Normetec Mechanism of Action

Pharmacologic Category: Angiotensin II Receptor Blocker (ARBs) and Calcium Channel Blocker.
Pharmacology: Pharmacodynamics: Amlodipine/Olmesartan Medoxomil (Normetec): Amlodipine/Olmesartan Medoxomil (Normetec) is a combination of an angiotensin II receptor antagonist, olmesartan medoxomil, and a calcium channel blocker, amlodipine. The combination of these active ingredients has an additive antihypertensive effect, reducing blood pressure to a greater degree than either component alone.
With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours.
The antihypertensive effect of Amlodipine/Olmesartan Medoxomil (Normetec) was similar irrespective of age and gender, and was similar in patients with and without diabetes.
In follow-up studies, the antihypertensive effect of Amlodipine/Olmesartan Medoxomil (Normetec) was sustained during long-term therapy. When required, addition of a diuretic (hydrochlorothiazide) increased the blood pressure lowering effect of Amlodipine/Olmesartan Medoxomil (Normetec).
Olmesartan Medoxomil: The olmesartan medoxomil component of Amlodipine/Olmesartan Medoxomil (Normetec) is a selective angiotensin II type 1 (AT1) receptor antagonist. Olmesartan medoxomil is rapidly converted to the pharmacologically active metabolite, olmesartan. Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system, and plays a significant role in the pathophysiology of hypertension. The effects of angiotensin II include vasoconstriction, stimulation of the synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Olmesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by blocking it's binding to the AT1 receptor in tissues, including vascular smooth muscle and the adrenal gland. The action of olmesartan is independent of the source or route of synthesis of angiotensin II. The selective antagonism of the angiotensin II (AT1) receptors by olmesartan results in increases in plasma renin levels and angiotensin I and II concentrations, and some decrease in plasma aldosterone concentrations.
In hypertension, olmesartan medoxomil causes a dose-dependent, long-lasting reduction in arterial blood pressure. There has been no evidence of first-dose hypotension, of tachyphylaxis during long-term treatment, or of rebound hypertension after abrupt cessation of therapy.
Following once daily administration to patients with hypertension, olmesartan medoxomil produces an effective and smooth reduction in blood pressure over the 24-hour dose interval. Once daily dosing produced similar decreases in blood pressure as twice daily dosing at the same total daily dose.
With continuous treatment, maximum reductions in blood pressure are achieved by 8 weeks after the initiation of therapy, although a substantial proportion of the blood pressure lowering effect is already observed after 2 weeks of treatment.
The effect of olmesartan medoxomil on mortality and morbidity is not yet known.
Amlodipine (as Besilate): The amlodipine component of Amlodipine/Olmesartan Medoxomil (Normetec) is a calcium channel blocker that inhibits the transmembrane influx of calcium ions through the potential-dependent L-type channels into the heart and smooth muscle. Experimental data indicate that amlodipine binds to both dihydropyridine and non-dihydropyridine binding sites. Amlodipine is relatively vessel-selective, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. The antihypertensive effect of amlodipine derives from a direct relaxant effect on arterial smooth muscle, which leads to a lowering of peripheral resistance and hence, of blood pressure.
In hypertensive patients, amlodipine causes a dose-dependent, long-lasting reduction in arterial blood pressure. There has been no evidence of first-dose hypotension, of tachyphylaxis during long-term treatment, or of rebound hypertension after abrupt cessation of therapy.
Following administration of therapeutic doses to patients with hypertension, amlodipine produces an effective reduction in blood pressure in the supine, sitting, and standing positions. Chronic use of amlodipine is not associated with significant changes in heart rate or plasma catecholamine levels. In hypertensive patients with normal renal function, therapeutic doses of amlodipine reduce renal vascular resistance and increase glomerular filtration rate and effective renal plasma flow, without changing filtration fraction or proteinuria.
Epidemiological studies have shown that long-term treatment with amlodipine monotherapy reduces the risk of cardiovascular mortality and morbidity.
Pharmacokinetics: Following oral intake of Amlodipine/Olmesartan Medoxomil (Normetec), peak plasma concentrations of olmesartan and amlodipine are reached at 1.5 hours to 2 hours and 6 to 8 hours, respectively. The rate and extent of absorption of the two active substances from Amlodipine/Olmesartan Medoxomil (Normetec) are equivalent to the rate and extent of absorption following intake of the two components as separate tablets. Food does not affect the bioavailability of olmesartan and amlodipine from Amlodipine/Olmesartan Medoxomil (Normetec).
Absorption and Distribution: Amlodipine/Olmesartan Medoxomil (Normetec): The pharmacokinetics of amlodipine and olmesartan from Amlodipine/Olmesartan Medoxomil (Normetec) are equivalent to the pharmacokinetics of amlodipine and olmesartan when administered separately. Food did not affect the pharmacokinetics of amlodipine or olmesartan when administered as Amlodipine/Olmesartan Medoxomil (Normetec) in healthy subjects.
Olmesartan medoxomil: Olmesartan medoxomil is a prodrug. It is rapidly converted to the pharmacologically active metabolite, olmesartan, by esterases in the gut mucosa and in portal blood during absorption from the gastrointestinal tract. No intact olmesartan medoxomil or intact side chain medoxomil moiety have been detected in plasma or excreta. The mean absolute bioavailability of olmesartan from a tablet formulation was 25.6%.
The mean peak plasma concentration (C_max) of olmesartan is reached within approximately 2 hours after oral dosing with olmesartan medoxomil, and olmesartan plasma concentrations increase approximately linearly with increasing single oral doses up to about 80 mg.
Food had minimal effect on the bioavailability of olmesartan; therefore, olmesartan medoxomil may be administered with or without food.
No clinically relevant gender-related differences in the pharmacokinetics of olmesartan have been observed.
Olmesartan is highly bound to plasma protein (99.7%), but the potential for clinically significant protein binding displacement interactions between olmesartan and other highly bound co-administered active substances is low (as confirmed by the lack of a clinically significant interaction between olmesartan medoxomil and warfarin). The binding of olmesartan to blood cells is negligible. The mean volume of distribution after intravenous dosing is low (16 L to 29 L).
Amlodipine (as besilate): After oral administration of therapeutic doses, amlodipine is slowly absorbed from the gastrointestinal tract. The absorption of amlodipine is unaffected by the concomitant intake of food. The absolute bioavailability of the unchanged compound is estimated to be 64% to 80%. Peak plasma levels are reached 6 hours to 12 hours post-dose. The volume of distribution is about 20 L/kg. The pK_a of amlodipine is 8.6. Plasma protein binding in vitro is approximately 98%.
Metabolism and Excretion: Olmesartan medoxomil: Total plasma clearance of olmesartan was typically 1.3 L/h (CV, 19%) and was relatively slow compared to hepatic blood flow (ca 90 L/h). Based on the systemic availability of 25.6%, it can be calculated that absorbed olmesartan is cleared by both renal excretion and hepato-biliary excretion. The terminal elimination half-life of olmesartan is between 10 hours and 15 hours after multiple oral dosing. Steady state is reached after the first few doses, and no further accumulation is evident after 14 days of repeated dosing. Renal clearance is approximately 0.5 L/h - 0.7 L/h and is independent of dose.
Amlodipine: The plasma elimination half-life (t_½) varies from 35 hours to 50 hours. Steady-state plasma levels are reached after 7 to 8 consecutive days. Amlodipine is extensively metabolized to inactive metabolites. About 60% of the administered dose is excreted in the urine, about 10% of which is in the form of unchanged amlodipine.
Pharmacokinetics in Special Populations: Elderly: Analysis indicated that age is not a significant predictor of olmesartan clearance. As age is correlated with creatinine clearance, any apparent effects of age on olmesartan clearance can be explained by changes in creatinine clearance. However, elderly patients have decreased clearance of amlodipine. In hypertensive patients, the olmesartan drug concentration in plasma area under the curve (AUC) is increased in elderly patients (65 years to 75 years old) and in very elderly patients (≥75 years old) compared with the younger age group. Following oral intake of amlodipine, the time to peak plasma concentration is comparable in young and in elderly patients. In elderly patients, the clearance of amlodipine tends to decline, resulting in increases in AUC and in elimination t_½.
Pediatric: No pharmacokinetic data in pediatric patients (below 18 years old) are available for olmesartan medoxomil.
Renal Impairment: In renally impaired patients, at steady state the olmesartan AUC was approximately tripled in patients with severe renal impairment, compared to healthy controls. Changes in amlodipine plasma concentration are not correlated with the degree of renal impairment. In these patients, amlodipine may be administered at the normal dosage. Amlodipine is not dialysable.
Hepatic Impairment: Increases in olmesartan AUC values are higher in hepatically impaired patients than in their corresponding matched healthy controls. Olmesartan mean C_max values are similar in hepatically-impaired and healthy subjects. Olmesartan medoxomil has not been evaluated in patients with severe hepatic impairment.
The clearance of amlodipine is decreased and the t_½ is prolonged in patients with impaired hepatic function, resulting in an increase in AUC of about 60%.
Olmesartan Pharmacokinetic Interactions: Drug Interaction with Bile Acid Sequestering Agent Colesevelam: Concomitant administration of 40 mg olmesartan medoxomil and 3,750 mg colesevelam hydrochloride in healthy subjects resulted in 28% reduction in C_max and 39% reduction in AUC, of olmesartan. Lesser effects, 4% and 15% reduction in C_max and AUC respectively, were observed when olmesartan medoxomil was administered 4 hours prior to colesevelam hydrochloride (see Interactions).
Toxicology: Preclinical Safety Data: Carcinogenecity, Mutagenesis, Impairment of Fertility: The mode of antihypertensive action of amlodipine (a direct relaxant effect on vascular smooth muscle) differs from, and is complementary to, that of olmesartan medoxomil (a long-acting angiotensin II receptor antagonist). Furthermore, based on the non-clinical toxicity profile of each substance, no exacerbation of toxicities for the combination is expected, because each substance has different targets, i.e., the kidneys for olmesartan medoxomil and the heart for amlodipine. A 3-month repeated dose toxicity study in rats demonstrated that the combined administration of olmesartan medoxomil and amlodipine neither augmented any of the previously reported and existing toxicities of the individual agents, nor induced any new toxicities, and no toxicologically synergistic effects were observed.
No additional mutagenicity, carcinogenicity, and reproductive toxicity studies for Amlodipine/Olmesartan Medoxomil (Normetec) have been conducted based on the well-understood safety profile of the individual compounds.
Clinical Trials: The Randomized Olmesartan And Diabetes Microalbuminuria Prevention (ROADMAP) clinical study included 4447 patients with type 2 diabetes, normoalbuminuria and at least one additional cardiovascular risk factor. Patients were randomized to olmesartan 40 mg daily or placebo. The trial met its primary endpoint, delayed onset of microalbuminuria. For the secondary endpoints, which the study was not designed to formally assess, cardiovascular events occurred in 96 patients (4.3%) with olmesartan and in 94 patients (4.2%) with placebo. The incidence of cardiovascular mortality was higher with olmesartan compared to placebo treatment (15 patients [0.67%] vs. 3 patients [0.14%] [HR=4.94, 95% CI=1.43-17.06]), but the risk of non-fatal myocardial infarction was lower with olmesartan (HR 0.64, 95% CI 0.35, 1.18).