DESCRIPTION
id: 65bb5a55-1c4f-0ea8-e053-2991aa0a6b30
displayName: DESCRIPTION SECTION
FDA Article Code: 34089-3
Amlodipine besylate, USP is a long-acting calcium channel blocker.
Amlodipine besylate, USP is chemically described as 3-Ethyl-5-methyl (±)-2-[(2-aminoethoxy)methyl]4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, monobenzenesulphonate. Its molecular formula is
C
20
H
25
CIN
2
O
5
•C
6
H
6
O
3
S, and its structural formula is:
Amlodipine besylate, USP is a white crystalline powder with a molecular weight of 567.1. It is slightly soluble in water and sparingly soluble in ethanol. Amlodipine besylate tablets are formulated as white tablets equivalent to 2.5, 5 and 10 mg of amlodipine for oral administration. In addition to the active ingredient, amlodipine besylate, USP, each tablet contains the following inactive ingredients:
microcrystalline cellulose, dibasic calcium phosphate anhydrous, sodium starch glycolate, and magnesium stearate.
Clinical Studies
id: 65bb5a55-1c51-0ea8-e053-2991aa0a6b30
displayName: CLINICAL STUDIES SECTION
FDA Article Code: 34092-7
Effects in Hypertension
Adult Patients: The antihypertensive efficacy of amlodipine besylate tablets has been demonstrated in a total of 15 double-blind, placebo-controlled, randomized studies involving 800 patients on amlodipine besylate tablets and 538 on placebo. Once daily administration produced statistically significant placebo-corrected reductions in supine and standing blood pressures at 24 hours postdose, averaging about 12/6 mmHg in the standing position and 13/7 mmHg in the supine position in patients with mild to moderate hypertension. Maintenance of the blood pressure effect over the 24-hour dosing interval was observed, with little difference in peak and trough effect. Tolerance was not demonstrated in patients studied for up to 1 year. The 3 parallel, fixed dose, dose response studies showed that the reduction in supine and standing blood pressures was dose-related within the recommended dosing range. Effects on diastolic pressure were similar in young and older patients. The effect on systolic pressure was greater in older patients, perhaps because of greater baseline systolic pressure. Effects were similar in black patients and in white patients.
Pediatric Patients: Two-hundred sixty-eight hypertensive patients aged 6 to 17 years were randomized first to amlodipine besylate tablets 2.5 or 5 mg once daily for 4 weeks and then randomized again to the same dose or to placebo for another 4 weeks. Patients receiving 5 mg at the end of 8 weeks had lower blood pressure than those secondarily randomized to placebo. The magnitude of the treatment effect is difficult to interpret, but it is probably less than 5 mmHg systolic on the 5 mg dose. Adverse events were similar to those seen in adults.
Effects in Chronic Stable Angina:
The effectiveness of 5 to 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 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).
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.
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 anejection 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 a 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
Table 1 below summarizes the significant 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 peripheralvascular disease did not demonstrate a significant difference between amlodipine and placebo.
Table 1. Incidence of Significant Clinical Outcomes for CAMELOT
Clinical Outcome
N(%)
|
Amlodipine
(N=663)
|
Placebo
(N=655)
|
Risk
Reduction
(p-value)
|
|
Composite CV
|
110
|
151
|
31%
|
|
Endpoint
|
(16.6)
|
(23.1)
|
(0.003)
|
|
|
|
|
| Hospitallization for |
51 |
84 |
42% |
Angina
*
|
(7.7) |
(12.8) |
(0.002) |
|
|
|
|
| Coronary |
78 |
103 |
27% |
Revascularization
*
|
(11.8) |
(15.7) |
(0.033) |
|
* Total patients with these events
|
Studies in Patients with Congestive 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 to 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 inhibitor (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.
CONTRAINDICATIONS
id: 65bb5a55-1c53-0ea8-e053-2991aa0a6b30
displayName: CONTRAINDICATIONS SECTION
FDA Article Code: 34070-3
Amlodipine besylate tablets are contraindicated in patients with known sensitivity to amlodipine.
WARNINGS
id: 65bb5a55-1c54-0ea8-e053-2991aa0a6b30
displayName: WARNINGS SECTION
FDA Article Code: 34071-1
Increased Angina and/or Myocardial Infarction: Rarely, patients, particularly those with severe obstructive coronary artery disease, have developed documented increased frequency, duration and/or severity of angina or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase. The mechanism of this effect has not been elucidated.
ADVERSE REACTIONS
id: 65bb5a55-1c56-0ea8-e053-2991aa0a6b30
displayName: ADVERSE REACTIONS SECTION
FDA Article Code: 34084-4
Amlodipine besylate has 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) in doses up to 10 mg to placebo (N=1250), discontinuation of amlodipine besylate tablets due to adverse reactions was required in only about 1.5% of patients and was not significantly different from placebo (about 1%). The most common side effects are headache and edema. The incidence (%) of side effects which occurred in a dose related manner are as follows:
Adverse Event
|
2.5mg
N=275
|
50mg
N=296
|
10.0mg
N=268
|
Placebo
N=520
|
| Edema |
1.8 |
3.0 |
10.8 |
0.6 |
| Dizziness |
1.1 |
3.4 |
3.4 |
1.5 |
| Flushing |
0.7 |
1.4 |
2.6 |
0.0 |
| Palpitation |
0.7 |
1.4 |
4.5 |
0.6 |
Other adverse experiences which were not clearly dose related but which were reported with an incidence greater than 1.0% in placebo-controlled clinical trials include the following:
|
Placebo-Controlled Studies
|
|
AMLODIPINE (%)
(N=1730)
|
PLACEBO (%)
(N=1250)
|
| Headache |
7.3 |
7.8 |
| Fatigue |
4.5 |
2.8 |
| Nausea |
2.9 |
1.9 |
| Abdominal Pain |
1.6 |
0.3 |
| Somnolence |
1.4 |
0.6 |
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:
|
AMLODIPINE
|
PLACEBO
|
|
Male=% |
Female=% |
Male=% |
Famale=% |
|
Adverse Event
|
|
|
|
|
|
(N=1218) |
(N=512) |
(N=914) |
(N=336) |
| Edema |
5.6 |
14.6 |
1.4 |
5.1 |
| Flushing |
1.5 |
4.5 |
0.3 |
0.9 |
| Palpitations |
1.4 |
3.3 |
0.9 |
0.9 |
| Somnolence |
1.3 |
1.6 |
0.8 |
0.3 |
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, hypotension, peripheral ischemia, syncope, tachycardia, postural dizziness, postural hypotension, vasculitis.
Central and Peripheral Nervous System: hypoesthesia, neuropathy peripheral, paresthesia, tremor, vertigo.
Gastrointestinal: anorexia, constipation, dyspepsia,
** dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia.
General: allergic reaction, asthenia,
** back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease.
Musculoskeletal System: arthralgia, arthrosis, muscle cramps,
** myalgia.
Psychiatric: sexual dysfunction (male
** and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization.
Respiratory System: dyspnea,
** epistaxis.
Skin and Appendages: angioedema, erythema multiforme, pruritus,
** rash,
** rash erythematous, rash maculopapular.
** 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.
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.
The following events occurred in <0.1% of patients: cardiac failure, pulse irregularity, extrasystoles, skin discoloration, urticaria, skin dryness, alopecia, dermatitis, muscle weakness, twitching, ataxia, hypertonia, migraine, cold and clammy skin, apathy, agitation, amnesia, gastritis, increased appetite, loose stools, coughing, rhinitis, dysuria, polyuria, parosmia, taste perversion, abnormal visual accommodation, and xerophthalmia.
Other reactions occurred sporadically and cannot be distinguished from medications or concurrent disease states such as myocardial infarction and angina.
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 PHARMACOLOGY
Clinical Studies
Studies in Patients with Coronary Artery Disease) the adverse event profile was similar to that reported previously (see above), with the most common adverse event being peripheral edema.
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.
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.
OVERDOSAGE
id: 65bb5a55-1c57-0ea8-e053-2991aa0a6b30
displayName: OVERDOSAGE SECTION
FDA Article Code: 34088-5
Single oral doses of amlodipine maleate equivalent to 40 mg amlodipine/kg and 100 mg amlodipine/kg in mice and rats, respectively, caused deaths. Single oral amlodipine maleate doses equivalent to 4 or more mg amlodipine/kg or higher in dogs (11 or more times the maximum recommended human dose on a mg/m
2 basis) caused a marked peripheral vasodilation and hypotension.
Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. In humans, experience with intentional overdosage of amlodipine besylate tablets is limited. Reports of intentional overdosage include a patient who ingested 250 mg and was asymptomatic and was not hospitalized; another (120 mg) was hospitalized, underwent gastric lavage and remained normotensive; the third (105 mg) was hospitalized and had hypotension (90/50 mmHg) which normalized following plasma expansion. A case of accidental drug overdose has been documented in a 19-month-old male who ingested 30 mg amlodipine (about 2 mg/kg). During the emergency room presentation, vital signs were stable with no evidence of hypotension, but a heart rate of 180 bpm. Ipecac was administered 3.5 hours after ingestion and on subsequent observation (overnight) no sequelae were noted.
If massive overdose should occur, active cardiac and respiratory monitoring should be instituted.
Frequent blood pressure measurements are essential. Should hypotension occur, cardiovascular support including elevation of the extremities and the judicious administration of fluids should be initiated. If hypotension remains unresponsive to these conservative measures, administration of vasopressors (such as phenylephrine) should be considered with attention to circulating volume and urine output.
Intravenous calcium gluconate may help to reverse the effects of calcium entry blockade. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.
DOSAGE AND ADMINISTRATION
id: 65bb5a55-1c58-0ea8-e053-2991aa0a6b30
displayName: DOSAGE & ADMINISTRATION SECTION
FDA Article Code: 34068-7
Adults: The usual initial antihypertensive oral dose of amlodipine besylate tablets is 5 mg once daily with a maximum dose of 10 mg once daily. Small, fragile, or elderly individuals, 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.
Dosage should be adjusted according to each patient’s need. In general, titration should proceed over 7 to 14 days so that the physician can fully assess the patient’s response to each dose level. Titration may proceed more rapidly, however, if clinically warranted, provided the patient is assessed frequently.
The recommended dose for chronic stable or vasospastic angina is 5 to 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. See
ADVERSE REACTIONS section for information related to dosage and side effects.
The recommended dose range for patients with coronary artery disease is 5 to 10 mg once daily. In clinical studies the majority of patients required 10 mg (see
CLINICAL PHARMACOLOGY
,
Clinical Studies
).
Children: The effective antihypertensive oral dose in pediatric patients ages 6 to 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
.
Co-administration with Other Antihypertensive and/or Antianginal Drugs: Amlodipine besylate tablets have been safely administered with thiazides, ACE inhibitors, beta-blockers, long-acting nitrates, and/or sublingual nitroglycerin.
HOW SUPPLIED
id: 65bb597e-2b88-4895-e053-2a91aa0ac0a1
displayName: HOW SUPPLIED SECTION
FDA Article Code: 34069-5
Amlodipine besylate–10 mg Tablets (amlodipine besylate, USP equivalent to 10 mg of amlodipine per tablet) are supplied as white, round, flat-faced, beveled edged tablets debossed with IG on one side and 239 on the other and supplied as follows:
NDC: 60760-0239-30 bottles of 30
NDC: 60760-0239-90 bottles of 90
Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature].
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
id: 65bb5a55-1c5a-0ea8-e053-2991aa0a6b30
displayName: PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
FDA Article Code: 51945-4
