Norvasc^® Indications

Hypertension

Amlodipine is indicated for the first-line treatment of hypertension and can be used as the sole agent to control blood pressure in the majority of patients. Patients not adequately controlled on a single antihypertensive agent may benefit from the addition of amlodipine, which has been used in combination with a thiazide diuretic, alpha blockers, beta adrenoceptor blocking agent, or an angiotensin-converting enzyme (ACE) inhibitor.¹

Coronary Artery Disease

Chronic Stable Angina

Amlodipine is indicated for the symptomatic treatment of chronic stable angina. Amlodipine may be used alone or in combination with other antianginal drugs.¹

Vasospastic Angina (Prinzmetal’s or variant angina)

Amlodipine is indicated for the treatment of confirmed or suspected vasospastic angina. Amlodipine may be used as monotherapy, or in combination with other antianginal drugs.¹

Angiographically Documented Coronary Artery Disease

In patients with recently documented coronary artery disease (CAD) by angiography and without heart failure or an ejection fraction <40%, amlodipine is indicated to reduce the risk of hospitalization due to angina and to reduce the risk of a coronary revascularization procedure.¹

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Amlodipine is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle.¹

The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect on vascular smooth muscle. The precise mechanism by which amlodipine relieves angina has not been fully determined, but amlodipine reduces total ischemic burden by the following two actions¹:

1. Amlodipine dilates peripheral arterioles and thus reduces the total peripheral resistance (afterload) against which the heart works. Since the heart rate remains stable, this unloading of the heart reduces myocardial energy consumption and oxygen requirements.
2. The mechanism of action of amlodipine also probably involves dilatation of the main coronary arteries and coronary arterioles, both in normal and ischemic regions. This dilatation increases myocardial oxygen delivery in patients with coronary artery spasm (Prinzmetal’s or variant angina) and blunts smoking-induced coronary vasoconstriction.

Adapted from Mason RP. et al. Arterioscler Thromb Vasc Biol. 2003; 23:2155-2163.

Calcium channel blockers (CCBs) were originally developed as potent vasodilators because of their ability to bind to and block the L-type calcium channel. This reduced calcium influx into the smooth muscle cell (SMC), resulting in smooth muscle relaxation and vasodilation. Amlodipine, not only easily penetrate the plasma membrane to interact with the L-type calcium channel but also have additional biologic or pleiotropic actions that are independent of interaction with the calcium channel. Furthermore, these CCBs have effects on cell types other than the Vascular smooth muscle cell (VSMC), cells in which L-type calcium channels are nonexistent or play only minor roles.²

The terminal plasma elimination half-life is about 35 to 50 hours and is consistent with once-daily dosing. Steady-state plasma levels are reached after 7 to 8 days of consecutive dosing.¹

In patients with hypertension, once-daily dosing provides clinically significant reductions in blood pressure in both the supine and standing positions throughout the 24-hour interval. Due to the slow onset of action, acute hypotension is not a feature of amlodipine administration.¹

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Norvasc^® is well tolerated. In patients with hypertension, once-daily dosing provides clinically significant reductions in blood pressure in both the supine and standing positions throughout the 24-hour interval. Due to the slow onset of action, acute hypotension is not a feature of amlodipine administration.¹

In patients with angina, once-daily administration of amlodipine increases total exercise time, time to angina onset, and time to 1 mm ST segment depression, and decreases both angina attack frequency and nitroglycerine tablet consumption. ¹

Amlodipine has not been associated with any adverse metabolic effects or changes in plasma lipids and is suitable for use in patients with asthma, diabetes, and gout.¹

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NORVASC^® (Amlodipine Besylate) is indicated for the treatment of

• Hypertension
• Chronic Stable Angina
• Vasospastic Angina (Prinzmetal’s or variant angina)
• Angiographically Documented Coronary Artery Disease

NORVASC^® is available in 5 mg, and 10 mg tablets¹

For both hypertension and angina, the usual initial dose is 5 mg amlodipine once daily, which may be increased to a maximum dose of 10 mg depending on the individual patient’s response.¹

For patients with coronary artery disease, the recommended dosage range is 5 mg to 10 mg once daily.¹

No dose adjustment of amlodipine is required upon concomitant administration of thiazide diuretics, beta-blockers, and Angiotensin-converting enzyme (ACE) inhibitors.¹

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Hypertension Treatment Guidelines:

2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines¹

Adapted from: Whelton PK, et al. J Am Coll Cardiol. 2018;71:e127-e248.

Core drug-treatment strategy for uncomplicated hypertension

The core algorithm is also appropriate for most patients with Hypertension-mediated organ damage (HMOD), cerebrovascular disease, diabetes, or peripheral arterial disease (PAD)²

Adapted from: Williams B, et al. Eur Heart J. 2018; 39: 3021-3104.

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Amlodipine has a wealth of clinical data supporting efficacy and safety

• Amlodipine is well-tolerated and has a proven quality, efficacy, and safety profile for the management of BP in patients with hypertension^1-4
• Amlodipine is indicated for the first-line treatment of hypertension and can be used as the sole agent to control blood pressure in the majority of patients¹
• With a long half-life, amlodipine maintains BP over 24-hrs¹ and lowers BP Variability⁵
• In patients with hypertension, once-daily dosing provides clinically significant reductions in blood pressure in both the supine and standing positions throughout the 24-hour interval¹
• Proven benefit in reducing mortality and morbidity in randomized controlled trials^1-4
• Effective in a wide range of patient populations^2-4,6
• Effective as combination therapy with antihypertensive agents of other classes¹
• Amlodipine is well-tolerated in both the elderly and younger patients at recommended doses¹

Treatment of Mild Hypertension Study (TOMHS)⁷

Objective: To compare six antihypertensive interventions for the treatment of mild hypertension.

Design: Randomized, double-blind, placebo-controlled clinical trial.

Setting: Four hypertension screening and treatment centers in the United States.

Participants: Hypertensive men and women, aged 45 to 69 years, with diastolic blood pressure less than 100 mm Hg.

Intervention: Sustained nutritional-hygienic advice to all participants to reduce weight, dietary sodium intake, and alcohol intake, and increase physical activity. Participants were randomly allocated to take (1) placebo (n=234); (2) chlorthalidone (n=136); (3) acebutolol (n=132); (4) doxazosin mesylate (n=134); (5) amlodipine maleate (n=131); or (6) enalapril maleate (n=135).

Main Outcome Measures: Blood pressure, quality of life, side effects, blood lipid levels and analysis of other serum components, echocardiographic and electrocardiographic changes, and incidence of cardiovascular events over an average of 4.4 years of follow-up.

Results: Blood pressure reductions were sizable in all six groups, and were significantly greater for participants assigned to drug treatment than placebo (-15.9 vs -9.1mm Hg for systolic blood pressure and -12.3 vs -8.6mm Hg for diastolic blood pressure; P<.0001). After 4 years, 59% of participants assigned to placebo and 72% of participants given drug treatment continued on their initial medication as monotherapy. A smaller percentage of participants assigned to the drug-treatment groups died or experienced a major nonfatal cardiovascular event than those assigned to the placebo group (5.1% vs 7.3%; P=.21). After including other clinical events, the percentage of participants affected was 11.1% for those in the drug-treatment groups and 16.2% for those in the placebo group (P=.03). Incidence rates of most resting electrocardiographic abnormalities were lower and quality of life was improved more for those assigned to drug-treatment groups rather than the placebo group. Differences among the five drug treatments did not consistently favor one group in terms of regression of left ventricular mass, blood lipid levels, and other outcome measures.

Conclusions: As an initial regimen, drug treatment in combination with nutritional-hygienic intervention was more effective in preventing cardiovascular and other clinical events than was nutritional-hygienic treatment alone. Drug-treatment group differences were minimal.

The Natrilix SR Versus Candesartan and Amlodipine in the Reduction of Systolic Blood Pressure in Hypertensive Patients (X-CELLENT)⁵

To investigate the effect of different antihypertensive agents on blood pressure (BP) variability (BPV) and the underlying mechanism, analysis was carried out on the ambulatory BP monitoring data of 577 patients before and after 3-month antihypertensive treatment, in the Natrilix SR Versus Candesartan and Amlodipine in the Reduction of Systolic Blood Pressure in Hypertensive Patients (X-CELLENT) Study, a multicenter, multinational, randomized, double-blind, placebo-controlled study with 4 parallel treatment arms (placebo, candesartan, indapamide sustained release, and amlodipine). Within-subject mean and SD of 24-hour BP, weighted by time interval between consecutive readings, were calculated in 3 time frames (daytime, nighttime, and 24 hours) to evaluate BP and BPV. The mean 24-hour heart rate (HR) and HR variability were calculated with the same algorithms. We found that the 3 antihypertensive drugs had a similar BP-lowering effect (P<0.001 for all), but amlodipine (P<0.007) and indapamide sustained release (P<0.04) were the only agents associated with a significantly decreased BPV after 3-month treatment. On the other hand, the major determinants of BPV at baseline were age, mean BP, and the corresponding HR variability. However, the reduction in BPV by amlodipine was significantly associated with the reduction in BP (P<0.006) and the reduction in HR variability (P<0.02), whereas the corresponding reduction by indapamide sustained release was only associated with the reduction in HR variability at night (P=0.004). In summary, 3-month amlodipine or indapamide sustained release treatment was associated with a significant reduction in BPV, and the mechanism of those reductions was possibly attributable to lowering BP or ameliorating the autonomic nervous system regulation or both. The combination of the 2 agents might help to optimize such properties.

Study Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)⁸

Context Antihypertensive therapy is well established to reduce hypertension-related morbidity and mortality, but the optimal first-step therapy is unknown.

Objective To determine whether treatment with a calcium channel blocker or an angiotensin-converting enzyme inhibitor lowers the incidence of coronary heart disease (CHD) or other cardiovascular disease (CVD) events vs treatment with a diuretic.

Design The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized, double-blind, active-controlled clinical trial conducted from February 1994 through March 2002.

Setting and Participants A total of 33 357 participants aged 55 years or older with hypertension and at least 1 other CHD risk factor from 623 North American centers.

Interventions Participants were randomly assigned to receive chlorthalidone, 12.5 to 25 mg/d (n = 15 255); amlodipine, 2.5 to 10 mg/d (n = 9048); or lisinopril, 10 to 40 mg/d (n = 9054) for planned follow-up of approximately 4 to 8 years.

Main Outcome Measures The primary outcome was combined fatal CHD or nonfatal myocardial infarction, analyzed by intent-to-treat. Secondary outcomes were all-cause mortality, stroke, combined CHD (primary outcome, coronary revascularization, or angina with hospitalization), and combined CVD (combined CHD, stroke, treated angina without hospitalization, heart failure [HF], and peripheral arterial disease).

Results Mean follow-up was 4.9 years. The primary outcome occurred in 2956 participants, with no difference between treatments. Compared with chlorthalidone (6-year rate, 11.5%), the relative risks (RRs) were 0.98 (95% CI, 0.90-1.07) for amlodipine (6-year rate, 11.3%) and 0.99 (95% CI, 0.91-1.08) for lisinopril (6-year rate, 11.4%). Likewise, all-cause mortality did not differ between groups. Five-year systolic blood pressures were significantly higher in the amlodipine (0.8 mm Hg, P = .03) and lisinopril (2 mm Hg, P<.001) groups compared with chlorthalidone, and 5-year diastolic blood pressure was significantly lower with amlodipine (0.8 mm Hg, P<.001). For amlodipine vs chlorthalidone, secondary outcomes were similar except for a higher 6-year rate of HF with amlodipine (10.2% vs 7.7%; RR, 1.38; 95% CI, 1.25-1.52). For lisinopril vs chlorthalidone, lisinopril had higher 6-year rates of combined CVD (33.3% vs 30.9%; RR, 1.10; 95% CI, 1.05-1.16); stroke (6.3% vs 5.6%; RR, 1.15; 95% CI, 1.02-1.30); and HF (8.7% vs 7.7%; RR, 1.19; 95% CI, 1.07-1.31).

Conclusion Thiazide-type diuretics are superior in preventing 1 or more major forms of CVD and are less expensive. They should be preferred for first-step antihypertensive therapy.

The Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT)²

Background—The results of angiographic studies have suggested that calcium channel– blocking agents may prevent new coronary lesion formation, the progression of minimal lesions, or both.

Methods and Results—The Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT) was a multicenter, randomized, placebo-controlled, double-masked clinical trial designed to test whether amlodipine would slow the progression of early coronary atherosclerosis in 825 patients with angiographically documented coronary artery disease. The primary outcome was the average 36-month angiographic change in mean minimal diameters of segments with a baseline diameter stenosis of 30%. A secondary hypothesis was whether amlodipine would reduce the rate of atherosclerosis in the carotid arteries as assessed with B-mode ultrasonography, which measured intimal-medial thicknesses (IMT). The rates of clinical events were also monitored. The placebo and amlodipine groups had nearly identical average 36-month reductions in the minimal diameter: 0.084 versus 0.095 mm, respectively (P=0.38). In contrast, amlodipine had a significant effect in slowing the 36-month progression of carotid artery atherosclerosis: the placebo group experienced a 0.033-mm increase in IMT, whereas there was a 0.0126-mm decrease in the amlodipine group (P=0.007). There was no treatment difference in the rates of all-cause mortality or major cardiovascular events, although amlodipine use was associated with fewer cases of unstable angina and coronary revascularization.

Conclusions—Amlodipine has no demonstrable effect on angiographic progression of coronary atherosclerosis or the risk of major cardiovascular events but is associated with fewer hospitalizations for unstable angina and revascularization.

Comparison of Amlodipine vs Enalapril to Limit Occurrences of Thrombosis (CAMELOT)³

Context The effect of antihypertensive drugs on cardiovascular events in patients with coronary artery disease (CAD) and normal blood pressure remains uncertain.

Objective To compare the effects of amlodipine or enalapril vs placebo on cardiovascular events in patients with CAD.

Design, Setting, and Participants Double-blind, randomized, multicenter, 24-month trial (enrollment April 1999-April 2002) comparing amlodipine or enalapril with placebo in 1991 patients with angiographically documented CAD (20% stenosis by coronary angiography) and diastolic blood pressure 100 mm Hg. A substudy of 274 patients measured atherosclerosis progression by intravascular ultrasound (IVUS).

Interventions Patients were randomized to receive amlodipine, 10 mg; enalapril, 20 mg; or placebo. IVUS was performed at baseline and study completion.

Main Outcome Measures The primary efficacy parameter was incidence of cardiovascular events for amlodipine vs placebo. Other outcomes included comparisons of amlodipine vs enalapril and enalapril vs placebo. Events included cardiovascular death, nonfatal myocardial infarction, resuscitated cardiac arrest, coronary revascularization, hospitalization for angina pectoris, hospitalization for congestive heart failure, fatal or nonfatal stroke or transient ischemic attack, and new diagnosis of peripheral vascular disease. The IVUS end point was change in percent atheroma volume.

Results Baseline blood pressure averaged 129/78 mm Hg for all patients; it increased by 0.7/0.6 mm Hg in the placebo group and decreased by 4.8/2.5 mm Hg and 4.9/2.4 mm Hg in the amlodipine and enalapril groups, respectively (P<.001 for both vs placebo). Cardiovascular events occurred in 151 (23.1%) placebo-treated patients, in 110 (16.6%) amlodipine-treated patients (hazard ratio [HR], 0.69; 95% CI, 0.54-0.88 [P=.003]), and in 136 (20.2%) enalapril-treated patients (HR, 0.85; 95% CI, 0.67-1.07

[P=.16]. Primary end point comparison for enalapril vs amlodipine was not significant (HR, 0.81; 95% CI, 0.63-1.04 [P=.10]). The IVUS substudy showed a trend toward less progression of atherosclerosis in the amlodipine group vs placebo (P=.12), with significantly less progression in the subgroup with systolic blood pressures greater than the mean (P=.02). Compared with baseline, IVUS showed progression in the placebo group (P<.001), a trend toward progression in the enalapril group (P=.08), and no progression in the amlodipine group (P=.31). For the amlodipine group, correlation between blood pressure reduction and progression was r=0.19, P=.07.

Conclusions Administration of amlodipine to patients with CAD and normal blood pressure resulted in reduced adverse cardiovascular events. Directionally similar, but smaller and nonsignificant, treatment effects were observed with enalapril. For amlodipine, IVUS showed evidence of slowing of atherosclerosis progression.

Valsartan Antihypertensive Long-Term Use Evaluation (VALUE)⁶

Background The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial was designed to test the hypothesis that for the same blood-pressure control, valsartan would reduce cardiac morbidity and mortality more than amlodipine in hypertensive patients at high cardiovascular risk.

Methods 15 245 patients, aged 50 years or older with treated or untreated hypertension and high risk of cardiac events participated in a randomised, double-blind, parallel-group comparison of therapy based on valsartan or amlodipine. Duration of treatment was event-driven and the trial lasted until at least 1450 patients had reached a primary endpoint, defined as a composite of cardiac mortality and morbidity. Patients from 31 countries were followed up for a mean of 4·2 years.

Findings Blood pressure was reduced by both treatments, but the effects of the amlodipine-based regimen were more pronounced, especially in the early period (blood pressure 4·0/2·1 mm Hg lower in amlodipine than valsartan group after 1 month; 1·5/1·3 mm Hg after 1 year; p<0·001 between groups). The primary composite endpoint occurred in 810 patients in the valsartan group (10·6%, 25·5 per 1000 patient-years) and 789 in the amlodipine group (10·4%, 24·7 per 1000 patient-years; hazard ratio 1·04, 95% CI 0·94–1·15, p=0·49).

Interpretation The main outcome of cardiac disease did not differ between the treatment groups. Unequal reductions in blood pressure might account for differences between the groups in cause-specific outcomes. The findings emphasise the importance of prompt blood-pressure control in hypertensive patients at high cardiovascular risk.

Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA)⁴

Background The apparent shortfall in prevention of coronary heart disease (CHD) noted in early hypertension trials has been attributed to disadvantages of the diuretics and blockers used. For a given reduction in blood pressure, some suggested that newer agents would confer advantages over diuretics and blockers. Our aim, therefore, was to compare the effect on non-fatal myocardial infarction and fatal CHD of combinations of atenolol with a thiazide versus amlodipine with perindopril.

Methods We did a multicentre, prospective, randomised controlled trial in 19 257 patients with hypertension who were aged 40–79 years and had at least three other cardiovascular risk factors. Patients were assigned either amlodipine 5–10 mg adding perindopril 4–8 mg as required (amlodipine-based regimen; n=9639) or atenolol 50–100 mg adding bendroflumethiazide 1·25–2·5 mg and potassium as required (atenolol-based regimen; n=9618). Our primary endpoint was non-fatal myocardial infarction (including silent myocardial infaction) and fatal CHD. Analysis was by intention to treat.

Findings The study was stopped prematurely after 5·5 years’ median follow-up and accumulated in total 106 153 patient years of observation. Though not significant, compared with the atenolol-based regimen, fewer individuals on the amlodipine-based regimen had a primary endpoint (429 vs 474; unadjusted HR 0·90, 95% CI 0·79–1·02, p=0·1052), fatal and non-fatal stroke (327 vs 422; 0·77, 0·66–0·89, p=0·0003), total cardiovascular events and procedures (1362 vs 1602; 0·84, 0·78–0·90, p=0·0001), and all-cause mortality (738 vs 820; 0·89, 0·81–0·99, p=0·025). The incidence of developing diabetes was less on the amlodipine-based regimen (567 vs 799; 0·70, 0·63–0·78, p=0·0001).

Interpretation The amlodipine-based regimen prevented more major cardiovascular events and induced less diabetes than the atenolol-based regimen. On the basis of previous trial evidence, these effects might not be entirely explained by better control of blood pressure, and this issue is addressed in the accompanying article. Nevertheless, the results have implications with respect to optimum combinations of antihypertensive agents.

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Note: Please refer to the full prescribing information before prescribing

NORVASC

Content: Amlodipine besylate

Indication: 1st-line treatment of Hypertension. Symptomatic treatment of chronic stable angina. Treatment of confirmed or suspected vasospastic angina. Reduce the risk of hospitalization (due to angina) & coronary revascularization procedure in angiographically-documented Coronary Artery Disease.

Dosage: Hypertension & angina Initially 5 mg once daily, may be increased to a max of 10 mg/day. Coronary Artery Disease 5-10 mg once daily.

Administration: Can be taken with or without food.

Contraindications: Hypersensitivity to amlodipine, dihydropyridines.

Special Precaution: New York Heart Association III & IV heart failure of nonischemic etiology; hepatic impairment. Pregnancy & lactation. Children.

Adverse Reaction: Flushing; dizziness, headache, somnolence; abdominal pain, nausea; palpitations, fatigue, oedema.

Drug Interaction: Increased exposure to simvastatin, tacrolimus, and mTOR inhibitors (sirolimus, temsirolimus, and everolimus). Increased bioavailability with grapefruit or grapefruit juice. Increased plasma concentration with CYP3A4 inhibitors (eg diltiazem, erythromycin, ketoconazole, itraconazole, ritonavir) & decreased plasma concentration with inducers (eg rifampicin, St John’s wort). Increased risk of hypotension with clarithromycin.

Product Presentation: Tablet 5 mg x 30’s. 10 mg x 30’s.

Pregnant Safety (US): Category C

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