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amlodipine besylate 5 mg tab (generic norvasc)

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Uses

Hypertension

Amlodipine is used alone or in combination with other classes of antihypertensive agents in the management of hypertension. Amlodipine in fixed combination with atorvastatin (Caduet) is used in patients for whom treatment with both amlodipine and atorvastatin is appropriate.

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.

In the Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study, the long-term cardiovascular morbidity and mortality benefit of a long-acting dihydropyridine calcium-channel blocker (amlodipine), a thiazide-like diuretic (chlorthalidone), and an ACE inhibitor (lisinopril) were compared in a broad population of patients with hypertension at risk for coronary heart disease. Although these antihypertensive agents were comparably effective in providing important cardiovascular benefit, apparent differences in certain secondary outcomes were observed. Patients receiving the ACE inhibitor experienced higher risks of stroke, combined cardiovascular disease, GI bleeding, and angioedema, while those receiving the calcium-channel blocker were at higher risk of developing heart failure. The ALLHAT investigators suggested that the favorable cardiovascular outcome may be attributable, at least in part, to the greater antihypertensive effect of the calcium-channel blocker compared with that of the ACE inhibitor, especially in women and black patients.

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 require 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 mmHg 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 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.

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, calcium-channel blockers are recommended as one of several preferred drugs for the initial treatment of hypertension; other options include ACE inhibitors, angiotensin II receptor antagonists, 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. Calcium-channel blockers may be particularly useful in the management of hypertension in black patients; these patients tend to have a greater blood pressure response to calcium-channel blockers and thiazide diuretics than to other antihypertensive drug classes (e.g., ACE inhibitors, angiotensin II receptor antagonists).(See Race under Hypertension: Other Special Considerations for Antihypertensive Therapy, in Uses.) Use of a calcium-channel blocker also may be beneficial in patients with certain coexisting conditions such as ischemic heart disease (e.g., angina) and in geriatric patients, including those with isolated systolic hypertension. (See Geriatric Age under Hypertension: Other Special Considerations for Antihypertensive Therapy, in Uses, and also see Ischemic Heart Disease under Hypertension: Antihypertensive Therapy for Patients with Underlying Cardiovascular or Other Risk Factors, in Uses.)

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 a calcium-channel blocker, the JNC 8 expert panel states that an ACE inhibitor, an angiotensin II receptor antagonist, or a thiazide diuretic 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-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 ACE inhibitors (or angiotensin II receptor antagonists) and/or β-blockers 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.

Diabetes Mellitus

Calcium-channel blockers, thiazide diuretics, ACE inhibitors, and angiotensin II receptor antagonists have all been recommended for use as initial antihypertensive therapy in patients with diabetes mellitus, although certain agents may be preferred. Some experts and clinicians have suggested that extended-release or intermediate- or long-acting calcium-channel blockers may be useful in the management of hypertension in patients with diabetes mellitus because these drugs appear to have few adverse effects on glucose homeostasis, lipid profiles, and renal function. The American Diabetes Association (ADA) states that the antihypertensive regimen of patients with diabetes and hypertension should include an ACE inhibitor or angiotensin II receptor antagonist because of the cardiovascular and renoprotective benefits of these drugs; if additional blood pressure control is required, a calcium-channel blocker or thiazide diuretic may be added. Because ACE inhibitors and angiotensin II receptor antagonists tend not to be as effective in black patients, some experts recommend a calcium-channel blocker or a thiazide diuretic as the initial antihypertensive drug of choice in black patients with diabetes.(See Race under Hypertension: Other Special Considerations for Antihypertensive Therapy, in Uses.)

Other Special Considerations for Antihypertensive Therapy

Race

Blood pressure response to calcium-channel blockers appears to be comparable in white and black patients. In general, black hypertensive patients tend to respond better to monotherapy with calcium-channel blockers or thiazide diuretics than to monotherapy with other drug classes (e.g., ACE inhibitors, angiotensin II receptor antagonists, β-blockers). In a prespecified subgroup analysis of the ALLHAT study, a calcium-channel blocker was more effective than an ACE inhibitor in lowering blood pressure and was associated with a substantially reduced rate of stroke in black patients. When compared with a thiazide diuretic, the calcium-channel blocker appeared to be less effective in preventing heart failure, but comparable with respect to other outcomes (e.g., cerebrovascular, cardiovascular, renal, mortality). However, the diminished response observed with these other antihypertensive drug classes is largely eliminated when β-blockers are administered concomitantly with a diuretic or when ACE inhibitors or angiotensin II receptor antagonists are administered concomitantly with a calcium-channel blocker or thiazide diuretic. In addition, some experts state that when use of ACE inhibitors, angiotensin II receptor antagonists, or β-blockers is indicated in hypertensive patients with underlying cardiovascular or other risk factors, these indications should be applied equally to black hypertensive patients.

Geriatric Age

Antihypertensive drugs recommended for initial therapy in geriatric patients, including those with isolated systolic hypertension, generally are the same as those recommended for younger patients. Antihypertensive therapy initiated with a calcium-channel blocking agent has been shown to reduce cardiovascular morbidity and mortality in older patients with isolated systolic hypertension. In several controlled studies, thiazide diuretics alone or in combination with other antihypertensive agents also have been shown to effectively reduce morbidity and mortality in patients 50 years of age or older, including those with isolated systolic hypertension. Although some experts state that calcium-channel blocking agents or diuretics may be preferred in geriatric patients, ACE inhibitors and angiotensin II receptor antagonists also have shown beneficial effects and may be considered in this population.

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.

Hypertensive Crises

Because of the slow onset of hypotensive effect with amlodipine, this drug is not suitable for use as acute therapy in rapidly reducing blood pressure in patients with severe hypertension in whom reduction of blood pressure is considered urgent (i.e., hypertensive urgencies) nor in hypertensive emergencies.

For additional information on the role of dihydropyridine calcium-channel blocking agents in the management of hypertension and angina, .

Coronary Artery Disease

Amlodipine in fixed combination with atorvastatin (Caduet) is used in patients for whom treatment with both amlodipine and atorvastatin is appropriate.

Angina

Amlodipine is used for the management of Prinzmetal variant angina and chronic stable angina pectoris. The drug has been used alone or in combination with other antianginal agents.

Angiographically Documented Coronary Artery Disease

Amlodipine is used in patients with recently documented coronary artery disease by angiography (without heart failure or an ejection fraction less than 40%), to reduce the risk of coronary revascularization procedure and hospitalization due to angina.

Dosage and Administration

Administration

Amlodipine besylate is administered orally. Amlodipine generally can be given without regard to meals.

Amlodipine in fixed combination with aliskiren (with or without hydrochlorothiazide) should be administered in a consistent manner relative to meals; administration with a high-fat meal decreases absorption of aliskiren.

Dosage

Dosage of amlodipine besylate is expressed in terms of amlodipine.

Hypertension

Amlodipine 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 amlodipine dosage of 2.5 mg once daily and a target dosage of 10 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 that the usual initial adult dosage of amlodipine is 2.5-5 mg once daily as monotherapy. In geriatric patients and small or frail individuals, an initial dosage of 2.5 mg once daily is recommended. This reduced initial dosage also can be used in adults when amlodipine is added to an existing antihypertensive drug regimen. Subsequent dosage of amlodipine should be adjusted according to the patient's blood pressure response and tolerance and usually should not exceed 10 mg once daily. Generally, dosage is increased gradually at 7- to 14-day intervals until optimum control of blood pressure is maintained. However, more rapid titration of dosage can be undertaken when clinically warranted, provided response and tolerance are assessed frequently. The manufacturers state that the usual maintenance dosage of amlodipine for the management of hypertension in adults is 5-10 mg once daily.

For the management of hypertension in children 6 years of age and older, the usual effective dosage of amlodipine is 2.5-5 mg once daily. The safety and efficacy of dosages exceeding 5 mg daily have not been established. For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients,

Blood pressure should be monitored regularly during therapy and, if necessary, dosage of the antihypertensive drug adjusted accordingly. If an adequate blood pressure response is not achieved with amlodipine 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 amlodipine, dosage reduction should be considered; if adverse effects worsen or fail to resolve, discontinuance of the calcium-channel blocker and initiation of another class of antihypertensive agent may be necessary.

Amlodipine/Aliskiren Fixed-combination Therapy

The fixed-combination preparation containing amlodipine and aliskiren can be used as a substitute for the individually administered drugs; patients may be switched to the fixed-combination preparation containing the corresponding individual doses of amlodipine and aliskiren or, alternatively, the dosage of one or both components can be increased for additional antihypertensive effects. In addition, the manufacturer states that patients who do not respond adequately to monotherapy with amlodipine (or another dihydropyridine-derivative calcium-channel blocker) or, alternatively, with aliskiren may be switched to therapy with the fixed-combination preparation containing amlodipine and aliskiren. Patients who experience dose-limiting adverse effects during monotherapy with amlodipine or aliskiren can be switched to a lower dosage of that drug, given as a fixed-combination preparation containing amlodipine and aliskiren, to achieve similar blood pressure control. If needed, dosage of the fixed-combination preparation may be increased to a maximum dosage of 10 mg of amlodipine and 300 mg of aliskiren given once daily; because most of the antihypertensive effect of a given dosage is achieved within 1-2 weeks, dosage may be adjusted after 2-4 weeks, if needed, to attain blood pressure control.

Commercially available preparations containing amlodipine in fixed combination with aliskiren 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 5 mg of amlodipine and 150 mg of aliskiren once daily. In patients whose baseline blood pressure is 157/100 mm Hg, the estimated probability of achieving control of systolic blood pressure (defined as systolic blood pressure of less than 140 mm Hg) is 49, 62, or 74% and of achieving control of diastolic blood pressure (defined as diastolic blood pressure of less than 90 mm Hg) is 50, 69, or 83% with aliskiren (300 mg daily) alone, amlodipine (10 mg daily) alone, or amlodipine combined with aliskiren (at the same dosages), respectively.

Amlodipine/Aliskiren/Hydrochlorothiazide Fixed-combination Therapy

The fixed-combination preparation containing amlodipine, aliskiren, 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 drugs: dihydropyridine-derivative calcium-channel blockers, aliskiren, or thiazide diuretics. Patients who experience dose-limiting adverse effects of amlodipine, aliskiren, 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 amlodipine, aliskiren, 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 10 mg of amlodipine, 300 mg of aliskiren, and 25 mg of hydrochlorothiazide given once daily). The commercially available preparation containing amlodipine in fixed combination with aliskiren and hydrochlorothiazide should not be used for the initial management of hypertension.

Amlodipine/Benazepril Fixed-combination Therapy

Therapy with the commercially available preparations containing amlodipine in fixed combination with benazepril hydrochloride usually should be initiated only after an adequate response is not achieved with amlodipine (or another dihydropyridine-derivative calcium-channel blocker) or benazepril (or another ACE inhibitor) alone. Alternatively, such fixed combinations may be used if amlodipine dosages necessary for adequate response have been associated with development of edema. The fixed combination containing amlodipine and benazepril also may be used as a substitute for the individually titrated drugs. The recommended initial dosage is amlodipine 2.5 mg in fixed combination with benazepril hydrochloride 10 mg once daily. Dosage of the fixed combination containing amlodipine and benazepril should be adjusted according to the patient's response. The antihypertensive effect of a given dosage is largely attained with 2 weeks; if necessary, dosage of the fixed combination may be increased up to a maximum dosage of 10 mg of amlodipine in fixed combination with 40 mg of benazepril hydrochloride once daily.

The addition of benazepril to amlodipine therapy usually does not provide additional antihypertensive effects in black patients; however, benazepril appears to reduce the development of amlodipine-associated edema regardless of race. The manufacturers state that when the fixed combinations containing 2.5-10 mg of amlodipine with 10-40 mg of benazepril hydrochloride have been used, the antihypertensive effects of these combinations have increased with increasing dosages of amlodipine in all patients; in addition, antihypertensive effects increased with increasing dosages of benazepril in nonblack patients.

Amlodipine/Olmesartan Fixed-combination Therapy

In patients who do not respond adequately to monotherapy with amlodipine (or another dihydropyridine-derivative calcium-channel blocker) or, alternatively, with olmesartan medoxomil (or another angiotensin II receptor antagonist), combined therapy with the drugs can be used to provide additional antihypertensive effects. The fixed-combination preparation containing amlodipine and olmesartan medoxomil also can be used as a substitute for the individually titrated drugs. The patient can be switched to the fixed-combination preparation containing the corresponding individual doses of amlodipine and olmesartan medoxomil; alternatively, the dosage of one or both components can be increased for additional antihypertensive effects. If needed, dosage of the fixed combination may be increased after 2 weeks. Dosage adjustments generally should involve one drug at a time, although dosages of both drugs can be increased to achieve more rapid blood pressure control. Daily dosages exceeding 10 mg of amlodipine given in fixed combination with 40 mg of olmesartan medoxomil are not recommended by the manufacturer.

Commercially available preparations containing amlodipine in fixed combination with olmesartan medoxomil 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 usually should be initiated at a dosage of 5 mg of amlodipine and 20 mg of olmesartan medoxomil once daily. If necessary, dosage of the fixed combination may be increased after 1-2 weeks for additional blood pressure control (but should not exceed a maximum dosage of 10 mg of amlodipine and 40 mg of olmesartan medoxomil once daily). 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 48, 46, or 68% and of achieving control of diastolic blood pressure (defined as diastolic blood pressure of less than 90 mm Hg) is 51, 60, or 85% with olmesartan medoxomil (40 mg daily) alone, amlodipine (10 mg daily) alone, or amlodipine combined with olmesartan medoxomil (at the same dosages), respectively.

Amlodipine/Olmesartan/Hydrochlorothiazide Fixed-combination Therapy

The fixed-combination preparation containing amlodipine, olmesartan, 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 given at maximally tolerated, labeled, or usual dosages: calcium-channel blockers, angiotensin II receptor antagonists, or diuretics. Patients who experience dose-limiting adverse effects of amlodipine, olmesartan, 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 amlodipine, olmesartan, 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 10 mg of amlodipine, 40 mg of olmesartan medoxomil, and 25 mg of hydrochlorothiazide once daily). The commercially available preparation containing amlodipine in fixed combination with olmesartan and hydrochlorothiazide should not be used for the initial management of hypertension.

Amlodipine/Perindopril Fixed-combination Therapy

The commercially available preparation containing amlodipine in fixed combination with perindopril arginine may be used in patients receiving amlodipine monotherapy when amlodipine dosages necessary for adequate response have been associated with development of edema. In addition, patients who do not respond adequately to monotherapy may be switched to therapy with the fixed combination of amlodipine and perindopril arginine. Dosage of the fixed-combination preparation should be adjusted according to the patient's response at intervals of 7-14 days.

Commercially available preparations containing amlodipine in fixed combination with perindopril 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 usually should be initiated at a dosage of 2.5 mg of amlodipine and 3.5 mg of perindopril arginine once daily. The decision to use the fixed combination of amlodipine and perindopril 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. Dosage may be adjusted as needed at intervals of 7-14 days to a maximum dosage of amlodipine 10 mg and perindopril arginine 14 mg once daily.

In patients whose baseline blood pressure is 170/105 mm Hg, the estimated probability of achieving control of systolic blood pressure (defined as systolic blood pressure of less than 140 mm Hg) is 26, 40, or 50% and of achieving control of diastolic blood pressure (defined as diastolic blood pressure of less than 90 mm Hg) is 31, 46, or 65% with perindopril erbumine (16 mg daily) alone, amlodipine (10 mg daily) alone, or amlodipine (10 mg daily) combined with perindopril arginine (14 mg daily), respectively.

In black patients and patients with diabetes mellitus, the addition of perindopril arginine (14 mg daily) to amlodipine (10 mg daily) did not provide additional antihypertensive effects beyond those achieved with amlodipine monotherapy.

Amlodipine/Telmisartan Fixed-combination Therapy

The fixed-combination preparation containing amlodipine and telmisartan can be used as a substitute for the individually administered drugs; patients may be switched to the fixed-combination preparation containing the corresponding individual doses of amlodipine and telmisartan or, alternatively, the dosage of one or both components can be increased for additional antihypertensive effects. In addition, the manufacturers state that patients who do not respond adequately to monotherapy with amlodipine (or another dihydropyridine-derivative calcium-channel blocker) or, alternatively, with telmisartan (or another angiotensin II receptor antagonist) may be switched to therapy with the fixed-combination preparation containing amlodipine and telmisartan. Patients who experience dose-limiting adverse effects (e.g., edema) during monotherapy with amlodipine 10 mg may be switched to the fixed combination containing amlodipine 5 mg and telmisartan 40 mg to achieve similar blood pressure control. If needed, dosage of the fixed-combination preparation may be increased to a maximum dosage of 10 mg of amlodipine and 80 mg of telmisartan given once daily; because most of the antihypertensive effect of a given dosage is achieved within 2 weeks, dosage may be adjusted after at least 2 weeks, if needed, to attain blood pressure control.

Commercially available preparations containing amlodipine in fixed combination with telmisartan 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 usually should be initiated at a dosage of 5 mg of amlodipine and 40 mg of telmisartan once daily. An initial dosage of 5 mg of amlodipine and 80 mg of telmisartan once daily may be used in patients requiring larger blood pressure reductions. The decision to use the fixed combination of amlodipine and telmisartan 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 160/110 mm Hg, the estimated probability of achieving control of systolic blood pressure (defined as systolic blood pressure of less than 140 mm Hg) is 46, 69, or 79% and of achieving control of diastolic blood pressure (defined as diastolic blood pressure of less than 90 mm Hg) is 26, 22, or 55% with telmisartan (80 mg daily) alone, amlodipine (10 mg daily) alone, or amlodipine combined with telmisartan (at the same dosages), respectively.

Amlodipine/Valsartan Fixed-combination Therapy

Patients whose hypertension is adequately controlled with amlodipine and valsartan 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 amlodipine (or another dihydropyridine-derivative calcium-channel blocker) or, alternatively, with valsartan (or another angiotensin II receptor antagonist) may be switched to therapy with the fixed-combination preparation containing amlodipine and valsartan. In addition, patients who experience dose-limiting adverse effects during monotherapy with amlodipine or valsartan can be switched to a lower dosage of that drug, given as a fixed-combination preparation containing amlodipine and valsartan, 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 to a maximum of 10 mg of amlodipine and 320 mg of valsartan 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 amlodipine in fixed combination with valsartan 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 5 mg of amlodipine and 160 mg of valsartan once daily in individuals without depletion of intravascular volume. The decision to use the fixed combination of amlodipine and valsartan 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 amlodipine combined with valsartan (at the same dosages), respectively.

Amlodipine/Valsartan/Hydrochlorothiazide Fixed-combination Therapy

The fixed-combination preparation containing amlodipine, valsartan, 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: calcium-channel blockers, angiotensin II receptor antagonists, or diuretics. Patients who experience dose-limiting adverse effects of amlodipine, valsartan, 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 amlodipine, valsartan, 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 10 mg of amlodipine, 320 mg of valsartan, and 25 mg of hydrochlorothiazide given once daily). The commercially available preparation containing amlodipine in fixed combination with valsartan and hydrochlorothiazide should not be used for the initial management of hypertension.

Amlodipine/Atorvastatin Fixed-combination Therapy

The fixed-combination preparation containing amlodipine and atorvastatin may be used as a substitute for individually titrated drugs. In patients currently receiving amlodipine and atorvastatin, the initial dosage of the fixed-combination preparation is the equivalent of titrated dosages of amlodipine and atorvastatin. Increased amounts of amlodipine, atorvastatin, or both components may be added for additional antihypertensive or antilipemic effects.

The fixed-combination preparation may be used to provide additional therapy for patients currently receiving one component of the preparation. The initial dosage of the fixed-combination preparation should be selected based on the dosage of the current component being used and the recommended initial dosage for the added monotherapy.

The fixed-combination preparation may be used to initiate treatment in patients with hypertension and dyslipidemias. The initial dosage of the fixed-combination preparation should be selected based on the recommended initial dosages of the individual components. For dosage recommendations for atorvastatin, The maximum dosage of amlodipine or atorvastatin in the fixed-combination preparation is 10 or 80 mg daily, respectively.

Blood Pressure Monitoring and Treatment Goals

Careful monitoring of blood pressure during initial titration or subsequent upward adjustment in dosage of amlodipine 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.(See Considerations in Initiating Antihypertensive Therapy under Uses: Hypertension.)

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

Coronary Artery Disease

Angina

For the management of Prinzmetal variant angina or chronic stable angina, the usual adult dosage of amlodipine is 5-10 mg once daily. The manufacturers state that adequate control of angina usually requires a maintenance dosage of 10 mg daily.

Amlodipine has been used concomitantly with other antihypertensive and antianginal drugs, including thiazide diuretics, angiotensin-converting enzyme inhibitors, β-adrenergic blocking agents, long-acting nitrates, and/or sublingual nitroglycerin.

Angiographically Documented Coronary Artery Disease

For the management of coronary artery disease, the recommended adult dosage of amlodipine is 5-10 mg once daily. In clinical studies the majority of patients required a dosage of 10 mg daily.

Amlodipine/Atorvastatin Combination Therapy in Coronary Artery Disease

The fixed-combination preparation containing amlodipine and atorvastatin may be used as a substitute for individually titrated drugs. In patients currently receiving amlodipine and atorvastatin, the initial dosage of the fixed-combination preparation is the equivalent of titrated dosages of amlodipine and atorvastatin. Increased amounts of amlodipine, atorvastatin, or both components may be added for additional antianginal or antilipemic effects.

The fixed-combination preparation may be used to provide additional therapy for patients currently receiving one component of the preparation. The initial dosage of the fixed-combination preparation should be selected based on the dosage of the current component being used and the recommended initial dosage for the added monotherapy.

The fixed-combination preparation may be used to initiate treatment in patients with angina and dyslipidemias. The initial dosage of the fixed-combination preparation should be selected based on the recommended initial dosages of the individual components. For dosage recommendations for atorvastatin, The maximum dosage of amlodipine or atorvastatin in the fixed-combination preparation is 10 or 80 mg daily, respectively.

Special Populations

Hepatic Impairment

Since the elimination of amlodipine may be impaired substantially in patients with hepatic impairment, resulting in increased exposure to the drug (area under the plasma concentration-time curve [AUC] increases of 40-60%), a reduced initial amlodipine dosage may be required and subsequent dosage should be titrated slowly in such patients.

For the management of hypertension in adults with hepatic insufficiency, an initial amlodipine dosage of 2.5 mg once daily generally is recommended. Subsequent dosage should be adjusted according to patient response and tolerance but usually should not exceed 10 mg once daily. Commercially available preparations containing amlodipine in fixed combination with aliskiren (with or without hydrochlorothiazide), olmesartan medoxomil (with or without hydrochlorothiazide), telmisartan, or valsartan (with or without hydrochlorothiazide) exceed the recommended initial dosage of amlodipine (2.5 mg daily) for patients with hepatic insufficiency. The manufacturer states that preparations containing amlodipine in fixed combination with perindopril are not recommended in patients with hepatic impairment, as insufficient data are available to support dosage recommendations.

For the management of Prinzmetal variant angina or chronic stable angina in patients with hepatic insufficiency, an amlodipine dosage of 5 mg daily is recommended. The manufacturers state that adequate control of angina usually requires a maintenance dosage of 10 mg daily.

Renal Impairment

Adjustment of amlodipine dosage generally is not necessary in patients with renal impairment since elimination of the drug is not altered substantially by such impairment. However, use of the commercially available preparation containing benazepril in fixed combination with amlodipine is not recommended for patients with severe renal impairment (creatinine clearance of 30 mL/minute or less). In addition, use of preparations containing amlodipine in fixed combination with olmesartan medoxomil and hydrochlorothiazide are not recommended in patients with severe renal impairment; a loop diuretic generally is preferred over a thiazide diuretic in such patients. The safety and efficacy of preparations containing amlodipine in fixed combination with aliskiren (with or without hydrochlorothiazide) or in fixed combination with valsartan (with or without hydrochlorothiazide) in patients with creatinine clearances less than 30 mL/minute have not been established. The manufacturer states that preparations containing amlodipine in fixed combination with perindopril are not recommended in patients with creatinine clearances of less than 60 mL/minute, as insufficient data are available to support dosage recommendations. Dosage of the fixed combination of amlodipine and telmisartan should be titrated slowly in patients with severe renal impairment.

Geriatric Patients

Since the elimination of amlodipine may be impaired substantially in geriatric patients, resulting in increased exposure to the drug (AUC increases of 40-60%), a reduced initial amlodipine dosage should be considered in such patients. For management of hypertension, some manufacturers recommend an initial amlodipine dosage of 2.5 mg once daily for geriatric patients; other manufacturers recommend this reduced dosage for geriatric patients 75 years of age or older. For management of Prinzmetal variant angina or chronic stable angina in geriatric patients, an amlodipine dosage of 5 mg daily is recommended; the manufacturers state that adequate control of angina usually requires a maintenance dosage of 10 mg once daily. Commercially available preparations containing amlodipine in fixed combination with aliskiren (with or without hydrochlorothiazide), olmesartan medoxomil (with or without hydrochlorothiazide), telmisartan, or valsartan (with or without hydrochlorothiazide) exceed the recommended initial dosage of amlodipine (2.5 mg daily) for geriatric patients. The manufacturer states that preparations containing amlodipine in fixed combination with perindopril are not recommended in geriatric patients, as insufficient data are available to support dosage recommendations.

Heart Failure

Patients with moderate to severe heart failure have an increased AUC for amlodipine similar to that of geriatric patients and those with hepatic impairment, but the manufacturers currently make no specific recommendations for dosage adjustment in patients with congestive heart failure. The manufacturer states that preparations containing amlodipine in fixed combination with perindopril are not recommended in patients with heart failure, as insufficient data are available to support dosage recommendations.

Cautions

Contraindications

Amlodipine is contraindicated in patients with known hypersensitivity to the drug.

Warnings/Precautions

Hypotension

Symptomatic hypotension may occur in patients receiving amlodipine, particularly in individuals with severe aortic stenosis; however, acute hypotension is unlikely because of the gradual onset of action of the drug.

Increased Angina or Acute Myocardial Infarction

Worsening of angina or acute myocardial infarction can occur, particularly in patients with severe obstructive coronary artery disease, upon initiation of amlodipine therapy or an increase in amlodipine dosage.

Use of Fixed Combinations

When amlodipine is used in fixed combination with other drugs (e.g., other antihypertensive agents, atorvastatin), cautions, precautions, contraindications, and interactions associated with the concomitant agent(s) should be considered in addition to those associated with amlodipine. Cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) also should be considered for each drug in the fixed combination.

Heart Failure

Although some calcium-channel blockers have been shown to worsen the clinical status of patients with heart failure, no evidence of worsening heart failure (based on exercise tolerance, New York Heart Association [NYHA] class, symptoms, or left ventricular ejection fraction) and no adverse effects on overall survival and cardiac morbidity were observed in controlled studies of amlodipine in patients with heart failure. Cardiac morbidity and overall mortality rates in these studies were similar in patients receiving amlodipine and those receiving placebo.

In patients with moderate to severe heart failure, amlodipine clearance is decreased and area under the concentration-time curve (AUC) is increased by about 40-60%.

Specific Populations

Pregnancy

Category C.

Lactation

It is not known whether amlodipine is distributed into milk; the manufacturer recommends discontinuance of nursing if amlodipine is used.

Pediatric Use

Safety and efficacy of amlodipine in children younger than 6 years of age have not been established. Efficacy of amlodipine (2.5-5 mg daily) for the treatment of hypertension has been established in pediatric patients 6-17 years of age.

Safety and efficacy of amlodipine in fixed combination with aliskiren (with or without hydrochlorothiazide), atorvastatin, benazepril, olmesartan (with or without hydrochlorothiazide), perindopril, telmisartan, or valsartan (with or without hydrochlorothiazide) have not been established in children.

Geriatric Use

In geriatric patients, amlodipine clearance is decreased and AUC is increased by about 40-60%. Therefore, amlodipine dosage should be selected carefully, usually initiating therapy with dosages at the lower end of the recommended range. The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.(See Geriatric Patients under Dosage and Administration: Special Populations.)

Clinical studies of amlodipine did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients; however, other clinical experience has not revealed age-related differences in response or tolerance. No substantial differences in safety and efficacy relative to younger adults have been observed in geriatric patients receiving amlodipine in fixed combination with aliskiren (with or without hydrochlorothiazide), benazepril, olmesartan (with or without hydrochlorothiazide), telmisartan, or valsartan (with or without hydrochlorothiazide), but increased sensitivity cannot be ruled out.

The manufacturer states that use of amlodipine in fixed combination with perindopril in geriatric patients is not recommended, as insufficient data are available to support dosage recommendations.

The manufacturers state that safety and efficacy of amlodipine in fixed combination with atorvastatin have not been established in geriatric patients.

Hepatic Impairment

In patients with hepatic impairment, amlodipine clearance is decreased and AUC is increased by about 40-60%. A reduced initial dosage of the drug is recommended, and subsequent dosage should be titrated slowly.(See Hepatic Impairment under Dosage and Administration: Special Populations.)

Common Adverse Effects

Adverse effects reported in 1% or more of patients receiving amlodipine include edema, dizziness, flushing, palpitations, fatigue, nausea, abdominal pain, and somnolence. Edema, flushing, palpitations, and somnolence may occur more commonly in women than in men. Edema is dose related and may be less frequent with concomitant use of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor antagonist.

Drug Interactions

When amlodipine is used in fixed combination with other drugs, interactions associated with the concomitant agent(s) must be considered in addition to those associated with amlodipine.

Drugs Affecting Hepatic Microsomal Enzymes

Concomitant use of amlodipine with moderate (e.g., diltiazem) or potent (e.g., clarithromycin, itraconazole) inhibitors of cytochrome P-450 (CYP) 3A isoenzymes (CYP3A) results in increased systemic exposure to amlodipine. Reduction of amlodipine dosage may be necessary; patients receiving concomitant therapy with CYP3A inhibitors should be monitored for symptoms of hypotension or edema, which may indicate a need for dosage adjustment.

Data on the effects of CYP3A inducers on amlodipine exposure are lacking; blood pressure should be closely monitored in patients receiving such concomitant therapy.

Alcohol

Concomitant administration of alcohol with amlodipine did not alter systemic exposure to alcohol.

Antacids

Concomitant administration of a magnesium- and aluminum hydroxide-containing antacid with amlodipine did not alter systemic exposure to amlodipine.

Cimetidine

Concomitant administration of cimetidine with amlodipine did not alter systemic exposure to amlodipine.

Digoxin

Concomitant administration of amlodipine with digoxin did not alter systemic exposure to digoxin.

Diltiazem

Concomitant use of diltiazem hydrochloride (180 mg daily) with amlodipine (5 mg) in geriatric patients with hypertension resulted in a 60% increase in amlodipine exposure.

Erythromycin

Concomitant administration of erythromycin with amlodipine did not substantially alter systemic exposure to amlodipine in healthy individuals.

Grapefruit Juice

The manufacturer states that concomitant administration of grapefruit juice with amlodipine did not alter systemic exposure to amlodipine. Although there is some evidence from healthy individuals that concomitant administration with grapefruit juice may increase oral bioavailability of the drug compared with concomitant administration with water, there currently is no evidence of altered amlodipine pharmacodynamics by concurrent ingestion of grapefruit juice in healthy individuals. Concomitant oral administration of other 1,4-dihydropyridine-derivative calcium-channel blocking agents (e.g., felodipine, nifedipine, nisoldipine) with grapefruit juice has resulted in potentially clinically important increases in the hemodynamic effects of these drugs.

HMG-CoA Reductase Inhibitors

Atorvastatin

Concomitant administration of amlodipine with atorvastatin did not alter systemic exposure to atorvastatin.

Simvastatin

Concomitant administration of amlodipine (multiple 10-mg doses) with simvastatin (80 mg) resulted in a 77% increase in simvastatin exposure compared with simvastatin alone. In patients receiving amlodipine, simvastatin dosage should not exceed 20 mg daily.

Immunosuppressants

Cyclosporine

Concomitant use of cyclosporine and amlodipine may result in increased systemic exposure to cyclosporine. Concomitant use of amlodipine with cyclosporine in renal allograft recipients resulted in a 40% increase in trough concentrations of the immunosuppressant. If concomitant use is required, cyclosporine concentrations should be monitored frequently and cyclosporine dosage adjusted as needed.

Tacrolimus

Concomitant use of tacrolimus and amlodipine may result in increased systemic exposure to tacrolimus. If concomitant use is required, tacrolimus concentrations should be monitored frequently and tacrolimus dosage adjusted as needed.

In healthy Chinese individuals who expressed the CYP3A5 isoenzyme, concomitant administration of amlodipine with tacrolimus resulted in a 2.5- to 4-fold increase in tacrolimus exposure compared with tacrolimus alone; this finding was not observed in individuals who did not express CYP3A5. However, in a renal transplant patient who did not express CYP3A5, a threefold increase in systemic exposure to tacrolimus was observed following initiation of amlodipine therapy for posttransplantation hypertension; reduction in tacrolimus dosage was required. Irrespective of CYP3A5 genotype, the possibility of an interaction between tacrolimus and amlodipine cannot be excluded.

Protein-bound Drugs

In vitro data indicate that amlodipine does not alter plasma protein binding of digoxin, indomethacin, phenytoin, or warfarin.

Sildenafil

Concomitant administration of sildenafil with amlodipine did not alter systemic exposure to amlodipine; however, additional reductions in blood pressure are possible with such concomitant use. Patients receiving sildenafil concomitantly with amlodipine should be monitored for hypotension.

Warfarin

Concomitant administration of amlodipine with warfarin did not alter prothrombin time.

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