Amlodipine

DESCRIPTION

Amlodipine besylate is a long-acting calcium channel blocker.

Amlodipine besylate is chemically described as (R.S.) 3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate benzenesulphonate. Its empirical formula is: C₂₀H₂₅ClN₂O₅·C₆H₆O₃S.

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: microcrystalline cellulose, dibasic calcium phosphate anhydrous, sodium starch glycolate, and magnesium stearate.

CLINICAL PHARMACOLOGY

Mechanism of Action

Amlodipine besylate is a dihydropyridine calcium antagonist (calcium ion antagonist or channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine besylate 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 besylate 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 besylate. Within the physiologic pH range, amlodipine besylate 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 besylate 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 besylate relieves angina have not been fully delineated, but are thought to include the following:

Exertional Angina: In patients with exertional angina, amlodipine besylate reduces the total peripheral resistance (after-load) 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 besylate has been demonstrated to block constriction and restore blood wflow 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 besylate in vasospastic (Prinzmetal's or variant) angina.

Pharmacokinetics and Metabolism

After oral administration of therapeutic doses of amlodipine besylate, 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 is not altered by the presence of food.

Amlodipine besylate 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 besylate are reached after 7 to 8 days of consecutive daily dosing.

The pharmacokinetics of amlodipine besylate 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.

Pharmacodynamics

Hemodynamics: Following administration of therapeutic doses to patients with hypertension, amlodipine besylate produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. Although the acute intravenous administration of amlodipine decreases arterial blood pressure and increases heart rate in hemodynamic studies of patients with chronic stable angina, chronic administration of oral amlodipine in clinical trials did not lead to clinically significant changes in heart rate or blood pressures in normotensive patients with angina.

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 besylate 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).

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 besylate 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 besylate has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when co-administered 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.

In a double-blind, placebo-controlled clinical trial involving 118 patients with well compensated heart failure (NYHA Class II and Class III), treatment with amlodipine besylate did not lead to worsened heart failure, based on measures of exercise tolerance, left ventricular ejection fraction and clinical symptomatology. Studies in patients with NYHA Class IV heart failure have not been performed and, in general, all calcium channel blockers should be used with caution in any patient with heart failure.

In hypertensive patients with normal renal function, therapeutic doses of amlodipine besylate 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.

Electrophysiologic Effects

Amlodipine besylate 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 besylate and concomitant beta blockers. In clinical studies in which amlodipine besylate 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 besylate therapy did not alter electrocardiographic intervals or produce higher degrees of AV blocks.

Effects in Hypertension

The antihypertensive efficacy of amlodipine besylate has been demonstrated in a total of 15 double-blind, placebo-controlled, randomized studies involving 800 patients on amlodipine besylate 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 and white patients.

Effects in Chronic Stable Angina

The effectiveness of 5-10 mg/day of amlodipine besylate in exercise-induced angina has been evaluated in 8 placebo-controlled, double-blind clinical trials of up to 6 weeks duration involving 1038 patients (648 amlodipine besylate, 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 10 mg, and averaged 7.9% (38 sec) for amlodipine besylate 5 mg. Amlodipine besylate 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 therapy decreased attacks by approximately 4/week compared with a placebo decrease of approximately 1/week (p<0.01). Two of 23 amlodipine besylate and 7 of 27 placebo patients discontinued from the study due to lack of clinical improvement.

INDICATIONS

1. Hypertension: Amlodipine besylate is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.

2. Chronic Stable Angina: Amlodipine besylate is indicated for the treatment of chronic stable angina. Amlodipine besylate may be used alone or in combination with other antianginal agents.

3. Vasospastic Angina (Prinzmetal's or Variant Angina): Amlodipine besylate is indicated for the treatment of confirmed or suspected vasospastic angina. Amlodipine besylate may be used as monotherapy or in combination with other antianginal drugs.

DOSAGE AND ADMINISTRATION

The usual initial antihypertensive oral dose of amlodipine besylate 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 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 5-10 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 for information related to dosage and side effects.

Co-administration with Other Antihypertensive and/or Antianginal Drugs: amlodipine besylate has been safely administered with thiazides, ACE inhibitors, beta-blockers, long-acting nitrates, and/or sublingual nitroglycerin.

HOW SUPPLIED

Norvasc 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.

Norvasc 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.

Norvasc 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.

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

PRODUCT LISTING

SIDE EFFECTS

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 was well-tolerated at doses up to 10 mg daily. Most adverse reactions reported during therapy with amlodipine besylate were of mild or moderate severity. In controlled clinical trials directly comparing amlodipine besylate (N=1730) in doses up to 10 mg to placebo (N=1250), discontinuation of amlodipine besylate 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 found in TABLE 1.

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 can be found in TABLE 2.

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 TABLE 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 casual 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.

Central and Peripheral Nervous System: Hypoesthesia, paresthesia, tremor, vertigo.

Gastrointestinal: Anorexia, constipation, dyspepsia,† dysphagia, diarrhea, flatulence, vomiting, gingival hyperplasia.

General: Asthenia,† back pain, hot flushes, malaise, pain, rigors, weight gain.

Musculo-skeletal 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: Pruritus,† rash,† rash erythematous, rash maculopapular.

*Based on patient weight of 50 kg.

†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, increased sweating.

Metabolic and Nutritional: thirst.

Hemopoietic: purpura.

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 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, creatinine or liver function tests.

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

DRUG INTERACTIONS

In vitro data in human plasma indicate that amlodipine besylate has no effect on the protein binding of drugs tested (digoxin, phenytoin, warfarin, and indomethacin). Special studies have indicated that the co-administration of amlodipine besylate with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers; that co-administration with cimetidine did not alter the pharmacokinetics of amlodipine; and that co-administration with warfarin did not change the warfarin prothrombin response time.

In clinical trials, amlodipine besylate 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.

WARNINGS

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.

PRECAUTIONS

General: Since the vasodilation induced by amlodipine besylate is gradual in onset, acute hypotension has rarely been reported after oral administration of amlodipine besylate. Nonetheless, caution should be exercised when administering amlodipine besylate as with any other peripheral vasodilator particularly in patients with severe aortic stenosis.

Use in Patients with Congestive Heart Failure: Although hemodynamic studies and a controlled trial in NYHA Class II-III heart failure patients have shown that amlodipine besylate did not lead to clinical deterioration as measured by exercise tolerance, left ventricular ejection fraction, and clinical symptomatology, studies have not been performed in patients with NYHA Class IV heart failure. In general, all calcium channel blockers should be used with caution in patients with heart failure.

Beta-Blocker Withdrawal: Amlodipine besylate is not a beta-blocker and therefore gives no protection against the dangers of abrupt beta-blocker withdrawal; any such withdrawal should be by gradual reduction of the dose of beta-blocker.

Patients with Hepatic Failure: Since amlodipine besylate is extensively metabolized by the liver and the plasma elimination half-life (t 1/2) is 56 hours in patients with impaired hepatic function, caution should be exercised when administering amlodipine besylate to patients with severe hepatic impairment.

Drug/Laboratory Test Interactions: None known.

Carcinogenesis, Mutagenesis, and Impairment of Fertility: Rats and mice treated with amlodipine in the diet for two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mg/kg/day showed no evidence carcinogenicity. The highest dose (for mice, similar to, and for rats twice* the maximum recommended clinical dose of 10 mg on a mg/m² basis), was close to the maximum tolerated dose for mice but not for rats.

Mutagenicity studies revealed no drug related effects at either the gene or chromosome levels.

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

Pregnancy Category C: No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats or rabbits were treated orally with up to 10 mg/kg amlodipine (respectively 8 times* and 23 times* the maximum recommended human dose of 10 mg on a mg/m² basis) during their respective periods of major organogenesis. However, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) in rats administered 10 mg/kg amlodipine for 14 days before mating and throughout mating and gestation. Amlodipine has been shown to prolong both the gestation period and the duration of labor in rats at this dose. There are no adequate and well-controlled studies in pregnant women. Amlodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers: It is not known whether amlodipine is excreted in human milk. In the absence of this information, it is recommended that nursing be discontinued while amlodipine besylate is administered.

Pediatric Use: Safety and effectiveness of amlodipine besylate in children have not been established.