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Amlodipine Besylate

Pronunciation

Class: Dihydropyridines
VA Class: CV200
CAS Number: 111470-99-6
Brands: Amturnide (combination), Azor (combination), Caduet, Exforge (combination), Exforge HCT (combination), Lotrel, Norvasc, Prestalia (combination), Tekamlo (combination), Tribenzor (combination), Twynsta (combination)

Introduction

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

Uses for Amlodipine Besylate

Hypertension

Management of hypertension (alone or in combination with other classes of antihypertensive agents);1 2 3 4 5 6 21 113 128 129 130 131 132 133 134 500 may be used in fixed combination with aliskiren, aliskiren and hydrochlorothiazide, benazepril, olmesartan, olmesartan and hydrochlorothiazide, perindopril, telmisartan, valsartan, or valsartan and hydrochlorothiazide when such combined therapy is indicated.21 113 128 129 130 131 132 133 134

Calcium-channel blockers are recommended as one of several preferred agents for the initial management of hypertension; other options include ACE inhibitors, angiotensin II receptor antagonists, and thiazide diuretics.501 502 503 504 While there may be individual differences with respect to specific outcomes, these antihypertensive drug classes all produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes.501 502 503 504 Individualize choice of therapy; consider patient characteristics (e.g., age, ethnicity/race, comorbidities, cardiovascular risk) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, cost).500 501 502 503 504 515

Calcium-channel blockers may be preferred in hypertensive patients with certain coexisting conditions (e.g., ischemic heart disease)523 and in geriatric patients, including those with isolated systolic hypertension.502 510

Black hypertensive patients generally tend to respond better to monotherapy with calcium-channel blockers or thiazide diuretics than to other antihypertensive drug classes (e.g., ACE inhibitors, angiotensin II receptor antagonists).69 70 95 108 109 500 501 504 However, diminished response to these other drug classes is largely eliminated when administered concomitantly with a calcium-channel blocker or thiazide diuretic.500 504

The optimum BP threshold for initiating antihypertensive drug therapy is controversial.501 504 505 506 507 508 515 523 530 Further study needed to determine optimum BP thresholds/goals; individualize treatment decisions.501 503 507 515 526 530

JNC 7 recommends initiation of drug therapy in all patients with uncomplicated hypertension and BP ≥140/90 mm Hg;500 JNC 8 panel recommends SBP threshold of 150 mm Hg for patients ≥60 years of age.501 Although many experts agree that SBP goal of <150 mm Hg may be appropriate for patients ≥80 years of age,502 504 505 530 application of this goal to those ≥60 years of age is controversial, especially for those at higher cardiovascular risk.501 502 505 506 508 511 515

In the past, initial antihypertensive drug therapy was recommended for patients with diabetes mellitus or chronic kidney disease who had BP ≥130/80 mm Hg;500 503 current hypertension management guidelines generally recommend a BP threshold of 140/90 mm Hg for these individuals (same as for the general population of patients without these conditions), although a goal of <130/80 mm Hg may still be considered.501 502 503 504 520 530 535 536 541

Amlodipine should not be used for acute management of hypertensive crises.1 500

Addition of an ACE inhibitor or angiotensin II receptor antagonist may reduce incidence of amlodipine-associated edema.21 134 504

May use amlodipine/atorvastatin fixed-combination preparation when treatment with both amlodipine (for hypertension) and atorvastatin (for dyslipidemias and prevention of cardiovascular events) is appropriate.107

CAD

Amlodipine is used for management of Prinzmetal variant angina and chronic stable angina pectoris;1 2 3 4 9 has been used alone or in combination with other antianginal agents.1 2 3 4 9 Calcium-channel blockers are considered the drugs of choice in management of Prinzmetal variant angina.b

Amlodipine is used in patients with recently documented CAD (by angiography) and without heart failure or an ejection fraction <40% to reduce the risk of coronary revascularization procedure and hospitalization due to angina.1

May use amlodipine/atorvastatin fixed-combination preparation when treatment with both amlodipine (for CAD) and atorvastatin (for dyslipidemias and prevention of cardiovascular events) is appropriate.107

Amlodipine Besylate Dosage and Administration

General

BP Monitoring and Treatment Goals

  • Carefully monitor BP during initial titration or subsequent upward adjustment in dosage.500 501

  • When available, use evidence-based dosing information (i.e., dosages shown in randomized controlled trials to reduce complications of hypertension) to determine target dosages; target dosages usually can be achieved within 2–4 weeks but may take up to several months.501

  • If adequate BP response not achieved with a single antihypertensive agent, add a second drug with demonstrated benefit; if goal BP still not achieved with optimal dosages of 2 antihypertensive agents, add a third drug.501 May maximize dosage of the first drug before adding a second drug, or add a second drug before maximizing dosage of the initial drug.501

  • Consider initiating antihypertensive therapy with a combination of drugs if patient's BP exceeds goal BP by >20/10 mm Hg.500 501 503 504

  • Goal is to achieve and maintain optimal control of BP; individualize specific target BP based on consideration of multiple factors, including patient age and comorbidities, and currently available evidence from clinical studies.500 501 (See Hypertension under Uses.)

Administration

Oral Administration

Administer amlodipine orally without regard to meals.1 2 3 5

Administer amlodipine in fixed combination with aliskiren (with or without hydrochlorothiazide) in a consistent manner relative to meals; administration with a high-fat meal decreases aliskiren absorption.128 131

Dosage

Available as amlodipine besylate; dosage expressed in terms of amlodipine.1

Pediatric Patients

Hypertension
Amlodipine Therapy for Hypertension
Oral

Children ≥6 years of age: Usual effective amlodipine dosage is 2.5–5 mg once daily.1 105

Adults

Hypertension
Amlodipine Therapy for Hypertension
Oral

JNC 8 expert panel recommends initial dosage of 2.5 mg once daily and target dosage of 10 mg once daily based on dosages used in randomized controlled studies.501

Manufacturers state usual initial dosage is 2.5–5 mg once daily.1 In small or frail individuals, initiate therapy with 2.5 mg once daily.1

When adding amlodipine to an existing antihypertensive regimen, use initial dosage of 2.5 mg once daily.1

Increase amlodipine dosage gradually, generally at 7- to 14-day intervals, until optimum control of BP is obtained (up to a maximum dosage of 10 mg daily).1 May increase more rapidly if symptoms so warrant and patient’s tolerance and response are frequently assessed.1

Manufacturers state usual maintenance dosage is 5–10 mg once daily.1

If intolerable adverse effects occur, consider dosage reduction; if adverse effects worsen or fail to resolve, may need to discontinue and switch to another antihypertensive drug class.501

Amlodipine/Aliskiren Fixed-combination Therapy for Hypertension
Oral

Fixed-combination amlodipine/aliskiren tablets may be used for initial treatment of hypertension in patients likely to require combination therapy with multiple antihypertensive agents to control BP.128

If the patient's baseline BP is 157/100 mm Hg, the estimated probability of achieving SBP control (SBP <140 mm Hg) is 49, 62, or 74% and of achieving DBP control (DBP <90 mm Hg) is 50, 69, or 83% with aliskiren (300 mg daily) alone, amlodipine (10 mg daily) alone, or amlodipine combined with aliskiren (same dosages), respectively.128

Can use the fixed combination as a substitute for the individually administered drugs.128 Can switch to the fixed-combination preparation containing the corresponding individual doses of amlodipine and aliskiren; alternatively, can increase the dosage of one or both components for additional antihypertensive effects.128

If BP is not adequately controlled by monotherapy with amlodipine (or another dihydropyridine-derivative calcium-channel blocker) or aliskiren, can switch to amlodipine/aliskiren fixed combination.128

If dose-limiting adverse effects have developed during monotherapy with aliskiren or amlodipine, can switch to an amlodipine/aliskiren fixed-combination preparation containing a lower dose of that drug to achieve similar BP control.128

When used for initial therapy of hypertension in patients likely to require combination therapy with multiple antihypertensive agents, recommended initial dosage is amlodipine 5 mg and aliskiren 150 mg once daily.128

May adjust dosage after 2–4 weeks at current dosage, up to maximum of 10 mg of amlodipine and 300 mg of aliskiren once daily; most of the antihypertensive effect of a given dosage is achieved within 1–2 weeks after a change in dosage.128

Amlodipine/Aliskiren/Hydrochlorothiazide Fixed-combination Therapy for Hypertension
Oral

Manufacturer states that amlodipine/aliskiren/hydrochlorothiazide fixed-combination preparation should not be used for initial treatment of hypertension.131

Can switch to amlodipine/aliskiren/hydrochlorothiazide fixed-combination tablets if BP is not adequately controlled by combined therapy with any 2 of the following: dihydropyridine-derivative calcium-channel blockers, aliskiren, or thiazide diuretics.131

In patients who experience dose-limiting adverse effects of amlodipine, aliskiren, or hydrochlorothiazide while receiving any dual combination of these drugs, may switch to the triple fixed-combination preparation containing a lower dose of that component.131

Can use the fixed combination as a substitute for the individually titrated drugs.131

May increase dosage of the fixed combination after 2 weeks if additional BP control is needed (up to maximum of amlodipine 10 mg, aliskiren 300 mg, and hydrochlorothiazide 25 mg once daily).131

Amlodipine/Benazepril Fixed-combination Therapy for Hypertension
Oral

Manufacturers state that amlodipine/benazepril fixed-combination preparation usually should be used only after therapy with either drug component alone has failed.21

In studies using amlodipine/benazepril fixed combination in dosages of amlodipine 2.5–10 mg daily and benazepril hydrochloride 10–40 mg daily, BP response increased with increasing amlodipine dosage in all patient groups and increased with increasing benazepril dosage in nonblack patient groups.21

If BP is not adequately controlled by monotherapy with amlodipine (or another dihydropyridine-derivative calcium-channel blocker) or benazepril (or another ACE inhibitor), can switch to amlodipine/benazepril fixed combination.21

If BP is adequately controlled by monotherapy with amlodipine, but edema has developed, can switch to amlodipine/benazepril fixed combination.21 Addition of benazepril to amlodipine therapy usually does not provide additional antihypertensive effects in black patients, but benazepril appears to reduce the development of amlodipine-associated edema regardless of race.21

If BP is controlled with amlodipine and benazepril (administered separately), can switch to the fixed-combination preparation containing the corresponding individual doses for convenience.21

Recommended initial dosage is amlodipine 2.5 mg and benazepril hydrochloride 10 mg once daily.21

Adjust dosage of amlodipine/benazepril fixed combination according to patient’s response, up to maximum of amlodipine 10 mg and benazepril hydrochloride 40 mg once daily; antihypertensive effect of a given dosage is largely attained with 2 weeks.21

Amlodipine/Olmesartan Fixed-combination Therapy for Hypertension
Oral

Fixed-combination amlodipine/olmesartan tablets may be used for initial treatment of hypertension in patients likely to require combination therapy with multiple antihypertensive agents to control BP.134

If the patient's baseline BP is 160/100 mm Hg, the estimated probability of achieving SBP control (SBP <140 mm Hg) is 48, 46, or 68% and of achieving DBP control (DBP <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 (same dosages), respectively.134

If BP is not adequately controlled by monotherapy with amlodipine (or another dihydropyridine-derivative calcium-channel blocker) or olmesartan (or another angiotensin II receptor antagonist), can switch to amlodipine/olmesartan fixed combination.134

Can use the fixed combination as a substitute for the individually titrated drugs.134 Can switch to the fixed-combination preparation containing the corresponding individual doses of amlodipine and olmesartan; alternatively, can increase the dosage of one or both components for additional antihypertensive effects.134

Adjust dosage of amlodipine/olmesartan fixed combination, up to a maximum of amlodipine 10 mg and olmesartan medoxomil 40 mg once daily, according to patient’s response after ≥2 weeks at the current dosage.134

When used for initial therapy of hypertension in patients likely to require combination therapy with multiple antihypertensive agents, recommended initial dosage is amlodipine 5 mg and olmesartan medoxomil 20 mg once daily.134 May increase dosage after 1–2 weeks for additional BP control, up to maximum of amlodipine 10 mg and olmesartan medoxomil 40 mg once daily.134

Amlodipine/Olmesartan/Hydrochlorothiazide Fixed-combination Therapy for Hypertension
Oral

Manufacturer states that amlodipine/olmesartan/hydrochlorothiazide fixed-combination preparation should not be used for initial treatment of hypertension.132

Can switch to fixed-combination amlodipine/olmesartan/hydrochlorothiazide tablets if BP is not adequately controlled by combined therapy with any 2 of the following drug classes at maximally tolerated, labeled, or usual dosages: calcium-channel blockers, angiotensin II receptor antagonists, or diuretics.132

In patients who experience dose-limiting adverse effects of olmesartan, amlodipine, or hydrochlorothiazide while receiving any dual combination of these drugs, may switch to the triple fixed-combination preparation containing a lower dose of that component.132

Can use the fixed combination as a substitute for the individually titrated drugs.132

May increase dosage of the fixed combination after 2 weeks if additional BP control is needed (up to maximum of amlodipine 10 mg, olmesartan medoxomil 40 mg, and hydrochlorothiazide 25 mg once daily).132

Amlodipine/Perindopril Fixed-combination Therapy for Hypertension
Oral

Fixed-combination amlodipine/perindopril tablets may be used for initial treatment of hypertension in patients likely to require combination therapy with multiple antihypertensive agents to control BP.130 Consider potential benefits and risks of initiating therapy with the fixed combination, including whether the patient is likely to tolerate the lowest available dosage of the combined drugs.130

If patient's baseline BP is 170/105 mm Hg, the estimated probability of achieving SBP control (SBP <140 mm Hg) is 26, 40, or 50% and of achieving DBP control (DBP <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

If BP is not adequately controlled by monotherapy with amlodipine (or another dihydropyridine-derivative calcium-channel blocker) or perindopril (or another ACE inhibitor), can switch to amlodipine/perindopril fixed combination.130

In black patients and patients with diabetes mellitus, 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

If BP is adequately controlled by monotherapy with amlodipine, but edema has developed, can switch to amlodipine/perindopril fixed combination to achieve BP control without edema.130

When used for initial therapy of hypertension in patients likely to require combination therapy with multiple antihypertensive agents, recommended initial dosage is amlodipine 2.5 mg and perindopril arginine 3.5 mg once daily.130

May adjust dosage at intervals of 7–14 days, up to maximum of amlodipine 10 mg and perindopril arginine 14 mg once daily.130

Amlodipine/Telmisartan Fixed-combination Therapy for Hypertension
Oral

Fixed-combination amlodipine/telmisartan tablets may be used for initial treatment of hypertension in patients likely to require combination therapy with multiple antihypertensive agents to control BP.129 Consider potential benefits and risks of initiating therapy with the fixed combination, including whether the patient is likely to tolerate the lowest available dosage of the combined drugs.129

If the patient’s baseline BP is 160/110 mm Hg, the estimated probability of achieving SBP control (SBP <140 mm Hg) is 46, 69, or 79% and of achieving DBP control (DBP <90 mm Hg) is 26, 22, or 55% with telmisartan (80 mg daily) alone, amlodipine (10 mg daily) alone, or amlodipine combined with telmisartan (same dosages), respectively.129

If BP is not adequately controlled by monotherapy with amlodipine (or another dihydropyridine-derivative calcium-channel blocker) or telmisartan (or another angiotensin II receptor antagonist), can switch to amlodipine/telmisartan fixed combination.129

If dose-limiting adverse effects (e.g., edema) have developed during monotherapy with amlodipine 10 mg, can switch to the fixed-combination preparation containing amlodipine 5 mg and telmisartan 40 mg to achieve similar BP control; adjust dosage according to patient’s response after ≥2 weeks of therapy.129

Can use the fixed combination as a substitute for the individually administered drugs.129 Can switch to the fixed-combination preparation containing the corresponding individual doses of amlodipine and telmisartan; alternatively, can increase the dosage of one or both components for additional antihypertensive effects.129

When used for initial therapy of hypertension in patients likely to require combination therapy with multiple antihypertensive agents, usual initial dosage is amlodipine 5 mg and telmisartan 40 mg once daily; initial dosage of amlodipine 5 mg and telmisartan 80 mg once daily may be used in patients requiring larger BP reductions.129

Increase to maximum dosage of amlodipine 10 mg and telmisartan 80 mg once daily, if needed, to control BP.129 May adjust dosage at intervals of at least 2 weeks, since most of the antihypertensive effect of a given dosage is achieved within 2 weeks after a change in dosage.129

Amlodipine/Valsartan Fixed-combination Therapy for Hypertension
Oral

Fixed-combination amlodipine/valsartan tablets may be used for initial treatment of hypertension in patients likely to require combination therapy with multiple antihypertensive agents to control BP.113 Consider potential benefits and risks of initiating therapy with the fixed combination, including whether the patient is likely to tolerate the lowest available dosage of the combined drugs.113

If the patient’s baseline BP is 160/100 mm Hg, the estimated probability of achieving SBP control (SBP <140 mm Hg) is 47, 67, or 80% and of achieving DBP control (DBP <90 mm Hg) is 62, 80, or 85% with valsartan (320 mg daily) alone, amlodipine (10 mg daily) alone, or amlodipine combined with valsartan (same dosages), respectively.113

In studies using amlodipine/valsartan fixed combination in dosages of amlodipine 5–10 mg daily and valsartan 160–320 mg daily, BP response increased with increasing dosages of the drugs.113

If BP is not adequately controlled by monotherapy with amlodipine (or another dihydropyridine-derivative calcium-channel blocker) or valsartan (or another angiotensin II receptor antagonist), can switch to amlodipine/valsartan fixed combination.113

If dose-limiting adverse effects have developed during monotherapy with amlodipine or valsartan, can switch to a fixed-combination preparation containing a lower dose of that drug to achieve similar BP control; adjust dosage according to patient’s response after 3–4 weeks of therapy.113

If BP is controlled with amlodipine and valsartan (administered separately), can switch to the fixed-combination preparation containing the corresponding individual doses for convenience.113

When used for initial therapy of hypertension in patients likely to require combination therapy with multiple antihypertensive agents, recommended initial dosage is amlodipine 5 mg and valsartan 160 mg once daily in those who are not volume depleted.113

Increase to maximum dosage of amlodipine 10 mg and valsartan 320 mg once daily, if needed, to control BP.113 May adjust dosage at intervals of 1–2 weeks, since most of the antihypertensive effect of a given dosage is achieved within 2 weeks after a change in dosage.113

Amlodipine/Valsartan/Hydrochlorothiazide Fixed-combination Therapy for Hypertension
Oral

Manufacturers state amlodipine/valsartan/hydrochlorothiazide fixed-combination preparation should not be used for initial treatment of hypertension.133

Can switch to fixed-combination amlodipine/valsartan/hydrochlorothiazide tablets if BP is not adequately controlled by combined therapy with any 2 of the following drug classes: calcium-channel blockers, angiotensin II receptor antagonists, or diuretics.133

In patients who experience dose-limiting adverse effects of amlodipine, valsartan, or hydrochlorothiazide while receiving any dual combination of these drugs, may switch to the triple fixed-combination preparation containing a lower dose of that component.133

Can use the fixed combination as a substitute for the individually titrated drugs.133

May increase dosage of the fixed combination after 2 weeks if additional BP control is needed (up to maximum of amlodipine 10 mg, valsartan 320 mg, and hydrochlorothiazide 25 mg once daily).133

Amlodipine/Atorvastatin Fixed-combination Therapy for Hypertension (Amlodipine) and for Dyslipidemias and Prevention of Cardiovascular Events (Atorvastatin)
Oral

Use the fixed combination as a substitute for the individually titrated drugs.107 Can switch to the fixed-combination preparation containing the corresponding individual doses of amlodipine and atorvastatin; alternatively, can increase the dosage of one or both components for additional antihypertensive and/or antilipemic effects.107

Use the fixed combination to provide additional therapy for patients currently receiving one component of the preparation.107 Select initial dosage of the fixed combination based on the current dosage of the component being used and the recommended initial dosage for the added monotherapy.107

Use the fixed combination to initiate treatment in patients requiring therapy for hypertension and dyslipidemias.107 Select initial dosage of the fixed combination based on recommended dosages of the individual components.107

CAD
Amlodipine Therapy for Angina
Oral

Usual amlodipine dosage is 5–10 mg once daily;1 2 adequate control usually requires a maintenance dosage of 10 mg daily.1

Amlodipine Therapy for Angiographically Documented CAD
Oral

Recommended amlodipine dosage is 5–10 mg once daily;1 adequate control usually requires a maintenance dosage of 10 mg daily.1

Amlodipine/Atorvastatin Fixed-combination Therapy for CAD (Amlodipine) and for Dyslipidemias and Prevention of Cardiovascular Events (Atorvastatin)
Oral

Use the fixed combination as a substitute for the individually titrated drugs.107 Can switch to the fixed-combination preparation containing the corresponding individual doses of amlodipine and atorvastatin; alternatively, can increase the dosage of one or both components for additional antianginal and/or antilipemic effects.107

Use the fixed combination to provide additional therapy for patients currently receiving one component of the preparation.107 Select initial dosage of the fixed combination based on the current dosage of the component being used and the recommended initial dosage for the added monotherapy.107

Use the fixed combination to initiate treatment in patients requiring therapy for angina and dyslipidemias.107 Select initial dosage of the fixed combination based on recommended dosages of the individual components.107

Prescribing Limits

Pediatric Patients

Hypertension
Oral

Children ≥6 years of age: Safety and efficacy of amlodipine dosages >5 mg daily not established.1

Adults

Hypertension
Oral

Maximum 10 mg of amlodipine once daily.1 107 113 134

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.21 107 113 134

Hepatic Impairment

Hypertension

Initially, amlodipine 2.5 mg once daily (as initial or add-on therapy).1 21 107 129 134 Titrate slowly.1 132

Amlodipine/perindopril fixed combination not recommended in patients with hepatic impairment; insufficient data to support dosage recommendations.130

Preparations containing amlodipine in fixed combination with aliskiren (with or without hydrochlorothiazide), olmesartan (with or without hydrochlorothiazide), telmisartan, or valsartan (with or without hydrochlorothiazide) exceed recommended initial dosage of amlodipine (2.5 mg daily) for patients with hepatic insufficiency.113 128 129 131 132 133 134

Angina

Initially, amlodipine 5 mg daily.1 107

Renal Impairment

Amlodipine dosage modification generally not necessary.1 2 3 5

Amlodipine/benazepril fixed combination not recommended in patients with Clcr ≤30 mL/minute.21

Amlodipine/olmesartan/hydrochlorothiazide fixed combination not recommended in patients with Clcr ≤30 mL/minute; loop diuretic generally preferred over hydrochlorothiazide.132

Amlodipine/perindopril fixed combination not recommended in patients with Clcr <60 mL/minute; insufficient data to support dosage recommendations.130

Safety and efficacy of preparations containing amlodipine in fixed combination with aliskiren (with or without hydrochlorothiazide) or in fixed combination with valsartan (with or without hydrochlorothiazide) in patients with Clcr <30 mL/minute not established.113 128 131 133

Manufacturers recommend slow titration of amlodipine/telmisartan dosage in patients with severe renal impairment.129

Geriatric Patients

Hypertension

Consider reduced initial amlodipine dosage.1 2 4 21 107 113 128 129 131 132 133 134 Some manufacturers recommend initial dosage of 2.5 mg once daily for geriatric patients;1 others recommend this reduced dosage for geriatric patients ≥75 years of age.113 129 132 134

Preparations containing amlodipine in fixed combination with aliskiren (with or without hydrochlorothiazide), olmesartan (with or without hydrochlorothiazide), telmisartan, or valsartan (with or without hydrochlorothiazide) exceed recommended initial dosage of amlodipine (2.5 mg daily) for geriatric patients.113 128 129 131 132 133 134

Amlodipine/perindopril fixed combination not recommended; insufficient data available to support geriatric dosage recommendations.130

Angina

Initially, amlodipine 5 mg daily.1 107

Heart Failure

Manufacturers make no specific dosage recommendations; however, amlodipine exposure in patients with moderate to severe heart failure similar to that in geriatric patients and those with hepatic impairment.1

Amlodipine/perindopril fixed combination not recommended in patients with heart failure; insufficient data to support dosage recommendations.130

Cautions for Amlodipine Besylate

Contraindications

  • Known hypersensitivity to amlodipine.1 21 107

Warnings/Precautions

Hypotension

Possible symptomatic hypotension, particularly in patients with severe aortic stenosis.1 Acute hypotension unlikely because of gradual onset of action.1

Increased Angina and/or Acute MI

Possible worsening of angina or acute MI, particularly in patients with severe obstructive CAD, upon initiation or dosage increase of amlodipine.1

Use of Fixed Combinations

When amlodipine is used in fixed combination with other drugs (e.g., other antihypertensive agents, atorvastatin), consider cautions, precautions, contraindications, and interactions associated with the concomitant agent(s).21 107 113 128 129 130 131 132 133 134 Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for each drug in the fixed combination.21 107 113 128 129 130 131 132 133 134

Heart Failure

Although some calcium-channel blockers have been shown to worsen clinical status of patients with heart failure, no evidence of worsening heart failure and no adverse effects on overall survival or cardiac morbidity observed in controlled studies of amlodipine in patients with heart failure.1 524

Specific Populations

Pregnancy

Category C.1

Lactation

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

Pediatric Use

Safety and efficacy of amlodipine in children <6 years of age not established.1 Efficacy of amlodipine 2.5–5 mg daily for treatment of hypertension established in pediatric patients 6–17 years of age.1

Safety and efficacy of amlodipine in fixed combination with aliskiren (with or without hydrochlorothiazide), atorvastatin, benazepril, olmesartan (with or without hydrochlorothiazide), perindopril, telmisartan, or valsartan (with or without hydrochlorothiazide) not established in children.21 107 113 128 129 130 131 132 133 134

Geriatric Use

Increased amlodipine exposure. 1 Select amlodipine dosage with caution; initiate with dosage at lower end of recommended range.1 113 (See Geriatric Patients under Dosage and Administration and see Special Populations under Pharmacokinetics.)

Amlodipine: Clinical studies included insufficient numbers of patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients; other clinical experience has not revealed age-related differences in response or tolerance.1

Amlodipine in fixed combination with aliskiren (with or without hydrochlorothiazide), benazepril, olmesartan (with or without hydrochlorothiazide), telmisartan, or valsartan (with or without hydrochlorothiazide): No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.21 113 128 129 131 132 133 134

Amlodipine in fixed combination with perindopril: Safety and efficacy not established in geriatric patients.130

Amlodipine in fixed combination with atorvastatin: Safety and efficacy not established in geriatric patients.107

Hepatic Impairment

Increased amlodipine exposure.1 Reduced initial dosage recommended;1 2 4 21 107 113 128 129 131 132 133 134 titrate slowly.1 129 (See Hepatic Impairment under Dosage and Administration and see Special Populations under Pharmacokinetics.)

Common Adverse Effects

Edema, dizziness, flushing, palpitations, fatigue, nausea, abdominal pain, somnolence.1 Edema, flushing, palpitations, and somnolence may be more common in women than men.1 Edema may be less frequent with concomitant ACE inhibitor or angiotensin II receptor antagonist therapy.21 134 504

Interactions for Amlodipine Besylate

The following information addresses potential interactions with amlodipine. When amlodipine is used in fixed combination with other drugs, consider interactions associated with the concomitant agent(s).21 107 113 128 129 130 131 132 133 134

Drugs Affecting Hepatic Microsomal Enzymes

Moderate or potent CYP3A inhibitors: Increased amlodipine exposure.1 Amlodipine dosage reduction may be necessary.1 Monitor patients for symptoms of hypotension or edema.1

CYP3A inducers: Data lacking; closely monitor BP.1

Specific Drugs and Food

Drug or Food

Interaction

Comments

Alcohol

No change in alcohol exposure1

Antacids (e.g., aluminum hydroxide and magnesium hydroxide)

No change in amlodipine exposure1

Antifungals, azole (e.g., itraconazole)

Possible increased amlodipine exposure1

Amlodipine dosage reduction may be necessary; monitor patients for hypotension and edema1

Cimetidine

No effects on amlodipine exposure1

Digoxin

No effects on digoxin exposure1

No change in plasma protein binding of digoxin1

Diltiazem

Increased amlodipine exposure1

Amlodipine dosage reduction may be necessary; monitor patients for hypotension and edema1

HMG-CoA reductase inhibitors (statins)

Atorvastatin: No effects on atorvastatin exposure1

Simvastatin: Increased simvastatin exposure1

Simvastatin: Limit simvastatin dosage to ≤20 mg daily1

Grapefruit juice

Altered amlodipine bioavailability possible but no evidence of altered pharmacodynamics;64 65 74 75 no change in amlodipine exposure in another study1

Immunosuppressants (cyclosporine, tacrolimus)

Cyclosporine: Increased cyclosporine trough concentrations1

Tacrolimus: Increased tacrolimus exposure, possibly irrespective of CYP3A5 genotype1

Frequently monitor blood concentrations of the immunosuppressant; adjust the immunosuppressant dosage as necessary1

Indomethacin

No change in plasma protein binding of indomethacin1

Macrolides (clarithromycin, erythromycin)

Clarithromycin: Possible increased amlodipine exposure1

Erythromycin: No substantial change in amlodipine exposure1

Clarithromycin: Amlodipine dosage reduction may be necessary; monitor patients for hypotension and edema1

Phenytoin

No change in plasma protein binding of phenytoin1

Sildenafil

Pharmacokinetic interaction unlikely; additional reduction of BP possible1

Monitor patients for hypotension1

Warfarin

No change in PT1

No change in plasma protein binding of warfarin1

Amlodipine Besylate Pharmacokinetics

Absorption

Bioavailability

Peak plasma amlodipine concentrations attained 6–12 hours after oral administration.1 Absolute bioavailability ranges from 64–90%.1

Duration

Antihypertensive effects of amlodipine persist for at least 24 hours after administration.1

Food

Food does not affect bioavailability of amlodipine.1 107 113 128 129 130 132 133 134

Distribution

Extent

Not known whether amlodipine is distributed into milk.1

Plasma Protein Binding

Approximately 93%.1

Elimination

Metabolism

Amlodipine is extensively (about 90%) metabolized to inactive metabolites in the liver.1

Elimination Route

Amlodipine is excreted in urine as metabolites (60%) and unchanged drug (10%).1

Half-life

Terminal elimination half-life of amlodipine is 30–50 hours.1

Special Populations

In geriatric patients, amlodipine clearance decreased and AUC increased about 40–60%.1

In pediatric patients 6–17 years of age, weight-adjusted clearance similar to values in adults.1

In patients with hepatic impairment, amlodipine clearance decreased and AUC increased about 40–60%.1

In patients with moderate to severe heart failure, amlodipine clearance decreased and AUC increased about 40–60%.1

Stability

Storage

Oral

Tablets

Amlodipine: Tight, light-resistant containers at 15–30°C.1

Amlodipine/aliskiren and amlodipine/aliskiren/hydrochlorothiazide fixed combinations: Original container at 25ºC (may be exposed to 15–30ºC); protect from heat and moisture.128 131

Amlodipine/perindopril, amlodipine/valsartan, and amlodipine/valsartan/hydrochlorothiazide fixed combinations: 25ºC (may be exposed to 15–30ºC); protect from moisture.113 130 133

Amlodipine/atorvastatin, amlodipine/olmesartan, and amlodipine/olmesartan/hydrochlorothiazide fixed combinations: 25°C (may be exposed to 15–30°C).107 132 134

Amlodipine/telmisartan fixed combination: Original blister packs at 25ºC (may be exposed to 15–30ºC); protect from light and moisture.129 Do not remove from blister pack until immediately before administration.129

Capsules

Amlodipine/benazepril fixed combination: Tight container at 25ºC (may be exposed to 15–30ºC).21

Actions

  • 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; acts directly on vascular smooth muscle causing reduction in peripheral vascular resistance and BP.1

  • Amlodipine reduces total peripheral resistance (afterload) and rate pressure product and thus myocardial oxygen demand at any given level of exercise in patients with exertional angina.1

  • Amlodipine 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

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).21 107 113 128 129 130 131 132 133 134

  • Importance of taking amlodipine/aliskiren or amlodipine/aliskiren/hydrochlorothiazide fixed-combination tablets in a consistent manner relative to meals.128 131

  • Importance of storing amlodipine/aliskiren or amlodipine/aliskiren/hydrochlorothiazide fixed-combination tablets in original container.128 131

  • Importance of not removing amlodipine/telmisartan fixed-combination tablets from blister pack 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.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Amlodipine Besylate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

2.5 mg (of amlodipine)*

Amlodipine Besylate Tablets

Norvasc

Pfizer

5 mg (of amlodipine)*

Amlodipine Besylate Tablets

Norvasc

Pfizer

10 mg (of amlodipine)*

Amlodipine Besylate Tablets

Norvasc

Pfizer

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Amlodipine Besylate Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

2.5 mg (of amlodipine) with Benazepril Hydrochloride 10 mg*

Amlodipine Besylate and Benazepril Hydrochloride Capsules

Lotrel

Novartis

5 mg (of amlodipine) with Benazepril Hydrochloride 10 mg*

Amlodipine Besylate and Benazepril Hydrochloride Capsules

Lotrel

Novartis

5 mg (of amlodipine) with Benazepril Hydrochloride 20 mg*

Amlodipine Besylate and Benazepril Hydrochloride Capsules

Lotrel

Novartis

5 mg (of amlodipine) with Benazepril Hydrochloride 40 mg*

Amlodipine Besylate and Benazepril Hydrochloride Capsules

Lotrel

Novartis

10 mg (of amlodipine) with Benazepril Hydrochloride 20 mg*

Amlodipine Besylate and Benazepril Hydrochloride Capsules

Lotrel

Novartis

10 mg (of amlodipine) with Benazepril Hydrochloride 40 mg*

Amlodipine Besylate and Benazepril Hydrochloride Capsules

Lotrel

Novartis

Tablets

2.5 mg (of amlodipine) with Perindopril Arginine 3.5 mg

Prestalia

Symplmed

5 mg (of amlodipine) with Olmesartan Medoxomil 20 mg

Azor

Daiichi-Sankyo

5 mg (of amlodipine) with Olmesartan Medoxomil 40 mg

Azor

Daiichi-Sankyo

5 mg (of amlodipine) with Perindopril Arginine 7 mg

Prestalia

Symplmed

10 mg (of amlodipine) with Olmesartan Medoxomil 20 mg

Azor

Daiichi-Sankyo

10 mg (of amlodipine) with Olmesartan Medoxomil 40 mg

Azor

Daiichi-Sankyo

10 mg (of amlodipine) with Perindopril Arginine 14 mg

Prestalia

Symplmed

Tablets, film-coated

2.5 mg (of amlodipine) with Atorvastatin Calcium 10 mg (of atorvastatin)*

Amlodipine Besylate and Atorvastatin Calcium Tablets

Caduet

Pfizer

2.5 mg (of amlodipine) with Atorvastatin Calcium 20 mg (of atorvastatin)*

Amlodipine Besylate and Atorvastatin Calcium Tablets

Caduet

Pfizer

2.5 mg (of amlodipine) with Atorvastatin Calcium 40 mg (of atorvastatin)*

Amlodipine Besylate and Atorvastatin Calcium Tablets

Caduet

Pfizer

5 mg (of amlodipine) with Aliskiren Hemifumarate 150 mg (of aliskiren)

Tekamlo

Novartis

5 mg (of amlodipine) with Aliskiren Hemifumarate 150 mg (of aliskiren) and Hydrochlorothiazide 12.5 mg

Amturnide

Novartis

5 mg (of amlodipine) with Aliskiren Hemifumarate 300 mg (of aliskiren)

Tekamlo

Novartis

5 mg (of amlodipine) with Aliskiren Hemifumarate 300 mg (of aliskiren) and Hydrochlorothiazide 12.5 mg

Amturnide

Novartis

5 mg (of amlodipine) with Aliskiren Hemifumarate 300 mg (of aliskiren) and Hydrochlorothiazide 25 mg

Amturnide

Novartis

5 mg (of amlodipine) with Atorvastatin Calcium 10 mg (of atorvastatin)*

Amlodipine Besylate and Atorvastatin Calcium Tablets

Caduet

Pfizer

5 mg (of amlodipine) with Atorvastatin Calcium 20 mg (of atorvastatin)*

Amlodipine Besylate and Atorvastatin Calcium Tablets

Caduet

Pfizer

5 mg (of amlodipine) with Atorvastatin Calcium 40 mg (of atorvastatin)*

Amlodipine Besylate and Atorvastatin Calcium Tablets

Caduet

Pfizer

5 mg (of amlodipine) with Atorvastatin Calcium 80 mg (of atorvastatin)*

Amlodipine Besylate and Atorvastatin Calcium Tablets

Caduet

Pfizer

5 mg (of amlodipine) with Hydrochlorothiazide 12.5 mg and Olmesartan Medoxomil 20 mg

Tribenzor

Daiichi Sankyo

5 mg (of amlodipine) with Hydrochlorothiazide 12.5 mg and Olmesartan Medoxomil 40 mg

Tribenzor

Daiichi Sankyo

5 mg (of amlodipine) with Hydrochlorothiazide 12.5 mg and Valsartan 160 mg*

Amlodipine Besylate, Valsartan, and Hydrochlorothiazide Tablets

Exforge HCT

Novartis

5 mg (of amlodipine) with Hydrochlorothiazide 25 mg and Olmesartan Medoxomil 40 mg

Tribenzor

Daiichi Sankyo

5 mg (of amlodipine) with Hydrochlorothiazide 25 mg and Valsartan 160 mg*

Amlodipine Besylate, Valsartan, and Hydrochlorothiazide Tablets

Exforge HCT

Novartis

5 mg (of amlodipine) with Valsartan 160 mg*

Amlodipine Besylate and Valsartan Tablets

Exforge

Novartis

5 mg (of amlodipine) with Valsartan 320 mg*

Amlodipine Besylate and Valsartan Tablets

Exforge

Novartis

10 mg (of amlodipine) with Aliskiren Hemifumarate 150 mg (of aliskiren)

Tekamlo

Novartis

10 mg (of amlodipine) with Aliskiren Hemifumarate 300 mg (of aliskiren)

Tekamlo

Novartis

10 mg (of amlodipine) with Aliskiren Hemifumarate 300 mg (of aliskiren) and Hydrochlorothiazide 12.5 mg

Amturnide

Novartis

10 mg (of amlodipine) with Aliskiren Hemifumarate 300 mg (of aliskiren) and Hydrochlorothiazide 25 mg

Amturnide

Novartis

10 mg (of amlodipine) with Atorvastatin Calcium 10 mg (of atorvastatin)*

Amlodipine Besylate and Atorvastatin Calcium Tablets

Caduet

Pfizer

10 mg (of amlodipine) with Atorvastatin Calcium 20 mg (of atorvastatin)*

Amlodipine Besylate and Atorvastatin Calcium Tablets

Caduet

Pfizer

10 mg (of amlodipine) with Atorvastatin Calcium 40 mg (of atorvastatin)*

Amlodipine Besylate and Atorvastatin Calcium Tablets

Caduet

Pfizer

10 mg (of amlodipine) with Atorvastatin Calcium 80 mg (of atorvastatin)*

Amlodipine Besylate and Atorvastatin Calcium Tablets

Caduet

Pfizer

10 mg (of amlodipine) with Hydrochlorothiazide 12.5 mg and Olmesartan Medoxomil 40 mg

Tribenzor

Daiichi Sankyo

10 mg (of amlodipine) with Hydrochlorothiazide 12.5 mg and Valsartan 160 mg*

Amlodipine Besylate, Valsartan, and Hydrochlorothiazide Tablets

Exforge HCT

Novartis

10 mg (of amlodipine) with Hydrochlorothiazide 25 mg and Olmesartan Medoxomil 40 mg

Tribenzor

Daiichi Sankyo

10 mg (of amlodipine) with Hydrochlorothiazide 25 mg and Valsartan 160 mg*

Amlodipine Besylate, Valsartan, and Hydrochlorothiazide Tablets

Exforge HCT

Novartis

10 mg (of amlodipine) with Hydrochlorothiazide 25 mg and Valsartan 320 mg*

Amlodipine Besylate, Valsartan, and Hydrochlorothiazide Tablets

Exforge HCT

Novartis

10 mg (of amlodipine) with Valsartan 160 mg*

Amlodipine Besylate and Valsartan Tablets

Exforge

Novartis

10 mg (of amlodipine) with Valsartan 320 mg*

Amlodipine Besylate and Valsartan Tablets

Exforge

Novartis

Tablets, multilayer

5 mg (of amlodipine) with Telmisartan 40 mg*

Telmisartan and Amlodipine Besylate Tablets

Twynsta

Boehringer Ingelheim

5 mg (of amlodipine) with Telmisartan 80 mg*

Telmisartan and Amlodipine Besylate Tablets

Twynsta

Boehringer Ingelheim

10 mg (of amlodipine) with Telmisartan 40 mg*

Telmisartan and Amlodipine Besylate Tablets

Twynsta

Boehringer Ingelheim

10 mg (of amlodipine) with Telmisartan 80 mg*

Telmisartan and Amlodipine Besylate Tablets

Twynsta

Boehringer Ingelheim

AHFS DI Essentials. © Copyright, 2004-2016, Selected Revisions November 18, 2015. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Pfizer Laboratories. Norvasc (amlodipine besylate) tablets prescribing information. New York; 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. [IDIS 305825] [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. [IDIS 305824] [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. [IDIS 298260] [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. [IDIS 311530] [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. [IDIS 260612] [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 besylate 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. [IDIS 352203] [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. [IDIS 352205] [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. [IDIS 353358] [PubMed 7648682]

31. Opie LH, Messerli FH. Nifedipine and mortality: grave defects in the dossier. Circulation. 1995; 92:1068-73. [IDIS 353353] [PubMed 7648646]

32. Kloner RA. Nifedipine in ischemic heart disease. Circulation. 1995; 92:1074-8. [IDIS 353354] [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. [IDIS 351406] [PubMed 7606987]

36. Horton R. Spinning the risks and benefits of calcium antagonists. Lancet. 1995; 346:586-7. [IDIS 353102] [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. [IDIS 284079] [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. [IDIS 308552] [PubMed 8421980]

39. Wagenknecht LE, Furberg CD, Hammon JW et al. Surgical bleeding: unexpected effect of a calcium antagonist. BMJ. 1995; 310:776-7. [IDIS 345035] [PubMed 7711582]

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. [IDIS 295953] [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. [IDIS 356631] [PubMed 7486476]

46. Reviewers’ comments (personal observations).

47. Pratt Pharmacueticals. 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. [IDIS 260789] [PubMed 2513047]

49. National Heart, Lung, and Blood Institute National High Blood Pressure Education Program. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). Bethesda, MD: National Institutes of Health; 1997 Nov. (NIH publication No. 98-4080.)

50. Kaplan NM. Choice of initial therapy for hypertension. JAMA. 1996; 275:1577-80. [IDIS 365188] [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. [IDIS 380501] [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. [IDIS 362953] [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. [IDIS 400553] [PubMed 9486993]

56. Pahor M, Psaty BM, Furberg CD. Treatment of hypertensive patients with diabetes. Lancet. 1998; 351:689-90. [IDIS 409001] [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. [IDIS 393279] [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. [IDIS 398935] [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. [IDIS 400554] [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. [IDIS 376224] [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. [IDIS 398865] [PubMed 9465845]

67. Spence JD. Drugs and grapefruit juice. Clin Pharmacol Ther. 1998; 63:87-8. [IDIS 398865] [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. [IDIS 490723] [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. [IDIS 490721] [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. [IDIS 456765] [PubMed 11130522]

72. Blood Pressure Lowering Treatment Trialists&#x2019; 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. [IDIS 451430] [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. [IDIS 457324] [PubMed 11069440]

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

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. [IDIS 200003] [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. [IDIS 394161] [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. [IDIS 452007] [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.

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.

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.

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.

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.

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.

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.

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.

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.

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. [IDIS 494836] [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.

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.

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. [IDIS 465816] [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. [IDIS 301129] [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. [PubMed 11904577]

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

105. National High Blood Pressure Education Program Working Group on Hypertension Control in Children and Adolescents. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics. 2004; 114(Suppl 2):555-76. [PubMed 15286277]

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. [IDIS 531054] [PubMed 15811979]

109. Neaton JD, Kuller LH. Diuretics are color blind. JAMA. 2005; 293:1663-6. Editorial. [IDIS 531056] [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. Editorial. [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. [IDIS 282107] [PubMed 2046107]

127. MRC Working Party. Medical Research Council trial of treatment of hypertension in older adults: principal results. BMJ. 1992; 304:405-12. [IDIS 292411] [PubMed 1445513]

128. Novartis Pharmaceuticals Corporation. Tekamlo (aliskiren hemifumarate and amlodipine besylate) tablets prescribing information. East Hanover, NJ; 2015 Mar.

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. Cincinatti, OH; 2015 Jan.

131. Novartis Pharmaceuticals Corporation. Amturnide (aliskiren, amlodipine and hydrochlorothiazide) tablets prescribing information. East Hanover, NJ; 2015 Mar.

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.

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]

520. American Diabetes Association. Standards of medical care in diabetes--2014. Diabetes Care. 2014; 37 Suppl 1:S14-80. [PubMed 24357209]

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. [PubMed 23166211]

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. [PubMed 23741058]

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. [PubMed 23247304]

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]

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.

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]

b. AHFS drug information 2015. McEvoy GK, ed. Nifedipine. Bethesda, MD: American Society of Hospital Pharmacists; 2015:.

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