Mechanism of Action
Felodipine is a member of the dihydropyridine
class of calcium channel antagonists (calcium channel blockers). It reversibly
competes with nitrendipine and/or other calcium channel blockers for
dihydropyridine binding sites, blocks voltage-dependent Ca++ currents
in vascular smooth muscle and cultured rabbit atrial cells, and blocks
potassium-induced contracture of the rat portal vein.
In vitro studies show that the effects of felodipine on
contractile processes are selective, with greater effects on vascular smooth
muscle than cardiac muscle. Negative inotropic effects can be detected in vitro ,
but such effects have not been seen in intact animals.
The effect of felodipine on blood pressure is principally a consequence
of a dose-related decrease of peripheral vascular resistance in man, with a
modest reflex increase in heart rate (see Cardiovascular Effects). With
the exception of a mild diuretic effect seen in several animal species and man,
the effects of felodipine are accounted for by its effects on peripheral
Pharmacokinetics and Metabolism
Following oral administration, felodipine is almost completely absorbed
and undergoes extensive first-pass metabolism. The systemic bioavailability of
PLENDIL is approximately 20%. Mean peak concentrations following the
administration of PLENDIL are reached in 2.5 to 5 hours. Both peak plasma
concentration and the area under the plasma concentration time curve (AUC)
increase linearly with doses up to 20 mg. Felodipine is greater than 99% bound
to plasma proteins.
Following intravenous administration, the plasma concentration of
felodipine declined triexponentially with mean disposition half-lives of 4.8
minutes, 1.5 hours, and 9.1 hours. The mean contributions of the three
individual phases to the overall AUC were 15, 40, and 45%, respectively, in the
order of increasing t½.
Following oral administration of the immediate-release formulation, the
plasma level of felodipine also declined polyexponentially with a mean terminal
t½ of 11 to 16 hours. The mean peak and trough steady-state plasma
concentrations achieved after 10 mg of the immediate-release formulation given
once a day to normal volunteers, were 20 and 0.5 nmol/L, respectively. The
trough plasma concentration of felodipine in most individuals was substantially
below the concentration needed to effect a half-maximal decline in blood
pressure (EC50) [4–6 nmol/L for felodipine], thus precluding once-a-day dosing
with the immediate-release formulation.
Following administration of a 10-mg dose of PLENDIL, the
extended-release formulation, to young, healthy volunteers, mean peak and
trough steady-state plasma concentrations of felodipine were 7 and 2 nmol/L,
respectively. Corresponding values in hypertensive patients (mean age 64) after
a 20-mg dose of PLENDIL were 23 and 7 nmol/L. Since the EC50 for felodipine is
4 to 6 nmol/L, a 5- to 10-mg dose of PLENDIL in some patients, and a 20-mg dose
in others, would be expected to provide an antihypertensive effect that
persists for 24 hours (see Cardiovascular Effects below and DOSAGE AND
The systemic plasma clearance of felodipine in young healthy subjects
is about 0.8 L/min, and the apparent volume of distribution is about 10 L/kg.
Following an oral or intravenous dose of 14C-labeled
felodipine in man, about 70% of the dose of radioactivity was recovered in
urine and 10% in the feces. A negligible amount of intact felodipine is
recovered in the urine and feces ( < 0.5%). Six metabolites, which account
for 23% of the oral dose, have been identified; none has significant
Following administration of PLENDIL to hypertensive patients, mean peak
plasma concentrations at steady state are about 20% higher than after a single
dose. Blood pressure response is correlated with plasma concentrations of
The bioavailability of PLENDIL is influenced by the presence of food.
When administered either with a high fat or carbohydrate diet, Cmax is
increased by approximately 60%; AUC is unchanged. When PLENDIL was administered
after a light meal (orange juice, toast, and cereal), however, there is no
effect on felodipine's pharmacokinetics. The bioavailability of felodipine was
increased approximately two-fold when taken with grapefruit juice. Orange juice
does not appear to modify the kinetics of PLENDIL. A similar finding has been
seen with other dihydropyridine calcium antagonists, but to a lesser extent
than that seen with felodipine.
Plasma concentrations of felodipine, after a single dose and at steady
state, increase with age. Mean clearance of felodipine in elderly hypertensives
(mean age 74) was only 45% of that of young volunteers (mean age 26). At steady
state mean AUC for young patients was 39% of that for the elderly. Data for
intermediate age ranges suggest that the AUCs fall between the extremes of the
young and the elderly.
In patients with hepatic disease, the clearance of felodipine was
reduced to about 60% of that seen in normal young volunteers.
Renal impairment does not alter the plasma concentration profile of
felodipine; although higher concentrations of the metabolites are present in
the plasma due to decreased urinary excretion, these are inactive.
Animal studies have demonstrated that felodipine crosses the
blood-brain barrier and the placenta.
Following administration of PLENDIL, a reduction in blood pressure
generally occurs within 2 to 5 hours. During chronic administration,
substantial blood pressure control lasts for 24 hours, with trough reductions
in diastolic blood pressure approximately 40–50% of peak reductions. The
antihypertensive effect is dose dependent and correlates with the plasma
concentration of felodipine.
A reflex increase in heart rate frequently occurs during the first week
of therapy; this increase attenuates over time. Heart rate increases of 5–10
beats per minute may be seen during chronic dosing. The increase is inhibited
by beta-blocking agents.
The P-R interval of the ECG is not affected by felodipine when
administered alone or in combination with a beta-blocking agent. Felodipine
alone or in combination with a beta-blocking agent has been shown, in clinical
and electrophysiologic studies, to have no significant effect on cardiac
conduction (P-R, P-Q, and H-V intervals).
In clinical trials in hypertensive patients without clinical evidence
of left ventricular dysfunction, no symptoms suggestive of a negative inotropic
effect were noted; however, none would be expected in this population (see PRECAUTIONS).
Renal vascular resistance is decreased by felodipine while glomerular filtration
rate remains unchanged. Mild diuresis, natriuresis, and kaliuresis have been
observed during the first week of therapy. No significant effects on serum
electrolytes were observed during short- and long-term therapy.
In clinical trials in patients with hypertension, increases in plasma
noradrenaline levels have been observed.
Felodipine produces dose-related decreases in systolic and diastolic
blood pressure as demonstrated in six placebo-controlled, dose response studies
using either immediate-release or extended-release dosage forms. These studies
enrolled over 800 patients on active treatment, at total daily doses ranging
from 2.5 to 20 mg. In those studies felodipine was administered either as
monotherapy or was added to beta blockers. The results of the 2 studies with
PLENDIL given once daily as monotherapy are shown in the table below:
MEAN REDUCTIONS IN BLOOD PRESSURE (mmHg)*
||Systolic/Diastolic Mean Peak Response
||Mean Trough Response
||Trough/ Peak Ratios (%s)
|Study 1 (8 weeks)
|Study 2 (4 weeks)
|*Placebo response subtracted
**Different number of patients available for peak and trough measurements