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WESTMINSTER PHA
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69367012103

irbesartan 300 mg tablet (generic avapro)

Generic
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Uses

Hypertension

Irbesartan is used alone or in combination with other classes of antihypertensive agents in the management of hypertension. Angiotensin II receptor antagonists, such as irbesartan, are considered one of several preferred antihypertensive drugs for the initial management of hypertension; other options include angiotensin-converting enzyme (ACE) inhibitors, calcium-channel blockers, and thiazide diuretics. While there may be individual differences with respect to specific outcomes, these antihypertensive drug classes all produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes. Angiotensin II receptor antagonists or ACE inhibitors may be particularly useful in the management of hypertension in patients with certain coexisting conditions such as diabetes mellitus or chronic kidney disease; angiotensin II receptor antagonists also may be preferred, generally as an alternative to ACE inhibitors, in hypertensive patients with heart failure or ischemic heart disease and/or postmyocardial infarction.

Efficacy of irbesartan for the management of hypertension has been established by controlled studies of 8-12 weeks' duration in patients with hypertension of mild to moderate severity in outpatient settings. Clinical studies have shown that the hypotensive effect of usual dosages of irbesartan in patients with mild to moderate hypertension is greater than that of placebo and comparable to that of usual dosages of losartan, enalapril, or atenolol.

Like ACE inhibitors, angiotensin II receptor antagonists such as irbesartan may produce a smaller blood pressure response in hypertensive black patients compared with nonblack patients.

For additional information on the management of hypertension, For information on overall principles and expert recommendations for treatment of hypertension,

Diabetic Nephropathy

Irbesartan is used in the management of diabetic nephropathy manifested by elevated serum creatinine and proteinuria (urinary protein excretion exceeding 300 mg daily) in patients with type 2 diabetes mellitus and hypertension.

Both angiotensin II receptor antagonists and ACE inhibitors have been shown to slow the rate of progression of renal disease in patients with diabetes mellitus and persistent albuminuria, and use of a drug from either class is recommended in such patients with modestly elevated (30-300 mg/24 hours) or higher (exceeding 300 mg/24 hours) levels of urinary albumin excretion. Some evidence suggests that these drugs may slow the progression of nephropathy by a mechanism independent of their antihypertensive effects.

Comparative trials evaluating the efficacy of angiotensin II receptor antagonists and ACE inhibitors for improving renal outcomes in diabetic patients are lacking. Evidence supporting use of ACE inhibitors generally is based on studies in patients with type 1 diabetes mellitus, while evidence supporting use of angiotensin II receptor antagonists generally is based on studies in patients with type 2 diabetes mellitus. Findings from these studies indicate that both drug classes delay progression of increased urinary albumin excretion in patients with diabetes mellitus and may also slow the decline in renal function. Because the available data are consistent, some experts suggest that the effects of both drug classes in improving renal outcomes in patients with diabetes mellitus and proteinuria are likely to be similar.

Drugs that inhibit the renin-angiotensin system (i.e., angiotensin II receptor antagonists, ACE inhibitors) also have been shown to delay the onset of albuminuria in patients with type 2 diabetes mellitus and hypertension who have normal levels of urinary albumin excretion.

Although combined therapy with ACE inhibitors and angiotensin II receptor antagonists appears to have additive effects in reducing albuminuria, such combinations provide no additional cardiovascular benefit and increase the risk of adverse effects (e.g., impaired renal function, hyperkalemia). The usual precautions of angiotensin II receptor antagonist therapy in patients with substantial renal impairment should be observed.

The current labeled indication for irbesartan in hypertensive patients with type 2 diabetes mellitus and nephropathy (indicated by an elevated serum creatinine and proteinuria exceeding 300 mg/day) is based principally on the results of a long-term (mean duration of follow-up: 2.6 years), multicenter, comparative controlled trial, the Irbesartan Diabetic Nephropathy Trial (IDNT). In the IDNT, therapy with irbesartan (dosage titrated from 75 to 300 mg daily) reduced the risk of the primary composite end point, which was defined as a doubling of the baseline serum creatinine concentration, end-stage renal disease (i.e., initiation of dialysis, renal transplantation, or a serum creatinine concentration of at least 6 mg/dL), or death, by 23% compared with amlodipine therapy (dosage titrated from 2.5 to 10 mg daily) and by 20% compared with placebo. Additional antihypertensive agents (diuretics, β-adrenergic blocking agents [β-blockers], peripheral α-adrenergic blocking agents, or central α2-adrenergic agonists) were used as needed in all treatment groups to achieve a trough blood pressure of 135/85 mm Hg or less in the sitting position or 10 mm Hg reduction in systolic blood pressure if higher than 160 mm Hg; ACE inhibitors, other angiotensin II receptor antagonists, and calcium-channel blocking agents could not be used. Most of the delay in time to occurrence of composite clinical events seen with irbesartan-containing therapy was the result of a reduction in the risk of doubling of serum creatinine concentration; irbesartan-containing therapy had no appreciable effect on overall mortality, onset of end-stage renal disease, or secondary composite cardiovascular end point (death from cardiovascular causes, nonfatal myocardial infarction, hospitalization for heart failure, stroke with permanent neurologic deficit, amputation) compared with other treatments. Mean blood pressure achieved with either irbesartan- or amlodipine-containing therapies was similar (142/77 or 142/76 mm Hg, respectively) and lower than that achieved with placebo plus other antihypertensive agents (145/79 mm Hg). Despite therapy with an average of 3 other nonstudy antihypertensive agents per patient in all treatment groups, none of the treatment groups achieved the target blood pressure goal.

Heart Failure

Angiotensin II receptor antagonists have been used in the management of heart failure.

Current guidelines for the management of heart failure in adults generally recommend a combination of drug therapies to reduce morbidity and mortality, including neurohormonal antagonists (e.g., ACE inhibitors, angiotensin II receptor antagonists, angiotensin receptor-neprilysin inhibitors [ARNIs], β-blockers, aldosterone receptor antagonists) that inhibit the detrimental compensatory mechanisms in heart failure. Additional agents (e.g., cardiac glycosides, diuretics, sinoatrial modulators [i.e., ivabradine]) added to a heart failure treatment regimen in selected patients have been associated with symptomatic improvement and/or reduction in heart failure-related hospitalizations. Experts recommend that all asymptomatic patients with reduced left ventricular ejection fraction (LVEF) (American College of Cardiology Foundation [ACCF]/American Heart Association [AHA] stage B heart failure) receive therapy with an ACE inhibitor and β-blocker to prevent symptomatic heart failure and reduce morbidity and mortality. In patients with prior or current symptoms of chronic heart failure with reduced LVEF (ACCF/AHA stage C heart failure), ACCF, AHA, and the Heart Failure Society of America (HFSA) recommend inhibition of the renin-angiotensin-aldosterone (RAA) system with an ACE inhibitor, angiotensin II receptor antagonist, or ARNI in conjunction with a β-blocker, and an aldosterone antagonist in selected patients, to reduce morbidity and mortality. While ACE inhibitors have been the preferred drugs for inhibition of the RAA system because of their established benefits in patients with heart failure and reduced ejection fraction, some evidence indicates that therapy with sacubitril/valsartan, an ARNI, may be more effective than ACE inhibitor therapy (enalapril) in reducing cardiovascular death and heart failure-related hospitalization. ACCF, AHA, and HFSA recommend that patients with chronic symptomatic heart failure and reduced LVEF (New York Heart Association [NYHA] functional class II or III) who are able to tolerate an ACE inhibitor or angiotensin II receptor antagonist be switched to therapy containing an ARNI to further reduce morbidity and mortality. However, in patients in whom an ARNI is not appropriate, continued use of an ACE inhibitor for all classes of heart failure with reduced ejection fraction remains strongly advised. In patients in whom an ARNI or ACE inhibitor is not appropriate, an angiotensin II receptor antagonist may be used. For additional information on the use of angiotensin II receptor antagonists in the management of heart failure, and .

Several clinical trials in patients with heart failure have evaluated the use of angiotensin II receptor antagonists as add-on therapy to conventional regimens compared with an ACE inhibitor, as add-on therapy to conventional regimens including an ACE inhibitor, as combination therapy with an ACE inhibitor compared with therapy with either type of agent alone, or as an alternative therapy in patients intolerant of ACE inhibitors. Data from these and other long-term placebo-controlled clinical trials indicate that angiotensin II receptor antagonists produce hemodynamic and neurohormonal effects associated with their suppression of the renin-angiotensin system; reduced hospitalizations and mortality also have been demonstrated. However, in some studies, these drugs did not show consistent effects on cardiac symptoms or exercise tolerance.

While angiotensin II receptor antagonists are considered reasonable alternatives in patients who are unable to tolerate ACE inhibitors (e.g., because of cough or angioedema), urticaria and angioedema (e.g., swelling of the face, lips, pharynx, and/or tongue) have been reported rarely during postmarketing experience in patients receiving irbesartan.(See Sensitivity Reactions under Cautions: Warnings/Precautions.)

Dosage and Administration

Administration

Irbesartan is administered orally. Since food does not affect the oral bioavailability of irbesartan, the manufacturer states that the drug can be taken without regard to meals.

Dosage

Hypertension

Dosage of irbesartan must be individualized and adjusted according to blood pressure response.

Irbesartan Therapy

The panel members appointed to the Eighth Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8 expert panel) state that evidence-based dosing information (i.e., dosages shown in randomized controlled trials to reduce complications of hypertension) should be used when available to determine target dosages of antihypertensive agents. Based on such information, an initial adult irbesartan dosage of 75 mg once daily and a target dosage of 300 mg once daily are recommended. The manufacturer states that the usual initial dosage of irbesartan in adults is 150 mg once daily in patients without depletion of intravascular volume; in adults with depletion of intravascular volume, the usual initial dosage is 75 mg once daily. If blood pressure response is inadequate with the initial dosage, dosage may be increased as tolerated to 300 mg daily or a diuretic may be added. Increasing irbesartan dosages beyond 300 mg daily or dividing the total daily dosage into 2 doses usually does not result in additional therapeutic effect. Addition of a diuretic generally has a greater effect on blood pressure reduction than dosage increases of irbesartan beyond 300 mg daily. Irbesartan also can be used concomitantly with other antihypertensive agents.

Antihypertensive therapy should be titrated until goal blood pressure is achieved. If an adequate blood pressure response is not achieved with irbesartan monotherapy, another antihypertensive agent with demonstrated benefit may be added; if goal blood pressure is still not achieved with the use of 2 antihypertensive agents at optimal dosages, a third drug may be added. In patients who experience intolerable adverse effects with irbesartan, dosage reduction should be considered; if adverse effects worsen or fail to resolve, it may be necessary to discontinue the angiotensin II receptor antagonist and initiate another class of antihypertensive agent.

Irbesartan/Hydrochlorothiazide Fixed-combination Therapy

In patients who do not respond adequately to monotherapy with irbesartan or, alternatively, with hydrochlorothiazide, combined therapy with the drugs can be used. The manufacturer states that combined therapy with the commercially available fixed-combination preparation containing 150 mg of irbesartan and 12.5 mg of hydrochlorothiazide, 300 mg of irbesartan and 12.5 mg of hydrochlorothiazide, or 300 mg of irbesartan and 25 mg of hydrochlorothiazide (in order of increasing mean effect) can be used in patients whose blood pressure is not adequately controlled by monotherapy with irbesartan or hydrochlorothiazide. The maximum antihypertensive effect is attained about 2-4 weeks after a change in dosage. Dosage of the fixed-combination preparation should not exceed 300 mg of irbesartan and 25 mg of hydrochlorothiazide once daily.

Irbesartan in fixed combination with hydrochlorothiazide also can be used for initial treatment of hypertension in patients who are likely to need multiple drugs to achieve their blood pressure goals. The decision to use irbesartan in fixed combination with hydrochlorothiazide as initial therapy should be based on an assessment of potential benefits and risks. Patients with moderate to severe hypertension are at relatively high risk for cardiovascular events (e.g., stroke, myocardial infarction, heart failure), kidney failure, and vision problems; therefore, prompt treatment is clinically important. The decision to use combination therapy as initial treatment should be individualized taking into account baseline blood pressure, target goal, and incremental likelihood of achieving blood pressure goal with combination therapy compared with monotherapy. In patients receiving fixed-combination tablets as initial therapy, the usual starting dosage is irbesartan 150 mg and hydrochlorothiazide 12.5 mg once daily. Dosage may be increased after 1-2 weeks of therapy to a maximum of irbesartan 300 mg and hydrochlorothiazide 25 mg once daily.

Blood Pressure Monitoring and Treatment Goals

Careful monitoring of blood pressure during initial titration or subsequent upward adjustment in dosage of irbesartan is recommended.

The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure; specific target levels of blood pressure should be individualized based on consideration of multiple factors, including patient age and comorbidities, and the currently available evidence from clinical studies.

For additional information on initiating and adjusting irbesartan dosage in the management of hypertension,

Diabetic Nephropathy

For the management of diabetic nephropathy in patients with type 2 diabetes mellitus, the recommended target maintenance dosage of irbesartan is 300 mg once daily. No data are available on the effects of lower dosages of irbesartan on diabetic nephropathy. In a large clinical trial, approximately 83% of patients had dosage titrated from 75 mg daily initially up to 300 mg daily and maintained that dosage for more than 50% of the study period.

Special Populations

Volume and/or salt depletion should be corrected prior to initiation of therapy or, alternatively, therapy should be initiated using a lower initial dosage (75 mg once daily). Fixed-combination tablets containing irbesartan and hydrochlorothiazide are not recommended as initial therapy in patients with intravascular volume depletion.

The manufacturer states that dosage modification of irbesartan is not necessary for adults with renal impairment; however, irbesartan should be used with caution in patients with renal impairment and depletion of intravascular volume. If concomitant diuretic therapy is required in patients with severe renal impairment (i.e., creatinine clearance less than 30 mL/minute), a loop diuretic is preferred to a thiazide diuretic. Therefore, commercially available preparations containing irbesartan in fixed combination with hydrochlorothiazide usually are not recommended for patients with severe renal impairment. Irbesartan is not removed by hemodialysis.

The manufacturer states that dosage adjustment is not necessary in patients with hepatic impairment.

The manufacturer states that dosage modification of irbesartan because of age in geriatric adults is not necessary. Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and/or drug therapy in geriatric patients, dosage of irbesartan in fixed combination with hydrochlorothiazide should be carefully selected in such patients. The manufacturer recommends that dosage of the fixed combination be initiated at the lower end of the usual range in geriatric patients.

Cautions

Contraindications

Known hypersensitivity to irbesartan or any ingredient in the formulation.

Concomitant use of irbesartan and aliskiren in patients with diabetes mellitus.(See Drug Interactions: Drugs that Block the Renin-Angiotensin System.)

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

Drugs that act directly on the renin-angiotensin system (e.g., angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists) can cause fetal and neonatal morbidity and mortality when used in pregnancy during the second and third trimesters. ACE inhibitors also may increase the risk of major congenital malformations when administered during the first trimester of pregnancy. Irbesartan should be discontinued as soon as possible when pregnancy is detected, unless continued use is considered life-saving. Nearly all women can be transferred successfully to alternative therapy for the remainder of their pregnancy. For additional information on the risk of such drugs during pregnancy, see Cautions: Pregnancy, Fertility, and Lactation, in and .

Sensitivity Reactions

Sensitivity reactions, including various anaphylactoid reactions and/or angioedema, have been reported with use of angiotensin II receptor antagonists, including irbesartan. Irbesartan is not recommended in patients with a history of angioedema associated with or unrelated to ACE inhibitor or angiotensin II receptor antagonist therapy.

Other Warnings and Precautions

Hypotension

Symptomatic hypotension has been reported in patients receiving irbesartan, especially in volume- and/or salt-depleted patients (e.g., those treated with diuretics or undergoing dialysis).(See Dosage and Administration: Special Populations.)

Transient hypotension is not a contraindication to additional doses; therapy may be reinstated cautiously after blood pressure is stabilized (e.g., with volume expansion).

Malignancies

In July 2010, the US Food and Drug Administration (FDA) initiated a safety review of angiotensin II receptor antagonists after a published meta-analysis suggested a possible association between the use of these agents and an increased risk of cancer. The meta-analysis, which combined cancer-related findings from 5 randomized, controlled trials in over 60,000 patients, found a modest but significant increase in the risk of new cancer occurrence in patients receiving an angiotensin II receptor antagonist (mostly telmisartan) compared with those in control groups (7.2 versus 6%, respectively; risk ratio 1.08). However, because of several limitations of the study (e.g., trials included in the meta-analysis were not specifically designed to evaluate cancer outcomes, lack of individual patient data), the validity of these findings has been questioned.

Subsequent studies, including a larger, more comprehensive meta-analysis conducted by FDA, have not shown an increased risk of cancer in patients receiving angiotensin II receptor antagonists. FDA's meta-analysis, which included trial-level data from 31 randomized studies (total of approximately 156,000 patients), found no evidence of an increased risk of cancer in patients who received an angiotensin II receptor antagonist compared with those who received other treatments (placebo or active control). The overall rate of new cancer occurrence was essentially the same in both groups of patients (1.82 and 1.84 cases per 100 patient-years, respectively). In addition, there was no difference in the risk of cancer-related death, breast cancer, lung cancer, or prostate cancer between the groups. Based on these results and a review of all currently available data related to this potential safety concern, FDA has concluded that use of angiotensin II receptor antagonists is not associated with an increased risk of cancer.

Renal Effects

Because the renin-angiotensin-aldosterone (RAA) system appears to contribute substantially to maintenance of glomerular filtration in patients with heart failure in whom renal perfusion is severely compromised, renal function may deteriorate markedly (e.g., oliguria, progressive azotemia, renal failure, death) in these patients during therapy with an ACE inhibitor or an angiotensin II receptor antagonist (e.g., irbesartan). Increases in BUN and serum creatinine may occur in patients with unilateral or bilateral renal artery stenosis.

Fixed-combination Preparations

When hydrochlorothiazide is used in fixed combination with irbesartan, the usual cautions, precautions, and contraindications associated with hydrochlorothiazide must be considered in addition to those associated with irbesartan.

Specific Populations

Pregnancy

Category D.

Irbesartan can cause fetal and neonatal morbidity and mortality when administered to a pregnant woman. Irbesartan should be discontinued as soon as possible when pregnancy is detected.(See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Warnings, in Cautions.)

Lactation

Irbesartan is distributed into milk in rats; it is not known whether the drug is distributed into human milk. Because of the potential risk in nursing infants, a decision should be made whether to discontinue nursing or the drug.

Pediatric Use

Administration of irbesartan in dosages of up to 4.5 mg/kg once daily did not appear to effectively lower blood pressure in pediatric patients 6-16 years of age. Safety and efficacy of irbesartan in children younger than 6 years of age have not been established.

Safety and efficacy of the fixed-combination preparation containing irbesartan and hydrochlorothiazide in pediatric patients have not been established.

For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients,

Geriatric Use

No substantial differences in safety or efficacy of irbesartan monotherapy or fixed-combination irbesartan/hydrochlorothiazide tablets have been observed in geriatric patients relative to younger adults, but increased sensitivity cannot be ruled out.

Renal Impairment

Irbesartan should be used with caution in patients with renal impairment.

Deterioration of renal function may occur in patients receiving irbesartan.

Use of irbesartan in fixed combination with hydrochlorothiazide is not recommended in patients with severe renal impairment.

Black Patients

Blood pressure reduction may be smaller in black patients compared with nonblack patients; clinicians should consider using irbesartan in combination with a diuretic or calcium-channel blocker.

Common Adverse Effects

Adverse effects occurring in at least 1% of patients with hypertension receiving irbesartan and at a higher incidence than with placebo include diarrhea, dyspepsia/heartburn, and fatigue. In patients receiving irbesartan for the treatment of diabetic nephropathy, dizziness, orthostatic dizziness, and orthostatic hypotension occurred with an incidence of at least 5% and were reported more frequently than in those receiving placebo.

Drug Interactions

Drugs Affecting Hepatic Microsomal Enzymes

Metabolized principally by cytochrome P-450 (CYP) 2C9 isoenzyme. Does not substantially induce or inhibit CYP1A1, 1A2, 2A6, 2B6, 2D6, 2E1, or 3A4. Potential pharmacokinetic interaction (decreased irbesartan metabolism) with CYP2C9 inhibitors.

Drugs that Block the Renin-Angiotensin System

Increased risk of renal impairment, hyperkalemia, and hypotension with concomitant use of other drugs that block the renin-angiotensin system (e.g., angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, aliskiren); when irbesartan is used concomitantly with such drugs, blood pressure, renal function, and serum electrolyte concentrations should be monitored closely.(See Drug Interactions: Aliskiren.)

Aliskiren

Concomitant use of irbesartan and aliskiren is contraindicated in patients with diabetes mellitus; in addition, such concomitant use should be avoided in patients with renal impairment (glomerular filtration rate [GFR] less than 60 mL/minute).

Digoxin

Pharmacologic and/or pharmacokinetic interactions unlikely when irbesartan is used concomitantly with digoxin.

Hydrochlorothiazide

Pharmacokinetic interactions unlikely when irbesartan is used concomitantly with hydrochlorothiazide.

Additive hypotensive effects expected when irbesartan is used concomitantly with hydrochlorothiazide.

Lithium

Lithium excretion may be reduced. Serum lithium concentrations should be carefully monitored.

Nifedipine

Decreased irbesartan metabolism in vitro observed with nifedipine; alteration of irbesartan pharmacokinetics not observed in vivo when irbesartan is used concomitantly with nifedipine.

Nonsteroidal Anti-inflammatory Agents

Potential pharmacologic interaction (attenuated hypotensive effects) when angiotensin II receptor antagonists are used concomitantly with nonsteroidal anti-inflammatory agents (NSAIAs), including selective cyclooxygenase-2 (COX-2) inhibitors.

Possible deterioration of renal function in elderly, volume-depleted (including those receiving concomitant diuretic therapy), or renally impaired patients; renal function should be monitored periodically in patients receiving concomitant therapy with irbesartan and an NSAIA, including selective COX-2 inhibitors.

Tolbutamide

Possible decreased irbesartan metabolism when irbesartan is used concomitantly with tolbutamide.

Warfarin

Pharmacologic and/or pharmacokinetic interaction unlikely when irbesartan is used concomitantly with warfarin.

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