Amlodipine 10 mg, Hydrochlorothiazide 25 mg, Olmesartan 40 mg Tablets

The active ingredients of olmesartan medoxomil, amlodipine and hydrochlorothiazide 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 AT 1receptor in vascular smooth muscle. Its action is, therefore, independent of the pathways for angiotensin II synthesis.

An AT 2receptor 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 AT 1receptor than for the AT 2receptor.

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.

Olmesartan medoxomil, amlodipine and hydrochlorothiazide.After oral administration of olmesartan medoxomil, amlodipine, and hydrochlorothiazide 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 olmesartan medoxomil, amlodipine, and hydrochlorothiazide are the same as when administered as individual dosage forms. Food does not affect the bioavailability of olmesartan medoxomil, amlodipine and hydrochlorothiazide.

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 C maxof 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 90%.

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.

Distribution — 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 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.

Amlodipine. Ex vivostudies 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 once-daily dosing.

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.

Geriatric Patients — 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; AUCѕѕ, τ was 33% higher in elderly patients, corresponding to an approximate 30% reduction in CL R.

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.

Male and Female Patients — 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 patients.