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Mechanism of Action

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MOA - BENICAR and BENICAR HCT at a glance

BENICAR and BENICAR HCT

BENICAR blocks the vasoconstrictor effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in vascular smooth muscle. Angiotensin II is a potent vasoconstrictor that increases blood pressure in the body.7

BENICAR HCT is a combination of BENICAR and HCTZ that works by blocking angiotensin II receptors in the blood vessels and increasing excretion of sodium and chloride in approximately equivalent amounts, resulting in lower systolic and diastolic blood pressure.8

Angiotensin II increases blood pressure by causing the constriction of blood vessels, while sodium and chloride reabsorption causes retention of water, increase in blood volume, and, ultimately, an increase in blood pressure. Therefore, BENICAR HCT reduces blood pressure by 2 complementary methods of action.8


MOA - BENICAR pharmacodynamics

BENICAR pharmacodynamics

Benicar Mechanism of Action
Benicar Mechanism of Action
Benicar Mechanism of Action
  • BENICAR 40 mg inhibited 74% of the BP-raising effect of angiotensin II at the 24th hour2

No information on effect of larger doses of valsartan was available. Pressor inhibition with losartan potassium was between 25% and 40%. Pressor inhibition refers to the blockade or interruption of any BP-raising mechanism in the body, including blockade of angiotensin II. Angiotensin II is a major contributor to vasoconstriction, which is a principal component of hypertension.

Clinical significance of pharmacodynamic data is unknown. These data are not based on head-to-head studies.

MOA - BENICAR pharmacokinetics

BENICAR pharmacokinetics

Benicar Pharmacokinetics

Clinical significance of pharmacokinetic data is unknown. These data are not based on head-to-head studies.

Benicar Pharmacokinetics

Clinical significance of pharmacokinetic data is unknown. These data are not based on head-to-head studies.

Benicar Pharmacokinetics
Benicar Pharmacokinetics
Benicar Pharmacokinetics

Clinical significance of pharmacokinetic data is unknown. These data are not based on head-to-head studies.

MOA - How BENICAR works

How BENICAR works

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. Two subtypes make up the angiotensin II receptor: AT1 and AT2. 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.7

An AT2 receptor is also found 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.7

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 medoxomil does not inhibit ACE, it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known.7

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.7


MOA - How BENICAR HCT works

How BENICAR HCT works

Along with the active ingredient in BENICAR, olmesartan medoxomil, BENICAR HCT also contains hydrochlorothiazide, 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.8

The mechanism of the antihypertensive effect of thiazides is not fully understood.8

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4 Prod - Important Safety Information

INDICATIONS:

BENICAR (olmesartan medoxomil), BENICAR HCT (olmesartan medoxomil-hydrochlorothiazide), AZOR (amlodipine and olmesartan medoxomil), and TRIBENZOR (olmesartan medoxomil, amlodipine, hydrochlorothiazide) are indicated for the treatment of hypertension to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including the class to which these drugs principally belong. There are no controlled trials demonstrating risk reduction with BENICAR, BENICAR HCT, AZOR, or TRIBENZOR.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals.

BENICAR, BENICAR HCT, AZOR, and TRIBENZOR can be used alone or with other antihypertensive agents.

AZOR is indicated as initial therapy in patients likely to need multiple antihypertensive agents to achieve their blood pressure goals.

Initial therapy with AZOR is not recommended in patients ≥75 years of age or in hepatically impaired patients.

BENICAR HCT and TRIBENZOR are not indicated for the initial therapy of hypertension.

Important Safety Information for BENICAR®, BENICAR HCT®, AZOR®, and TRIBENZOR®

WARNING: FETAL TOXICITY

  • When pregnancy is detected, discontinue BENICAR, BENICAR HCT, AZOR, or TRIBENZOR as soon as possible
  • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. See WARNINGS AND PRECAUTIONS: Fetal Toxicity

CONTRAINDICATIONS

Do not co-administer aliskiren with BENICAR, BENICAR HCT, AZOR, or TRIBENZOR in patients with diabetes.

BENICAR HCT and TRIBENZOR are contraindicated in patients with anuria. BENICAR HCT is contraindicated in patients with hypersensitivity to any component of BENICAR HCT. TRIBENZOR is contraindicated in patients with hypersensitivity to other sulfonamide-derived drugs.

WARNINGS AND PRECAUTIONS

Morbidity in Infants: Children <1 year of age must not receive BENICAR for hypertension. Safety and effectiveness of AZOR, BENICAR HCT or TRIBENZOR have not been established in pediatric patients.

Fetal Toxicity: BENICAR, BENICAR HCT, AZOR, and TRIBENZOR are Pregnancy Category D.

Hypotension in Volume- or Salt-Depleted Patients: In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (eg, those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of treatment with BENICAR, BENICAR HCT, AZOR, or TRIBENZOR.

Impaired Renal Function:

Patients whose renal function may depend in part upon the activity of the renin-angiotensin-aldosterone system (eg. patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion), may be at particular risk of developing acute renal failure on BENICAR, BENICAR HCT, AZOR and TRIBENZOR. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on BENICAR, BENICAR HCT, AZOR and TRIBENZOR.

Safety and effectiveness of BENICAR HCT in patients with severe renal impairment (CrCl ≤ 30 mL/min) have not been established. Avoid use of TRIBENZOR in patients with severely impaired renal function (creatinine clearance ≤30 mL/min). If progressive renal impairment becomes evident, consider withholding or discontinuing TRIBENZOR.

Sprue-like Enteropathy: Severe, chronic diarrhea with substantial weight loss has been reported in patients taking olmesartan months to years after drug initiation. Intestinal biopsies of patients often demonstrated villous atrophy. If a patient develops these symptoms during treatment with olmesartan, exclude other etiologies. Consider discontinuation of BENICAR, BENICAR HCT, AZOR, or TRIBENZOR in cases where no other etiology is identified.

Hepatic Impairment: Initial therapy with AZOR or TRIBENZOR is not recommended in hepatically impaired patients. In patients with severe hepatic impairment, exercise caution with AZOR and avoid use of TRIBENZOR. Thiazides (a component in BENICAR HCT and TRIBENZOR) may cause minor alterations of fluid and electrolyte balance that may precipitate hepatic coma in patients with impaired hepatic function or progressive liver disease.

Electrolyte and Metabolic Imbalances: BENICAR HCT and TRIBENZOR contain hydrochlorothiazide which can cause hypokalemia and hyponatremia. Hypomagnesemia can result in hypokalemia which may be difficult to treat despite potassium repletion. BENICAR, BENICAR HCT, AZOR and TRIBENZOR also contain olmesartan, a drug that inhibits the renin-angiotensin system (RAS). Drugs that inhibit the RAS can cause hyperkalemia. Monitor serum electrolytes periodically.

Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides.

Hypersensitivity Reaction: Hypersensitivity reactions to HCTZ (a component in BENICAR HCT and TRIBENZOR) may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history.

Systemic Lupus Erythematosus: Thiazides (a component in BENICAR HCT and TRIBENZOR) have been reported to cause exacerbation or activation of systemic lupus erythematosus.

Acute Myopia and Secondary Angle-Closure Glaucoma: Thiazides can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Discontinue HCTZ (a component in BENICAR HCT and TRIBENZOR) as rapidly as possible in these patients.

Vasodilation: Although vasodilation attributable to amlodipine (a component in AZOR and TRIBENZOR) is gradual in onset, acute hypotension has rarely been reported after oral administration. Patients with severe aortic stenosis may be at particular risk.

Increased Angina and/or Myocardial Infarction: Patients taking AZOR or TRIBENZOR, particularly those with severe obstructive coronary artery disease, may develop increased frequency, duration, or severity of angina or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dose increase.

Laboratory Tests: There was a greater decrease in hemoglobin and hematocrit with AZOR compared to either component alone. Other lab abnormalities may include increased blood creatinine levels and hyperkalemia (olmesartan medoxomil), hepatic enzyme elevations (amlodipine), and increased cholesterol and triglyceride levels (HCTZ).

DRUG INTERACTIONS

Non-Steroidal Anti-Inflammatory Agents: Concurrent administration of non-steroidal anti-inflammatory drugs (NSAIDs) may lead to increased risk of renal impairment (including possible acute renal failure) and loss of antihypertensive effect of BENICAR, BENICAR HCT, AZOR, and TRIBENZOR.

Dual Blockade of the Renin-Angiotensin System (RAS): Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function, and electrolytes in patients on BENICAR, BENICAR HCT, AZOR, or TRIBENZOR and other agents that affect the RAS.

Do not co-administer aliskiren with BENICAR, BENICAR HCT, AZOR, or TRIBENZOR in patients with diabetes. Avoid use of aliskiren with BENICAR, BENICAR HCT, AZOR, or TRIBENZOR in patients with renal impairment (GFR <60 mL/min).

Concurrent Use with Colesevelam Hydrochloride: Concurrent administration of colesevelam hydrochloride with BENICAR, BENICAR HCT, AZOR, or TRIBENZOR reduces the systemic exposure and peak plasma concentration of olmesartan. Consider administering olmesartan at least 4 hours before the colesevelam hydrochloride dose.

Effect of Amlodipine on Simvastatin: Due to increased exposure to simvastatin, when co-administered with amlodipine (a component in AZOR and TRIBENZOR), do not exceed doses of greater than 20 mg daily of simvastatin.

Lithium: Increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of olmesartan or thiazide diuretics. Monitor lithium levels in patients receiving BENICAR, BENICAR HCT, AZOR, or TRIBENZOR and lithium.

Antidiabetic drugs: Dosage adjustment of the antidiabetic drug may be required due to hydrochlorothiazide (a component of BENICAR HCT and TRIBENZOR).

Cholestyramine and colestipol: Reduced absorption of thiazides. Consider administering BENICAR HCT 4 hours before or 4-6 hours after the administration of the resin.

Corticosteroids, ACTH: Intensified electrolyte depletion, particularly hypokalemia due to hydrochlorothiazide (a component of BENICAR HCT and TRIBENZOR).

ADVERSE REACTIONS

BENICAR: The only adverse reaction that occurred in >1% of patients treated with BENICAR and more frequently than placebo was dizziness (3% vs 1%).

BENICAR HCT: Adverse reactions reported in >2% of patients taking BENICAR HCT and more frequently than placebo included nausea (3% vs 0%), hyperuricemia (4% vs 2%), dizziness (9% vs 2%), and upper respiratory tract infection (7% vs 0%).

AZOR: The most common adverse reaction (incidence ≥3%) in patients treated with AZOR was edema.

TRIBENZOR: The most frequently reported adverse reaction was dizziness (5.8% to 8.9%). The other most frequent adverse reactions occurring in ≥2% of patients treated with TRIBENZOR were peripheral edema (7.7%), headache (6.4%), fatigue (4.2%), nasopharyngitis (3.5%), muscle spasms (3.1%), nausea (3.0%), upper respiratory tract infection (2.8%), diarrhea (2.6%), urinary tract infection (2.4%), and joint swelling (2.1%).

USE IN SPECIFIC PATIENT POPULATIONS

Nursing Mothers: Avoid use while nursing; discontinue either nursing or the drug.

Please see Full Prescribing Information for BENICARBENICAR HCTAZOR, and TRIBENZOR.

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