Mechanism Of Action
The active ingredients of Tribenzor target three separate
mechanisms involved in blood pressure regulation. Specifically, amlodipine
blocks the contractile effects of calcium on cardiac and vascular smooth muscle
cells; olmesartan medoxomil blocks the vasoconstriction and sodium retaining
effects of angiotensin II on cardiac, vascular smooth muscle, adrenal and renal
cells; and hydrochlorothiazide directly promotes the excretion of sodium and
chloride in the kidney leading to reductions in intravascular volume. For a
more detailed description of the mechanisms of action for each individual
component, see below.
Olmesartan medoxomil. Angiotensin II is formed
from angiotensin I in a reaction catalyzed by ACE, kininase II. Angiotensin II
is the principal pressor agent of the renin-angiotensin system, with effects
that include vasoconstriction, stimulation of synthesis and release of
aldosterone, cardiac stimulation, and renal reabsorption of sodium. Olmesartan
blocks the vasoconstrictor effects of angiotensin II by selectively blocking
the binding of angiotensin II to the AT1 receptor in vascular smooth muscle.
Its action is, therefore, independent of the pathways for angiotensin II
An AT2 receptor is found also in many tissues, but this
receptor is not known to be associated with cardiovascular homeostasis.
Olmesartan has more than a 12,500-fold greater affinity for the AT1 receptor than
for the AT2 receptor.
Blockade of the renin-angiotensin system with ACE
inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin
I, is a mechanism of many drugs used to treat hypertension.
Angiotensin-converting enzyme inhibitors also inhibit the degradation of
bradykinin, a reaction also catalyzed by ACE. Because olmesartan does not
inhibit ACE (kininase II), it does not affect the response to bradykinin.
Whether this difference has clinical relevance is not yet known.
Blockade of the angiotensin II receptor inhibits the
negative regulatory feedback of angiotensin II on renin secretion, but the
resulting increased plasma renin activity and circulating angiotensin II levels
do not overcome the effect of olmesartan on blood pressure.
Amlodipine. Amlodipine is a dihydropyridine
calcium channel blocker that inhibits the transmembrane influx of calcium ions
into vascular smooth muscle and cardiac muscle. Experimental data suggests that
amlodipine binds to both dihydropyridine and nonhydropyridine 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 effect.
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.
Hydrochlorothiazide. Hydrochlorothiazide is a
thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte
reabsorption, directly increasing excretion of sodium and chloride in
approximately equivalent amounts. Indirectly, the diuretic action of
hydrochlorothiazide reduces plasma volume, with consequent increases in plasma
renin activity, increases in aldosterone secretion, increases in urinary
potassium loss, and decreases in serum potassium. The renin-aldosterone link is
mediated by angiotensin II, so co-administration of an angiotensin II receptor
antagonist tends to reverse the potassium loss associated with these diuretics.
The mechanism of the antihypertensive effect of thiazides
is not fully understood.
Tribenzor has been shown to be effective in lowering
blood pressure. The three components of Tribenzor (olmesartan medoxomil,
amlodipine, and hydrochlorothiazide) lower the blood pressure through
complementary mechanisms, each working at a separate site and blocking
different effects or pathways. The pharmacodynamics of each individual
component is described below.
Olmesartan medoxomil. Olmesartan medoxomil doses
of 2.5 to 40 mg inhibit the pressor effects of angiotensin I infusion. The
duration of the inhibitory effect was related to dose, with doses of olmesartan
medoxomil > 40 mg giving > 90% inhibition at 24 hours.
Plasma concentrations of angiotensin I and angiotensin II
and plasma renin activity (PRA) increase after single and repeated
administration of olmesartan medoxomil to healthy subjects and hypertensive
patients. Repeated administration of up to 80 mg olmesartan medoxomil had
minimal influence on aldosterone levels and no effect on serum potassium.
Amlodipine. Following administration of
therapeutic doses to patients with hypertension, amlodipine 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.
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 amlodipine 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 patients experienced no clinically significant change in blood
pressures (+1/-2 mmHg).
In hypertensive patients with normal renal function, therapeutic
doses of amlodipine 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 amlodipine 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, amlodipine 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
Amlodipine does not change sinoatrial nodal function or
atrioventricular conduction in intact animals or man. In clinical studies in
which amlodipine was administered in combination with beta-blockers to patients
with either hypertension or angina, no adverse effects on electrocardiographic
parameters were observed.
Hydrochlorothiazide. After oral administration of
hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours,
and lasts about 6 to 12 hours.
Alcohol, Barbiturates, or Narcotics: Potentiation
of orthostatic hypotension may occur.
Skeletal muscle relaxants, non-depolarizing (e.g.,
tubocurarine): Possible increased responsiveness to the muscle relaxant.
Tribenzor. After oral administration of Tribenzor
in normal healthy adults, peak plasma concentrations of olmesartan, amlodipine,
and hydrochlorothiazide are reached in about 1.5 to 3 hours, 6 to 8 hours, and
1.5 to 2 hours, respectively. The rate and extent of absorption of olmesartan
medoxomil, amlodipine, and hydrochlorothiazide from Tribenzor are the same as
when administered as individual dosage forms. Food does not affect the
bioavailability of Tribenzor.
Olmesartan medoxomil. Olmesartan medoxomil is
rapidly and completely bioactivated by ester hydrolysis to olmesartan during
absorption from the gastrointestinal tract. The absolute bioavailability of
olmesartan medoxomil is approximately 26%. After oral administration, the Cmax of
olmesartan is reached after 1 to 2 hours. Food does not affect the
bioavailability of olmesartan medoxomil.
Amlodipine. After oral administration of
therapeutic doses of amlodipine, absorption produces peak plasma concentrations
between 6 and 12 hours. Absolute bioavailability is estimated between 64% and
Hydrochlorothiazide. When plasma levels have been
followed for at least 24 hours, the plasma half-life has been observed to vary
between 5.6 and 14.8 hours.
Olmesartan medoxomil. The volume of distribution
of olmesartan is approximately 17 L. Olmesartan is highly bound to plasma
proteins (99%) and does not penetrate red blood cells. The protein binding is
constant at plasma olmesartan concentrations well above the range achieved with
In rats, olmesartan crossed the blood-brain barrier
poorly, if at all. Olmesartan passed across the placental barrier in rats and
was distributed to the fetus. Olmesartan was distributed to milk at low levels
Amlodipine. Ex vivo studies have shown that approximately
93% of the circulating drug is bound to plasma proteins in hypertensive
patients. Steady-state plasma levels of amlodipine are reached after 7 to 8
days of consecutive daily dosing.
Hydrochlorothiazide. Hydrochlorothiazide crosses
the placental but not the blood-brain barrier and is excreted in breast milk.
Metabolism And Excretion
Olmesartan medoxomil. Following the rapid and
complete conversion of olmesartan medoxomil to olmesartan during absorption,
there is virtually no further metabolism of olmesartan. Total plasma clearance
of olmesartan is 1.3 L/h, with a renal clearance of 0.6 L/h. Approximately 35%
to 50% of the absorbed dose is recovered in urine while the remainder is
eliminated in feces via the bile.
Olmesartan appears to be eliminated in a biphasic manner
with a terminal elimination half-life of approximately 13 hours. Olmesartan
shows linear pharmacokinetics following single oral doses of up to 320 mg and
multiple oral doses of up to 80 mg. Steady-state levels of olmesartan are
achieved within 3 to 5 days and no accumulation in plasma occurs with
Amlodipine. Amlodipine is extensively (about 90%)
converted to inactive metabolites via hepatic metabolism. Elimination from the
plasma is biphasic with a terminal elimination half-life of about 30 to 50
hours. Ten percent of the parent compound and 60% of the metabolites are
excreted in the urine.
Hydrochlorothiazide. Hydrochlorothiazide is not
metabolized but is eliminated rapidly by the kidney. At least 61% of the oral
dose is eliminated unchanged within 24 hours.
Olmesartan medoxomil. The pharmacokinetics of
olmesartan medoxomil were studied in the elderly ( ≥ 65 years). Overall,
maximum plasma concentrations of olmesartan were similar in young adults and
the elderly. Modest accumulation of olmesartan was observed in the elderly with
repeated dosing; AUCssss, τ was 33% higher in elderly patients,
corresponding to an approximate 30% reduction in CLR.
Amlodipine. Elderly patients have decreased
clearance of amlodipine with a resulting increase in AUC of approximately 40%
to 60%, and a lower initial dose may be required.
Population pharmacokinetic analysis indicated that gender
had no effect on the clearance of olmesartan and amlodipine. Female patients
had approximately 20% smaller clearances of hydrochlorothiazide than male
Olmesartan medoxomil. Minor differences were
observed in the pharmacokinetics of olmesartan medoxomil in women compared to
men. Area under the curve and Cmax were 10% to 15% higher in women than in men.
Olmesartan medoxomil. In patients with renal
insufficiency, serum concentrations of olmesartan were elevated compared to
subjects with normal renal function. After repeated dosing, the AUC was
approximately tripled in patients with severe renal impairment (creatinine
clearance < 20 mL/min). The pharmacokinetics of olmesartan medoxomil in
patients undergoing hemodialysis has not been studied.
Amlodipine. The pharmacokinetics of amlodipine are
not significantly influenced by renal impairment.
Olmesartan medoxomil. Increases in AUC0-∞ and
Cmax were observed in patients with moderate hepatic impairment compared to
those in matched controls, with an increase in AUC of about 60%.
Amlodipine. Patients with hepatic insufficiency
have decreased clearance of amlodipine with a resulting increase in AUC of
approximately 40% to 60%.
Amlodipine. Patients with heart failure have
decreased clearance of amlodipine with a resulting increase in AUC of
approximately 40% to 60%.
Simvastatin: 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
CYP3A inhibitors: 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 INTERACTIONS].
Cyclosporine: In a prospective study in renal
transplant patients, an average 40% increase in trough cyclosporine levels was
observed in the presence of amlodipine. [see DRUG INTERACTIONS].
Colesevelam: Concomitant administration of 40 mg
olmesartan medoxomil and 3750 mg colesevelam hydrochloride in healthy subjects
resulted in 28% reduction in Cmax and 39% reduction in AUC of olmesartan.
Lesser effects, 4% and 15% reduction in Cmax and AUC respectively, were
observed when olmesartan medoxomil was administered 4 hours prior to
colesevelam hydrochloride [see DRUG INTERACTIONS].
Cimetidine: Co-administration of amlodipine with
cimetidine did not alter the pharmacokinetics of amlodipine.
Grapefruit juice: Co-administration of 240 mL of
grapefruit juice with a single oral dose of amlodipine 10 mg in 20 healthy volunteers
had no significant effect on the pharmacokinetics of amlodipine.
Maalox® (antacid): Co-administration
of the antacid Maalox® with a single dose of amlodipine had no significant
effect on the pharmacokinetics of amlodipine.
Sildenafil: A single 100 mg dose of sildenafil in
subjects with essential hypertension had no effect on the pharmacokinetic
parameters of amlodipine. When amlodipine and sildenafil were used in
combination, each agent independently exerted its own blood pressure lowering
Atorvastatin: Co-administration of multiple 10 mg
doses of amlodipine with 80 mg of atorvastatin resulted in no significant
change in the steady state pharmacokinetic parameters of atorvastatin.
Digoxin: Co-administration of amlodipine with
digoxin did not change serum digoxin levels or digoxin renal clearance in
Ethanol (alcohol): Single and multiple 10 mg doses
of amlodipine had no significant effect on the pharmacokinetics of ethanol.
Warfarin: Co-administration of amlodipine with
warfarin did not change the warfarin prothrombin response time. No significant
drug interactions were reported in studies in which olmesartan medoxomil was
coadministered with warfarin in healthy volunteers.
Digoxin: No significant drug interactions were
reported in studies in which olmesartan medoxomil was coadministered with
digoxin in healthy volunteers.
Antacids: The bioavailability of olmesartan
medoxomil was not significantly altered by the co-administration of antacids
The antihypertensive efficacy of Tribenzor was studied in
a double-blind, active-controlled study in hypertensive patients. A total of
2492 patients with hypertension (mean baseline blood pressure 169/101 mmHg)
received olmesartan medoxomil/amlodipine/hydrochlorothiazide 40/10/25 mg (627
patients), olmesartan medoxomil/amlodipine 40/10 mg (628 patients), olmesartan
medoxomil/hydrochlorothiazide 40/25 mg (637 patients ), or amlodipine/hydrochlorothiazide
10/25 mg (600 patients). Each subject was randomized to one of the three dual
therapy combinations for two to four weeks.
Patients were then randomized to continue on the dual
therapy they were receiving or to receive triple therapy. A total of 53% of
patients were male, 19% were 65 years or older, 67% were white, 30% were black,
and 15% were diabetic.
After 8 weeks of treatment, the triple combination
therapy produced greater reductions in both systolic and diastolic blood
pressures (p < 0.0001) compared to each of the 3 dual combination therapies.
The full blood pressure lowering effects were attained within 2 weeks after a
change in dose.
The seated blood pressure reductions attributable to the
addition of a single high-dose drug to each high-dose dual drug combination are
shown in Table 2.
Table 2 : Additional blood pressure reductions on
high-dose Tribenzor compared to high doses of dual combination drugs
|Olmesartan medoxomil 40 / amlodipine 10 mg
||HCTZ 25 mg
|Olmesartan medoxomil 40 / HCTZ 25 mg
||Amlodipine 10 mg
|Amlodipine 10 / HCTZ 25 mg
||Olmesartan medoxomil 40 mg
|*all highly statistically significant.
There were no apparent differences in terms of seated
diastolic blood pressure (SeDBP) or seated systolic blood pressure (SeSBP)
reductions in black and non-black patients treated with Tribenzor [see Use
in Specific Populations].
There were no apparent differences in terms of SeDBP or
SeSBP reductions in diabetic and non-diabetic patients treated with Tribenzor.
A total of 440 patients participated in the ambulatory
blood pressure monitoring portion of the study. Over the 24-hour period, there
was a greater reduction in diastolic and systolic ambulatory blood pressure for
olmesartan medoxomil/amlodipine/hydrochlorothiazide 40/10/25 mg compared to
each of the dual combination therapies (see Figure 1 and Figure 2).
Figure 1: Mean Ambulatory Diastolic Blood Pressure at
Endpoint by Treatment and Hour
Figure 2: Mean Ambulatory Systolic Blood Pressure at
Endpoint by Treatment and Hour
The blood pressure lowering effects of lower dose
strengths of Tribenzor (olmesartan medoxomil/amlodipine/hydrochlorothiazide
20/5/12.5 mg, 40/5/12.5 mg, 40/10/12.5 mg, and 40/5/25 mg) have not been
All of the dose strengths of the triple combination are
expected to provide superior blood pressure lowering effects compared to their
respective mono and dual combination components. The order of the blood
pressure lowering effects among the different dose strengths of Tribenzor
(olmesartan medoxomil /amlodipine /hydrochlorothiazide) is expected to be
20/5/12.5 mg < 40/5/12.5 mg < (40/10/12.5 mg ≈ 40/5/25 mg) <
There are no trials of Tribenzor demonstrating reductions
in cardiovascular risk in patients with hypertension, but at least one
pharmacologically similar drug has demonstrated such benefits.