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INDICATIONS:

BENICAR, AZOR, and TRIBENZOR 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, 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 HCT is indicated for the treatment of hypertension. BENICAR HCT is not indicated for initial therapy.

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.

TRIBENZOR is not indicated for the initial therapy of hypertension.

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

Please see the following Important Safety Information for BENICAR:

Morbidity in Infants

Children <1 year of age must not receive BENICAR for hypertension. Drugs that act directly on the renin-angiotensin-aldosterone system (RAAS) can have effects on the development of immature kidneys.

Please see the following Important Safety Information for BENICAR, BENICAR HCT, AZOR, and TRIBENZOR:

Contraindication

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

Fetal Toxicity
Pregnancy Category D

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue BENICAR, BENICAR HCT, AZOR, or TRIBENZOR as soon as possible.

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. Treatment should start under close medical supervision.

Impaired Renal Function

In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen (BUN) have been reported. There has been no long-term use of olmesartan medoxomil in patients with unilateral or bilateral renal artery stenosis, but similar results may be expected.

Non-Steroidal Anti-Inflammatory Agents

In patients who are elderly, volume-depleted (including those on diuretics), or with compromised renal function, co-administration of olmesartan medoxomil and NSAIDs, including COX-2 inhibitors, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in these patients. The antihypertensive effect of olmesartan medoxomil may be attenuated by NSAIDs, including COX-2 inhibitors.

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. Closely monitor blood pressure, renal function and electrolytes in patients on BENICAR, BENICAR HCT, AZOR, or TRIBENZOR and other agents that affect the RAS.

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 bile acid sequestering agent colesevelam hydrochloride reduces the systemic exposure and peak plasma concentration of olmesartan. Consider administering olmesartan at least 4 hours before the colesevelam hydrochloride dose.

Nursing Mothers

Avoid use while nursing; discontinue either nursing or the drug.

Due to the hydrochlorothiazide component, BENICAR HCT and TRIBENZOR have the following Important Safety Information:

Contraindications

BENICAR HCT and TRIBENZOR are contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.

Fetal/Neonatal Morbidity and Mortality

Thiazides cross the placental barrier and appear in cord blood. There is a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.

Impaired Renal Function

BENICAR HCT is not recommended in patients with severe renal impairment. 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.

Thiazides may precipitate azotemia in patients with renal disease. Cumulative effects of the drug may develop in patients with impaired renal function.

Hepatic Impairment

Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. Avoid use of TRIBENZOR in patients with severely impaired hepatic function.

Electrolyte and Metabolic Imbalances

Due to the hydrochlorothiazide component, observe patients for clinical signs of fluid or electrolyte imbalance.

Hypersensitivity Reaction

Hypersensitivity reactions to hydrochlorothiazide 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

Thiazide diuretics 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. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Discontinue hydrochlorothiazide as rapidly as possible in these patients. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Lithium Interaction

Lithium generally should not be given with thiazides.

Due to the amlodipine component, AZOR and TRIBENZOR have the following Important Safety Information:

Vasodilation

Although vasodilation attributable to amlodipine 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, 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 dosage increase.

Hepatic Impairment

Since amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t_1/2) is 56 hours in patients with severely impaired hepatic function, caution should be exercised when administering AZOR to patients with severe hepatic impairment. Initial therapy with AZOR is not recommended in hepatically impaired patients. Avoid use of TRIBENZOR in patients with severely impaired hepatic function.

Effect of Amlodipine on Simvastatin

Due to increased exposure to simvastatin, if simvastatin is co-administered with amlodipine, do not exceed doses of greater than 20 mg daily of simvastatin.

Geriatric Use

Elderly patients have decreased clearance of amlodipine. Initial therapy with AZOR is not recommended in patients ≥75 years old.

Adverse Reactions

BENICAR/BENICAR HCT

The withdrawal rates due to adverse reactions were similar with BENICAR and BENICAR HCT to placebo: BENICAR (2.4% vs 2.7%); BENICAR HCT (2.0% vs 2.0%).

The incidence of adverse reactions with BENICAR and BENICAR HCT was similar to placebo.

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

– 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 only adverse reaction that occurred in greater than or equal to 3% of patients treated with AZOR and more frequently than placebo was edema. The placebo-subtracted incidence was 5.7% (5/20 mg), 6.2% (5/40 mg), 13.3% (10/20 mg), and 11.2% (10/40 mg). The edema incidence for placebo was 12.3%.

Adverse reactions seen at lower rates but at about the same or greater incidence as in patients receiving placebo included hypotension, orthostatic hypotension, rash, pruritus, palpitation, urinary frequency, and nocturia.

In individual clinical trials of amlodipine and olmesartan medoxomil, other commonly reported adverse reactions included headache, dizziness, and flushing.

TRIBENZOR

The most frequently reported adverse reaction was dizziness (5.8 to 8.9%). The other most frequent adverse reactions occurring in greater than or equal to 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%).

Laboratory Tests

There was a greater decrease in hemoglobin and hematocrit with AZOR compared to either component alone.

Dosage and Administration

No initial dosage adjustments are recommended with BENICAR in elderly or in moderate to marked renal impairment (creatinine clearance <40 mL/min)/hepatic dysfunction.

– In patients with possible depletion of intravascular volume (eg, patients on diuretics, particularly with impaired renal function), BENICAR should be initiated under close medical supervision and consideration given to use of a lower starting dose

BENICAR HCT is not indicated for initial therapy. Dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range.

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

TRIBENZOR is not indicated for initial therapy. Avoid use of TRIBENZOR in patients with severely impaired hepatic function and in patients with severely impaired renal function (creatinine clearance ≤30 mL/min).

Please see Full Prescribing Information for BENICAR, BENICAR HCT, AZOR, and TRIBENZOR.