients (age 265 years) and in GENERAL DISCUSSION
patients with renal impairment suggest that modifi- Question from the floor. First, what is the incidence of
cations to the dosage regimen are unnecessary for side effects with respect to the dosage of amlodipine? Sec-
ond, Dr. Abernethy mentioned an increase in serum con-
these categories of patient. Amlodipine was also well
centration and prolongation of half-life with long-term ad-
tolerated by patients with mild hepatic impairment, ministration of amlodipine. Would you expect any increas-
but the dose required to achieve efficacy will proba- ed incidence of side effects with long-term administration?
bly be lower than for other patients. I. Osterloh. To answer the first question on the relation-
In conclusion, the good safety profile of amlo- ship between side effects and dose, there was a slightly in-
dipine, the relative lack of adverse events commonly creased incidence of side effects in patients who received 10
encountered with other classes of cardiovascular mg compared with those receiving 5 mg; the difference was
agents, and the relative lack of contraindications in not that large. In clinical trials, doses as large as 20 mg have
 November 1999
I I 20 Osterloh American Heart Journal

been used, and when the dose is above 10 mg, we start to full data available, but it may help to answer the question
see increases in the incidence of edema and some other side you raised.
effects. There seems to be very little dose-response rela- W. S. Hillis. Our mean LV end-diastolic pressure was 11
tionship up to about 10 mg. The data presented are from mm Hg; I believe that six of our patients had LV dysfunc-
more than 2000 patients, and many of these patients have tion if you define it as >lO mm Hg. In those patients the
received amlodipine for a long period of time. The side ef- mean rise in pressure (I only presented mean data) was only
fect incidence might well be reduced during long-term 2 mm Hg. Thus we have seen no significant increases in our
treatment because there are no fluctuations in the plasma patients.
levels of the drug caused by rapid elimination; thus tran- S. H. Taylor. Severe LV insufficiency is important in pa-
sient and excessive vasodilatation, which might be ex- tients with angina after transmural infarction. We investi-
pected with short-acting drugs, does not seem to be a gated a group of patients under similar conditions in our
problem. We also have not seen problems with palpitations earlier studies with short-term intravenous amlodipine UY-
or an increase in the frequency of angina that might be ex- ing a combination of hemodynamic and radionuclide meth-
pected for such a drug. If anything the prolonged elimina- ods. We did not find any increase in LV volume with am-
tion appears to be an advantage rather than a disadvantage lodipine, which I believe is the main hemodynamic point at
for the toleration of this drug. issue.
D. A. Abernethy. Amlodipine has linear kinetics; there- Question from the floor. Amlodipine appears to have a
fore its half-life does not prolong with continued dosing. low frequency of nuisance side effects, but we are some-
The data that I presented showed a prolongation of half- times concerned about a low frequency of severe side
life with diltiazem, and the reason for showing those data effects that may occur during treatment with drugs. Could
was to compare those two drugs. you comment on cumulative exposure to amlodipine in pa-
F. Follath. Are there any data on the hemodynamics of tients with coronary artery disease and if there are any data
this drug in patients with preexisting left ventricular (LV) on the frequency of severe side effects, such as death or in-
failure? It is always said that nifedipine does not impair LV cidence of myocardial infarction?
function, but several papers show that in patients with I. Osterloh. There have been examples of myocardial in-
preexisting LV dysfunction, a worsening of the hemody- farction and death in the clinical trials program, but these
namics can appear. In Dr Hillis’ study in which only mean have occurred in patients receiving placebo and other ac-
values were presented, a few patients might have tive comparative therapy, as well as those receiving amlo-
had a worsening of the hemodynamics. Can you he sure dipine. In all cases that have occurred, the death or the
that the drug is safe in patients with a clear-cut LV myocardial infarction has been attributed to causes other
dysfunction? than trial drug therapy, and the incidence has been similar
1. Osterloh. Most of the trials have been done in patients for both placebo and amlodipine. Thus there is no evidence
without severe cardiac impairment. There is a trial ongo- to suggest that we are provoking serious events in these
ing in patients who have heart failure. We do not yet have patients.