1.1 Hypertension

Amlodipine besylate tablets are indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including amlodipine besylate tablets.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program's Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.

Amlodipine besylate tablets may be used alone or in combination with other antihypertensive agents.

1.2 Coronary Artery Disease (CAD)

 

Chronic Stable Angina

Amlodipine besylate tablets are indicated for the symptomatic treatment of chronic stable angina. They may be used alone or in combination with other antianginal agents.

 

Vasospastic Angina (Prinzmetal's or Variant Angina)

Amlodipine besylate tablets are indicated for the treatment of confirmed or suspected vasospastic angina. They may be used as monotherapy or in combination with other antianginal agents.

 

Angiographically Documented CAD

In patients with recently documented CAD by angiography and without heart failure or an ejection fraction <40%, amlodipine besylate tablets are indicated to reduce the risk of hospitalization for angina and to reduce the risk of a coronary revascularization procedure.

2.1 Adults

The usual initial antihypertensive oral dose of amlodipine besylate tablets is 5 mg once daily, and the maximum dose is 10 mg once daily.

Small, fragile, or elderly patients, or patients with hepatic insufficiency may be started on 2.5 mg once daily and this dose may be used when adding amlodipine besylate tablets to other antihypertensive therapy.

Adjust dosage according to blood pressure goals. In general, wait 7 to 14 days between titration steps. Titrate more rapidly, however, if clinically warranted, provided the patient is assessed frequently.

Angina: The recommended dose for chronic stable or vasospastic angina is 5–10 mg, with the lower dose suggested in the elderly and in patients with hepatic insufficiency. Most patients will require 10 mg for adequate effect.

Coronary artery disease: The recommended dose range for patients with coronary artery disease is 5–10 mg once daily. In clinical studies, the majority of patients required 10 mg [see Clinical Studies (14.4)].

2.2 Children

The effective antihypertensive oral dose in pediatric patients ages 6–17 years is 2.5 mg to 5 mg once daily. Doses in excess of 5 mg daily have not been studied in pediatric patients [see Clinical Pharmacology (12.4), Clinical Studies (14.1)].

5.1 Hypotension

Symptomatic hypotension is possible, particularly in patients with severe aortic stenosis. Because of the gradual onset of action, acute hypotension is unlikely.

5.2 Increased Angina or Myocardial Infarction

Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of amlodipine besylate tablets, particularly in patients with severe obstructive coronary artery disease.

5.3 Patients with Hepatic Failure

Because amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t 1/2) is 56 hours in patients with impaired hepatic function, titrate slowly when administering amlodipine besylate tablets to patients with severe hepatic impairment.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Amlodipine besylate tablets have been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. In general, treatment with amlodipine besylate tablets was well-tolerated at doses up to 10 mg daily. Most adverse reactions reported during therapy with amlodipine besylate tablets were of mild or moderate severity. In controlled clinical trials directly comparing amlodipine besylate tablets (N=1730) at doses up to 10 mg to placebo (N=1250), discontinuation of amlodipine besylate tablets because of adverse reactions was required in only about 1.5% of patients and was not significantly different from placebo (about 1%). The most commonly reported side effects more frequent than placebo are reflected in the table below. The incidence (%) of side effects that occurred in a dose related manner are as follows:

Other adverse reactions that were not clearly dose related but were reported with an incidence greater than 1.0% in placebo-controlled clinical trials include the following:

For several adverse experiences that appear to be drug and dose related, there was a greater incidence in women than men associated with amlodipine treatment as shown in the following table:

The following events occurred in <1% but >0.1% of patients in controlled clinical trials or under conditions of open trials or marketing experience where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship:

Cardiovascular: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, peripheral ischemia, syncope, tachycardia, vasculitis.

Central and Peripheral Nervous System: hypoesthesia, neuropathy peripheral, paresthesia, tremor, vertigo.

Gastrointestinal: anorexia, constipation, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia.

General: allergic reaction, asthenia,1 back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease.

Musculoskeletal System: arthralgia, arthrosis, muscle cramps,1 myalgia.

Psychiatric: sexual dysfunction (male1 and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization.

Respiratory System: dyspnea,1 epistaxis.

Skin and Appendages: angioedema, erythema multiforme, pruritus,1 rash,1 rash erythematous, rash maculopapular.

Special Senses: abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus.

Urinary System: micturition frequency, micturition disorder, nocturia.

Autonomic Nervous System: dry mouth, sweating increased.

Metabolic and Nutritional: hyperglycemia, thirst.

Hemopoietic: leukopenia, purpura, thrombocytopenia.

Amlodipine besylate tablet therapy has not been associated with clinically significant changes in routine laboratory tests. No clinically relevant changes were noted in serum potassium, serum glucose, total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or creatinine.

In the CAMELOT and PREVENT studies [see Clinical Studies (14.4)], the adverse event profile was similar to that reported previously (see above), with the most common adverse event being peripheral edema.

1

These events occurred in less than 1% in placebo-controlled trials, but the incidence of these side effects was between 1% and 2% in all multiple dose studies.

6.2 Postmarketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following postmarketing event has been reported infrequently where a causal relationship is uncertain: gynecomastia. In postmarketing experience, jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported in association with use of amlodipine.

Postmarketing reporting has also revealed a possible association between extrapyramidal disorder and amlodipine.

Amlodipine besylate tablets have been used safely in patients with chronic obstructive pulmonary disease, well-compensated congestive heart failure, coronary artery disease, peripheral vascular disease, diabetes mellitus, and abnormal lipid profiles.

7.1 Impact of Other Drugs on Amlodipine

7.2 Impact of Amlodipine on Other Drugs

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Amlodipine besylate tablets (2.5 to 5 mg daily) are effective in lowering blood pressure in patients 6 to 17 years [see Clinical Studies (14.1)]. Effect of amlodipine on blood pressure in patients less than 6 years of age is not known.

8.5 Geriatric Use

Clinical studies of amlodipine besylate tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Elderly patients have decreased clearance of amlodipine with a resulting increase of AUC of approximately 40–60%, and a lower initial dose may be required [see Dosage and Administration (2.1)].

12.1 Mechanism of Action

Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect.

Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.

The precise mechanisms by which amlodipine relieves angina have not been fully delineated, but are thought to include the following:

12.2 Pharmacodynamics

12.3 Pharmacokinetics

After oral administration of therapeutic doses of amlodipine besylate tablets, absorption produces peak plasma concentrations between 6 and 12 hours. Absolute bioavailability has been estimated to be between 64 and 90%. The bioavailability of amlodipine besylate tablets is not altered by the presence of food.

Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine. Ex vivo studies have shown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients. Elimination from the plasma is biphasic with a terminal elimination half-life of about 30–50 hours. Steady-state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing.

The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial dose.

Elderly patients and patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40–60%, and a lower initial dose may be required. A similar increase in AUC was observed in patients with moderate to severe heart failure.

12.4 Pediatric Patients

Sixty-two hypertensive patients aged 6 to 17 years received doses of amlodipine besylate tablets between 1.25 mg and 20 mg. Weight-adjusted clearance and volume of distribution were similar to values in adults.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Rats and mice treated with amlodipine maleate in the diet for up to two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 amlodipine mg/kg/day, showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on a mg/m2 basis, similar to the maximum recommended human dose of 10 mg amlodipine/day.2 For the rat, the highest dose was, on a mg/m2 basis, about twice the maximum recommended human dose.2

Mutagenicity studies conducted with amlodipine maleate revealed no drug related effects at either the gene or chromosome level.

There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses up to 10 mg amlodipine/kg/day (8 times the maximum recommended human dose2 of 10 mg/day on a mg/m2 basis).

2

Based on patient weight of 50 kg

14.1 Effects in Hypertension

14.2 Effects in Chronic Stable Angina

The effectiveness of 5–10 mg/day of amlodipine besylate tablets in exercise-induced angina has been evaluated in 8 placebo-controlled, double-blind clinical trials of up to 6 weeks duration involving 1038 patients (684 amlodipine besylate tablets, 354 placebo) with chronic stable angina. In 5 of the 8 studies, significant increases in exercise time (bicycle or treadmill) were seen with the 10 mg dose. Increases in symptom-limited exercise time averaged 12.8% (63 sec) for amlodipine besylate tablets 10 mg, and averaged 7.9% (38 sec) for amlodipine besylate tablets 5 mg. Amlodipine besylate tablets 10 mg also increased time to 1 mm ST segment deviation in several studies and decreased angina attack rate. The sustained efficacy of amlodipine besylate tablets in angina patients has been demonstrated over long-term dosing. In patients with angina, there were no clinically significant reductions in blood pressures (4/1 mmHg) or changes in heart rate (+0.3 bpm).

14.3 Effects in Vasospastic Angina

In a double-blind, placebo-controlled clinical trial of 4 weeks duration in 50 patients, amlodipine besylate tablet therapy decreased attacks by approximately 4/week compared with a placebo decrease of approximately 1/week (p<0.01). Two of 23 amlodipine besylate tablet patients and 7 of 27 placebo patients discontinued from the study due to lack of clinical improvement.

14.4 Effects in Documented Coronary Artery Disease

In PREVENT, 825 patients with angiographically documented coronary artery disease were randomized to amlodipine besylate tablets (5–10 mg once daily) or placebo and followed for 3 years. Although the study did not show significance on the primary objective of change in coronary luminal diameter as assessed by quantitative coronary angiography, the data suggested a favorable outcome with respect to fewer hospitalizations for angina and revascularization procedures in patients with CAD.

CAMELOT enrolled 1318 patients with CAD recently documented by angiography, without left main coronary disease and without heart failure or an ejection fraction <40%. Patients (76% males, 89% Caucasian, 93% enrolled at US sites, 89% with a history of angina, 52% without PCI, 4% with PCI and no stent, and 44% with a stent) were randomized to double-blind treatment with either amlodipine besylate tablets (5–10 mg once daily) or placebo in addition to standard care that included aspirin (89%), statins (83%), beta-blockers (74%), nitroglycerin (50%), anti-coagulants (40%), and diuretics (32%), but excluded other calcium channel blockers. The mean duration of follow-up was 19 months. The primary endpoint was the time to first occurrence of one of the following events: hospitalization for angina pectoris, coronary revascularization, myocardial infarction, cardiovascular death, resuscitated cardiac arrest, hospitalization for heart failure, stroke/TIA, or peripheral vascular disease. A total of 110 (16.6%) and 151 (23.1%) first events occurred in the amlodipine besylate tablet and placebo groups, respectively, for a hazard ratio of 0.691 (95% CI: 0.540–0.884, p = 0.003). The primary endpoint is summarized in Figure 1 below. The outcome of this study was largely derived from the prevention of hospitalizations for angina and the prevention of revascularization procedures (see Table 1). Effects in various subgroups are shown in Figure 2.

In an angiographic substudy (n=274) conducted within CAMELOT, there was no significant difference between amlodipine and placebo on the change of atheroma volume in the coronary artery as assessed by intravascular ultrasound.

Figure 1 - Kaplan-Meier Analysis of Composite Clinical Outcomes for Amlodipine versus Placebo

Figure 2 – Effects on Primary Endpoint of Amlodipine versus Placebo across Sub-Groups

Table 1 below summarizes the significant composite endpoint and clinical outcomes from the composites of the primary endpoint. The other components of the primary endpoint including cardiovascular death, resuscitated cardiac arrest, myocardial infarction, hospitalization for heart failure, stroke/TIA, or peripheral vascular disease did not demonstrate a significant difference between amlodipine and placebo.

14.5 Studies in Patients with Heart Failure

Amlodipine besylate tablets have been compared to placebo in four 8–12 week studies of patients with NYHA Class II/III heart failure, involving a total of 697 patients. In these studies, there was no evidence of worsened heart failure based on measures of exercise tolerance, NYHA classification, symptoms, or left ventricular ejection fraction. In a long-term (follow-up at least 6 months, mean 13.8 months) placebo-controlled mortality/morbidity study of amlodipine besylate tablets 5–10 mg in 1153 patients with NYHA Classes III (n=931) or IV (n=222) heart failure on stable doses of diuretics, digoxin, and ACE inhibitors, amlodipine had no effect on the primary endpoint of the study which was the combined endpoint of all-cause mortality and cardiac morbidity (as defined by life-threatening arrhythmia, acute myocardial infarction, or hospitalization for worsened heart failure), or on NYHA classification, or symptoms of heart failure. Total combined all-cause mortality and cardiac morbidity events were 222/571 (39%) for patients on amlodipine besylate tablets and 246/583 (42%) for patients on placebo; the cardiac morbid events represented about 25% of the endpoints in the study.

Another study (PRAISE-2) randomized patients with NYHA Class III (80%) or IV (20%) heart failure without clinical symptoms or objective evidence of underlying ischemic disease, on stable doses of ACE inhibitors (99%), digitalis (99%), and diuretics (99%), to placebo (n=827) or amlodipine besylate tablets (n=827) and followed them for a mean of 33 months. There was no statistically significant difference between amlodipine besylate tablets and placebo in the primary endpoint of all-cause mortality (95% confidence limits from 8% reduction to 29% increase on amlodipine). With amlodipine besylate tablets, there were more reports of pulmonary edema.

2.5 mg Tablets

Amlodipine Besylate – 2.5 mg Tablets (amlodipine besylate equivalent to 2.5 mg of amlodipine per tablet) are supplied as white, diamond, flat-faced, beveled edged engraved with "NORVASC" on one side and "2.5" on the other side and supplied as follows:

Amlodipine Besylate – 2.5 mg Tablets (amlodipine besylate equivalent to 2.5 mg of amlodipine per tablet) are supplied as white, diamond, flat-faced, beveled edged engraved with "G1520" on one side and "2.5" on the other side and supplied as follows:

5 mg Tablets

Amlodipine Besylate – 5 mg Tablets (amlodipine besylate equivalent to 5 mg of amlodipine per tablet) are white, elongated octagon, flat-faced, beveled edged engraved with both "NORVASC" and "5" on one side and plain on the other side and supplied as follows:

Amlodipine Besylate – 5 mg Tablets (amlodipine besylate equivalent to 5 mg of amlodipine per tablet) are white, elongated octagon, flat-faced, beveled edged engraved with "G1530" on one side and "5" on the other side and supplied as follows:

10 mg Tablets

Amlodipine Besylate – 10 mg Tablets (amlodipine besylate equivalent to 10 mg of amlodipine per tablet) are white, round, flat-faced, beveled edged engraved with both "NORVASC" and "10" on one side and plain on the other side and supplied as follows:

Amlodipine Besylate – 10 mg Tablets (amlodipine besylate equivalent to 10 mg of amlodipine per tablet) are white, round, flat-faced, beveled edged engraved with "G1540" on one side and "10" on the other side and supplied as follows:

Storage

Store bottles at controlled room temperature, 59° to 86°F (15° to 30°C) and dispense in tight, light-resistant containers (USP).