AHFS Class:

• Dihydropyridines 24:28.08

Generic Name(s):

• amLODIPine Besylate

• amLODIPine Benzoate

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 in the treatment of hypertension, to lower blood pressure, in adults and children 6 years of age and older.1,  2,  3,  4,  5,  21,  113,  129,  132,  133,  134,  135,  136,  1200

Amlodipine is commercially available for the treatment of hypertension as single-entity preparations (amlodipine besylate oral solution [e.g., Norliqva^®], amlodipine besylate tablets [e.g., Norvasc^®], amlodipine benzoate oral suspension [e.g., Katerzia^®])1,  135,  136 and also in fixed combination with benazepril (e.g., Lotrel^®), olmesartan medoxomil (e.g., Azor^®),134 olmesartan medoxomil and hydrochlorothiazide (e.g., Tribenzor^®),132 telmisartan,129 valsartan (e.g., Exforge^®),113 and valsartan and hydrochlorothiazide (e.g., Exforge^® HCT).107 Amlodipine in fixed combination with atorvastatin (Caduet^®) is used in patients for whom treatment with both amlodipine and atorvastatin is appropriate.107

Clinical Experience

Amlodipine Monotherapy

Safety and efficacy of amlodipine for the treatment of hypertension in adults have been established in 15 double-blind, placebo-controlled, randomized studies involving 1338 patients.1,  135,  136 These studies demonstrated statistically significant placebo-corrected reductions in blood pressure at 24 hours post-dose averaging approximately 12/6 mm Hg in the standing position and 13/7 mm Hg in the supine position following once-daily amlodipine administration in patients with mild to moderate hypertension.1,  135,  136 Maintenance of the blood pressure effect over the 24-hour dosing interval was observed with little difference in peak and trough effect, and tolerance was not demonstrated in patients who were evaluated for up to 1 year.1,  135,  136 Dose-related supine and standing blood pressure reductions following administration of amlodipine within the recommended dosage range were observed in 3 parallel, fixed-dose, dose response studies.1,  135,  136

Safety and efficacy of amlodipine for the treatment of pediatric patients 6-17 years of age with hypertension have been established in an 8 week trial of 268 patients.1,  135,  136 Patients received amlodipine 2.5 or 5 mg once daily for 4 weeks, and then were randomized to either the same dosage or placebo for an additional 4 weeks.1,  135,  136 Patients receiving amlodipine 2.5 or 5 mg at the end of 8 weeks had significantly lower systolic blood pressure than those secondarily randomized to placebo.1,  135,  136 The magnitude of the treatment effect was difficult to interpret, but probably less than 3.3 mm Hg systolic with the 2.5 mg dose and less than 5 mm Hg systolic with the 5 mg dose; adverse events in these pediatric patients were similar to those seen in adults.1,  135,  136

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

Amlodipine/Benazepril Fixed-combination Therapy

Safety and efficacy of the fixed combination of amlodipine and benazepril (amlodipine/benazepril) in the treatment of hypertension are based on the results of 6 double-blind, placebo-controlled studies in over 950 patients.21 The antihypertensive effect of a single dose of the fixed combination persisted for 24 hours, with peak reductions achieved 2 to 8 hours after dosing.21 Once-daily doses of amlodipine/benazepril using benazepril doses of 10-20 mg and amlodipine doses of 2.5-10 mg decreased seated systolic/diastolic pressures by about 10-25/6-13 mm Hg 24 hours after dosing.21 In 2 studies in patients not adequately controlled on either benazepril 40 mg alone or amlodipine 10 mg alone, once-daily doses of amlodipine/benazepril 10/40 mg further decreased seated blood pressure compared to the respective monotherapy alone.21

Amlodipine/Olmesartan Fixed-combination Therapy

Safety and efficacy of the fixed combination of amlodipine and olmesartan medoxomil (amlodipine/olmesartan medoxomil) for the treatment of hypertension are based on the results of an 8-week multicenter, randomized, double-blind, placebo controlled, parallel group factorial study in 1940 patients with mild to severe hypertension (mean baseline blood pressure 164/102 mm Hg).134 Patients discontinued their prior antihypertensive treatment and were randomized to placebo, monotherapy with amlodipine 5 mg or 10 mg, monotherapy with olmesartan medoxomil 10 mg, 20 mg, or 40 mg, or combination therapy with amlodipine/olmesartan medoxomil at doses of 5/10 mg, 5/20 mg, 5/40 mg, 10/10 mg, 10/20 mg, and 10/40 mg.134 Treatment with amlodipine/olmesartan medoxomil resulted in statistically significant greater reductions in diastolic and systolic blood pressure compared to their respective monotherapy components, and the blood pressure lowering effect was maintained throughout the 24-hour period.134 Dose related placebo-adjusted reductions from baseline in blood pressure were progressively greater with increasing doses of both amlodipine and olmesartan medoxomil components in the fixed combination.134 The study estimated the likelihood of reaching blood pressure goals with amlodipine/olmesartan compared with amlodipine or olmesartan monotherapy.134 For example, 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 less than 140 mm Hg) is 48, 46, and 68% with olmesartan medoxomil (40 mg daily) alone, amlodipine (10 mg daily) alone, and amlodipine combined with olmesartan medoxomil (at the same dosages), respectively, and the estimated probability of achieving control of diastolic blood pressure (defined as diastolic blood pressure less than 90 mm Hg) is 51, 60, and 85% with these respective treatments.134

Amlodipine/Olmesartan/Hydrochlorothiazide Fixed-combination Therapy

Safety and efficacy of the fixed combination of amlodipine, olmesartan medoxomil, and hydrochlorothiazide (amlodipine/olmesartan medoxomil/hydrochlorothiazide) in the treatment of hypertension are based on the results of a double-blind, active-controlled study in 2492 hypertensive patients (mean baseline blood pressure 169/101 mm Hg).132 Patients were randomized to receive once daily dual therapy (olmesartan medoxomil/amlodipine 40/10 mg, olmesartan medoxomil/hydrochlorothiazide 40/25 mg, or amlodipine/hydrochlorothiazide 10/25 mg) for 2-4 weeks followed by randomization to continue the dual therapy or to receive triple therapy (olmesartan medoxomil/amlodipine/hydrochlorothiazide 40/10/25 mg).132 Triple combination therapy (olmesartan medoxomil/amlodipine/hydrochlorothiazide) produced greater reductions in both systolic and diastolic blood pressures compared to each of the 3 dual combination therapies after 8 weeks of treatment.132 The blood pressure lowering effects of lower dose strengths of the fixed combination (olmesartan medoxomil/amlodipine/hydrochlorothiazide 20/5/12.5 mg, 40/5/12.5 mg, 40/10/12.5 mg, and 40/5/25 mg) have not been studied, but are expected to be superior to their respective individual and dual-combination components.132

Amlodipine/Telmisartan Fixed-combination Therapy

Safety and efficacy of the fixed combination of amlodipine and telmisartan (amlodipine/telmisartan) for the treatment of hypertension are based on the results of one placebo-controlled and two active-controlled trials.129 In an 8-week randomized, double-blind, placebo-controlled, parallel group factorial study, 1461 patients with baseline systolic blood pressure between 117 and 179 mm Hg (mean 153 mm Hg) and baseline diastolic blood pressure between 90 and 119 mm Hg (mean 102 mm Hg) were randomized to one of 16 treatment groups to receive once daily amlodipine monotherapy, telmisartan monotherapy, amlodipine/telmisartan, or placebo.129 Statistically significant reductions in systolic and diastolic blood pressure were observed in the four key treatment combinations (including combinations of telmisartan 40 or 80 mg and amlodipine 5 or 10 mg) compared to their respective individual monotherapies.129 In a double-blind, active-controlled study in 1097 patients with mild to severe hypertension (mean baseline systolic/diastolic blood pressure of 149.5/96.6 mmHg) who were not adequately controlled on amlodipine 5 mg, diastolic and systolic blood pressure reduction was significantly superior in patients who received the fixed combination of telmisartan and amlodipine (40/5 mg or 80/5 mg) compared to both amlodipine monotherapy doses (5 mg or 10 mg); edema related events (peripheral edema, generalized edema, and edema) were significantly lower in the amlodipine/telmisartan groups compared to those receiving amlodipine 10 mg (4.3% versus 27.2%, respectively).129 In a second double-blind, active-controlled study in 947 patients with mild to severe hypertension (mean baseline blood pressure of 147.5/95.6 mm Hg) who were not adequately controlled on amlodipine 10 mg, diastolic and systolic blood pressure reduction was significantly greater in patients who received the fixed combination of telmisartan and amlodipine (40/10 mg or 80/10 mg) compared to amlodipine alone (10 mg).129 The study estimated the likelihood of reaching blood pressure goals with amlodipine/telmisartan compared with amlodipine or telmisartan monotherapy.129 For example, 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 less than 140 mm Hg) is 46, 69, and 79% with telmisartan (80 mg daily) alone, amlodipine (10 mg daily) alone, and amlodipine combined with telmisartan (at the same dosages), respectively, and the probability of achieving control of diastolic blood pressure (defined as diastolic blood pressure less than 90 mm Hg) is 26, 22, and 55% with these respective treatments.129

Amlodipine/Valsartan Fixed-combination Therapy

Safety and efficacy of the fixed combination of amlodipine and valsartan (amlodipine/valsartan) for the treatment of hypertension are based on the results of 2 placebo-controlled and 4 active-controlled trials in hypertensive patients.113 In an 8-week double-blind, placebo-controlled study, 1012 patients with mild to moderate hypertension were randomized to once daily amlodipine/valsartan (5/80, 5/160, or 5/320 mg), amlodipine 5 mg, valsartan monotherapy (80, 160, or 320 mg), or placebo.113 Patients randomized to amlodipine/valsartan 5/320 mg were initiated at a dose of 5/160 mg and titrated to the 5/320 mg dose after 1 week.113 Combination treatments were statistically significantly superior to their monotherapy components in reduction of diastolic and systolic blood pressures at week 8.113 In another 8-week double-blind, placebo-controlled study, 1246 patients with mild to moderate hypertension were randomized to once daily amlodipine/valsartan (10/160 or 10/320 mg), amlodipine 10 mg, valsartan monotherapy (160 or 320 mg), or placebo.113 Patients randomized to amlodipine/valsartan 10/320 mg were initiated at a dose of 5/160 mg and titrated to the 10/320 mg dose after 1 week.113 Combination treatments were statistically significantly superior to their monotherapy components in reduction of diastolic and systolic blood pressures at week 8.113 In a double-blind, active-controlled study, a total of 947 patients with mild to moderate hypertension that was not adequately controlled on valsartan 160 mg, diastolic and systolic blood pressure reduction at week 8 was significantly superior in patients who received amlodipine/valsartan (10/160 or 5/160 mg) compared to valsartan 160 mg monotherapy.113 In a double-blind, active-controlled study, a total of 944 patients with mild to moderate hypertension who were not adequately controlled on amlodipine 10 mg, diastolic and systolic blood pressure reduction at week 8 was significantly superior in patients who received amlodipine/valsartan 10/160 mg compared to amlodipine 10 mg monotherapy.113 In a double-blind, active-controlled study of 572 black patients with moderate to severe hypertension, patients were randomized to amlodipine/valsartan or amlodipine monotherapy for 12 weeks.113 Patients were initiated on amlodipine/valsartan 5/160 mg or amlodipine 5 mg for 2 weeks with forced titration to 10/160 mg or 10 mg, respectively; optional titration to amlodipine/valsartan 10/320 mg (amlodipine/valsartan group only) and/or the addition of hydrochlorothiazide 12.5 mg (either group) was allowed for 4 weeks.113 At the primary endpoint of 8 weeks, the treatment difference between amlodipine/valsartan and amlodipine was 6.7/2.8 mm Hg.113 In another study of similar design, a total of 646 patients with moderate to severe hypertension (mean supine systolic BP ≥160 mm Hg and <200 mm Hg) were randomized to amlodipine/valsartan or amlodipine monotherapy for 8 weeks.113 Patients were initiated on amlodipine/valsartan 5/160 mg or amlodipine 5 mg for 2 weeks with forced titration to 10/160 mg or 10 mg, respectively; optional addition of hydrochlorothiazide 12.5 mg (either group) was allowed for 4 weeks.113 At the primary endpoint of 4 weeks, the treatment difference between amlodipine/valsartan and amlodipine was 6.6/3.9 mm Hg.113 The study estimated the likelihood of reaching blood pressure goals with amlodipine/valsartan compared with amlodipine or valsartan monotherapy.113 For example, 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 less than 140 mm Hg) is 47, 67, and 80% with valsartan (320 mg daily) alone, amlodipine (10 mg daily) alone, and amlodipine combined with valsartan (at the same dosages), respectively, and the probability of achieving control of diastolic blood pressure (defined as diastolic blood pressure less than 90 mm Hg) is 62, 80, and 85% with these respective treatments.113

Amlodipine/Valsartan/Hydrochlorothiazide Fixed-combination Therapy

Safety and efficacy of the fixed combination of amlodipine, valsartan and hydrochlorothiazide (amlodipine/valsartan/hydrochlorothiazide) for the treatment of hypertension are based on the results of a double-blind, active controlled study in 2271 patients with moderate to severe hypertension (mean baseline systolic/diastolic blood pressure of 170/107 mm Hg).133 Patients were randomized to receive once daily amlodipine/valsartan/hydrochlorothiazide 10/320/25 mg, valsartan/hydrochlorothiazide 320/25 mg, amlodipine/valsartan 10/320 mg, or hydrochlorothiazide/amlodipine 25/10 mg.133 Triple combination therapy produced greater reductions in diastolic and systolic blood pressures than each of the 3 dual combination treatments at week 8.133 The reductions in systolic/diastolic blood pressure were 7.6/5.0, 6.2/3.3, and 8.2/5.3 mm Hg greater with amlodipine/valsartan/hydrochlorothiazide than with valsartan/hydrochlorothiazide, amlodipine/valsartan, and amlodipine/hydrochlorothiazide, respectively.133 The full blood pressure lowering effect was achieved 2 weeks after being on the maximal dose of amlodipine/valsartan/hydrochlorothiazide.133

Amlodipine/Atorvastatin Fixed-combination Therapy

Safety and efficacy of the fixed combination of amlodipine and atorvastatin (amlodipine/atorvastatin) for the treatment of hypertension are based on the results of a double-blind, placebo-controlled study in 1660 patients with co-morbid hypertension and dyslipidemia; risk factors included diabetes mellitus (15%), smoking (22%), and a family history of cardiovascular disease (14%).107 Patients received once daily treatment with amlodipine/atorvastatin (5/10, 10/10, 5/20, 10/20, 5/40, 10/40, 5/80, or 10/80 mg), amlodipine monotherapy (5 or 10 mg), atorvastatin monotherapy (10, 20, 40, or 80 mg), or placebo.107 Statistically significant dose-related reductions in blood pressure (systolic and diastolic) and LDL-cholesterol were observed in all amlodipine/atorvastatin combination-treatment groups compared to placebo at 8 weeks.107

Clinical Perspective

The principal goal of preventing and treating hypertension is to reduce the risk of cardiovascular and renal morbidity and mortality, including target organ damage.1200,  1300 The relationship between blood pressure and cardiovascular disease is continuous, consistent, and independent of other risk factors.1200,  1300 The higher the blood pressure, the more likely the development of coronary artery disease, heart failure, stroke, and chronic kidney disease across all ages and ethnic groups.1200,  1300 Each 20-mm Hg increment in systolic blood pressure or 10-mm Hg increment in diastolic blood pressure has been shown to double the risk of death from stroke, heart disease, or other vascular disease.171,  1200,  1300

Accurate blood pressure measurement in the office or clinic is essential for proper diagnosis and management of hypertension.1200,  1300,  1302 Out-of-office blood pressure measurements are recommended to confirm the diagnosis of hypertension.1200 Blood pressure categories range from normal to different grades/stages of hypertension and are intended to align therapeutic approaches with blood pressure levels.1300,  1302 According to most major guidelines, hypertension is diagnosed when systolic blood pressure is ≥140 mm Hg and/or diastolic blood pressure is ≥90 mm Hg as measured in the office or clinic.1300,  1302 Some guidelines consider a systolic blood pressure of 130-139 mm Hg and/or a diastolic blood pressure of 80-89 mm Hg to be stage 1 hypertension,1200 whereas other guidelines consider this a high-normal blood pressure; however, treatment recommendations are generally the same (nonpharmacologic therapy with consideration of pharmacologic therapy based on cardiovascular risk).1200,  1300,  1302

Comprehensive guidelines for the management of hypertension have been published by various authoritative groups.501,  1200,  1300,  1301,  1302 The first such guideline was published by the National Heart Lung and Blood Institute (NHLBI) in 1977, followed by a series of Joint National Committee (JNC) guidelines with JNC8 being the last iteration of these guidelines in 2014.501,  1200 The American College of Cardiology (ACC), American Heart Association (AHA), and other experts, including the International Society of Hypertension (ISH), have published more recent clinical practice guidelines for the treatment of hypertension.1200,  1300,  1302 These guidelines all state that lifestyle/behavioral modifications (e.g., weight reduction in patients who are overweight or obese, dietary changes, sodium reduction, potassium supplementation, increased physical activity, moderation of alcohol intake, smoking cessation) are essential in the management of hypertension and should be implemented as first-line therapy to lower blood pressure and reduce total cardiovascular risk.1200,  1300,  1302 The decision whether to initiate antihypertensive drug therapy should be based on the office blood pressure level while also considering cardiovascular risk factors.1200,  1219,  1300,  1302 Most guidelines agree that antihypertensive drug treatment should be offered in addition to lifestyle modifications to patients with grade 2 (blood pressure 160-179/100-109 mm Hg) or grade 3 (systolic blood pressure ≥180/110 mm Hg) hypertension; however, there is some controversy regarding whether patients with grade 1 hypertension (blood pressure 140-159/90-99) should be treated with antihypertensive drug therapy.1200,  1300,  1302 Some guidelines recommend immediate drug treatment in patients with grade 1 hypertension (blood pressure 140-159/90-99) who have high cardiovascular risk or comorbid conditions (cardiovascular disease, chronic kidney disease, diabetes mellitus or hypertension-mediated organ damage) and a trial of lifestyle intervention first in those with low to moderate cardiovascular risk who do not have these comorbid conditions,1302 whereas other guidelines recommend that all hypertensive patients, including those with grade 1 hypertension, receive blood pressure-lowering treatment, irrespective of their cardiovascular risk.1300 In some guidelines, drug treatment is recommended in patients with blood pressure in the high-normal range (≥130/80 mm Hg) who have cardiovascular disease.1200,  1210,  1300

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 or thiazide-like 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 risk reduction benefits.1,  501,  503,  1200,  1300,  1302 However, recommendations for initial drug selection and use in specific patient populations may vary across these guidelines.501,  503,  1200 This variability is due, in part, to differences in the guideline development process and the types of studies included in the evidence reviews (e.g., randomized controlled studies only versus a range of studies with different study designs).501,  503,  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,  503,  510,  1200,  1300,  1302 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).69,  70,  108,  109,  501,  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) and in geriatric patients, including those with isolated systolic hypertension.510,  1200 Other antihypertensive drugs such as beta blockers, direct vasodilators, alpha-1 blockers, loop diuretics, and aldosterone antagonists are available, but generally recommended as second-line agents or only in specific clinical situations.1200

Because most patients with hypertension will require at least 2 antihypertensive drugs to achieve adequate blood pressure control, use of single pill combinations are generally recommended when available.1,  1302 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 Antihypertensive drug dosages should be adjusted and/or other agents substituted or added until goal blood pressure is achieved.1200 After initiation of antihypertensive drug therapy, a blood pressure goal of less than 130/80 mm Hg within 3 months is generally recommended if tolerated, but should be individualized.1200,  1301,  1302 While there is evidence from a randomized controlled study (SPRINT) demonstrating that intensive systolic blood pressure lowering (to <120 mm Hg) may be beneficial in patients with increased risk of cardiovascular disease, the study excluded patients with diabetes mellitus or prior stroke, and those younger than 50 years of age, which may decrease the generalizability of these findings.1210,  1219

Specific guidelines for the management of hypertension in pregnancy have been published by experts such as AHA and the American College of Obstetricians and Gynecologists (ACOG).1305,  1306 First-line oral antihypertensive drugs generally recommended in pregnant patients include labetalol, nifedipine (extended-release), or methyldopa.1200,  1302,  1305 Other oral dihydropyridine calcium-channel blockers such as nicardipine or amlodipine may also be considered.1302,  1304,  1305 In patients requiring immediate blood pressure lowering (i.e., eclampsia, HELLP [preeclampsia/hemolysis, elevated liver enzymes and low platelets]), IV labetalol, nicardipine, or magnesium sulfate may be used.1300,  1302 Renin-angiotensin system (RAS) blockers (e.g., ACE inhibitors, angiotensin II receptor blockers, direct renin inhibitors) are contraindicated during pregnancy due to adverse fetal and neonatal outcomes.1200,  1300,  1302,  1305

The American Academy of Pediatrics (AAP) has published a clinical practice guideline for the management of high blood pressure in children and adolescents.1150 The guideline recommends calcium-channel blockers (e.g., nifedipine, amlodipine), ACE inhibitors, angiotensin II receptor antagonists, and thiazide diuretics for the initial management of hypertension in children requiring drug therapy.1150

Coronary Artery Disease

Amlodipine is used alone or in combination with other antianginal agents for the treatment of chronic stable angina and confirmed or suspected vasospastic angina (Prinzmetal or variant).1,  2,  3,  4,  135,  136 Amlodipine is also used to reduce the risk of hospitalization for angina and to reduce the risk of a coronary revascularization procedure in patients with angiographically documented coronary artery disease (without heart failure or an ejection fraction <40%).1,  133,  134

Amlodipine is commercially available as single-entity preparations (amlodipine besylate oral solution [e.g., Norliqva^®], amlodipine besylate tablets [e.g., Norvasc^®], amlodipine benzoate oral suspension [e.g., Katerzia^®]) for this use.1,  135,  136 The drug is also available in fixed combination with atorvastatin (Caduet^®) for use in patients for whom treatment with both amlodipine and atorvastatin is appropriate.107

Angina

Safety and effectiveness of amlodipine in the treatment of chronic stable angina have been evaluated in 8 placebo-controlled, double-blind clinical trials of up to 6 weeks' duration in 1038 patients.1,  135,  136 Treatment with amlodipine 10 mg resulted in significant improvement in exercise-induced angina as evidenced by increases in exercise time on a bicycle or treadmill in 5 of the 8 studies.1,  135,  136 Increases in symptom-limited exercise time averaged 7.9% (38 sec) with amlodipine 5 mg and 12.8% (63 sec) with amlodipine 10 mg.1,  135,  136 In several studies, amlodipine 10 mg also increased time to 1 mm ST segment deviation and decreased angina attack rate.1,  135,  136 The sustained efficacy of amlodipine in angina patients has been demonstrated with long-term dosing.1,  135,  136 No clinically significant reductions in blood pressure or changes in heart rate were observed.1,  135,  136

Safety and effectiveness of amlodipine in vasospastic angina have been evaluated in a 4-week, double-blind, placebo-controlled trial in 50 patients.1,  135,  136 Angina attacks decreased by approximately 4 per week in patients receiving amlodipine compared with a decrease of approximately 1 attack per week in patients receiving placebo.1,  135,  136 Discontinuance due to lack of clinical improvement occurred in more patients who received placebo (7 of 27) than those who received amlodipine (2 of 23).1,  135,  136

Angiographically Documented Coronary Artery Disease

The effects of amlodipine in patients with angiographically documented coronary artery disease and normal blood pressure were evaluated in the CAMELOT study, a double-blind, randomized, multicenter study.1,  22,  135,  136 A total of 1318 patients were randomized to receive amlodipine or placebo in the study.1,  22,  135,  136 The majority of patients were male (76%) and Caucasian (89%); 89% had a history of angina, 4% had PCI with no stent, and 44% had PCI with stent placement.1,  135,  136 Patients were randomized to amlodipine (5-10 mg once daily) or placebo in addition to standard of care that included aspirin, statins, beta-blockers, nitroglycerin, anticoagulants, and diuretics, but excluded other calcium channel blockers.1,  135,  136 The mean duration of follow-up was 19 months.1,  135,  136 The primary efficacy outcome was the incidence of cardiovascular events (defined as hospitalization for angina, coronary revascularization, myocardial infarction, cardiovascular death, resuscitated cardiac arrest, hospitalization for heart failure, stroke/transient ischemic attack, or peripheral vascular disease), which occurred in 16.6% of patients who received amlodipine and 23.1% of patients who received placebo.1,  22,  135,  136 The reduction in the primary outcome was largely derived from the prevention of hospitalizations for angina and the prevention of revascularization procedures.1,  135,  136 Although there was a trend toward less progression of atherosclerosis in the amlodipine group versus placebo in an angiographic substudy of CAMELOT, the difference was not statistically significant.1,  22 In another placebo-controlled study in 825 patients with angiographically documented coronary artery disease (PREVENT), amlodipine also did not demonstrate a significant effect on angiographic progression of coronary atherosclerosis or the risk of major cardiovascular events, but was associated with reduced hospitalizations for unstable angina and revascularization.1,  23,  135,  136

Clinical Perspective

The 2023 American Heart Association/American College of Cardiology (AHA/ACC) clinical practice guideline for the management of patients with chronic coronary disease addresses the treatment of patients with stable angina symptoms (or ischemic equivalents).1303 The practice guideline recommends the use of beta-adrenergic blocking agents, calcium-channel blocking agents, or long-acting nitrates for relief of angina or equivalent symptoms in patients with chronic coronary disease.1303 The goal of therapy is to maximize relief of symptoms of angina without exacerbating comorbidities or adverse effects.1303

Selection of drug therapy should be individualized and consider comorbid conditions, which may justify the use of one agent over another.1303 Calcium-channel blockers (used alone or in combination with nitrates) are considered first-line for the management of vasospastic angina.1303 In patients with microvascular angina (nonobstructive coronary artery disease), calcium-channel blockers may be used second-line when beta-adrenergic blockers are not tolerated or ineffective.1303 Nondihydropyridine calcium-channel blockers (e.g., diltiazem, verapamil) should not be used in patients with significant left ventricular dysfunction because these drugs further depress left ventricular function.1303 Due to an increased potential for synergistic induction or exacerbation of bradycardia and left ventricular dysfunction, nondihydropyridine calcium-channel blockers should be used with caution in patients receiving beta-adrenergic blockers.1303 In patients with angina refractory to a single agent, symptom control may be improved by the addition of a second agent (e.g., addition of a long-acting nitrate to a calcium-channel or beta-adrenergic blocking agent).1303

Pulmonary Arterial Hypertension

Expert consensus guidelines for the treatment of pulmonary arterial hypertension (PAH)† in adults state that a calcium-channel blocker may be used to treat patients with PAH who have demonstrated acute vasoreactivity and who do not have right-sided heart failure or any contraindications to calcium-channel blocking therapy.1309 Long-acting nifedipine or diltiazem, or amlodipine is suggested; verapamil should be avoided due to its potential negative inotropic effects.1309 Patients should be closely followed for safety and efficacy, and reassessed at 3 months; if improvement to WHO functional class I or II PAH is not achieved, alternative or additional drug therapy should be instituted.1309

Raynaud's Phenomenon

Calcium channel blockers have been used in the management of Raynaud's phenomenon†.1326,  1327,  1328 Dihydropyridine calcium channel blockers (e.g., nifedipine, amlodipine) have been studied and used more frequently than nondihydropyridine calcium channel blockers; among the dihydropyridine class, nifedipine has the most evidence for use.1326,  1327,  1328 Amlodipine has reduced the frequency of attacks in patients with this condition.1328 Experts state calcium channel blockers may be more effective in primary compared to secondary Raynaud's phenomenon, higher doses may be more effective than lower doses, and long-acting or extended-release agents are preferred.1326,  1327,  1328

General

Pretreatment Screening

• In patients being treated for hypertension, obtain baseline blood pressure measurements.1200

Patient Monitoring

• In patients being treated for hypertension, follow-up evaluation of adherence and response to drug treatment should occur at monthly intervals until blood pressure control is achieved.1200
• Periodically reinforce adherence to lifestyle modifications (e.g., heart-healthy diet, sodium intake reduction, increased physical activity).1200
• Monitor for signs and symptoms of edema, especially in patients with heart failure with reduced ejection fraction.1,  135,  136,  1200

Dispensing and Administration Precautions

• The Institute for Safe Medication Practices (ISMP) includes amLODIPine and aMILoride on the ISMP List of Confused Drug Names and recommends special safeguards to ensure the accuracy of prescriptions for these drugs.24

Administration

Amlodipine is administered orally (as tablets, solution, or suspension) without regard to meals, preferably at the same time each day.1,  2,  3,  5,  135,  136 Amlodipine is also commercially available in fixed combination with benazepril (e.g., Lotrel^®),21 olmesartan medoxomil (e.g., Azor^®),134 olmesartan medoxomil and hydrochlorothiazide (e.g., Tribenzor^®),132 telmisartan,129 valsartan (e.g., Exforge^®),113 valsartan and hydrochlorothiazide (e.g., Exforge^® HCT),133 and atorvastatin (e.g., Caduet^®).107 See the full prescribing information for additional administration instructions for each specific combination product.

If a dose of amlodipine is missed, the missed dose may be administered as soon as possible.1 If the dose is missed for more than 12 hours, do not take the dose and resume treatment with the next scheduled dose.1

Amlodipine besylate tablets: Store the tablets at 15-30°C; dispense in a tight, light-resistant container.1

Amlodipine besylate oral solution (Norliqva^®): Store the oral solution at 20-25°C (excursions permitted to 15-30°C).136 Store and dispense in the original packaging (amber glass bottle).136

Amlodipine benzoate oral suspension (Katerzia^®): Shake the suspension well and measure each dose with a calibrated measuring device; do not use a household teaspoon or tablespoon.135,  137 Store the oral suspension at 2-8°C and protect from light.135 Avoid freezing and excessive heat.135

Dosage

Dosage of amlodipine besylate and amlodipine benzoate is expressed in terms of amlodipine.1,  135,  136

Hypertension

Amlodipine Monotherapy in Adults

The recommended initial adult dosage of amlodipine for the management of hypertension is 5 mg once daily; the maximum dosage is 10 mg once daily.1,  135,  136 In geriatric patients and small or frail individuals, an initial dosage of 2.5 mg once daily may be used.1,  135,  136 This reduced initial dosage also can be used in adults when amlodipine is added to an existing antihypertensive drug regimen.1,  135,  136 Subsequent dosage of amlodipine should be adjusted according to the patient's blood pressure response and tolerance.1,  135,  136 Generally, dosage is increased gradually at 7- to 14-day intervals until optimum control of blood pressure is maintained.1,  135,  136 However, more rapid titration of dosage can be undertaken when clinically warranted, provided response and tolerance are assessed frequently.1,  135,  136 The usual maintenance dosage of amlodipine for the management of hypertension in adults is 2.5-10 mg once daily.1,  1200

Amlodipine Monotherapy in Pediatric Patients

The recommended effective dosage of amlodipine for the management of hypertension in pediatric patients 6-17 years of age is 2.5-5 mg once daily.1,  135,  136 Some experts recommend an initial dosage of 2.5 mg once daily and a maximum dosage of 10 mg once daily, however the manufacturer states doses in excess of 5 mg have not been studied in pediatric patients.1,  135,  136,  1150 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 The manufacturer states that the safety and efficacy of amlodipine have not been established in pediatric patients younger than 6 years of a 1,  135,  136 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) have been recommended by some experts.1150

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 antihypertensive response is not achieved with amlodipine or benazepril 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

Amlodipine/Olmesartan Fixed-combination Therapy

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

Amlodipine/Olmesartan/Hydrochlorothiazide Fixed-combination Therapy

The fixed-combination preparation containing amlodipine, olmesartan, and hydrochlorothiazide may be used alone or with other antihypertensive agents to lower blood pressure.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 The dose selection for the fixed-combination preparation should be individualized based on previous therapy.132 If necessary, dosage of the fixed-combination preparation may be increased after 2 weeks for additional blood pressure control (up to a maximum dosage of 10 mg of amlodipine, 40 mg of olmesartan medoxomil, and 25 mg of hydrochlorothiazide once daily).132

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 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 Initial therapy with the fixed combination of amlodipine and telmisartan is not recommended in patients ≥75 years of age and those with hepatic impairment.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

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 part of 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 The fixed-combination preparation containing amlodipine, valsartan, and hydrochlorothiazide may be used with other antihypertensive agents.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 antihyperlipidemic 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 dyslipidemia.107 The initial dosage of the fixed-combination preparation should be selected based on the recommended initial dosages of the individual components (e.g., 5 mg of amlodipine and 10 to 20 mg of atorvastatin) based on patient-specific factors (e.g., age, drug interactions).107 The maximum dosage of amlodipine and atorvastatin in the fixed-combination preparation is 10 and 80 mg daily, respectively.107

Coronary Artery Disease

Angina

For the management of vasospastic (Prinzmetal or variant) angina or chronic stable angina, the recommended adult dosage of amlodipine is 5-10 mg once daily.1,  2,  135,  136 The manufacturers state that adequate control of angina usually requires a maintenance dosage of 10 mg daily.1,  135,  136

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,  135,  136 In clinical studies, the majority of patients required a dosage of 10 mg daily.1,  135,  136

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 antihyperlipidemic 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 dyslipidemia.107 The initial dosage of the fixed-combination preparation should be selected based on the recommended initial dosages of the individual components (e.g., 5 mg of amlodipine and 20 mg of atorvastatin) based on patient-specific factors (e.g., age, drug interactions).107 The maximum dosage of amlodipine and atorvastatin in the fixed-combination preparation is 10 and 80 mg daily, respectively.107

Special Populations

The following information addresses dosage of amlodipine in special populations. Dosages of drugs administered in fixed combination with amlodipine also may require adjustment in certain patient populations; the need for such dosage adjustments must be considered in the context of cautions, precautions, and contraindications specific to that population and drug.21,  107,  113,  129,  132,  133,  134

Hepatic Impairment

For the management of hypertension in adults with hepatic insufficiency, an initial amlodipine dosage of 2.5 mg once daily generally is recommended.1,  135,  136 Subsequent dosage should be adjusted slowly in patients with severe hepatic impairment.1,  135,  136

For the management of vasospastic (Prinzmetal variant) angina or chronic stable angina in patients with hepatic insufficiency, an amlodipine dosage of 5 mg daily is recommended.1,  135,  136 The manufacturers state that adequate control of angina usually requires a maintenance dosage of 10 mg daily.1,  135,  136

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,  135,  136

Geriatric Patients

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 For management of hypertension, some manufacturers recommend an initial amlodipine dosage of 2.5 mg once daily for geriatric patients.1,  135,  136,  113,  129,  132,  134 For management of vasospastic (Prinzmetal variant) angina or chronic stable angina in geriatric patients, an amlodipine dosage of 5 mg daily is recommended; adequate control of angina usually requires a maintenance dosage of 10 mg once daily.1

Contraindications

Amlodipine is contraindicated in patients with known hypersensitivity to the drug.1,  135,  136,  21,  107,  113,  129,  132,  133,  134

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,  135,  136

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,  135,  136

Patients with Hepatic Failure

Amlodipine is extensively metabolized in the liver.1,  135,  136 Amlodipine clearance is decreased, AUC is increased 40-60%, and the plasma elimination half-life is increased to 56 hours in patients with impaired hepatic function.1 Reduce the initial dosage to 2.5 mg once daily and titrate the drug slowly in patients with severe hepatic impairment.1

Use of Fixed Combinations

When amlodipine is used in fixed combination with other drugs (e.g., other antihypertensive agents, atorvastatin), the cautions, precautions, contraindications, and drug interactions associated with the other drug(s), including any boxed warnings, must be considered in addition to those associated with amlodipine.21,  107,  113,  129,  132,  133,  134

Specific Populations

Pregnancy

The manufacturers state that there are limited data on use of amlodipine in pregnant women to inform a drug-associated risk for major birth defects and miscarriage.1,  135,  136 There is some data indicating that amlodipine crosses the placenta in measurable quantities in the third trimester of pregnancy.138

Hypertension in pregnancy is a major cause of maternal, fetal or neonatal morbidity and mortality.1,  1300 Maternal risks include pre-eclampsia, gestational diabetes, premature delivery, placental abruption, delivery complications (e.g., need for cesarean section, postpartum hemorrhage), stroke, pulmonary edema, thromboembolic events, multiple organ failure (liver, kidney) and disseminated intravascular coagulation.1,  1300,  1302 Fetal risks include intrauterine growth restriction, prematurity, and intrauterine death.1,  1300 Neonates may require prolonged high-level care and experience morbidity.1,  1300 Pregnant women with hypertension should be carefully monitored and managed accordingly.1

Teratogenicity or other embryo-fetal toxicity was not observed when pregnant rats and rabbits were treated orally with a different salt form of amlodipine (amlodipine maleate) at doses up to 10 mg/kg per day (approximately 10 and 20 times the maximum recommended human dose [MRHD] based on body surface area, respectively) during their respective periods of major organogenesis.1 However, when amlodipine maleate at doses up to 10 mg amlodipine/kg per day was administered to rats for 14 days prior to mating and throughout gestation, litter size decreased approximately 50%, and a 5-fold increase in the number of intrauterine deaths was observed at this dose equivalent to 10 times the MDRD.1 Amlodipine maleate has also been shown to prolong both the gestation period and the duration of labor in rats at this dose.1

Lactation

The manufacturer states limited available data from a published clinical lactation study reported that amlodipine is present in human milk at an estimated median relative infant dose of 4.2%.1 No adverse effects of amlodipine on the breastfed infant have been observed; there is no available information on the effects of amlodipine on milk production.1

Females and Males of Reproductive Potential

There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses up to 10 mg amlodipine/kg per day (8 times the MRHD of 10 mg/day on a mg/m² basis).1

Pediatric Use

Safety and efficacy of amlodipine in children younger than 6 years of age have not been established.1,  135,  136 Safety and effectiveness of amlodipine (2.5-5 mg daily) for the treatment of pediatric patients 6-17 years of age with hypertension have been established in a trial of 8 weeks' duration.1,  135,  136

Safety and efficacy of amlodipine in fixed combination with atorvastatin, benazepril, olmesartan (with or without hydrochlorothiazide), telmisartan, or valsartan (with or without hydrochlorothiazide) have not been established in pediatric patients.21,  107,  113,  129,  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 (i.e., 2.5 mg daily).1 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

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

Hepatic Impairment

In patients with hepatic impairment, amlodipine clearance is decreased and AUC is increased by about 40-60%; the plasma elimination half-life is increased to 56 hours.1 A reduced initial dosage of the drug is recommended.1,  2,  4 Titrate slowly when administering amlodipine to patients with severe hepatic impairment.1

Renal Impairment

The pharmacokinetics of amlodipine are not significantly influenced by renal impairment; therefore, patients with renal impairment may receive the usual initial dosage.1

Common Adverse Effects

Adverse effects reported in 1% or more of patients receiving amlodipine include dose-related edema, dizziness, flushing, and palpitations; fatigue, nausea, abdominal pain, and somnolence also reported.1,  135,  136 Adverse effects reported in the clinical trial in pediatric patients with hypertension were similar to those that have been reported in adults.1

Amlodipine is a weak inhibitor of cytochrome P-450 (CYP) 3A isoenzymes.1,  135,  136

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,  132,  133,  134

Drugs Affecting Hepatic Microsomal Enzymes

Concomitant use of amlodipine with moderate (e.g., diltiazem) or strong (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 or plasma protein binding of 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

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 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, each agent independently exerted its own blood pressure lowering effect.1 Patients receiving sildenafil concomitantly with amlodipine should be monitored for hypotension.1

Warfarin

Concomitant administration of amlodipine with warfarin did not alter warfarin plasma protein binding or 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 Amlodipine inhibits transmembrane influx of extracellular calcium ions across the membranes of myocardial cells and vascular smooth muscle cells, without changing serum calcium concentrations.1 Amlodipine is a peripheral arterial vasodilator; it acts directly on vascular smooth muscle causing reduction in peripheral vascular resistance and blood pressure.1 In patients with exertional angina, amlodipine reduces total peripheral resistance (afterload) and rate pressure product, and thus myocardial oxygen demand, at any given level of exercise.1 In patients with vasospastic angina, amlodipine inhibits coronary spasm; the drug blocks constriction and restores blood flow in coronary arteries in response to calcium, potassium, epinephrine, serotonin, and thromboxane A₂ analog in animal studies and human vessels in vitro.1

Following oral administration of amlodipine besylate tablets and solution (Norliqva^®), peak plasma concentrations of the drug are attained within 6-12 and 6.5 hours, respectively.1,  136 With chronic once-daily administration, the antihypertensive effects of amlodipine persist for at least 24 hours.1 Steady-state amlodipine plasma levels are reached after 7-8 days.1 Absolute bioavailability ranges from 64-90%;1 food does not affect bioavailability of amlodipine.1,  107,  113,  129,  132,  133,  134 The peak plasma concentration and AUC of amlodipine benzoate (Katerzia^®) suspension are similar to amlodipine besylate (Norvasc^®) tablets.135 A standard high-fat, high-calorie breakfast, compared to fasted state administration, did not have a significant effect on the absorption of amlodipine benzoate suspension.135 Administration of amlodipine besylate (Norliqva^®) solution with a high-fat, high-calorie meal did not have a significant effect on peak plasma concentration and AUC.136 Amlodipine is approximately 93% bound to plasma proteins.1 Amlodipine is present in human milk (4.2% estimated median relative infant dose) and in cord blood.1,  138 Amlodipine 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; in patients with impaired hepatic function, the plasma elimination half-life is 56 hours.1 Geriatric patients and patients with hepatic insufficiency or moderate to severe heart failure have decreased amlodipine clearance resulting in an approximately 40-60% higher AUC.1 Amlodipine pharmacokinetics are not influenced by renal impairment.1 In pediatric patients 6-17 years of age, weight-adjusted clearance and volume of distribution were similar to values in adults.1

Advice to Patients

• When amlodipine is used in fixed combination with other drugs, advise patients of important cautionary information about the concomitant agent(s).21,  107,  113,  129,  132,  133,  134
• Advise patients that amlodipine is administered once a day, at any time of day, with or without food.1
• Advise patients and caregivers on how to administer the oral suspension or solution formulations.136,  137,  136
• If a dose of amlodipine is missed, advise patients to take the next dose as soon as possible.1 If it has been more than 12 hours since the dose was missed, do not take the dose; wait and take the next dose at the regularly scheduled time.1
• Advise patients to inform their clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1,  135,  136
• Advise women to inform clinicians if they suspect they are or plan to become pregnant or plan to breast-feed.1,  135,  136
• Advise patients of other important precautionary information.1,  135,  136

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Pfizer Laboratories. Norvasc^® (amlodipine besylate) tablets prescribing information. New York, NY; 2019 Jan.

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]

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