VA Class:CV200

AHFS Class:

• Dihydropyridines 24:28.08

Generic Name(s):

• amLODIPine Besylate

Amlodipine is a 1,4-dihydropyridine-derivative calcium-channel blocking agent with an intrinsically long duration of action.1,2,3

Hypertension

Amlodipine is used alone or in combination with other classes of antihypertensive agents in the management of hypertension.1,2,3,4,6,21,113,129,130,132,133,134,1200 Amlodipine in fixed combination with atorvastatin (Caduet^®) is used in patients for whom treatment with both amlodipine and atorvastatin is appropriate.107

Current evidence-based practice guidelines for the management of hypertension in adults generally recommend the use of drugs from 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.501,502,503,504,1200,1213 However, recommendations for initial drug selection and use in specific patient populations may vary across these expert guidelines.501,502,503,504,1200 This variability is due, in part, to differences in the guideline development process and the types of studies (e.g., randomized controlled studies only versus a range of studies with different study designs) included in the evidence reviews.501,502,503,515,1200 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).501,502,503,504,515,1200,1201 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.102,104,501,502,523,1202

Disease Overview

Worldwide, hypertension is the most common modifiable risk factor for cardiovascular events and mortality.1205 The lifetime risk of developing hypertension in the US exceeds 80%, with higher rates observed among African Americans and Hispanics compared with whites or Asians.1200 The systolic blood pressure and diastolic blood pressure values defined as hypertension in adults (see Blood Pressure Classification under Uses: Hypertension) in a 2017 multidisciplinary guideline of the American College of Cardiology (ACC), American Heart Association (AHA), and a number of other professional organizations (subsequently referred to as the 2017 ACC/AHA hypertension guideline in this monograph)1200 are lower than those defined in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines,500 which results in an increase of approximately 14% in the prevalence of hypertension in the US.1200,1222 However, this change in definition results in only a 2% increase in the percentage of patients requiring antihypertensive drug therapy because nonpharmacologic treatment is recommended for most adults now classified by the 2017 ACC/AHA hypertension guideline as hypertensive who would not meet the JNC 7 definition of hypertension.500,1200,1222 Among US adults receiving antihypertensive drugs, approximately 53% have inadequately controlled blood pressure according to current ACC/AHA treatment goals.1206

Cardiovascular and Renal Sequelae

The principal goal of preventing and treating hypertension is to reduce the risk of cardiovascular and renal morbidity and mortality, including target organ damage.502,1200 The relationship between blood pressure and cardiovascular disease is continuous, consistent, and independent of other risk factors.1200 It is important that very high blood pressure be managed promptly to reduce the risk of target organ damage.1200 The higher the blood pressure, the more likely the development of myocardial infarction (MI), heart failure, stroke, and renal disease.502,1200 For adults 40-70 years of age, each 20-mm Hg increment in systolic blood pressure or 10-mm Hg increment in diastolic blood pressure doubles the risk of developing cardiovascular disease across the entire blood pressure range of 115/75 to 185/115 mm Hg.171,1200 For those older than 50 years of age, systolic blood pressure is a much more important risk factor for developing cardiovascular disease than is diastolic blood pressure.217,502 The rapidity with which treatment is required depends on the patient's clinical presentation (presence of new or worsening target organ damage) and the presence or absence of cardiovascular complications; the 2017 ACC/AHA hypertension guideline states that treatment of very high blood pressure should be initiated within at least 1 week.1200

Blood Pressure Classification

Accurate blood pressure measurement is essential for the proper diagnosis and management of hypertension.1200,1225,1226 Error in measuring blood pressure is a major cause of inadequate blood pressure control and may lead to overtreatment.1225,1226 Because a patient's blood pressure may vary in an unpredictable fashion, a single blood pressure measurement is not sufficient for clinical decision-making.1200 An average of 2 or 3 blood pressure measurements obtained on 2-3 separate occasions using proper technique should be used to minimize random error and provide a more accurate blood pressure reading.1200 Out-of-office blood pressure measurements may be useful for confirming and managing hypertension.1200 The 2017 ACC/AHA hypertension guideline document (available on the ACC and AHA websites) should be consulted for key steps on properly measuring blood pressure.1200

According to the 2017 ACC/AHA hypertension guideline, blood pressure in adults is classified into 4 categories: normal, elevated, stage 1 hypertension, and stage 2 hypertension.1200 (See Table 1.) The 2017 ACC/AHA hypertension guideline lowers the blood pressure threshold used to define hypertension in the US; previous hypertension guidelines (JNC 7) considered adults with systolic blood pressure of 120-139 mm Hg or diastolic blood pressure of 80-89 mm Hg to have prehypertension, those with systolic blood pressure of 140-159 mm Hg or diastolic blood pressure of 90-99 mm Hg to have stage 1 hypertension, and those with systolic blood pressure of 160 mm Hg or higher or diastolic blood pressure of 100 mm Hg or higher to have stage 2 hypertension.500,1200 The blood pressure definitions in the 2017 ACC/AHA hypertension guideline are based upon data from studies evaluating the association between systolic blood pressure/diastolic blood pressure and cardiovascular risk and the benefits of blood pressure reduction.1200 Individuals with systolic blood pressure and diastolic blood pressure in 2 different categories should be designated as being in the higher blood pressure category.1200

The blood pressure thresholds used to define hypertension, when to initiate drug therapy, and the ideal target blood pressure values remain controversial.505,506,507,508,515,523,530,1200,1201,1207,1209,1222,1223,1229 The 2017 ACC/AHA hypertension guideline recommends a blood pressure goal of less than 130/80 mm Hg in all adults who have confirmed hypertension and known cardiovascular disease or a 10-year atherosclerotic cardiovascular disease (ASCVD) event risk of 10% or higher; the ACC/AHA guideline also states that this blood pressure goal is reasonable to attempt to achieve in adults with confirmed hypertension who do not have increased cardiovascular risk.1200 The lower blood pressure values used to define hypertension and the lower target blood pressure goals outlined in the 2017 ACC/AHA hypertension guideline are based on clinical studies demonstrating a substantial reduction in the composite end point of major cardiovascular disease events and the combination of fatal and nonfatal stroke when a lower systolic blood pressure/diastolic blood pressure value (i.e., 130/80 mm Hg) was used to define hypertension.521,1210,1223 These lower target blood pressure goals also are based upon clinical studies demonstrating continuing reduction of cardiovascular risk at progressively lower levels of systolic blood pressure.1200,1202,1210 A linear relationship has been demonstrated between cardiovascular risk and blood pressure even at low systolic blood pressures (e.g., 120-124 mm Hg).1207 The 2017 ACC/AHA hypertension guideline recommends estimating a patient's ASCVD risk using the ACC/AHA Pooled Cohort equations (available online at [Web]), which are based on a variety of factors including age, race, gender, cholesterol levels, statin use, blood pressure, treatment for hypertension, history of diabetes mellitus, smoking status, and aspirin use.1200,1202 While the 2017 ACC/AHA hypertension guideline has lowered the threshold for diagnosing hypertension in adults, the threshold for initiating drug therapy has only been lowered for those patients who are at high risk of cardiovascular disease.1200,1222 Clinicians who support the 2017 ACC/AHA hypertension guideline believe that these recommendations have the potential to increase hypertension awareness, encourage lifestyle modification, and focus antihypertensive drug initiation and intensification in those adults at high risk for cardiovascular disease.1227

The lower blood pressure goals advocated in the 2017 ACC/AHA hypertension guideline have been questioned by some clinicians who have concerns regarding the guideline's use of extrapolated observational data, the lack of generalizability of some of the randomized trials (e.g., SPRINT) used to support the guideline, the difficulty of establishing accurate representative blood pressure values in typical clinical practice settings, and the accuracy of the cardiovascular risk calculator used in the guideline.1224,1229 Some clinicians state the lower blood pressure threshold used to define hypertension in the 2017 ACC/AHA hypertension guideline is not fully supported by clinical data, and these clinicians have expressed concerns about the possible harms (e.g., adverse effects of antihypertensive therapy) associated with classifying more patients as being hypertensive.1222,1223,1229 Some clinicians also state that using this guideline, a large number of young, low-risk patients would need to be treated in order to observe a clinical benefit,1200,1224 while other clinicians state that the estimated gains in life-expectancy attributable to long-term use of blood pressure-lowering drugs are correspondingly greater in this patient population.1200

Treatment Benefits

In clinical trials, antihypertensive therapy has been found to reduce the risk of developing stroke by about 34-40%, MI by about 20-25%, and heart failure by more than 50%.173,201,217,500 In a randomized, controlled study (SPRINT) that included hypertensive patients without diabetes mellitus who had a high risk of cardiovascular disease, intensive systolic blood pressure lowering of approximately 15 mm Hg was associated with a 25% reduction in cardiovascular disease events and a 27% reduction in all-cause mortality.1210,1219 However, the exclusion of patients with diabetes mellitus, prior stroke, and those younger than 50 years of age may decrease the generalizability of these findings.1210 Some experts estimate that if the systolic blood pressure goals of the 2017 ACC/AHA hypertension guideline are achieved, major cardiovascular disease events may be reduced by an additional 340,000 and total deaths by an additional 156,000 compared with implementation of the JNC 8 expert panel guideline goals but these benefits may be accompanied by an increase in the frequency of adverse events.1228 While there was no overall difference in the occurrence of serious adverse events in patients receiving intensive therapy for blood pressure control (systolic blood pressure target of less than 120 mm Hg) compared with those receiving less intense control (systolic blood pressure target of less than 140 mm Hg) in the SPRINT study, hypotension, syncope, electrolyte abnormalities, and acute kidney injury or acute renal failure occurred in substantially more patients receiving intensive therapy.1210

In the Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT), 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.69,70,108,109,110,111 Although these antihypertensive agents were comparably effective in providing important cardiovascular benefit, apparent differences in certain secondary outcomes were observed.69,70 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.110,111 The ALLHAT investigators suggested that the observed differences in 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.110,111 (See Clinical Benefits of Thiazides in Hypertension under Hypertension in Adults: Treatment Benefits in Uses in the Thiazides General Statement 40:28.20.)

General Considerations for Initial and Maintenance Antihypertensive Therapy

Nonpharmacologic Therapy

Nonpharmacologic measures (i.e., lifestyle/behavioral modifications) that are effective in lowering blood pressure include weight reduction (for those who are overweight or obese), dietary changes to include foods such as fruits, vegetables, whole grains, and low-fat dairy products that are rich in potassium, calcium, magnesium, and fiber (i.e., adoption of the Dietary Approaches to Stop Hypertension [DASH] eating plan), sodium reduction, increased physical activity, and moderation of alcohol intake.1200 Such lifestyle/behavioral modifications, including smoking cessation, enhance antihypertensive drug efficacy and decrease cardiovascular risk and remain an indispensable part of the management of hypertension.502,504,1200 Lifestyle/behavioral modifications without antihypertensive drug therapy are recommended for adults classified by the 2017 ACC/AHA hypertension guideline as having elevated blood pressure (systolic blood pressure 120-129 mm Hg and diastolic blood pressure less than 80 mm Hg) and in those with stage 1 hypertension (systolic blood pressure 130-139 mm Hg or diastolic blood pressure 80-89 mm Hg) who do not have preexisting cardiovascular disease or an estimated 10-year ASCVD risk of 10% or greater.1200

Initiation of Drug Therapy

Drug therapy in the management of hypertension must be individualized and adjusted based on the degree of blood pressure elevation while also considering cardiovascular risk factors.502,1200,1201 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, especially increased cardiovascular risk, require more prompt or aggressive therapy;1200 however, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial.504,505,506,507,508,515,523,530,1200,1207,1209

The 2017 ACC/AHA hypertension guideline and many experts currently state that the treatment of hypertension should be based not only on blood pressure values but also on patients' cardiovascular risk factors.502,1200,1219 For secondary prevention of recurrent cardiovascular disease events in adults with clinical cardiovascular disease or for primary prevention in adults with an estimated 10-year ASCVD risk of 10% or higher, the 2017 ACC/AHA hypertension guideline recommends initiation of antihypertensive drug therapy in conjunction with lifestyle/behavioral modifications at an average systolic blood pressure of 130 mm Hg or an average diastolic blood pressure of 80 mm Hg or higher.1200 For primary prevention of cardiovascular disease events in adults with a low (less than 10%) estimated 10-year risk of ASCVD, the 2017 ACC/AHA hypertension guideline recommends initiation of antihypertensive drug therapy in conjunction with lifestyle/behavioral modifications at a systolic blood pressure of 140 mm Hg or higher or a diastolic blood pressure of 90 mm Hg or higher.1200 After initiation of antihypertensive drug therapy, regardless of the ASCVD risk, the 2017 ACC/AHA hypertension guideline generally recommends a blood pressure goal of less than 130/80 mm Hg in all patients.1200,1202 In addition, a systolic blood pressure goal of less than 130 mm Hg also is recommended for noninstitutionalized ambulatory patients 65 years of age or older.1200 While these blood pressure goals are lower than those recommended for most patients in previous guidelines, they are based upon clinical studies demonstrating continuing reduction of cardiovascular risk at progressively lower levels of systolic blood pressure.1200,1202,1210

Most data indicate that patients with a higher cardiovascular risk will benefit the most from tighter blood pressure control; however, some experts state this treatment goal also may be beneficial in those at lower cardiovascular risk.1200 Other clinicians believe that the benefits of such blood pressure lowering do not outweigh the risks in those patients considered to be at lower risk of cardiovascular disease and that reclassifying individuals formerly considered to have prehypertension as having hypertension may potentially lead to use of drug therapy in such patients without consideration of cardiovascular risk.1201,1222,1223,1229 Previous hypertension guidelines, such as those from the JNC 8 expert panel, generally recommended initiation of antihypertensive treatment in patients with a systolic blood pressure of at least 140 mm Hg or diastolic blood pressure of at least 90 mm Hg, targeted a blood pressure goal of less than 140/90 mm Hg regardless of cardiovascular risk, and used higher systolic blood pressure thresholds and targets in geriatric patients.501 Some clinicians continue to support the target blood pressures recommended by the JNC 8 expert panel because of concerns that such recommendations in the 2017 ACC/AHA hypertension guideline are based on extrapolation of data from the high-risk population in the SPRINT study to a lower-risk population.1223,1224 Also, because more than 90% of patients in SPRINT were already receiving antihypertensive drugs at baseline, data are lacking on the effects of initiating drug therapy at a lower blood pressure threshold (130/80 mm Hg) in patients at high risk of cardiovascular disease.1223 The potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs should be considered when deciding a patient's blood pressure treatment goal.1200,1220,1229

The 2017 ACC/AHA hypertension guideline recommends an ASCVD risk assessment for all adults with hypertension; however, experts state that it can be assumed that patients with hypertension and diabetes mellitus or chronic kidney disease (CKD) are at high risk for cardiovascular disease and that antihypertensive drug therapy should be initiated in these patients at a blood pressure of 130/80 mm Hg or higher.1200 The 2017 ACC/AHA hypertension guideline also recommends a blood pressure goal of less than 130/80 mm Hg in patients with hypertension and diabetes mellitus or CKD.1200 These recommendations are based on a systematic review of high-quality evidence from randomized controlled trials, meta-analyses, and post hoc analyses that have demonstrated substantial reductions in the risk of important clinical outcomes (e.g., cardiovascular events) regardless of comorbid conditions or age when systolic blood pressure is lowered to less than 130 mm Hg.1200,1213 However, some clinicians have questioned the generalizability of findings from some of the trials (e.g., SPRINT) used to support the 2017 ACC/AHA hypertension guideline.1224 For example, SPRINT included adults (mean age: 68 years) without diabetes mellitus who were at high risk of cardiovascular disease.1209,1210 While benefits of intensive blood pressure control were observed in this patient population, some clinicians have questioned whether these findings apply to younger patients who have a low risk of cardiovascular disease.1223 In patients with CKD in the SPRINT trial, intensive blood pressure management (achieving a mean systolic blood pressure of approximately 122 mm Hg compared with 136 mm Hg with standard treatment) provided a similar beneficial reduction in the composite cardiovascular disease primary outcome and all-cause mortality as in the full patient cohort.1200,1210 Because most patients with CKD die from cardiovascular complications, the findings of this study further support a lower blood pressure target of less than 130/80 mm Hg.1200

Data are lacking to determine the ideal blood pressure goal in adult patients with hypertension and diabetes mellitus; also, studies evaluating the benefits of intensive blood pressure control in patients with diabetes mellitus have provided conflicting results.521,1200,1213 Clinical studies reviewed for the 2017 ACC/AHA hypertension guideline have shown similar quantitative benefits from blood pressure lowering in hypertensive patients with or without diabetes mellitus.1213 In a randomized, controlled study (ACCORD-BP) that compared a higher (systolic blood pressure less than 140 mm Hg) versus lower (systolic blood pressure less than 120 mm Hg) blood pressure goal in patients with diabetes mellitus, there was no difference in the incidence of cardiovascular outcomes (e.g., composite outcome of cardiovascular death, nonfatal MI, and nonfatal stroke).521,1214 However, some experts state that this study was underpowered to detect a difference between the 2 treatment groups and that the factorial design of the study complicated interpretation of the results.1200,1216 Although SPRINT did not include patients with diabetes mellitus, patients in this study with prediabetes demonstrated a similar cardiovascular benefit from intensive treatment of blood pressure as normoglycemic patients.1200 A meta-analysis of data from the ACCORD and SPRINT studies suggests that the findings of both studies are consistent and that patients with diabetes mellitus benefit from more intensive blood pressure control.1202,1217 These data support the 2017 ACC/AHA hypertension guideline recommendation of a blood pressure treatment goal of less than 130/80 mm Hg in adult patients with hypertension and diabetes mellitus.1200 Alternatively, the American Diabetes Association (ADA) recommends a blood pressure goal of less than 140/90 mm Hg in patients with diabetes mellitus.1214 The ADA states that a lower blood pressure goal (e.g., less than 130/80 mm Hg) may be appropriate for patients with a high risk of cardiovascular disease and diabetes mellitus if it can be achieved without undue treatment burden.1214

Further study is needed to more clearly define optimum blood pressure goals in patients with hypertension, particularly in high-risk groups (e.g., patients with diabetes mellitus, cardiovascular disease, or cerebrovascular disease; black patients); when determining appropriate blood pressure goals, individual risks and benefits should be considered in addition to the evidence from clinical studies.501,503,507,515,526,530,1200

Choice of 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 preferred options include ACE inhibitors, angiotensin II receptor antagonists, and thiazide diuretics.501,502,503,504,1200 (See Hypertension: Treatment Benefits, in Uses.) The 2017 ACC/AHA adult hypertension guideline states that a calcium-channel blocker, ACE inhibitor, angiotensin II receptor antagonist, or thiazide or thiazide-like diuretic (preferably chlorthalidone) are all acceptable choices for initial antihypertensive drug therapy in the general population of nonblack patients, including those with diabetes mellitus;1200 drugs from any of these classes generally produce similar benefits in terms of overall mortality and cardiovascular, cerebrovascular, and renal outcomes.501,502,504,1200,1213 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).501,504,1200 (See Race under Hypertension: Other Special Considerations for Antihypertensive Therapy, in Uses.) In black patients, including those with diabetes mellitus, the initial drug choice should include a thiazide diuretic or calcium-channel blocker.1200 Use of a calcium-channel blocker also may be beneficial in patients with certain coexisting conditions such as ischemic heart disease (e.g., angina)523 and in geriatric patients, including those with isolated systolic hypertension.502,510 (See Considerations for Drug Therapy in Patients with Underlying Cardiovascular and Other Risk Factors and also see Other Special Considerations for Antihypertensive Drug Therapy, under Uses: Hypertension in Adults, in the Thiazides General Statement 40:28.20.) Because many patients eventually will need more than one antihypertensive drug to achieve blood pressure control, any of the recommended drug classes may be considered for add-on therapy.1200

Experts state that in patients with stage 1 hypertension (especially the elderly, those with a history of hypotension, or those who have experienced adverse drug effects), it is reasonable to initiate drug therapy using the stepped-care approach in which one drug is initiated and titrated and other drugs are added sequentially to achieve the target blood pressure.1200 Although some patients can begin treatment with a single antihypertensive agent, starting with 2 first-line drugs in different pharmacologic classes (either as separate agents or in a fixed-dose combination) is recommended in patients with stage 2 hypertension and an average blood pressure more than 20/10 mm Hg above their target blood pressure.1200 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).102,104,1200 Drug regimens with complementary activity, where a second antihypertensive agent is used to block compensatory responses to the first agent or affect a different pressor mechanism, can result in additive blood pressure lowering and are preferred.1200 Drug combinations that have similar mechanisms of action or clinical effects (e.g., the combination of an ACE inhibitor and an angiotensin II receptor antagonist) generally should be avoided.1200 Many patients who begin therapy with a single antihypertensive agent will subsequently require at least 2 drugs from different pharmacologic classes to achieve their blood pressure goal.1200 Experts state that other patient-specific factors, such as age, concurrent medications, drug adherence, drug interactions, the overall treatment regimen, cost, and comorbidities, also should be considered when deciding on an antihypertensive drug regimen.1200 For any stage of hypertension, antihypertensive drug dosages should be adjusted and/or other agents substituted or added until goal blood pressure is achieved.1200 (See Follow-up and Maintenance Drug Therapy under Hypertension: General Considerations for Initial and Maintenance Antihypertensive Therapy, in Uses.)

Follow-up and Maintenance Drug Therapy

Several strategies are used for the titration and combination of antihypertensive drugs; these strategies, which are generally based on those used in randomized controlled studies, 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).1200 Combined use of an ACE inhibitor and angiotensin II receptor antagonist should be avoided because of the potential risk of adverse renal effects.1200 After initiating a new or adjusted antihypertensive drug regimen, patients should have their blood pressure reevaluated monthly until adequate blood pressure control is achieved.1200 Effective blood pressure control can be achieved in most hypertensive patients, but many will ultimately require therapy with 2 or more antihypertensive drugs.1200 In addition to measuring blood pressure, clinicians should evaluate patients for orthostatic hypotension, adverse drug effects, adherence to drug therapy and lifestyle modifications, and the need for drug dosage adjustments.1200 Laboratory testing such as electrolytes and renal function status and other assessments of target organ damage also should be performed.1200

Considerations for Drug Therapy in Patients with Underlying Cardiovascular and 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.102,502,1200 (See Table 2: Compelling Indications for Drug Classes based on Comorbid Conditions, in Considerations for Drug Therapy in Patients with Underlying Cardiovascular and Other Risk Factors under Uses: Hypertension in Adults, in the Thiazides General Statement 40:28.20.)

Other Special Considerations for Antihypertensive Therapy

Race

Most patients with hypertension, especially black patients, will require at least 2 antihypertensive drugs to achieve adequate blood pressure control.1200 Blood pressure response to calcium-channel blockers appears to be comparable in white and black patients.18,69,70 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).69,70,95,108,109,501,504,1200 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.501 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).501 (See Clinical Benefits of Thiazides in Hypertension under Hypertension in Adults: Treatment Benefits, in Uses in the Thiazides General Statement 40:28.20.) However, the combination of an ACE inhibitor or an angiotensin II receptor antagonist with a calcium-channel blocker or thiazide diuretic produces similar blood pressure lowering in black patients as in other racial groups.1200 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.95 (See Considerations for Drug Therapy in Patients with Underlying Cardiovascular and Other Risk Factors under Uses: Hypertension in Adults, in the Thiazides General Statement 40:28.20.)

Advanced 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.501,502,1200 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.502,510

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.502,504

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

Hypertensive Crises

Because of the slow onset of hypotensive effect with amlodipine,1,2,3,5 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.1

For additional information on the role of dihydropyridine calcium-channel blocking agents in the management of hypertension and angina, see Uses in Nifedipine 24:28.08.

Coronary Artery Disease

Amlodipine in fixed combination with atorvastatin (Caduet^®) is used in patients for whom treatment with both amlodipine and atorvastatin is appropriate.107

Angina

Amlodipine is used for the management of Prinzmetal variant angina and chronic stable angina pectoris.1,2,3,4,9 The drug has been used alone or in combination with other antianginal agents.1,2,3,4,9

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.1

Administration

Amlodipine besylate is administered orally.1,2,3,5 Amlodipine generally can be given without regard to meals.1

Dosage

Dosage of amlodipine besylate is expressed in terms of amlodipine.1

Hypertension

Amlodipine Therapy

The manufacturers state that the usual initial adult dosage of amlodipine is 2.5-5 mg once daily as monotherapy.1 In geriatric patients and small or frail individuals, an initial dosage of 2.5 mg once daily is recommended.1,21 This reduced initial dosage also can be used in adults when amlodipine is added to an existing antihypertensive drug regimen.1 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.1 Generally, dosage is increased gradually at 7- to 14-day intervals until optimum control of blood pressure is maintained.1 However, more rapid titration of dosage can be undertaken when clinically warranted, provided response and tolerance are assessed frequently.1 The usual maintenance dosage of amlodipine for the management of hypertension in adults is 2.5-10 mg once daily.1,1200

The manufacturer states that the safety and efficacy of amlodipine have not been established in pediatric patients younger than 6 years of a 1 however, for the management of hypertension in children 1-5 years of age†, an initial dosage of 0.1 mg/kg once daily and a maximum dosage of 0.6 mg/kg daily (up to 5 mg daily) has been recommended by some experts.1150 In children 6 years of age and older, some experts recommend an initial dosage of 2.5 mg once daily and a maximum dosage of 10 mg once daily.1150 However, the manufacturer states that the safety and efficacy of dosages exceeding 5 mg daily have not been established in pediatric patients.1 The manufacturer states that the usual effective dosage of amlodipine in children 6 years of age and older is 2.5-5 mg once daily.1 Experts state that the drug should be initiated at the low end of the dosage ran the dosage may be increased every 2-4 weeks until blood pressure is controlled, the maximum dosage is reached, or adverse effects occur.1150 For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.

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.21 Alternatively, such fixed combinations may be used if amlodipine dosages necessary for adequate response have been associated with development of edema.21 The fixed combination containing amlodipine and benazepril also may be used as a substitute for the individually titrated drugs.21 The recommended initial dosage is amlodipine 2.5 mg in fixed combination with benazepril hydrochloride 10 mg once daily.21 Dosage of the fixed combination containing amlodipine and benazepril should be adjusted according to the patient's response.21 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.21

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.21 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.21

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.134 The fixed-combination preparation containing amlodipine and olmesartan medoxomil also can be used as a substitute for the individually titrated drugs.134 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.134 If needed, dosage of the fixed combination may be increased after 2 weeks.134 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.134 Daily dosages exceeding 10 mg of amlodipine given in fixed combination with 40 mg of olmesartan medoxomil are not recommended by the manufacturer.134

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.134 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.134 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).134 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.134

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.132 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.132 The fixed-combination preparation containing amlodipine, olmesartan, and hydrochlorothiazide also can be used as a substitute for the individually titrated drugs.132 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).132 The commercially available preparation containing amlodipine in fixed combination with olmesartan and hydrochlorothiazide should not be used for the initial management of hypertension.132

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.130 In addition, patients who do not respond adequately to monotherapy may be switched to therapy with the fixed combination of amlodipine and perindopril arginine.130 Dosage of the fixed-combination preparation should be adjusted according to the patient's response at intervals of 7-14 days.130

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.130 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.130 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.130 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.130

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.130

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.130

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.129 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.129 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.129 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.129

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.129 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.129 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.129 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.129 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.129

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.113 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.113 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.113 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.113

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.113 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.113 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.113 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.113

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.133 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.133 The fixed-combination preparation containing amlodipine, valsartan, and hydrochlorothiazide also can be used as a substitute for the individually titrated drugs.133 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).133 The commercially available preparation containing amlodipine in fixed combination with valsartan and hydrochlorothiazide should not be used for the initial management of hypertension.133

Amlodipine/Atorvastatin Fixed-combination Therapy

The fixed-combination preparation containing amlodipine and atorvastatin may be used as a substitute for individually titrated drugs.107 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.107 Increased amounts of amlodipine, atorvastatin, or both components may be added for additional antihypertensive or antilipemic effects.107

The fixed-combination preparation may be used to provide additional therapy for patients currently receiving one component of the preparation.107 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.107

The fixed-combination preparation may be used to initiate treatment in patients with hypertension and dyslipidemias.107 The initial dosage of the fixed-combination preparation should be selected based on the recommended initial dosages of the individual components.107 For dosage recommendations for atorvastatin, see Dosage and Administration: Dosage, in Atorvastatin 24:06.08. The maximum dosage of amlodipine or atorvastatin in the fixed-combination preparation is 10 or 80 mg daily, respectively.107

Blood Pressure Monitoring and Treatment Goals

Blood pressure monitoring using an out-of-office (home [self-monitored]) or ambulatory method (using a device that measures blood pressure over a 24-hour period) as an adjunct to in-office monitoring generally is recommended to provide a more reliable assessment of blood pressure; studies suggest that out-of-office blood pressure may be a better predictor of hypertension-induced organ damage and cardiovascular risk than office blood pressure.502,503,504,538,1200 Periodic determination of blood pressure in both the morning and evening (before taking the morning or evening dose) is useful in monitoring daytime control and ensuring that the surge in blood pressure that occurs with arising has been modulated adequately.217,538 Occasionally, particularly in geriatric patients and those with orthostatic symptoms, monitoring should include blood pressure determinations in both the seated position and, to recognize possible postural hypotension, after standing quietly for 2-5 minutes.538,1200

Once antihypertensive drug therapy has been initiated, dosage generally is adjusted at approximately monthly intervals if blood pressure control is inadequate at a given dosa additional drugs may need to be added to an antihypertensive drug regimen to achieve adequate blood pressure control.1200 Once blood pressure has been stabilized, follow-up visits generally can be scheduled at 3- to 6-month intervals, depending on patient status.1200

Blood pressure should be monitored regularly (i.e., monthly) during therapy and dosage of the antihypertensive drug adjusted until blood pressure is controlled.1200 In patients who develop unacceptable adverse effects with amlodipine, the drug should be discontinued and another antihypertensive agent from a different pharmacologic class should be initiated.1200,1216 If an adequate blood pressure response is not achieved with amlodipine monotherapy, another antihypertensive agent with demonstrated benefit and preferably a complementary mechanism of action (e.g., angiotensin-converting enzyme [ACE] inhibitor, angiotensin II receptor antagonist, thiazide diuretic) may be added; if goal blood pressure is still not achieved with the use of 2 antihypertensive agents, a third drug may be added.1200,1216 (See Uses: Hypertension.)

The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure.1200 However, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial.505,506,507,508,515,523,530,1201,1207,1209,1222 While other hypertension guidelines have based target blood pressure goals on age and comorbidities,501,504,536 the 2017 American College of Cardiology (ACC)/ American Heart Association (AHA) hypertension guideline incorporates underlying cardiovascular risk into decision making regarding treatment and generally recommends the same target blood pressure (i.e., less than 130/80 mm Hg) for all adults.1200 Many patients will require at least 2 drugs from different pharmacologic classes to achieve this blood pressure goal; the potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs also should be considered when deciding a patient's blood pressure treatment goal.1200,1220 (See General Considerations for Initial and Maintenance Antihypertensive Therapy under Uses: Hypertension.)

For additional information on target levels of blood pressure and on monitoring therapy in the management of hypertension, see Blood Pressure Monitoring and Treatment Goals under Dosage: Hypertension, in Dosage and Administration in the Thiazides General Statement 40:28.20.

In children with hypertension with or without diabetes mellitus, blood pressure should be reduced to less than the corresponding age-adjusted 90th percentile value and to less than 130/80 mm Hg in adolescents at least 13 years of age.1150 In children and adolescents with hypertension and chronic kidney disease (CKD), the 24-hour mean arterial pressure (MAP) as determined by ambulatory blood pressure monitoring should be decreased to a value less than the 50th percentile.1150

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.1,2 The manufacturers state that adequate control of angina usually requires a maintenance dosage of 10 mg daily.1

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.1,2,3,4,6

Angiographically Documented Coronary Artery Disease

For the management of coronary artery disease, the recommended adult dosage of amlodipine is 5-10 mg once daily.1 In clinical studies the majority of patients required a dosage of 10 mg daily.1

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.107 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.107 Increased amounts of amlodipine, atorvastatin, or both components may be added for additional antianginal or antilipemic effects.107

The fixed-combination preparation may be used to provide additional therapy for patients currently receiving one component of the preparation.107 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.107

The fixed-combination preparation may be used to initiate treatment in patients with angina and dyslipidemias.107 The initial dosage of the fixed-combination preparation should be selected based on the recommended initial dosages of the individual components.107 For dosage recommendations for atorvastatin, see Dosage and Administration: Dosage, in Atorvastatin 24:06.08. The maximum dosage of amlodipine or atorvastatin in the fixed-combination preparation is 10 or 80 mg daily, respectively.107

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%),1,2,3,4,5 a reduced initial amlodipine dosage may be required1,2,4,21,107,113,129,132,133,134 and subsequent dosage should be titrated slowly in such patients.1,129

For the management of hypertension in adults with hepatic insufficiency, an initial amlodipine dosage of 2.5 mg once daily generally is recommended.1,21,107,129,134 Subsequent dosage should be adjusted according to patient response and tolerance but usually should not exceed 10 mg once daily.1 Commercially available preparations containing amlodipine in fixed combination with 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.113,129,132,133,134 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.130

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.1,107 The manufacturers state that adequate control of angina usually requires a maintenance dosage of 10 mg daily.1,107

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.1,2,3,5 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).21 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.132 The safety and efficacy of preparations containing amlodipine in fixed combination with valsartan (with or without hydrochlorothiazide) in patients with creatinine clearances less than 30 mL/minute have not been established.113,133 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.130 Dosage of the fixed combination of amlodipine and telmisartan should be titrated slowly in patients with severe renal impairment.129

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%),1,2,3,4,5 a reduced initial amlodipine dosage should be considered in such patients.1,2,4,21,107,113,129,132,133,134 For management of hypertension, some manufacturers recommend an initial amlodipine dosage of 2.5 mg once daily for geriatric patients;1 other manufacturers recommend this reduced dosage for geriatric patients 75 years of age or older.113,129,132,134 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.1,107 Commercially available preparations containing amlodipine in fixed combination with 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.113,129,132,133,134 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.130

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.1 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.130

Contraindications

Amlodipine is contraindicated in patients with known hypersensitivity to the drug.1

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.1

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.1

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.21,107,113,129,130,132,133,134 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.21,107,113,129,130,132,133,134

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.1,524 Cardiac morbidity and overall mortality rates in these studies were similar in patients receiving amlodipine and those receiving placebo.1

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%.1

Specific Populations

Pregnancy

Category C.1 (See Users Guide.)

Lactation

It is not known whether amlodipine is distributed into milk; the manufacturer recommends discontinuance of nursing if amlodipine is used.1

Pediatric Use

Safety and efficacy of amlodipine in children younger than 6 years of age have not been established.1 Efficacy of amlodipine (2.5-5 mg daily) for the treatment of hypertension has been established in pediatric patients 6-17 years of age.1

Safety and efficacy of amlodipine in fixed combination with atorvastatin, benazepril, olmesartan (with or without hydrochlorothiazide), perindopril, telmisartan, or valsartan (with or without hydrochlorothiazide) have not been established in children.21,107,113,129,130,132,133,134

Geriatric Use

In geriatric patients, amlodipine clearance is decreased and AUC is increased by about 40-60%.1 Therefore, amlodipine dosage should be selected carefully, usually initiating therapy with dosages at the lower end of the recommended range.1,113 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.1 (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.1 No substantial differences in safety and efficacy relative to younger adults have been observed in geriatric patients receiving amlodipine in fixed combination with benazepril, olmesartan (with or without hydrochlorothiazide), telmisartan, or valsartan (with or without hydrochlorothiazide), but increased sensitivity cannot be ruled out.21,113,129,132,133,134

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.130

The manufacturers state that safety and efficacy of amlodipine in fixed combination with atorvastatin have not been established in geriatric patients.107

Hepatic Impairment

In patients with hepatic impairment, amlodipine clearance is decreased and AUC is increased by about 40-60%.1 A reduced initial dosage of the drug is recommended,1,2,4,21,107,113,129,132,133,134 and subsequent dosage should be titrated slowly.1,129 (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.1 Edema, flushing, palpitations, and somnolence may occur more commonly in women than in men.1 Edema is dose related1 and may be less frequent with concomitant use of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor antagonist.21,134,504

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.21,107,113,129,130,132,133,134

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.1 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.1

Data on the effects of CYP3A inducers on amlodipine exposure are lacking; blood pressure should be closely monitored in patients receiving such concomitant therapy.1

Alcohol

Concomitant administration of alcohol with amlodipine did not alter systemic exposure to alcohol.1

Antacids

Concomitant administration of a magnesium- and aluminum hydroxide-containing antacid with amlodipine did not alter systemic exposure to amlodipine.1

Cimetidine

Concomitant administration of cimetidine with amlodipine did not alter systemic exposure to amlodipine.1

Digoxin

Concomitant administration of amlodipine with digoxin did not alter systemic exposure to digoxin.1

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.1

Erythromycin

Concomitant administration of erythromycin with amlodipine did not substantially alter systemic exposure to amlodipine in healthy individuals.1

Grapefruit Juice

The manufacturer states that concomitant administration of grapefruit juice with amlodipine did not alter systemic exposure to amlodipine.1 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,64,65,74,75 there currently is no evidence of altered amlodipine pharmacodynamics by concurrent ingestion of grapefruit juice in healthy individuals.64,74 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.64,68,74,75 (See Drug Interactions: Grapefruit Juice, in Nifedipine 24:28.08.)

HMG-CoA Reductase Inhibitors

Atorvastatin

Concomitant administration of amlodipine with atorvastatin did not alter systemic exposure to atorvastatin.1

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.1 In patients receiving amlodipine, simvastatin dosage should not exceed 20 mg daily.1

Immunosuppressants

Cyclosporine

Concomitant use of cyclosporine and amlodipine may result in increased systemic exposure to cyclosporine.1 Concomitant use of amlodipine with cyclosporine in renal allograft recipients resulted in a 40% increase in trough concentrations of the immunosuppressant.1 If concomitant use is required, cyclosporine concentrations should be monitored frequently and cyclosporine dosage adjusted as needed.1

Tacrolimus

Concomitant use of tacrolimus and amlodipine may result in increased systemic exposure to tacrolimus.1 If concomitant use is required, tacrolimus concentrations should be monitored frequently and tacrolimus dosage adjusted as needed.1

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 CYP3A5.1 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.1 Irrespective of CYP3A5 genotype, the possibility of an interaction between tacrolimus and amlodipine cannot be excluded.1

Protein-bound Drugs

In vitro data indicate that amlodipine does not alter plasma protein binding of digoxin, indomethacin, phenytoin, or warfarin.1

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.1 Patients receiving sildenafil concomitantly with amlodipine should be monitored for hypotension.1

Warfarin

Concomitant administration of amlodipine with warfarin did not alter prothrombin time.1

Description

Amlodipine is a 1,4-dihydropyridine-derivative calcium-channel blocking agent that is structurally related to felodipine, nifedipine, and nimodipine.1,2 Unlike other currently available agents in the dihydropyridine class, amlodipine has an intrinsically long duration of action.1,2,3

Following oral administration of amlodipine besylate, peak plasma concentrations of the drug are attained within 6-12 hours.1 Absolute bioavailability ranges from 64-90%;1 food does not affect bioavailability of amlodipine.1,107,113,129,130,132,133,134 Amlodipine is approximately 93% bound to plasma proteins.1 The drug is extensively (approximately 90%) metabolized to inactive metabolites in the liver.1 Amlodipine is excreted in urine as metabolites (60%) and unchanged drug (10%).1 The terminal elimination half-life of amlodipine is 30-50 hours.1

Advice to Patients

When amlodipine is used in fixed combination with other drugs, importance of informing patients of important cautionary information about the concomitant agent(s).21,107,113,129,130,132,133,134

Importance of instructing patients not to remove tablets containing amlodipine in fixed combination with telmisartan from the blister package until immediately before administration.129

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

Importance of advising patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Pfizer Laboratories. Norvasc^® (amlodipine besylate) tablets prescribing information. New York, NY; 2015 Mar.

2. Murdoch D, Heel RC. Amlodipine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in cardiovascular disease. Drugs . 1991; 41:478-505. [PubMed 1711448]

3. Burges RA, Dodd MG. Amlodipine. Cardiovasc Drug Rev . 1990; 8:25-44.

4. Anon. Amlodipine—a new calcium-channel blocker. Med Lett Drugs Ther . 1992; 34:99-100. [PubMed 1406450]

5. Meredith PA, Elliott HL. Clinical pharmacokinetics of amlodipine. Clin Pharmacokinet . 1992; 22:22-31. [PubMed 1532771]

6. Julius S. Amlodipine in hypertension: an overview of the clinical dossier. J Cardiovasc Pharmacol . 1988; 12(Suppl 7):S27-33.

9. DiBianco R, Schoomaker FW, Singh JB et al. Amlodipine combined with beta blockade for chronic angina: results of a multicenter, placebo-controlled, randomized double-blind study. Clin Cardiol . 1992; 15:519-24. [PubMed 1354085]

10. Thadani U and the Amlodipine Study Group. Amlodipine: A once-daily calcium antagonist in the treatment of angina pectoris—a parallel dose-response, placebo controlled study. Am Heart J . 1989; 118(5 Part 2):1135. [PubMed 2530876]

11. Taylor SH, Lee P, Jackson N et al. A four-week double-blind, placebo-controlled, parallel dose-response study of amlodipine in patients with stable exertional angina pectoris. Am Heart J . 1989; 118(5 Part 2):1133-4. [PubMed 2530875]

13. Sandoz Pharmaceuticals Corp. DynaCirc^® (isradipine) capsules prescribing information. East Hanover, NJ; 1992 Jun.

14. Lopez LM, Santiago TM. Isradipine—another calcium-channel blocker for the treatment of hypertension and angina. Ann Pharmacother . 1992; 26:789-99. [PubMed 1535246]

15. Fitton A, Benfield P. Isradipine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in cardiovascular disease. Drugs . 1990; 40:31-74. [PubMed 2143980]

16. Walton T, Symes LR. Felodipine and isradipine: new calcium-channel blocking agents for the treatment of hypertension. Clin Pharm . 1993; 12:261-75. [PubMed 8458178]

17. Prisant LM, Carr AA, Nelson EB et al. Isradipine vs propranolol in hydrochlorothiazide-treated hypertensives: a multicenter evaluation. Arch Intern Med . 1989; 149:2453-7. [PubMed 2530945]

18. Anon. Isradipine for hypertension. Med Lett Drugs Ther . 1991; 33:51-4. [PubMed 1827655]

19. Alderman MH. Which antihypertensive drugs first—and why! JAMA . 1992; 267:2786-7. Editorial.

20. Weber MA, Laragh JH. Hypertension: steps forward and steps backward: the Joint National Committee fifth report. Arch Intern Med . 1993; 153:149-52. [PubMed 8422205]

21. Novartis. Lotrel^® (amlodipine and benazepril hydrochloride) capsules prescribing information. East Hanover, NJ; 2015 May.

22. Glasser SP, Clark PI, Lipicky RJ et al. Exposing patients with chronic, stable, exertional angina to placebo periods in drug trials. JAMA . 1991; 265:1550-4. [PubMed 1671885]

23. National Heart, Lung, and Blood Institute. NHLBI panel reviews safety of calcium channel blockers. Rockville, MD; 1995 Aug 31. Press release.

24. National Heart, Lung, and Blood Institute. New analysis regarding the safety of calcium-channel blockers: a statement for health professionals from the National Heart, Lung, and Blood Institute. Rockville, MD; 1995 Sep 1.

25. Anon. NHLBI panel stands by JNC V in response to Circulation CCB article; AIM report supports use of beta blockers for prevention of sudden cardiac death. F-D- C Rep . 1995; 57(Sep 4):3-4.

26. American Heart Association. Public advisory statement on calcium channel blocker drugs. Dallas, TX; 1995 Aug 28.

27. Psaty BM, Heckbert SR, Koepsell TD et al. The risk of myocardial infarction associated with antihypertensive drug therapies. JAMA . 1995; 274:620-5. [PubMed 7637142]

28. Psaty BM, Heckbert SR, Koepsell TD et al. The risk of incident myocardial infarction associated with anti- hypertensive drug therapies. Circulation . 1995; 91:925.

29. Buring JE, Glynn RJ, Hennekens CH. Calcium channel blockers and myocardial infarction: a hypothesis formulated but not yet tested. JAMA . 1995; 274:654-5. [PubMed 7637148]

30. Furberg CD, Psaty BM, Meyer JV. Nifedipine: dose-related increase in mortality in patients with coronary heart disease. Circulation . 1995; 92:1326-31. [PubMed 7648682]

31. Opie LH, Messerli FH. Nifedipine and mortality: grave defects in the dossier. Circulation . 1995; 92:1068-73. [PubMed 7648646]

32. Kloner RA. Nifedipine in ischemic heart disease. Circulation . 1995; 92:1074-8. [PubMed 7648647]

33. Yusuf S. Calcium antagonists in coronary artery disease and hypertension: time for reevaluation? Circulation . 1995; 92:1079-82. Editorial.

34. Lenfant C. The calcium channel blocker scare: lessons for the future. Circulation . 1995; 91:2855-6. [PubMed 7796490]

35. Habib GB. Are calcium antagonists harmful in hypertensive patients? Distinguishing hype from reality. Chest . 1995; 108:3-5. [PubMed 7606987]

36. Horton R. Spinning the risks and benefits of calcium antagonists. Lancet . 1995; 346:586-7. [PubMed 7650997]

37. Yusuf S, Held P, Furberg C. Update of effects of calcium antagonists in myocardial infarction or angina in light of the Second Danish Verapamil Infarction Trial (DAVIT-II) and other recent studies. Am J Cardiol . 1991; 67:1295-7. [PubMed 2035457]

38. Egstrup K, Andersen PE Jr. Transient myocardial ischemia during nifedipine therapy in stable angina pectoris, and its relation to coronary collateral flow and comparison with metoprolol. Am J Cardiol . 1993; 71:177-83. [PubMed 8421980]

39. Wagenknecht LE, Furberg CD, Hammon JW et al. Surgical bleeding: unexpected effect of a calcium antagonist. BMJ . 1995; 310:776-7. [PubMed 7711582][PubMedCentral]

40. Miles Inc. American Heart Association, Dr. Psalty and Miles Inc. release statements qualifying possible risks of calcium channel blockers. West Haven, CT; 1995 Mar 15. Press release.

41. Dear healthcare professional letter regarding calcium-channel blockers and increased risk of heart attack. Chicago:Searle. 1995 Mar 17.

42. McClellan K. Unexpected results from MIDAS in atherosclerosis. Inpharma Wkly . 1994; Apr 9:4.

43. Anon. Groups act to dispel concerns about calcium-channel blockers. Am J Health- Syst Pharm . 1995; 52:1154, 58. [PubMed 7656105]

44. Waters D. Proischemic complications of dihydropyridine calcium channel blockers. Circulation . 1991; 84:2598-600. [PubMed 1959210]

45. Messerli FH. Case-control study, meta-analysis, and bouillabaisse: putting the calcium antagonist scare into context. Ann Intern Med . 1995; 123:888-9. [PubMed 7486476]

46. Reviewers' comments (personal observations).

47. Pratt Pharmaceuticals. Procardia^® (nifedipine) capsules prescribing information (dated 1993 Feb). In: Physicians' desk reference. 49th ed. Montvale, NJ: Medical Economics Company Inc; 1995:1906-7.

48. Held PH, Yusuf S, Furberg CD. Calcium channel blockers in acute myocardial infarction and unstable angina: an overview. BMJ . 1989; 299:1187-92. [PubMed 2513047][PubMedCentral]

50. Kaplan NM. Choice of initial therapy for hypertension. JAMA . 1996; 275:1577-80. [PubMed 8622249]

51. Psaty BM, Smith NL, Siscovich DS et al. Health outcomes associated with antihypertensive therapies used as first-line agents: a systematic review and meta-analysis. JAMA . 1997; 277:739-45. [PubMed 9042847]

54. Velussi M, Brocco E, Frigato F et al. Effects of cilazapril and amlodipine on kidney function in hypertensive NIDDM patients. Diabetes . 1996; 45:216-22. [PubMed 8549868]

55. Estacio RO, Jeffers BW, Hiatt WR et al. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. N Engl J Med . 1998; 338:645-52. [PubMed 9486993]

56. Pahor M, Psaty BM, Furberg CD. Treatment of hypertensive patients with diabetes. Lancet . 1998; 351:689-90. [PubMed 9504510]

57. Tatti P, Pahor M, Byington RP et al. Outcome results of the Fosinopril versus Amlodipine Cardiovascular Events randomized Trial (FACET) in patients

58. Byington RP, Craven TE, Furberg CD et al. Isradipine, raised glycosylated haemoglobin, and risk of cardiovascular events. Lancet . 1997; 350:1075-6. [PubMed 10213554]

59. Alderman M, Madhavan S, Cohen H. Calcium antagonists and cardiovascular events in patients with hypertension and diabetes. Lancet . 1998; 351:216-7. [PubMed 9449897]

60. Josefson D. Infarction risk found with calcium channel blocker. BMJ . 1998; 316:797.

61. Cutler JA. Calcium-channel blockers for hypertension—uncertainty continues. N Engl J Med . 1998; 338:679-81. [PubMed 9486999]

62. Bayer, West Haven, CT: Personal communication.

63. Bakris GL, Copley JB, Vicknair N et al. Calcium channel blockers versus other antihypertensive therapies on progression of NIDDM associated nephropathy. Kidney Int . 1996; 50:1641-50. [PubMed 8914031]

64. Joseffson M, Zackrisson AL, Ahlner J. Effect of grapefruit juice on the pharmacokineitcs of amlodipine. Eur J Clin Pharmacol . 1996; 51:189-93. [PubMed 8911887]

65. Ameer B, Weintraub RA. Drug interactions with grapefruit juice. Clin Pharmacokinet . 1997; 33:103-21. [PubMed 9260034]

66. Roller L. Drugs and grapefruit juice. Clin Pharmacol Ther . 1998; 63:87. [PubMed 9465845]

67. Spence JD. Drugs and grapefruit juice. Clin Pharmacol Ther . 1998; 63:87-8. [PubMed 9465845]

68. Bailey DG, Arnold JMO, Spence JD. Grapefruit juice and drugs: how significant is the interaction? Clin Pharmacokin . 1994; 26:91-8.

69. Appel LJ. The verdict from ALLHAT—thiazide diuretics are the preferred initial therapy for hypertension. JAMA . 2002; 288:3039-42. [PubMed 12479770]

70. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA . 2002; 288:2981-97. [PubMed 12479763]

71. Pahor M, Psaty BM, Alderman MH et al. Health outcomes associated with calcium channel antagonists compared with other first-line antihypertensive therapies: a meta-analysis of randomized control trails. Lancet . 2000; 356:1949-54. [PubMed 11130522]

72. Blood Pressure Lowering Treatment Trialists' Collaboration. Effects of ACE inhibitors, calcium antagonists, and other blood pressure-lowering drugs: results of prospectively designed overviews of randomized trials. Lancet . 2000; 355:1955-64. [PubMed 10859041]

73. Brown MJ, Palmer CR, Castaigne A et al. Morbidity and mortality in patients randomized to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet . 2000; 356:366-72. [PubMed 10972368]

74. Vincent J, Harris SI, Foulds G et al. Lack of effect on grapefruit juice on the pharmacokinetics and pharmacodynamics of amlodipine. Br J Clin Pharmacol . 2000; 50:455-63. [PubMed 11069440][PubMedCentral]

75. Vincent J, Harris S, Foulds G et al. Amlodipine and grapefruit juice. Br J Clin Pharmacol . 2002; 53:406. [PubMedCentral]

76. Riley LJ Jr, Vlasses PH, Ferguson RK. Clinical pharmacology and therapeutic applications of the new oral converting enzyme inhibitor, enalapril. Am Heart J . 1985; 109:1085-9. [PubMed 2986440]

77. Kaplan NM. Initial treatment of adult patients with essential hypertension. Part 2: alternating monotherapy is the preferred treatment. Pharmacotherapy . 1985; 5:195-200. [PubMed 4034407]

79. Izzo JL, Levy D, Black HR. Importance of systolic blood pressure in older Americans. Hypertension . 2000; 35:1021-4. [PubMed 10818056]

80. Frohlich ED. Recognition of systolic hypertension for hypertension. Hypertension . 2000; 35:1019-20. [PubMed 10818055]

81. Bakris GL, Williams M, Dworkin L et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis . 2000; 36:646-61. [PubMed 10977801]

83. Neal B, MacMahon S, Chapman N. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs. Lancet . 2000;356:1955-64. [PubMed 11130523]

84. Cushman WC, Ford CE, Cutler JA, et al. Success and predictors of blood pressure control in diverse North American settings: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). J Clin Hypertens (Greenwich) . 2002;4:393-404. [PubMed 12461301]

85. Black HR, Elliott WJ, Neaton JD et al. Baseline characteristics and elderly blood pressure control in the CONVINCE trial. Hypertension . 2001; 37:12-18. [PubMed 11208750]

86. Black HR, Elliott WJ, Grandits G, et al. Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial. JAMA . 2003;289:2073-2082. [PubMed 12709465]

87. Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint Reduction in Hypertension Study (LIFE). Lancet . 2002;359:995-1003. [PubMed 11937178]

88. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med . 2000;342:145-153. [PubMed 10639539]

89. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet . 2001;358:1033-41. [PubMed 11589932]

90. Wing LMH, Reid CM, Ryan P, et al, for Second Australian National Blood Pressure Study Group. A comparison of outcomes with angiotensin-converting-enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med . 2003;348:583-92. [PubMed 12584366]

92. Hager WD, Davis BR, Riba A, et al, for the Survival and Ventricular Enlargement (SAVE) Investigators. Absence of a deleterious effect of calcium channel blockers in patients with left ventricular dysfunction after myocardial infarction: the SAVE Study Experience. Am Heart J . 1998;135:406-13. [PubMed 9506325]

93. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med . 2003;348:1309-1321. [PubMed 12668699]

95. Douglas JG, Bakris GL, Epstein M et al. Management of high blood pressure in African Americans: Consensus statement of the Hypertension in African Americans Working Group of the International Society on Hypertension in Blacks. Arch Intern Med . 2003; 163:525-41. [PubMed 12622600]

96. Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult. J Am Coll Cardiol . 2001;38:2101-2113. [PubMed 11738322]

97. β-Blocker Heart Attack Trial Research Group. A randomized trial of propranolol in patients with acute myocardial infarction: I. Mortality results. JAMA . 1982; 247:1707-14. [PubMed 7038157]

98. The Capricorn Investigators. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the Capricorn randomized trial. Lancet . 2001; 357:1385-90. [PubMed 11356434]

99. Pfeffer MA, Braunwald E, Moye LA et al for the SAVE Investigators Group. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the Survival and Ventricular Enlargment Trial. N Engl J Med . 1992; 327:669. [PubMed 1386652]

101. Hajjar I, Kotchen TA. Trends in prevalence, awareness, treatment, and control of hypertension in the United States, 1988-2000. JAMA . 2003; 290:199-206. [PubMed 12851274]

102. The Guidelines Subcommittee of the WHO/ISH Mild Hypertension Liaison Committee. 1999 guidelines for the management of hypertension. J Hypertension . 1999; 17:392-403.

103. National Kidney Foundation Guideline. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Kidney Disease Outcome Quality Initiative. Am J Kidney Dis . 2002; 39(Suppl 2):S1-246.

104. Reviewers' comments (personal observations) on the Thiazides General Statement 40:28.

107. Pfizer Labs. Caduet^® (amlodipine besylate/atorvastatin calcium) tablets prescribing information. New York, NY; 2015 Mar.

108. Wright JT, Dunn JK, Cutler JA et al. Outcomes in hypertensive black and nonblack patients treated with chlorthalidone, amlodipine, and lisinopril. JAMA . 2005; 293:1595-607. [PubMed 15811979]

109. Neaton JD, Kuller LH. Diuretics are color blind. JAMA . 2005; 293:1663-6. [PubMed 15811986]

110. Leenen FHH, Nwachuku CE, Black HR et al. Clinical events in high-risk hypertensive patients randomly assigned to calcium-channel blocker versus angiotensin-converting enzyme inhibitor in the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial. Hypertension . 2006; 48:374-84. [PubMed 16864749]

111. Messerli FH, Staessen JA. Amlodipine better than lisinopril: how one randomized clinical trial ended fallacies from observational studies. Hypertension . 2006; 48:359-61. [PubMed 16894055]

113. Novartis Pharmaceuticals Corp. Exforge^® (amlodipine and valsartan) tablets prescribing information. East Hanover, NJ; 2014 Sep.

125. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA . 1991; 265:3255-64. [PubMed 2046107]

127. MRC Working Party. Medical Research Council trial of treatment of hypertension in older adults: principal results. BMJ . 1992; 304:405-12. [PubMed 1445513][PubMedCentral]

129. Boehringer Ingelhein Pharmaceuticals, Inc. Twynsta^® (telmisartan and amlodipine besylate) tablets prescribing information. Ridgefield, CT; 2014 Dec.

130. Symplmed, LLC. Prestalia^® (perindopril arginine and amlodipine besylate) tablets prescribing information. Cincinnati, OH; 2015 Jan.

132. Daiichi Sankyo, Inc. Tribenzor^® (olmesartan medoxomil, amlodipine, hydrochlorothiazide) tablets prescribing information. Parsippany, NJ; 2014 Sep.

133. Novartis Pharmaceuticals Corporation. Exforge HCT^® (amlodipine, valsartan, hydrochlorothiazide) tablets prescribing information. East Hanover, NJ; 2014 Sep.

134. Daiichi Sankyo, Inc. Azor^® (amlodipine and olmesartan medoxomil) tablets prescribing information. Parsippany, NJ; 2014 Sep.

171. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specific relevance of usual blood pressure to vascular mortality. Lancet . 2002;360:1903-13. [PubMed 12493255]

173. Neal B, MacMahon S, Chapman N. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs. Lancet . 2000;356:1955-64. [PubMed 11130523]

178. Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint Reduction in Hypertension Study (LIFE). Lancet . 2002;359:995-1003. [PubMed 11937178]

201. Ogden LG, He J, Lydick E, Whelton PK. Long-term absolute benefit of lowering blood pressure in hypertensive patients according to the JNC VI risk stratification. Hypertension . 2000;35:539-543. [PubMed 10679494]

217. The Guidelines Subcommittee of the WHO/ISH Mild Hypertension Liaison Committee. 1999 guidelines for the management of hypertension. J Hypertension . 1999; 17:392-403.

500. National Heart, Lung, and Blood Institute National High Blood Pressure Education Program. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7). Bethesda, MD: National Institutes of Health; 2004 Aug. (NIH publication No. 04-5230.)

501. James PA, Oparil S, Carter BL et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA . 2014; 311:507-20. [PubMed 24352797]

502. Mancia G, Fagard R, Narkiewicz K et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens . 2013; 31:1281-357. [PubMed 23817082]

503. Go AS, Bauman MA, Coleman King SM et al. An effective approach to high blood pressure control: a science advisory from the American Heart Association, the American College of Cardiology, and the Centers for Disease Control and Prevention. Hypertension . 2014; 63:878-85. [PubMed 24243703]

504. Weber MA, Schiffrin EL, White WB et al. Clinical practice guidelines for the management of hypertension in the community: a statement by the American Society of Hypertension and the International Society of Hypertension. J Clin Hypertens (Greenwich) . 2014; 16:14-26. [PubMed 24341872]

505. Wright JT, Fine LJ, Lackland DT et al. Evidence supporting a systolic blood pressure goal of less than 150 mm Hg in patients aged 60 years or older: the minority view. Ann Intern Med . 2014; 160:499-503. [PubMed 24424788]

506. Mitka M. Groups spar over new hypertension guidelines. JAMA . 2014; 311:663-4. [PubMed 24549531]

507. Peterson ED, Gaziano JM, Greenland P. Recommendations for treating hypertension: what are the right goals and purposes?. JAMA . 2014; 311:474-6. [PubMed 24352710]

508. Bauchner H, Fontanarosa PB, Golub RM. Updated guidelines for management of high blood pressure: recommendations, review, and responsibility. JAMA . 2014; 311:477-8. [PubMed 24352759]

510. Staessen JA, Fagard R, Thijs L et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet . 1997; 350:757-64. [PubMed 9297994]

511. JATOS Study Group. Principal results of the Japanese trial to assess optimal systolic blood pressure in elderly hypertensive patients (JATOS). Hypertens Res . 2008; 31:2115-27. [PubMed 19139601]

515. Thomas G, Shishehbor M, Brill D et al. New hypertension guidelines: one size fits most?. Cleve Clin J Med . 2014; 81:178-88. [PubMed 24591473]

516. Wright JT, Bakris G, Greene T et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA . 2002; 288:2421-31. [PubMed 12435255]

521. ACCORD Study Group, Cushman WC, Evans GW et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med . 2010; 362:1575-85. [PubMed 20228401][PubMedCentral]

522. Patel A, ADVANCE Collaborative Group, MacMahon S et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet . 2007; 370:829-40. [PubMed 17765963]

523. Fihn SD, Gardin JM, Abrams J et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation . 2012; 126:e354-471.

524. WRITING COMMITTEE MEMBERS, Yancy CW, Jessup M et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation . 2013; 128:e240-327.

525. Smith SC, Benjamin EJ, Bonow RO et al. AHA/ACCF Secondary Prevention and Risk Reduction Therapy for Patients with Coronary and other Atherosclerotic Vascular Disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation. Circulation . 2011; 124:2458-73. [PubMed 22052934]

526. Kernan WN, Ovbiagele B, Black HR et al. Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke . 2014; :. [PubMed 24788967]

527. O'Gara PT, Kushner FG, Ascheim DD et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation . 2013; 127:e362-425. [PubMedCentral]

530. Myers MG, Tobe SW. A Canadian perspective on the Eighth Joint National Committee (JNC 8) hypertension guidelines. J Clin Hypertens (Greenwich) . 2014; 16:246-8. [PubMed 24641124]

531. . Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet . 2000; 355:253-9. [PubMed 10675071]

535. Taler SJ, Agarwal R, Bakris GL et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for management of blood pressure in CKD. Am J Kidney Dis . 2013; 62:201-13. [PubMed 23684145][PubMedCentral]

536. Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group. KDIGO clinical practice guideline for the management of blood pressure in chronic kidney disease. Kidney Int Suppl . 2012: 2: 337-414.

538. Pickering TG, White WB, American Society of Hypertension Writing Group. When and how to use self (home) and ambulatory blood pressure monitoring. J Am Soc Hypertens . 2008 May-Jun; 2:119-24.

541. Perk J, De Backer G, Gohlke H et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart J . 2012; 33:1635-701. [PubMed 22555213]

800. Yancy CW, Jessup M, Bozkurt B et al. 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation . 2016; :.

1150. Flynn JT, Kaelber DC, Baker-Smith CM et al. Clinical practice guideline for screening and management of high blood pressure in children and adolescents. Pediatrics . 2017; 140 [PubMed 28827377]

1200. Whelton PK, Carey RM, Aronow WS et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension . 2018; 71:el13-e115. [PubMed 29133356]

1201. Bakris G, Sorrentino M. Redefining hypertension - assessing the new blood-pressure guidelines. N Engl J Med . 2018; 378:497-499. [PubMed 29341841]

1202. Carey RM, Whelton PK, 2017 ACC/AHA Hypertension Guideline Writing Committee. Prevention, detection, evaluation, and management of high blood pressure in adults: synopsis of the 2017 American College of Cardiology/American Heart Association hypertension guideline. Ann Intern Med . 2018; 168:351-358. [PubMed 29357392]

1205. Aronow WS, Frishman WH. Implications of the New National Guidelines for Hypertension. Cardiol Rev . 2018 Mar/Apr; 26:55-61. [PubMed 29419560]

1206. Benjamin EJ, Virani SS, Callaway CW et al. Heart Disease and Stroke Statistics-2018 Update: A Report From the American Heart Association. Circulation . 2018; 137:e67-e492. [PubMed 29386200]

1207. Burnier M, Oparil S, Narkiewicz K et al. New 2017 American Heart Association and American College of Cardiology guideline for hypertension in the adults: major paradigm shifts, but will they help to fight against the hypertension disease burden?. Blood Press . 2018; 27:62-65. [PubMed 29447001]

1209. Qaseem A, Wilt TJ, Rich R et al. Pharmacologic treatment of hypertension in adults aged 60 years or older to higher versus lower blood pressure targets: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med . 2017; 166:430-437. [PubMed 28135725]

1210. SPRINT Research Group, Wright JT, Williamson JD et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med . 2015; 373:2103-16. [PubMed 26551272]

1213. Reboussin DM, Allen NB, Griswold ME et al. Systematic review for the 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol . 2017; [PubMed 29146534]

1214. American Diabetes Association. 9. Cardiovascular disease and risk management: standards of medical care in diabetes 2018. Diabetes Care . 2018; 41:S86-S104. [PubMed 29222380]

1215. de Boer IH, Bangalore S, Benetos A et al. Diabetes and hypertension: a position statement by the American Diabetes Association. Diabetes Care . 2017; 40:1273-1284. [PubMed 28830958]

1216. Taler SJ. Initial treatment of hypertension. N Engl J Med . 2018; 378:636-644. [PubMed 29443671]

1217. Perkovic V, Rodgers A. Redefining Blood-Pressure Targets--SPRINT Starts the Marathon. N Engl J Med . 2015; 373:2175-8. [PubMed 26551394]

1218. Messerli FH, Bangalore S, Bavishi C et al. Angiotensin-Converting Enzyme Inhibitors in Hypertension: To Use or Not to Use?. J Am Coll Cardiol . 2018; 71:1474-1482. [PubMed 29598869]

1219. Karmali KN, Lloyd-Jones DM. Global risk assessment to guide blood pressure management in cardiovascular disease prevention. Hypertension . 2017; 69:e2-e9. [PubMed 28115516]

1220. Cifu AS, Davis AM. Prevention, detection, evaluation, and management of high blood pressure in adults. JAMA . 2017; 318:2132-2134. [PubMed 29159416]

1222. Bell KJL, Doust J, Glasziou P. Incremental benefits and harms of the 2017 American College of Cardiology/American Heart Association high blood pressure guideline. JAMA Intern Med . 2018; 178:755-7. [PubMed 29710197]

1223. LeFevre M. ACC/AHA hypertension guideline: what is new? what do we do?. Am Fam Physician . 2018; 97(6):372-3. [PubMed 29671534]

1224. Brett AS. New hypertension guideline is released. From NEJM Journal Watch website. Accessed 2018 Jun 18. [Web]

1225. Einstadter D, Bolen SD, Misak JE et al. Association of repeated measurements with blood pressure control in primary care. JAMA Intern Med . 2018; 178(6):858-60. [PubMed 29710186]

1226. Baron RB. Treating blood pressure correctly by measuring it correctly. JAMA Intern Med . 2018; 178(6):860-1. [PubMed 29710072]

1227. Muntner P, Carey RM, Gidding S et al. Potential US population impact of the 2017 ACC/AHA high blood pressure guideline. Circulation . 2018; 137(2):109-18. [PubMed 29133599]

1228. Bundy JD, Mills KT, Chen J et al. Estimating the association of the 2017 and 2014 hypertension guidelines with cardiovascular events and deaths in US adults. An analysis of national data. JAMA Cardiol . Published online ahead of print May 23, 2018; [PubMed 29800138]

1229. Ioannidis JPA. Diagnosis and treatment of hypertension in the 2017 ACC/AHA guidelines and in the real world. JAMA . 2018; 319(2):115-6. [PubMed 29242891]

1230. Vasan RS, Larson MG, Leip EP et al. Impact of high-normal blood pressure on the risk of cardiovascular disease. N Engl J Med . 2001; 345(18):1291-7. [PubMed 11794147]