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Uses

Hypertension

Valsartan is used alone or in combination with other classes of antihypertensive agents (e.g., thiazide diuretics) in the management of hypertension. Efficacy of valsartan 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. The efficacy of valsartan for long-term use (i.e., exceeding 12 weeks) has been established in noncontrolled, follow-up studies in which the drug was used for up to 2 years without apparent loss of clinical effect. Clinical studies have shown that the hypotensive effect of usual dosages of valsartan in patients with mild to moderate hypertension is greater than that of placebo and comparable to that of usual dosages of amlodipine, enalapril, lisinopril, or hydrochlorothiazide.

Current evidence-based practice guidelines for the management of hypertension in adults generally recommend the use of 4 classes of antihypertensive agents (angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics); data from clinical outcome trials indicate that lowering blood pressure with any of these drug classes can reduce the complications of hypertension and provide similar cardiovascular protection. However, recommendations for initial drug selection and use in specific patient populations may vary across these expert guidelines. Ultimately, choice of antihypertensive therapy should be individualized, considering the clinical characteristics of the patient (e.g., age, ethnicity/race, comorbid conditions, cardiovascular risk factors) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, costs). Because many patients eventually will need drugs from 2 or more antihypertensive classes, experts generally state that the emphasis should be placed on achieving appropriate blood pressure control rather than on identifying a preferred drug to achieve that control.

Considerations in Initiating Antihypertensive Therapy

Drug therapy generally is reserved for patients who respond inadequately to nondrug therapy (i.e., lifestyle modifications such as diet [including sodium restriction and adequate potassium and calcium intake], regular aerobic physical activity, moderation of alcohol consumption, and weight reduction) or in whom the degree of blood pressure elevation or coexisting risk factors requires more prompt or aggressive therapy; however, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial.

While the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommended antihypertensive drug therapy in all patients with systolic/diastolic blood pressure of 140/90 mm Hg or higher who fail to respond to lifestyle/behavioral modifications, other experts, including the panel members appointed to the Eighth Joint National Committee (JNC 8 expert panel) recommend a higher systolic blood pressure threshold for older individuals (e.g., the JNC 8 expert panel recommends a threshold of 150 mm Hg for patients 60 years of age or older).

In addition, there is some variation in the blood pressure thresholds and treatment goals recommended for patients with diabetes mellitus or chronic kidney disease. In the past, initial antihypertensive drug therapy was recommended for patients with diabetes mellitus or chronic kidney disease who had blood pressures of 130/80 mm Hg or higher; however, current hypertension management guidelines generally recommend the same blood pressure threshold of 140/90 mm Hg for initiating antihypertensive drug therapy in these individuals as for the general population of patients without these conditions, although a lower goal (e.g., less than 130/80 mm Hg) may still be considered.

Further study is needed to more clearly define optimum blood pressure goals in patients with hypertension; when determining appropriate blood pressure goals, individual risks and benefits should be considered in addition to the evidence from clinical studies. For additional details,

Antihypertensive drug therapy generally should be initiated gradually and titrated at intervals of approximately 2-4 weeks to achieve the target blood pressure. The goal is to reduce blood pressure to levels below the threshold used for initiating drug therapy. Addition of a second drug should be initiated when use of monotherapy in adequate dosages fails to achieve goal blood pressure. Some experts state that initial antihypertensive therapy with a combination of drugs may be considered in patients with systolic/diastolic blood pressure greater than 20/10 mm Hg above goal blood pressure. Such combined therapy may increase the likelihood of achieving goal blood pressure in a more timely fashion, but also may increase the risk of adverse effects (e.g., orthostatic hypotension) in some patients (e.g., elderly). Initial combined therapy may be particularly useful in patients with markedly high baseline blood pressures and those with additional risk factors.

Initial Drug Therapy

In current hypertension management guidelines, angiotensin II receptor antagonists are recommended as one of several preferred drugs for the initial treatment of hypertension; other options include 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.(See Antihypertensive Therapy for Patients with Underlying Cardiovascular or Other Risk Factors under Uses: Hypertension.)

Follow-up and Maintenance Therapy

Several strategies are recommended for the titration and combination of antihypertensive drugs; these strategies include maximizing the dosage of the first drug before adding a second drug, adding a second drug before achieving maximum dosage of the initial drug, or initiating therapy with 2 drugs simultaneously (either as separate preparations or as a fixed-dose combination). In patients who fail to respond adequately to initial monotherapy with an angiotensin II receptor antagonist, the JNC 8 expert panel states that a thiazide diuretic or a calcium-channel blocker may be added. If goal blood pressure is not achieved with optimal dosages of these 2 drugs, a third antihypertensive agent from one of the recommended drug classes may be added; if more than 3 drugs are required, other antihypertensive agents (e.g., β-adrenergic blocking agents (β-blockers), aldosterone antagonists, centrally acting agents) may be considered. Combined use of an ACE inhibitor and angiotensin II receptor antagonist should be avoided because of the potential risk of adverse renal effects. If the blood pressure goal cannot be achieved using the above recommended strategies, consultation with a hypertension specialist should be considered.

Antihypertensive Therapy for Patients with Underlying Cardiovascular or Other Risk Factors

Drug therapy in patients with hypertension and underlying cardiovascular or other risk factors should be carefully individualized based on the underlying disease(s), concomitant drugs, tolerance to drug-induced adverse effects, and blood pressure goal.

Ischemic Heart Disease

The selection of an appropriate antihypertensive agent in patients with ischemic heart disease should be based on individual patient characteristics. Many experts recommend the use of an ACE inhibitor (or an angiotensin II receptor antagonist if ACE inhibitors are not tolerated) and/or a β-blocker in hypertensive patients with stable ischemic heart disease because of the cardioprotective benefits of these drugs; all patients who have survived a myocardial infarction should be treated with a β-blocker because of the demonstrated mortality benefit of these agents. Other antihypertensive drugs such as calcium-channel blockers or thiazide diuretics may be added to the regimen as necessary to achieve blood pressure goals.

Heart Failure

While available evidence suggests that angiotensin II receptor antagonists as single therapies are not superior to other antihypertensive agents in the reduction of cardiovascular outcomes, angiotensin II receptor antagonists, usually in conjunction with other agents such as cardiac glycosides, diuretics, and β-blockers, have been shown to reduce morbidity and mortality in patients with existing heart failure. Because of the established benefits of ACE inhibitors in patients with heart failure, the American College of Cardiology Foundation (ACCF), American Heart Association (AHA), and Heart Failure Society of America (HFSA) recommend the use of these drugs in all patients with symptomatic or asymptomatic (i.e., structural heart disease but no signs or symptoms) heart failure with reduced left ventricular ejection fraction (LVEF). Experts recommend an angiotensin II receptor antagonist as an alternative to therapy with an ACE inhibitor in patients with symptomatic or asymptomatic (i.e., structural heart disease but no signs or symptoms) heart failure with reduced LVEF.(See Uses: Heart Failure.)

Diabetes Mellitus

Angiotensin II receptor antagonists, ACE inhibitors, calcium-channel blockers, and thiazide diuretics have all been recommended for initial antihypertensive therapy in patients with diabetes mellitus, although certain agents may be preferred. Results of several studies indicate that adequate control of blood pressure in patients with type 2 diabetes mellitus reduces the development or progression of complications of diabetes (e.g., death related to diabetes, stroke, heart failure, microvascular disease). Angiotensin II receptor antagonists have been shown to retard the progression of albuminuria and the development and progression of nephropathy in patients with diabetes mellitus; in addition, there is some evidence suggesting that the drugs may also provide cardioprotective benefits. According to the American Diabetes Association (ADA), drugs that inhibit the renin-angiotensin system (i.e., angiotensin II receptor antagonists, ACE inhibitors) may have advantages with respect to cardiovascular outcomes when used for initial or early treatment of hypertension in diabetic patients, and should therefore be included in the antihypertensive regimen of such patients; the renoprotective effect of these drugs provides another compelling reason for their use in diabetic patients who may have albuminuria or renal insufficiency.(See Uses: Diabetic Nephropathy.) If additional blood pressure control is required, a calcium-channel blocker or thiazide diuretic may be added. Because angiotensin II receptor antagonists and ACE inhibitors tend not to be as effective in black patients, some experts recommend a thiazide diuretic or a calcium-channel blocker as the initial antihypertensive drug of choice in black patients with diabetes.(See Race under Hypertension: Other Special Considerations for Antihypertensive Therapy, in Uses.)

Chronic Kidney Disease

Hypertensive patients with chronic kidney disease (glomerular filtration rate [GFR] less than 60 mL/minute per 1.73 m or kidney damage for 3 or more months) usually will require more than one antihypertensive agent to reach target blood pressure. Use of angiotensin II receptor antagonists or ACE inhibitors is recommended in patients with diabetic or nondiabetic chronic kidney disease; these drugs have been shown to slow the progression of kidney disease, but evidence of a cardiovascular benefit is not as clear. Evidence of a renoprotective benefit is strongest in those with higher levels of albuminuria. Although angiotensin II receptor antagonists and ACE inhibitors generally are not recommended as the drugs of first choice for initial antihypertensive therapy in black patients, some experts suggest that these drugs be used for their renoprotective effects in black patients with chronic kidney disease and proteinuria because of the high likelihood that these patients will progress to end-stage renal disease. Diuretics also may be useful in the management of chronic kidney disease, and may potentiate the effects of angiotensin II receptor antagonists, ACE inhibitors, and other antihypertensive agents when used in combination.

Other Special Considerations for Antihypertensive Therapy

Race

Like ACE inhibitors, angiotensin II receptor antagonists may produce a smaller blood pressure response in hypertensive black patients compared with nonblack patients. In general, black patients tend to respond better to thiazide diuretics or calcium-channel blocking agents than to angiotensin II receptor antagonists. However, such diminished response to an angiotensin II receptor antagonist is largely eliminated when the drug is administered concomitantly with a thiazide diuretic or a calcium-channel blocker. In addition, some experts state that when use of angiotensin II receptor antagonists is indicated in hypertensive patients with underlying cardiovascular or other risk factors, these indications should be applied equally to black hypertensive patients.

For further information on overall principles and expert recommendations for treatment of hypertension, see Uses: Hypertension in Adults, in the Thiazides General Statement 40:28.20.

Diabetic Nephropathy

Both angiotensin II receptor antagonists (e.g., valsartan) 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. The usual precautions of angiotensin II receptor antagonist or ACE inhibitor therapy in patients with substantial renal impairment should be observed.(See Renal Effects under Warnings/Precautions: Other Warnings/Precautions, in Cautions.) For additional information on the use of angiotensin II receptor antagonists in the treatment of diabetic nephropathy, and in

Heart Failure

Valsartan is 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 LVEF (ACCF/AHA stage B heart failure) receive therapy with an ACE inhibitor and β-blocker to prevent symptomatic heart failure and to 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 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 in such patients. ACCF, AHA, and HFSA recommend that patients with chronic symptomatic heart failure and reduced LVEF (New York Heart Association [NYHA] 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.

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), angioedema has been reported rarely with the use of valsartan during postmarketing experience.(See Sensitivity Reactions under Cautions: Warnings/Precautions.)

Several clinical trials have evaluated the use of angiotensin II receptor antagonists in patients with heart failure 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. In a large, double-blind, placebo-controlled study (Valsartan Heart Failure Trial [Val-HeFT]) in patients with mild to severe (NYHA class II-IV) heart failure and LVEF less than 40%, addition of valsartan 40 mg twice daily (initial dosage, with dosage doubled every 2 weeks to a target dosage of 160 mg twice daily) to standard therapy (principally ACE inhibitors, diuretics, digoxin, and β-blockers) was associated with a reduction in the composite end point of heart failure-related morbidity and mortality (defined as cardiac arrest with resuscitation, hospitalization for worsening heart failure, or administration of IV inotropic or vasodilator drugs for 4 or more hours without hospitalization) after an average of approximately 23 months. Valsartan therapy also improved secondary cardiovascular outcomes such as NYHA class, ejection fraction, and symptoms of heart failure (dyspnea, fatigue, edema, rales), and prevented deterioration of the patients' well-being (as determined by quality of life measurements). However, improvement in heart failure morbidity occurred principally in patients not receiving adjunctive therapy with an ACE inhibitor, and overall mortality was not affected by valsartan therapy. For additional details of studies on the use of angiotensin II receptor antagonists in the management of heart failure,

Data from 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, these drugs did not show consistent effects on cardiac symptoms or exercise tolerance in some studies. In one comparative (Evaluation of Losartan in the Elderly [ELITE]) study in geriatric patients 65 years of age and older who received losartan (up to 50 mg daily) or captopril (up to 150 mg daily) in addition to conventional therapy for 48 weeks, patients receiving losartan had a 46% lower risk of death and also experienced a lower incidence of adverse effects than those receiving captopril. However, after interim analysis of data, the difference in survival was no longer statistically significant and no difference in morbidity and mortality or frequency in hospitalizations for heart failure was found between the 2 therapies. Results of a follow-up study (ELITE II) failed to confirm a survival benefit for losartan therapy compared with captopril. In this study, losartan did not provide a statistically significant difference in reduction of overall death, sudden cardiac death, and/or resuscitated cardiac arrest compared with captopril, although ELITE II was not designed to demonstrate equivalence between the 2 therapies. In addition, results of another study (Randomized Evaluation of Strategies for Left Ventricular Dysfunction [RESOLVD]) in patients with ischemic or nonischemic dilated cardiomyopathy and mild to moderate heart failure showed no differences in exercise capacity or risk of cardiac events in patients receiving candesartan (up to 16 mg daily), enalapril (up to 20 mg daily), or a combination of candesartan and enalapril, in addition to conventional therapy.

Heart Failure or Left Ventricular Dysfunction after Acute Myocardial Infarction

Valsartan is used to reduce the risk of cardiovascular mortality following acute myocardial infarction in clinically stable patients with demonstrated clinical evidence of heart failure (signs, symptoms, radiologic evidence) or left ventricular systolic dysfunction (i.e., LVEF 40% or less). Efficacy of valsartan for reducing risk of mortality from any cause has been evaluated in a large, double-blind, randomized, long-term (median follow-up: 24.7 months) study (VALsartan In Acute myocardial iNfarcTion trial [VALIANT]) involving 14,703 patients with acute myocardial infarction complicated by heart failure or left ventricular systolic dysfunction. The primary end point of this study was death from any cause, while secondary end points included time to cardiovascular mortality and time to the first occurrence of cardiovascular reinfarction or hospitalization for heart failure. A prespecified analysis was designed to demonstrate the noninferiority or equivalence of valsartan to captopril in the event that valsartan would not clearly be shown to be superior to the ACE inhibitor. Such analysis also was based on results from previous placebo-controlled studies, in which administration of ACE inhibitors has been associated with reduction in mortality. Results of this study indicate that when compared with those receiving captopril (titrated to 50 mg 3 times daily) or the combination of valsartan (titrated to 80 mg twice daily) and captopril (titrated to 50 mg 3 times daily), valsartan therapy (titrated to 160 mg twice daily) initiated 0.5-10 days after an acute myocardial infarction was associated with a reduction of all-cause mortality similar to the reduction observed among those receiving captopril or the combination of valsartan and captopril. Nine hundred and seventy-nine (19.9%) patients receiving valsartan died (hazard ratio of 1; 97.5% confidence interval: 0.9-1.11) compared with 958 (19.5%) of those receiving captopril. In addition, 941 (19.3%) patients receiving valsartan in combination with captopril died (compared with 19.5% of those receiving captopril) (hazard ratio of 0.98; 97.5% confidence interval: 0.89-1.09). Valsartan therapy also was comparable to ACE inhibitor therapy in terms of the composite end point of fatal and nonfatal cardiovascular events (hospitalization for heart failure and recurrent nonfatal myocardial infarction). Benefits associated with valsartan were not affected by age, gender, race, or baseline therapies. In this study, combined therapy with valsartan and captopril increased the rate of adverse effects without providing further benefit on survival. Although findings of this study provide evidence of comparable benefit, at least in high-risk patients, most experts continue to recommend that angiotensin II receptor antagonists be reserved for patients who do not tolerate ACE inhibitors since the latter drugs generally are less expensive and experience with them is more extensive.

Dosage and Administration

Administration

Valsartan is administered orally. Although food may decrease the rate and extent (e.g., by about 40%) of valsartan absorption, the manufacturers state that the drug can be administered without regard to meals.

Valsartan may be administered as an extemporaneously prepared oral suspension in pediatric patients who are unable to swallow tablets or in those for whom the calculated daily dosage does not correspond to the available tablet strengths. An extemporaneous suspension containing valsartan 4 mg/mL can be prepared in the following manner. First, 80 mL of suspending vehicle (e.g., Ora-Plus) is added to an amber glass bottle containing eight 80-mg tablets of valsartan, and the contents are shaken for at least 2 minutes. The concentrated suspension should be allowed to stand for at least 1 hour following reconstitution and then should be shaken for at least an additional minute. The concentrated suspension of valsartan should be diluted with 80 mL of sweetening vehicle (e.g., Ora-Sweet SE), and the container then shaken for at least 10 seconds to disperse the contents. The suspension should be shaken for at least 10 seconds before each dose is dispensed. When stored in an amber glass bottle with child-resistant screw-cap closure at a temperature of less than 30°C or at 2-8°C, the extemporaneous suspension is stable for up to 30 or up to 75 days, respectively.

Dosage

Hypertension

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

Valsartan 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 valsartan dosage of 40-80 mg once daily and a target dosage of 160-320 mg once daily are recommended. Target dosages of antihypertensive agents generally can be achieved within 2-4 weeks, but it may take up to several months.

The manufacturers state the usual initial dosage of valsartan as monotherapy in adults is 80 or 160 mg once daily in patients without depletion of intravascular volume; patients requiring greater reductions in blood pressure initially may be started at the higher dosage. If blood pressure response is inadequate with the initial dosage, dosage may be increased as tolerated up to a maximum of 320 mg daily or a diuretic may be added. The manufacturers state that the usual maintenance dosage of valsartan is 80-320 mg given once daily. However, addition of a diuretic generally has a greater effect on blood pressure reduction than dosage increases of valsartan as dosage exceeds 80 mg daily. Valsartan also can be used concomitantly with other antihypertensive agents.

The usual initial dosage of valsartan in children and adolescents 6-16 years of age with hypertension is 1.3 mg/kg (up to 40 mg) once daily. Dosage should be adjusted according to blood pressure response. Dosages exceeding 2.7 mg/kg (up to 160 mg) once daily have not been evaluated in pediatric patients. Because systemic exposure to valsartan is 1.6 times greater when the drug is administered as an extemporaneously prepared suspension compared with administration as the commercially available tablets, children being switched from the suspension to the oral tablets may require an increase in dosage of the drug. For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients,

Antihypertensive therapy should be titrated until goal blood pressure is achieved. If an adequate blood pressure response is not achieved with valsartan 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 valsartan, 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.

Valsartan/Hydrochlorothiazide Fixed-combination Therapy

Commercially available preparations containing valsartan in fixed combination with hydrochlorothiazide can be used as a substitute for the individually titrated drugs. Alternatively, in patients who do not respond adequately to monotherapy with valsartan (or another angiotensin II receptor antagonist) or, alternatively, with hydrochlorothiazide, combined therapy with the drugs can be used. The manufacturers state that patients who do not respond adequately to monotherapy with valsartan (or another angiotensin II receptor antagonist) or hydrochlorothiazide may be switched to therapy with the fixed-combination preparation at an initial dosage of valsartan 160 mg and hydrochlorothiazide 12.5 mg once daily. In addition, patients who experience dose-limiting adverse effects during monotherapy with valsartan or hydrochlorothiazide can be switched to a lower dosage of that drug, given as a fixed-combination preparation containing valsartan and hydrochlorothiazide, to achieve similar blood pressure control. If needed, dosage of the fixed combination may be increased up to a maximum of 320 mg of valsartan and 25 mg of hydrochlorothiazide (given once daily) after 3-4 weeks. The maximum antihypertensive effect is attained within 2-4 weeks after initiation of therapy or a change in dosage.

Commercially available preparations containing valsartan in fixed combination with hydrochlorothiazide may be used for initial treatment of hypertension in patients likely to require combined therapy with multiple antihypertensive drugs to achieve blood pressure control. In such patients, therapy with the fixed-combination preparation should be initiated at a dosage of 160 mg of valsartan and 12.5 mg of hydrochlorothiazide once daily. Dosage should be adjusted according to the patient's response after 1-2 weeks of therapy. The decision to use the fixed combination of valsartan and hydrochlorothiazide for initial treatment of hypertension should be based on assessment of potential benefits and risks of such therapy. The fixed combination of valsartan and hydrochlorothiazide is not recommended as initial therapy in patients with depletion of intravascular volume. In patients whose baseline blood pressure is 160/100 mm Hg, the estimated probability of achieving control of systolic blood pressure (defined as systolic blood pressure of less than 140 mm Hg) is 41, 50, or 84% and of achieving control of diastolic blood pressure (defined as diastolic blood pressure of less than 90 mm Hg) is 60, 57, or 80% with valsartan (320 mg daily) alone, hydrochlorothiazide (25 mg daily) alone, or valsartan combined with hydrochlorothiazide (at the same dosages), respectively.

Valsartan/Amlodipine Fixed-combination Therapy

Patients whose hypertension is adequately controlled with valsartan and amlodipine administered separately may be switched to the fixed-combination preparation containing the corresponding individual doses. Alternatively, the manufacturers state that patients who do not respond adequately to monotherapy with valsartan (or another angiotensin II receptor antagonist) or, alternatively, with amlodipine (or another dihydropyridine-derivative calcium-channel blocker) may be switched to therapy with the fixed-combination preparation containing valsartan and amlodipine. In addition, patients who experience dose-limiting adverse effects during monotherapy with valsartan or amlodipine can be switched to a lower dosage of that drug, given as a fixed-combination preparation containing valsartan and amlodipine, to achieve similar blood pressure control; dosage should be adjusted according to the patient's response after 3-4 weeks of therapy. If needed, dosage of the fixed-combination preparation may be increased up to a maximum of 320 mg of valsartan and 10 mg of amlodipine given once daily; because most of the antihypertensive effect of a given dosage is achieved within 2 weeks, dosage may be adjusted after 1-2 weeks, if needed, to attain blood pressure control.

Commercially available preparations containing valsartan in fixed combination with amlodipine may be used for initial treatment of hypertension in patients likely to require combined therapy with multiple antihypertensive drugs to achieve blood pressure control. In such patients, therapy with the fixed-combination preparation should be initiated at a dosage of 160 mg of valsartan and 5 mg of amlodipine once daily in individuals without depletion of intravascular volume. The decision to use the fixed combination of valsartan and amlodipine for initial management of hypertension should be based on assessment of potential benefits and risks of such therapy, including consideration of whether the patient is likely to tolerate the lowest available dosage of the combined drugs. In patients whose baseline blood pressure is 160/100 mm Hg, the estimated probability of achieving control of systolic blood pressure (defined as systolic blood pressure of less than 140 mm Hg) is 47, 67, or 80% and of achieving control of diastolic blood pressure (defined as diastolic blood pressure of less than 90 mm Hg) is 62, 80, or 85% with valsartan (320 mg daily) alone, amlodipine (10 mg daily) alone, or valsartan combined with amlodipine (at the same dosages), respectively.

Valsartan/Amlodipine/Hydrochlorothiazide Fixed-combination Therapy

The fixed-combination preparation containing valsartan, amlodipine, and hydrochlorothiazide may be used to provide additional blood pressure control in patients who do not respond adequately to combination therapy with any 2 of the following classes of antihypertensive agents: angiotensin II receptor antagonists, calcium-channel blockers, or diuretics. Patients who experience dose-limiting adverse effects of valsartan, amlodipine, or hydrochlorothiazide while receiving any dual combination of these drugs may be switched to a lower dosage of that drug, given as a fixed-combination preparation containing all 3 of these drugs, to achieve similar blood pressure reductions. The fixed-combination preparation containing valsartan, amlodipine, and hydrochlorothiazide also can be used as a substitute for the individually titrated drugs. If necessary, dosage of the fixed-combination preparation may be increased after 2 weeks for additional blood pressure control (but should not exceed a maximum dosage of 320 mg of valsartan, 10 mg of amlodipine, and 25 mg of hydrochlorothiazide once daily). The commercially available preparation containing valsartan in fixed combination with amlodipine and hydrochlorothiazide should not be used for the initial management of hypertension.

Blood Pressure Monitoring and Treatment Goals

Careful monitoring of blood pressure during initial titration or subsequent upward adjustment in dosage of valsartan 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 valsartan dosage in the management of hypertension,

Heart Failure

For the management of heart failure (New York Heart Association [NYHA] class II-IV) in patients unable to tolerate therapy with angiotensin-converting enzyme (ACE) inhibitors, the manufacturers recommend an initial valsartan dosage of 40 mg twice daily; some experts recommend an initial dosage of 20-40 mg twice daily in patients with chronic heart failure and reduced left ventricular ejection fraction (LVEF) (American College of Cardiology Foundation [ACCF]/American Heart Association [AHA] stage C heart failure). Dosage of valsartan should be increased until a dosage of 160 mg twice daily (the maximum dosage used in clinical trials) or the highest tolerated dosage is reached. While patients with heart failure generally have some reduction in blood pressure with valsartan therapy, discontinuance of therapy usually is not necessary when dosage recommendations are followed. Consideration should be given to reducing the dosage of concurrent diuretic therapy.

Heart Failure or Left Ventricular Dysfunction after Acute Myocardial Infarction

When used after myocardial infarction in adults with clinical signs of heart failure or left ventricular systolic dysfunction, valsartan therapy may be initiated as early as 12 hours after the myocardial infarction. An initial dosage of 20 mg twice daily is recommended. Dosage may be increased within 7 days to 40 mg twice daily with subsequent titrations to a target maintenance dosage of 160 mg twice daily, as tolerated. If hypotension or renal dysfunction occurs, dosage reduction should be considered. While post-myocardial infarction patients generally have some reduction in blood pressure with valsartan therapy, discontinuance of therapy usually is not necessary when dosage recommendations are followed. Valsartan may be given with other standard post-myocardial infarction therapy (e.g., thrombolytics, aspirin, β-adrenergic blocking agents [β-blockers], hydroxymethylglutaryl-CoA [HMG-CoA] reductase inhibitors [statins]).

Special Populations

The manufacturers state that modification of valsartan dosage is not necessary for patients with mild to moderate renal impairment; however, valsartan has not been studied in patients with creatinine clearances of less than 10 mL/minute and should be used with caution in adults with severe renal impairment. Valsartan is not removed by hemodialysis. Use of valsartan in pediatric patients with glomerular filtration rates of less than 30 mL/minute per 1.73 m has not been studied. Safety and efficacy of commercially available preparations containing valsartan in fixed combination with hydrochlorothiazide have not been established in patients with severe renal impairment.

The manufacturers state that valsartan should be used with caution in patients with hepatic impairment. Although systemic exposure to valsartan (as measured by area under the serum concentration-time curve [AUC]) is increased approximately twofold in patients with mild to moderate chronic liver disease, the manufacturers state that modification of valsartan dosage is not necessary for these patients. The amount of amlodipine in fixed-combination preparations containing valsartan and amlodipine exceeds the recommended initial dosage of amlodipine (2.5 mg daily) for patients with hepatic impairment.

The manufacturers state that modification of valsartan dosage is not necessary for geriatric patients. However, the amount of amlodipine in fixed-combination preparations containing valsartan and amlodipine exceeds the recommended initial dosage of amlodipine (2.5 mg daily) for geriatric patients.

Cautions

Contraindications

Known hypersensitivity to valsartan or any ingredient in the formulation.

Concomitant use of valsartan 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. Valsartan 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 (i.e., angiotensin II antagonists and ACE inhibitors) during pregnancy, and in .

Sensitivity Reactions

Sensitivity reactions, including various anaphylactoid reactions and/or angioedema, have been reported in patients receiving angiotensin II receptor antagonists, including valsartan. These drugs should be used with extreme caution in patients with a history of angioedema associated with or unrelated to ACE inhibitor or angiotensin II receptor antagonist therapy. The manufacturer states that valsartan should not be readministered to patients with a history of angioedema.

Other Warnings/Precautions

Cardiovascular Effects

Valsartan rarely is associated with severe hypotension in patients with uncomplicated hypertension. Symptomatic hypotension may occur in patients with an activated renin-angiotensin system (e.g., patients with volume or salt depletion secondary to salt restriction or high-dose diuretic therapy). Volume and/or salt depletion should be corrected before starting valsartan therapy, or therapy should be initiated under close medical supervision.

Patients with heart failure and those with clinical signs of left ventricular systolic dysfunction following acute myocardial infarction generally have some reduction in blood pressure with valsartan therapy, but drug discontinuance generally is not necessary when recommended dosages are used. Caution should be observed when initiating valsartan therapy in these patients.

If symptomatic hypotension occurs, the patient should be placed in the supine position; if hypotension is severe, IV infusion of 0.9% sodium chloride injection to expand fluid volume should be considered. Transient hypotension is not a contraindication to additional doses of valsartan, and therapy with the drug can be reinstated cautiously after blood pressure has been 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., renal failure) in these patients during therapy with an ACE inhibitor or an angiotensin II receptor antagonist (e.g., valsartan). Dosage reduction or discontinuance of valsartan or diuretic therapy may be required. Renal artery stenosis, preexisting renal impairment, and concomitant diuretic therapy also are risk factors for renal impairment during therapy with drugs that inhibit the RAA system. Although reports received to date have involved patients treated with ACE inhibitors, this adverse effect also would be expected to occur when drugs with similar pharmacologic activity (e.g., angiotensin II receptor antagonists) are used in a similar manner.

Hyperkalemia

Hyperkalemia may occur in patients receiving valsartan, especially in those with heart failure and preexisting renal impairment. Dosage reduction or discontinuance of valsartan therapy may be required.

Fixed-combination Preparations

When valsartan is used as a fixed combination that includes amlodipine and/or hydrochlorothiazide, the cautions, precautions, and contraindications associated with the concomitant agent(s) must be considered in addition to those associated with valsartan.

Specific Populations

Pregnancy

Category D.

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

Lactation

Valsartan is distributed into milk in rats. It is not known whether valsartan is distributed into human milk. A decision should be made whether to discontinue nursing or the drug because of the potential risk in nursing infants.

Pediatric Use

Safety and efficacy of valsartan have been established in a randomized, double-blind clinical trial in pediatric patients 6-16 years of age with hypertension; adverse effects of the drug in this age group were similar to those observed in adults. Although there was some evidence of efficacy in randomized, double-blind clinical trials in pediatric patients 6 months to 5 years of age with hypertension, 2 deaths and 3 cases of transaminase elevations were observed in a one-year open-label extension study in patients 1-5 years of age. A causal relationship to the drug has not been established; however, use of valsartan in pediatric patients younger than 6 years of age is not recommended. In pediatric patients with hypertension in whom underlying renal abnormalities may be more common, renal function and serum potassium should be carefully monitored. Pharmacokinetics of the drug have been studied in pediatric patients 1-16 years of age.

Safety and efficacy of valsartan in fixed combination with hydrochlorothiazide and/or amlodipine in pediatric patients have not been established.

Safety and efficacy of valsartan in pediatric patients with glomerular filtration rates of less than 30 mL/minute per 1.73 m 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 and efficacy of valsartan in geriatric patients relative to younger adults have been observed, but increased sensitivity cannot be ruled out.

Hepatic Impairment

Valsartan should be used with caution in patients with obstructive biliary disease or hepatic impairment since the drug is eliminated primarily by biliary excretion and clearance of the drug may be reduced.

Renal Impairment

Valsartan should be used with caution in patients with severe renal impairment. (See Renal Effects and also see Hyperkalemia under Warning/Precautions: Other Warnings/Precautions, in Cautions.)

Common Adverse Effects

Adverse effects occurring in 1% or more of adults with hypertension receiving valsartan and more frequently than with placebo include viral infection, fatigue, and abdominal pain; adverse effects in pediatric patients 6-16 years of age generally are similar to those in adults.

Adverse effects occurring in 2% or more of patients with heart failure receiving valsartan and more frequently than with placebo include dizziness, hypotension, diarrhea, arthralgia, fatigue, back pain, postural dizziness, hyperkalemia, and postural hypotension. In patients receiving valsartan following acute myocardial infarction, the most common adverse effects resulting in discontinuance of the drug included hypotension, cough, and increased serum creatinine concentration.

Drug Interactions

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

In vitro studies suggest valsartan is minimally metabolized by cytochrome P-450 (CYP) microsomal isoenzyme 2C9 and does not inhibit CYP enzymes at therapeutic concentrations. Therefore, drug interactions mediated by CYP enzymes are considered unlikely with valsartan.

Drugs That Inhibit Hepatic Transport Systems

In vitro data suggest that valsartan is a substrate of organic anion transporter protein (OATP) 1B1 (hepatic uptake transporter) and multidrug resistance protein MRP2 (hepatic efflux transporter). Use of valsartan concomitantly with inhibitors of OATP 1B1 (e.g., cyclosporine, rifampin) or MRP2 (e.g., ritonavir) may result in increased systemic exposure to valsartan.

Drugs that Block the Renin-Angiotensin System

Concomitant use of valsartan with other drugs that block the renin-angiotensin system (e.g., angiotensin-converting enzyme [ACE] inhibitors, aliskiren) may increase the risk of renal impairment, hyperkalemia, and hypotension; when valsartan is used concomitantly with such drugs, blood pressure, renal function, and serum concentrations of electrolytes should be monitored closely. Concomitant use of valsartan with 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 per 1.73 m).

Drugs or Foods That Increase Serum Potassium Concentration

Concomitant use of potassium-sparing diuretics (e.g., amiloride, spironolactone, triamterene), potassium supplements, potassium-containing salt substitutes, or other drugs that may increase serum potassium concentrations (e.g., heparin) with valsartan may result in increased hyperkalemic effects and, in patients with heart failure, increases in serum creatinine concentration. Monitoring of serum potassium concentrations is recommended during concomitant use.

Atenolol

Antihypertensive effect of combined atenolol and valsartan therapy exceeds that of either drug alone, but the reduction in heart rate with the drugs in combination does not exceed that observed with atenolol alone. Pharmacokinetic interaction is unlikely.

Hydrochlorothiazide

Hypotensive effects of valsartan and hydrochlorothiazide are additive; pharmacokinetic interaction is unlikely.

Lithium

Increased lithium concentrations and clinical toxicity have been reported in patients receiving valsartan concomitantly with lithium. Monitoring of serum lithium concentrations is recommended during concomitant use.

Nonsteroidal Anti-inflammatory Agents

Hypotensive effects of angiotensin II receptor antagonists may be attenuated when these agents are used concomitantly with nonsteroidal anti-inflammatory agents (NSAIAs), including selective cyclooxygenase-2 (COX-2) inhibitors.

Deterioration of renal function may occur when angiotensin II receptor antagonists are used concomitantly with NSAIAs, including selective COX-2 inhibitors, in geriatric patients, patients with volume depletion (including those receiving concomitant diuretic therapy), or patients with renal impairment; renal function should be monitored periodically in patients receiving concomitant therapy with valsartan and an NSAIA.

Warfarin

Concurrent use of valsartan and warfarin did not affect the pharmacokinetics of valsartan or the anticoagulant effect of warfarin.

Other Drugs

Pharmacokinetic interactions with amlodipine, cimetidine, digoxin, furosemide, glyburide, and indomethacin are unlikely.

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