General Information

Benicar (olmesartan medoxomil) is an angiotensin II receptor blocker (ARB). Benicar HCT includes hydrochlorothiazide, a thiazide diuretic.

Benicar is specifically indicated for the treatment of hypertension in adult and pediatric patients six years of age and older, alone or with other antihypertensive agents, to lower blood pressure.

Benicar HCT is specifically indicated for the treatment of hypertension, to lower blood pressure in adults.

Benicar and Benicar HCT are both supplied as tablets for oral administration. The recommended dosing is as follows:

Benicar

Benicar HCT

The recommended starting dose of Benicar HCT is 40/12.5 mg once daily in patients whose blood pressure is not adequately controlled with olmesartan monotherapy. Dose can be titrated up to 40 /25 mg if necessary. The recommended starting dose of Benicar HCT is 20/12.5 mg once daily in patients whose blood pressure is not adequately controlled with HCT monotherapy or who experience dose limiting adverse reactions with hydrochlorothiazide. Dose can be titrated up to 40 /25 mg if necessary. Patients titrated to the individual components (olmesartan and hydrochlorothiazide) may instead receive the corresponding dose of Benicar HCT.

Mechanism of Action

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 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 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.

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.

Side Effects

Adverse effects associated with the use of Benicar and Benicar HCT may include, but are not limited to, the following:

• nausea
• hyperuricemia
• dizziness
• upper respiratory infection

Clinical Trial Results

Approval of Benicar is supported by 7 placebo-controlled studies, with doses ranging from 2.5 to 80 mg, given for six to 12 weeks. The trials included more than 3275 subjects with essential hypertension. All seven studies reported significant reductions in peak and trough levels of diastolic and systolic blood pressure. Response was dose-related, with 20 mg and 40 mg doses inducing the desired effect and doses over 40 mg having little additional effect. The blood pressure lowering effect from using Benicar once-daily was maintained throughout the 24 hour period, with trough-to-peak ratios for systolic and diastolic response between 60 and 80%.

Approval of Benicar HCT:  In clinical trials 1230 patients were exposed to the combination of olmesartan medoxomil (2.5 mg to 40 mg) and hydrochlorothiazide (12.5 mg to 25 mg). These trials included one placebo controlled factorial trial in mild-moderate hypertensive patients (n=502) with combinations of olmesartan medoxomil (10 mg, 20 mg, 40 mg, or placebo) and hydrochlorothiazide (12.5 mg, 25 mg, or placebo). The antihypertensive effect of the combination on trough blood pressure was related to the dose of each component. Once-daily dosing with 20 mg olmesartan medoxomil and 12.5 mg hydrochlorothiazide, 40 mg olmesartan medoxomil and 12.5 mg hydrochlorothiazide or 40 mg olmesartan medoxomil and 25 mg hydrochlorothiazide produced mean placebo-adjusted blood pressure reductions at trough (24 hours post-dosing) ranging from 17/8 to 24/14 mm Hg. The antihypertensive effect had onset within 1 week and was near maximal at 4 weeks.