Hydrochlorothiazide 12.5 mg, Olmesartan 20 mg Tablets

Olmesartan medoxomil — 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 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 angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity (PRA) and circulating angiotensin II levels do not overcome the effect of olmesartan on 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.

Absorption — Olmesartan : Olmesartan medoxomil is completely bioactivated by ester hydrolysis to olmesartan during absorption from the gastrointestinal tract. The absolute bioavailability of olmesartan is approximately 26%. After oral administration, the peak plasma concentration (C max) of olmesartan is reached after 1 to 2 hours. Food does not affect the bioavailability of olmesartan.

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.

Hydrochlorothiazide: The estimated absolute bioavailability of hydrochlorothiazide after oral administration is about 70%. Peak plasma hydrochlorothiazide concentrations (C max) are reached within 2 to 5 hours after oral administration. There is no clinically significant effect of food on the bioavailability of hydrochlorothiazide.

The pharmacokinetics of hydrochlorothiazide is dose proportional in the range of 12.5 to 75 mg.

Distribution — Olmesartan : 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.

Hydrochlorothiazide : Hydrochlorothiazide binds to albumin (40 to 70%) and distributes into erythrocytes. Following oral administration, plasma hydrochlorothiazide concentrations decline bi-exponentially, with a mean distribution half-life of about 2 hours and an elimination half-life of about 10 hours.

Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.

Metabolism — Olmesartan : Olmesartan does not undergo further metabolism.

Hydrochlorothiazide : Hydrochlorothiazide is not metabolized.

Elimination — Olmesartan: Olmesartan appears to be eliminated in a biphasic manner with a terminal elimination half-life of approximately 13 hours. 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.

Hydrochlorothiazide : About 70% of an orally administered dose of hydrochlorothiazide is eliminated in the urine as unchanged drug.

Olmesartan medoxomil — Pediatric Patients:The pharmacokinetics of olmesartan were studied in pediatric hypertensive patients aged 1 to16 years. The clearance of olmesartan in pediatric patients was similar to that in adult patients when adjusted by the body weight. Olmesartan pharmacokinetics have not been investigated in pediatric patients less than 1 year of age.

Geriatric Patients: The pharmacokinetics of olmesartan 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; AUC ss, τwas 33% higher in elderly patients, corresponding to an approximate 30% reduction in CL R.

Male and Female Patients:Minor differences were observed in the pharmacokinetics of olmesartan in women compared to men. AUC and C maxwere 10-15% higher in women than in men.

Patients with Renal Impairment: 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 in patients undergoing hemodialysis has not been studied.

Patients with Hepatic Impairment: Increases in AUC 0-∞and C maxfor olmesartan were observed in patients with moderate hepatic impairment compared to those in matched controls, with an increase in AUC of about 60%.