Mechanism Of Action
Amlodipine is a dihydropyridine calcium antagonist
(calcium ion antagonist or slow-channel blocker) that inhibits the
transmembrane influx of calcium ions into vascular smooth muscle and cardiac
muscle. Experimental data suggest that amlodipine binds to both dihydropyridine
and nondihydropyridine binding sites. The contractile processes of cardiac
muscle and vascular smooth muscle are dependent upon the movement of
extracellular calcium ions into these cells through specific ion channels.
Amlodipine inhibits calcium ion influx across cell membranes selectively, with
a greater effect on vascular smooth muscle cells than on cardiac muscle cells.
Negative inotropic effects can be detected in vitro but such effects have not
been seen in intact animals at therapeutic doses. Serum calcium concentration
is not affected by amlodipine. Within the physiologic pH range, amlodipine is
an ionized compound (pKa=8.6), and its kinetic interaction with the calcium
channel receptor is characterized by a gradual rate of association and
dissociation with the receptor binding site, resulting in a gradual onset of
Amlodipine is a peripheral arterial vasodilator that acts
directly on vascular smooth muscle to cause a reduction in peripheral vascular
resistance and reduction in blood pressure.
The precise mechanisms by which amlodipine relieves
angina have not been fully delineated, but are thought to include the
In patients with exertional angina, NORVASC reduces the
total peripheral resistance (afterload) against which the heart works and
reduces the rate pressure product, and thus myocardial oxygen demand, at any
given level of exercise.
NORVASC has been demonstrated to block constriction and
restore blood flow in coronary arteries and arterioles in response to calcium,
potassium epinephrine, serotonin, and thromboxane A2 analog in experimental
animal models and in human coronary vessels in vitro. This inhibition of
coronary spasm is responsible for the effectiveness of NORVASC in vasospastic (Prinzmetal's
or variant) angina.
Following administration of therapeutic doses to patients
with hypertension, NORVASC produces vasodilation resulting in a reduction of
supine and standing blood pressures. These decreases in blood pressure are not
accompanied by a significant change in heart rate or plasma catecholamine
levels with chronic dosing. Although the acute intravenous administration of
amlodipine decreases arterial blood pressure and increases heart rate in
hemodynamic studies of patients with chronic stable angina, chronic oral
administration of amlodipine in clinical trials did not lead to clinically
significant changes in heart rate or blood pressures in normotensive patients
With chronic once daily oral administration,
antihypertensive effectiveness is maintained for at least 24 hours. Plasma
concentrations correlate with effect in both young and elderly patients. The
magnitude of reduction in blood pressure with NORVASC is also correlated with
the height of pretreatment elevation; thus, individuals with moderate
hypertension (diastolic pressure 105-114 mmHg) had about a 50% greater response
than patients with mild hypertension (diastolic pressure 90-104 mmHg). Normotensive
subjects experienced no clinically significant change in blood pressures (+1/-2
In hypertensive patients with normal renal function,
therapeutic doses of NORVASC resulted in a decrease in renal vascular
resistance and an increase in glomerular filtration rate and effective renal plasma
flow without change in filtration fraction or proteinuria.
As with other calcium channel blockers, hemodynamic
measurements of cardiac function at rest and during exercise (or pacing) in
patients with normal ventricular function treated with NORVASC have generally
demonstrated a small increase in cardiac index without significant influence on
dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic
studies, NORVASC has not been associated with a negative inotropic effect when
administered in the therapeutic dose range to intact animals and man, even when
co-administered with beta-blockers to man. Similar findings, however, have been
observed in normal or well-compensated patients with heart failure with agents
possessing significant negative inotropic effects.
NORVASC does not change sinoatrial nodal function or
atrioventricular conduction in intact animals or man. In patients with chronic stable
angina, intravenous administration of 10 mg did not significantly alter A-H and
H-V conduction and sinus node recovery time after pacing. Similar results were
obtained in patients receiving NORVASC and concomitant beta-blockers. In clinical
studies in which NORVASC was administered in combination with beta-blockers to
patients with either hypertension or angina, no adverse effects on
electrocardiographic parameters were observed. In clinical trials with angina
patients alone, NORVASC therapy did not alter electrocardiographic intervals or
produce higher degrees of AV blocks.
When amlodipine and sildenafil were used in combination,
each agent independently exerted its own blood pressure lowering effect [see DRUG
After oral administration of therapeutic doses of
NORVASC, absorption produces peak plasma concentrations between 6 and 12 hours.
Absolute bioavailability has been estimated to be between 64 and 90%. The
bioavailability of NORVASC is not altered by the presence of food.
Amlodipine is extensively (about 90%) converted to
inactive metabolites via hepatic metabolism with 10% of the parent compound and
60% of the metabolites excreted in the urine. Ex vivo studies have shown that
approximately 93% of the circulating drug is bound to plasma proteins in
hypertensive patients. Elimination from the plasma is biphasic with a terminal
elimination half-life of about 30-50 hours. Steady-state plasma levels of
amlodipine are reached after 7 to 8 days of consecutive daily dosing.
The pharmacokinetics of amlodipine are not significantly
influenced by renal impairment. Patients with renal failure may therefore
receive the usual initial dose.
Elderly patients and patients with hepatic insufficiency
have decreased clearance of amlodipine with a resulting increase in AUC of
approximately 40-60%, and a lower initial dose may be required. A similar
increase in AUC was observed in patients with moderate to severe heart failure.
In vitro data indicate that amlodipine has no effect on
the human plasma protein binding of digoxin, phenytoin, warfarin, and
Impact Of Other Drugs On Amlodipine
Co-administered cimetidine, magnesium-and aluminum
hydroxide antacids, sildenafil, and grapefruit juice have no impact on the
exposure to amlodipine.
Co-administration of a 180 mg daily dose of diltiazem
with 5 mg amlodipine in elderly hypertensive patients resulted in a 60%
increase in amlodipine systemic exposure. Erythromycin co-administration in
healthy volunteers did not significantly change amlodipine systemic exposure. However,
strong inhibitors of CYP3A (e.g., itraconazole, clarithromycin) may increase
the plasma concentrations of amlodipine to a greater extent [see DRUG
Impact Of Amlodipine On Other Drugs
Amlodipine is a weak inhibitor of CYP3A and may increase
exposure to CYP3A substrates. Co-administered amlodipine does not affect the
exposure to atorvastatin, digoxin, ethanol and the warfarin prothrombin
Co-administration of multiple doses of 10 mg of
amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to
simvastatin compared to simvastatin alone [see DRUG INTERACTIONS].
A prospective study in renal transplant patients (N=11)
showed on an average of 40% increase in trough cyclosporine levels when
concomitantly treated with amlodipine [see DRUG INTERACTIONS].
A prospective study in healthy Chinese volunteers (N=9)
with CYP3A5 expressers showed a 2.5- to 4-fold increase in tacrolimus exposure
when concomitantly administered with amlodipine compared to tacrolimus alone.
This finding was not observed in CYP3A5 non-expressers (N= 6). However, a
3-fold increase in plasma exposure to tacrolimus in a renal transplant patient
(CYP3A5 nonexpresser) upon initiation of amlodipine for the treatment of
post-transplant hypertension resulting in reduction of tacrolimus dose has been
reported. Irrespective of the CYP3A5 genotype status, the possibility of an
interaction cannot be excluded with these drugs [see DRUG INTERACTIONS].
Sixty-two hypertensive patients aged 6 to 17 years
received doses of NORVASC between 1.25 mg and 20 mg. Weight-adjusted clearance
and volume of distribution were similar to values in adults.
Effects In Hypertension
The antihypertensive efficacy of NORVASC has been
demonstrated in a total of 15 double-blind, placebo-controlled, randomized
studies involving 800 patients on NORVASC and 538 on placebo. Once daily
administration produced statistically significant placebo-corrected reductions
in supine and standing blood pressures at 24 hours postdose, averaging about
12/6 mmHg in the standing position and 13/7 mmHg in the supine position in
patients with mild to moderate hypertension. Maintenance of the blood pressure
effect over the 24-hour dosing interval was observed, with little difference in
peak and trough effect. Tolerance was not demonstrated in patients studied for
up to 1 year. The 3 parallel, fixed dose, dose response studies showed that the
reduction in supine and standing blood pressures was dose-related within the
recommended dosing range. Effects on diastolic pressure were similar in young and
older patients. The effect on systolic pressure was greater in older patients,
perhaps because of greater baseline systolic pressure. Effects were similar in
black patients and in white patients.
Two hundred sixty-eight hypertensive patients aged 6 to
17 years were randomized first to NORVASC 2.5 or 5 mg once daily for 4 weeks
and then randomized again to the same dose or to placebo for another 4 weeks.
Patients receiving 2.5 mg or 5 mg at the end of 8 weeks had significantly lower
systolic blood pressure than those secondarily randomized to placebo. The
magnitude of the treatment effect is difficult to interpret, but it is probably
less than 5 mmHg systolic on the 5 mg dose and 3.3 mmHg systolic on the 2.5 mg
dose. Adverse events were similar to those seen in adults.
Effects In Chronic Stable Angina
The effectiveness of 5-10 mg/day of NORVASC in
exercise-induced angina has been evaluated in 8 placebo-controlled,
double-blind clinical trials of up to 6 weeks duration involving 1038 patients
(684 NORVASC, 354 placebo) with chronic stable angina. In 5 of the 8 studies,
significant increases in exercise time (bicycle or treadmill) were seen with
the 10 mg dose. Increases in symptom-limited exercise time averaged 12.8% (63
sec) for NORVASC 10 mg, and averaged 7.9% (38 sec) for NORVASC 5 mg. NORVASC 10
mg also increased time to 1 mm ST segment deviation in several studies and
decreased angina attack rate. The sustained efficacy of NORVASC in angina
patients has been demonstrated over long-term dosing. In patients with angina,
there were no clinically significant reductions in blood pressures (4/1 mmHg)
or changes in heart rate (+0.3 bpm).
Effects In Vasospastic Angina
In a double-blind, placebo-controlled clinical trial of 4
weeks duration in 50 patients, NORVASC therapy decreased attacks by
approximately 4/week compared with a placebo decrease of approximately 1/week
(p<0.01). Two of 23 NORVASC and 7 of 27 placebo patients discontinued from
the study due to lack of clinical improvement.
Effects In Documented Coronary Artery Disease
In PREVENT, 825 patients with angiographically documented
coronary artery disease were randomized to NORVASC (5-10 mg once daily) or
placebo and followed for 3 years. Although the study did not show significance
on the primary objective of change in coronary luminal diameter as assessed by quantitative
coronary angiography, the data suggested a favorable outcome with respect to
fewer hospitalizations for angina and revascularization procedures in patients
CAMELOT enrolled 1318 patients with CAD recently
documented by angiography, without left main coronary disease and without heart
failure or an ejection fraction <40%. Patients (76% males, 89% Caucasian,
93% enrolled at US sites, 89% with a history of angina, 52% without PCI, 4%
with PCI and no stent, and 44% with a stent) were randomized to double-blind
treatment with either NORVASC (5-10 mg once daily) or placebo in addition to
standard care that included aspirin (89%), statins (83%), betablockers (74%),
nitroglycerin (50%), anti-coagulants (40%), and diuretics (32%), but excluded
other calcium channel blockers. The mean duration of follow-up was 19 months.
The primary endpoint was the time to first occurrence of one of the following
events: hospitalization for angina pectoris, coronary revascularization,
myocardial infarction, cardiovascular death, resuscitated cardiac arrest, hospitalization
for heart failure, stroke/TIA, or peripheral vascular disease. A total of 110
(16.6%) and 151 (23.1%) first events occurred in the NORVASC and placebo
groups, respectively, for a hazard ratio of 0.691 (95% CI: 0.540-0.884, p =
0.003). The primary endpoint is summarized in Figure 1 below. The outcome of
this study was largely derived from the prevention of hospitalizations for angina
and the prevention of revascularization procedures (see Table 1). Effects in
various subgroups are shown in Figure 2.
In an angiographic substudy (n=274) conducted within
CAMELOT, there was no significant difference between amlodipine and placebo on
the change of atheroma volume in the coronary artery as assessed by
Figure 1 : Kaplan-Meier Analysis of Composite Clinical
Outcomes for NORVASC versus Placebo
Figure 2 : Effects on Primary Endpoint of NORVASC versus
Placebo across Sub-Groups
Table 1 below summarizes the significant composite
endpoint and clinical outcomes from the composites of the primary endpoint. The
other components of the primary endpoint including cardiovascular death,
resuscitated cardiac arrest, myocardial infarction, hospitalization for heart
failure, stroke/TIA, or peripheral vascular disease did not demonstrate a significant
difference between NORVASC and placebo.
Table 1: Incidence of Significant Clinical Outcomes
|Clinical Outcomes N (%)
|Risk Reduction (p-value)
|*Total patients with these events
Studies In Patients With Heart Failure
NORVASC has been compared to placebo in four 8-12 week
studies of patients with NYHA Class II/III heart failure, involving a total of
697 patients. In these studies, there was no evidence of worsened heart failure
based on measures of exercise tolerance, NYHA classification, symptoms, or left
ventricular ejection fraction. In a long-term (follow-up at least 6 months,
mean 13.8 months) placebo-controlled mortality/morbidity study of NORVASC 5-10
mg in 1153 patients with NYHA Classes III (n=931) or IV (n=222) heart failure
on stable doses of diuretics, digoxin, and ACE inhibitors, NORVASC had no effect
on the primary endpoint of the study which was the combined endpoint of
all-cause mortality and cardiac morbidity (as defined by life-threatening
arrhythmia, acute myocardial infarction, or hospitalization for worsened heart
failure), or on NYHA classification, or symptoms of heart failure. Total
combined all-cause mortality and cardiac morbidity events were 222/571 (39%)
for patients on NORVASC and 246/583 (42%) for patients on placebo; the cardiac
morbid events represented about 25% of the endpoints in the study.
Another study (PRAISE-2) randomized patients with NYHA
Class III (80%) or IV (20%) heart failure without clinical symptoms or
objective evidence of underlying ischemic disease, on stable doses of ACE
inhibitors (99%), digitalis (99%), and diuretics (99%), to placebo (n=827) or
NORVASC (n=827) and followed them for a mean of 33 months. There was no
statistically significant difference between NORVASC and placebo in the primary
endpoint of all-cause mortality (95% confidence limits from 8% reduction to 29%
increase on NORVASC). With NORVASC there were more reports of pulmonary edema.
2Based on patient weight of 50 kg