CLINICAL PHARMACOLOGY: Amlodipine is the besylate salt of Amlodipine.

Mechanism of Action: Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. 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.

Exertional Angina: Amlodipine reduces the total peripheral resistance (afterload) against which the heart works and reduces the rate pressure product.

Vasospastic Angina: Amlodipine has been demonstrated to block constriction and restore blood flow in coronary arteries and arterioles; this inhibition of coronary spasm is responsible for the effectiveness of Amlodipine in vasospastic (Prinzmetal's or variant) angina.

Pharmacokinetics and Metabolism: After oral administration of therapeutic doses of Amlodipine, 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 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. The pharmacokinetics of Amlodipine are not significantly influenced by renal impairment. Elderly patients and patients with hepatic insufficiency have decreased clearance of Amlodipine.

Pharmacodynamics: With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. 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).

Effects in Hypertension: 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.

Effects in Chronic Stable Angina:  The effectiveness of 5-10 mg/day of Amlodipine in exercise-induced angina has been evaluated significant increases in exercise time (bicycle or treadmill) were seen with the 10 mg dose.

Effects in Vasospastic Angina:   Amlodipine therapy decreased attacks by approximately 4/week compared with a placebo decrease of approximately 1/week.

WARNINGS: 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.

PRECAUTIONS:

General: Since the vasodilation induced by Amlodipine is gradual in onset, acute hypotension has rarely been reported after oral administration of Amlodipine.

Use in Patients with Congestive Heart Failure: In general, calcium channel blockers should be used with caution in patients with heart failure.

Patients with Hepatic Failure: Caution should be exercised when administering Amlodipine to patients with severe hepatic impairment.

Pregnancy Category C  

Nursing Mothers: it is recommended that nursing be discontinued while Amlodipine is administered.

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

Geriatric Use: Elderly patients have decreased clearance of Amlodipine, and a lower initial dose may be required.

Drug Interactions: When Amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect. 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.  

SIDE EFFECTS:

The most common side effects are headache and edema. The incidence (%) of side effects which occurred in a dose related manners are as follows:

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:

OVERDOSAGE: 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: The usual initial antihypertensive oral dose of Amlodipine 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 to other antihypertensive therapy. Amlodipine has been safely administered with thiazides, ACE inhibitors, beta-blockers, long-acting nitrates, and/or sublingual nitroglycerin.

How Supplied: Each pack of Ruz-Amlodipine 5 mg tablets contains 30 tablets in 3 blisters.                     

storage: Store at controlled room temperature, 15° to 30°C and dispense in tight, light-resistant containers.

Reference: PDR 2000, page 2358-60

                  USPDI for Professional Health Care, 2004, Page 104-110

                  Martindale 2005, Page 862