"The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has recommended the marketing of selexipag (Uptravi, Actelion Registration Ltd) for the treatment of adults with pulmonary arterial hypertension (PAH)./"...
Mechanism Of Action
Azor is a combination of two antihypertensive drugs: a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker), amlodipine besylate, and an angiotensin II receptor blocker, olmesartan medoxomil. The amlodipine component of Azor inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle, and the olmesartan medoxomil component of Azor blocks the vasoconstrictor effects of angiotensin II.
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.
Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (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 synthesis.
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. ACE 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.
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 subjects 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 normals or well-compensated patients with heart failure with agents possessing significant negative inotropic effects.
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.
Olmesartan medoxomil doses of 2.5 mg 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.
The pharmacokinetics of amlodipine and olmesartan medoxomil from Azor are equivalent to the pharmacokinetics of amlodipine and olmesartan medoxomil when administered separately. The bioavailability of both components is well below 100%, but neither component is affected by food. The effective half-lives of amlodipine (45±11 hours) and olmesartan (7±1 hours) result in a 2-to 3-fold accumulation for amlodipine and negligible accumulation for olmesartan with once-daily dosing.
After oral administration of therapeutic doses of amlodipine, absorption produces peak plasma concentrations between 6 and 12 hours. Absolute bioavailability is estimated as between 64% and 90%.
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 peak plasma concentration (Cmax) of olmesartan is reached after 1 to 2 hours. Food does not affect the bioavailability of olmesartan medoxomil.
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.
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 recommended doses.
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 in rats.
Metabolism and Excretion
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.
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 once-daily dosing.
The pharmacokinetic properties of Azor in the elderly are similar to those of the individual components.
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.
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; AUCss, τ was 33% higher in elderly patients, corresponding to an approximate 30% reduction in CLR.
Sixty-two hypertensive patients aged 6 to 17 years received doses of amlodipine between 1.25 mg and 20 mg. Weight-adjusted clearance and volume of distribution were similar to values in adults.
The pharmacokinetics of olmesartan medoxomil have not been investigated in patients < 18 years of age.
Population pharmacokinetic analysis indicated that female patients had approximately 15% smaller clearances of olmesartan than male patients. Gender had no effect on the clearance of amlodipine.
Minor differences were observed in the pharmacokinetics of olmesartan medoxomil in women compared to men. AUC and Cmax were 10% to 15% higher in women than in men.
The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial dose.
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. No initial dosage adjustment is recommended for patients with moderate to marked renal impairment (creatinine clearance < 40 mL/min).
Patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40% to 60%.
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%.
Patients with heart failure have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40% to 60%.
Bile acid sequestering agent 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].
An 8-week multicenter, randomized, double-blind, placebo controlled, parallel group factorial study in patients with mild to severe hypertension was conducted to determine if treatment with Azor was associated with clinically significant reduction in blood pressure compared to the respective monotherapies. The study randomized 1940 patients equally to one of the following 12 treatment arms: placebo, monotherapy treatment with amlodipine 5 mg or 10 mg, monotherapy treatment with olmesartan medoxomil 10 mg, 20 mg, or 40 mg, or combination therapy with amlodipine/ olmesartan medoxomil at doses of 5/10 mg, 5/20 mg, 5/40 mg, 10/10 mg, 10/20 mg, and 10/40 mg. Patients discontinued their prior antihypertensive treatment. The mean baseline blood pressure of the study population was 164/102 mmHg. Of the total cohort, 970 patients were treated with the combination as initial therapy.
Treatment with Azor resulted in statistically significant greater reductions in diastolic and systolic blood pressure compared to the respective monotherapy components.
The following table presents the results for mean reduction in seated systolic and diastolic blood pressure following 8 weeks of treatment with Azor. Placebo-adjusted reductions from baseline in blood pressure were progressively greater with increases in dose of both amlodipine and olmesartan medoxomil components of Azor.
Reduction in Seated Systolic/Diastolic Blood Pressure
(mmHg): Combination Therapy vs. Monotherapy Components (Double-Blind Treatment
|(mmHg)||Placebo||10 mg||20 mg||40 mg|
Placebo-Adjusted Mean Change
|5 mg||Mean Change
Placebo-Adjusted Mean Change
|10 mg||Mean Change
Placebo-Adjusted Mean Change
The antihypertensive effect of Azor was similar in patients with and without prior antihypertensive medication use, in patients with and without diabetes, in patients ≥ 65 years of age and < 65 years of age, and in women and men. Limited data exist in patients ≥ 75 years of age.
Azor was effective in treating black patients (usually a low-renin population), and the magnitude of blood pressure reduction in black patients approached that observed for non-Black patients. This effect in black patients has been seen with ACE inhibitors, angiotensin receptor blockers, and beta-blockers.
The blood pressure lowering effect was maintained throughout the 24-hour period with Azor once daily, with trough-to-peak ratios for systolic and diastolic response between 71% and 82%.
Upon completing the 8-week, double-blind, placebo-controlled study, 1684 patients entered a 44-week open-label extension and received combination therapy with amlodipine 5 mg plus olmesartan medoxomil 40 mg. During the open-label extension, patients whose blood pressure was not adequately controlled (i.e., did not achieve a blood pressure goal of < 140/90 mmHg, or < 130/80 mmHg for those patients with diabetes) on amlodipine/olmesartan medoxomil 5/40 mg were titrated to amlodipine /olmesartan medoxomil 10/40 mg. Patients whose blood pressure was still not adequately controlled were offered additional hydrochlorothiazide 12.5 mg and subsequently 25 mg as required to achieve adequate blood pressure goal.
There are no trials of Azor demonstrating reductions in cardiovascular risk in patients with hypertension, but at least one pharmacologically similar drug has demonstrated such benefits.
The antihypertensive efficacy of amlodipine has been demonstrated in a total of 15 double-blind, placebo-controlled, randomized studies involving 800 patients on amlodipine and 538 on placebo. Once daily administration produced statistically significant placebo-corrected reductions in supine and standing blood pressures at 24 hours post-dose, 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.
The antihypertensive effects of olmesartan medoxomil have been demonstrated in seven placebo-controlled studies at doses ranging from 2.5 mg to 80 mg for 6 to 12 weeks, each showing statistically significant reductions in peak and trough blood pressure. A total of 2693 patients (2145 olmesartan medoxomil; 548 placebo) with essential hypertension were studied. The blood pressure lowering effect was maintained throughout the 24-hour period with olmesartan medoxomil once daily, with trough-to-peak ratios for systolic and diastolic response between 60% and 80%.
Last reviewed on RxList: 6/27/2014
This monograph has been modified to include the generic and brand name in many instances.
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