AMLODIPINE BESYLATE tablet
[STAT RX USA LLC]
|Category||DEA Schedule||Marketing Status|
|HUMAN PRESCRIPTION DRUG LABEL||Abbreviated New Drug Application|
Amlodipine besylate is the besylate salt of amlodipine, a long-acting calcium channel blocker.
Amlodipine besylate is chemically described as 3-Ethyl-5-methyl (±)-2-[(2-aminoethoxy) methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, monobenzene-sulphonate. Its molecular formula is C20H25CIN2O5• C6H6O3S, and its structural formula is:
Amlodipine besylate 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, each tablet contains the following inactive ingredients: sodium starch glycolate, mannitol, microcrystalline cellulose, dibasic calcium phosphate anhydrous, colloidal silicon dioxide and magnesium stearate.
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:
Exertional Angina: In patients with exertional angina, amlodipine reduces the total peripheral resistance (afterload) against which the heart works and reduces the rate pressure product, and thus myocardial oxygen demand, at any given level of exercise.
Vasospastic Angina: Amlodipine has been demonstrated to block constriction and restore blood flow in coronary arteries and arterioles in response to calcium, potassium epinephrine, serotonin, and thromboxane A2 analog in experimental animal models and in human coronary vessels in vitro. This inhibition of coronary spasm is responsible for the effectiveness of amlodipine in vasospastic (Prinzmetal's or variant) angina.
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.
With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with amlodipine is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105-114 mmHg) had about a 50% greater response than patients with mild hypertension (diastolic pressure 90-104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressures (+1/-2 mmHg).
In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.
As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when coadministered with beta-blockers to man. Similar findings, however, have been observed in normals or well-compensated patients with heart failure with agents possessing significant negative inotropic effects.
Electrophysiologic Effects: Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or man. In patients with chronic stable angina, intravenous administration of 10 mg did not significantly alter A-H and H-V conduction and sinus node recovery time after pacing. Similar results were obtained in patients receiving amlodipine and concomitant beta-blockers. In clinical studies in which amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed. In clinical trials with angina patients alone, amlodipine therapy did not alter electrocardiographic intervals or produce higher degrees of AV blocks.
Adult Patients: The antihypertensive efficacy of amlodipine has been demonstrateed in a total of 15 double-blind, placebo-controlled, randomized studies involving 800 patients on amlodipine and 538 on placebo. Once daily administration produced statistically significant placebo-corrected reductions in supine and standing blood pressures at 24 hours post-dose, 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 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 mm Hg 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 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, 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 10 mg, and averaged 7.9% (38 sec) for amlodipine 5 mg. Amlodipine 10 mg also increased time to 1 mm ST segment deviation in several studies and decreased angina attack rate. The sustained efficacy of amlodipine 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 therapy decreased attacks by approximately 4/week compared with a placebo decrease of approximately 1/week (p<0.01). Two of 23 amlodipine 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 (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 (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 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
Figure 2 – Effects on primary endpoint of amlodipine versus placebo across sub-groups
| Clinical Outcomes|
|Composite CV Endpoint||110|
|Hospitalization for |
Studies in Patients with Congestive Heart Failure:
Amlodipine has 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 5 to10 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 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 (n=827) and followed them for a mean of 33 months. There was no statistically significant difference between amlodipine and placebo in the primary endpoint of all cause mortality (95% confidence limits from 8% reduction to 29% increase on amlodipine). With amlodipine there were more reports of pulmonary edema.
- Hypertension Amlodipine is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.
- Coronary Artery Disease (CAD)
Amlodipine is indicated for the symptomatic treatment of chronic stable angina. Amlodipine may be used alone or in combination with other antianginal agents.
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.
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 due to angina and to reduce the risk of a coronary revascularization procedure.
In general, calcium channel blockers should be used with caution in patients with heart failure. Amlodipine (5 to 10 mg per day) has been studied in a placebo-controlled trial of 1153 patients with NYHA Class III or IV heart failure (see CLINICAL PHARMACOLOGY) on stable doses of ACE inhibitor, digoxin, and diuretics. Follow-up was at least 6 months, with a mean of about 14 months. There was no overall adverse effect on survival or cardiac morbidity (as defined by life-threatening arrhythmia, acute myocardial infarction, or hospitalization for worsened heart failure). Amlodipine has 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 LVEF.
Effect of other agents on amlodipine.
CIMETIDINE: Coadministration of amlodipine with cimetidine did not alter the pharmacokinetics of amlodipine.
GRAPEFRUIT JUICE: Coadministration of 240 mL of grapefruit juice with a single oral dose of amlodipine10 mg in 20 healthy volunteers had no significant effect on the pharmacokinetics of amlodipine.
MAALOX (antacid): Coadministration of the antacid Maalox with a single dose of amlodipine had no significant effect on the pharmacokinetics of amlodipine.
SILDENAFIL: A single 100 mg dose of sildenafil (Viagra®) in subjects with essential hypertension had no effect on the pharmacokinetic parameters of amlodipine. When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.
Effect of amlodipine on other agents.
ATORVASTATIN: Coadministration of multiple 10 mg doses of amlodipine with 80 mg of atorvastatin resulted in no significant change in the steady state pharmacokinetic parameters of atorvastatin.
DIGOXIN: Coadministration of amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers.
ETHANOL (alcohol): Single and multiple 10 mg doses of amlodipine had no significant effect on the pharmacokinetics of ethanol.
WARFARIN: Coadministration of amlodipine with warfarin did not change the warfarin prothrombin response time.
In clinical trials, amlodipine has been safely administered with thiazide diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, non-steroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic drugs.
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 dose of 10 mg/day on a mg/m2 basis).
*Based on patient weight of 50 kg.
Adverse Event 2.5 mg 5 mg 10 mg Placebo
N=275 N=296 N=268 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% in placebo-controlled clinical trials include the following:
Amlodipine (%) PLACEBO (%)
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:
Adverse Event Amlodipine PLACEBO
Male=% Female=% Male=% Female=%
(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:
**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.
he 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 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 StudiesStudies 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 has 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 might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. In humans, experience with intentional overdosage of amlodipine 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 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 5-10 mg once daily. In clinical studies the majority of patients required 10 mg (see CLINICAL PHARMACOLOGY, Clinical Studies).
NDC 64679-421-01 Bottle of 90
NDC 64679-421-02 Bottle of 1000
NDC 64679-421-03 Unit Dose package of 100
NDC 64679-421-04 Bottle of 100
Amlodipine besylate tablets-5 mg Tablets (amlodipine besylate equivalent to 5 mg of amlodipine per tablet) are supplied as white to off-white, caplet, flat-beveled, debossed with “W” on one side and “422” on the other side and supplied as follows:
NDC 64679-422-01 Bottle of 90
NDC 64679-422-02 Bottle of 1000
NDC 64679-422-03 Unit Dose package of 100
NDC 64679-422-04 Bottle of 100
NDC 64679-422-05 Bottle of 300
Amlodipine besylate tablets-10 mg Tablets (amlodipine besylate equivalent to 10 mg of amlodipine per tablet) are supplied as white to off-white, round, flat-beveled, debossed with “ W ” on one side and plain on the other side and supplied as follows:
NDC 64679-423-01 Bottle of 90
NDC 64679-423-02 Bottle of 1000
NDC 64679-423-03 Unit Dose package of 100
NDC 64679-423-04 Bottle of 100
Store at 200 to 250C (680 to 770F) (USP Controlled Room Temperature) and dispense in tight, light-resistant containers (USP).
Viagra® is a registered trademark of Pfizer.
Maalox® is a registered trademark of Novartis.
Wockhardt USA LLC.
20 Waterview Blvd.
Parsippany, NJ 07054
What is amlodipine?
Amlodipine is a type of medicine known as a calcium channel blocker (CCB). It is used to treat high blood pressure (hypertension) and a type of chest pain called angina. It can be used by itself or with other medicines to treat these conditions.
High Blood Pressure (hypertension)
High blood pressure comes from blood pushing too hard against your blood vessels. Amlodipine relaxes your blood vessels which lets your blood flow more easily and helps lower your blood pressure. Drugs that lower blood pressure lower your risk of having a stroke or heart attack.
Angina is a pain or discomfort that keeps coming back when part of your heart does not get enough blood. Angina feels like a pressing or squeezing pain, usually in your chest under the breastbone. Sometimes you can feel it in your shoulders, arms, neck, jaws, or back. Amlodipine can relieve this pain.
Who should not use amlodipine?
Do not use amlodipine if you are allergic to amlodipine, (the active ingredient in amlodipine besylate tablets), or to the inactive ingredients. Your doctor or pharmacist can give you a list of these ingredients.
What should I tell my doctor before taking amlodipine?
Tell your doctor about any prescription and non-prescription medicines you are taking, including natural or herbal remedies.
Tell your doctor if you:
- ever had heart disease
- ever had liver problems
- are pregnant, or plan to become pregnant. Your doctor will decide if amlodipine is the best treatment for you.
- are breast-feeding. Do not breast feed while taking amlodipine. You can stop breastfeeding or take a different medicine.
- Take amlodipine once a day, with or without food. You can take amlodipine with most drinks, including grapefruit juice.
- It may be easier to take your dose if you do it at the same time every day, such as with breakfast, dinner, or at bedtime. Do not take more than one dose of amlodipine at a time.
- If you miss a dose, take it as soon as you remember. Do not take amlodipine if it has been more than 12 hours since you missed your last dose. Wait and take the next dose at your regular time.
- Other medicines: You can use nitroglycerin and amlodipine together. If you take nitroglycerin for angina, don't stop taking it while you are taking amlodipine.
- While you are taking amlodipine, do not stop taking your other prescription medicines, including any other blood pressure medicines, without talking to your doctor.
- If you took too much amlodipine, call your doctor or Poison Control Center, or go to the nearest hospital emergency room right away.
- Do not breastfeed. It is not known if amlodipine will pass through your milk.
- Do not start any new prescription or non-prescription medicines or supplements, unless you check with your doctor first.
Amlodipine may cause the following side effects. Most side effects are mild or moderate:
- swelling of your legs or ankles
- tiredness, extreme sleepiness
- stomach pain, nausea
- flushing (hot or warm feeling in your face)
- arrhythmia (irregular heartbeat)
- heart palpitations (very fast heartbeat)
If that happens, call your doctor right away or go directly to a hospital emergency room.
Tell your doctor if you are concerned about any side effects you experience. These are not all the possible side effects of amlodipine. For a complete list, ask your doctor or pharmacist.
How do I store amlodipine?
Keep amlodipine besylate tablets away from children. Store amlodipine besylate tablets at room temperature (between 68 and 77 degrees Fahrenheit).
Keep amlodipine besylate tablets out of the light. Do not store in the bathroom.
Keep amlodipine besylate tablets in a dry place.
General advice about amlodipine
Sometimes, doctors will prescribe a medicine for a condition that is not written in the patient information leaflets. Only use amlodipine the way your doctor told you to. Do not give amlodipine to other people, even if they have the same symptoms you have. It may harm them.
You can ask your pharmacist or doctor for information about amlodipine besylate tablets, or you can visit the Wockhardt website at www.wockhardtusa.com or call 1-800-346-6854.
Wockhardt USA LLC.
20 Waterview Blvd.
Parsippany, NJ 07054
amlodipine besylate tablet
|Labeler - STAT RX USA LLC (786036330)|
|STAT RX USA LLC||786036330||repack, relabel|