Amlodipine besilate

Amlodipine besilate

5mg Tablet

10mg Tablet

Drug Category: Anti-hypertensive / Calcium Channel Blocker

Pharmacodynamic Properties

Mechanism of Action:

Amlodipine is a calcium ion influx inhibitor of the dihydropyridine group (slow channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle.

The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect on vascular smooth muscle. The precise mechanism by which amlodipine relieves angina has not been fully determined but amlodipine reduces total ischemic burden by the following two actions.

1. Amlodipine dilates peripheral arterioles and thus, reduces the total peripheral resistance (afterload) against which the heart works. Since the heart rate remains stable, this unloading of the heart reduces myocardial energy consumption and oxygen requirements.
2. The mechanism of action of amlodipine also probably invovles dilation of the main coronary arteries and coronary arterioles, both in normal and ischemic regions. This dilation increases myocardial oxygen delivery in patients with coronary artery spasm (Prinzmetal's or variant angina).

In patients with hypertension, once daily dosing provides clinical significant reductions of blood pressure in both the supine and standing positions throughout the 24 hour interval. Due to the slow onset of action, acute hypotension is not a feature of amlodipine administration.

In patients with angina, once daily administration of amlodipine increases total exercise time, time to angina onset, and time to 1mm ST segment depression, and decreases both angina attack frequency and glyceryl trinitrate tablet consumption.

Amlodipine has not been associated with any adverse metabolic effects or changes in plasma lipids and is suitable for use in patients with asthma, diabetes and gout.

Use in Patients with Heart Failure: Hemodynamic studies and exercise based controlled clinical trials in NYHA Class II-IV heart failure patients have shown that amlodipine did not lead to clinical deterioration as measured by exercise tolerance, left ventricular ejection fraction and clinical symptomatology.

A placebo controlled study designed to evaluate patients in NYHA Class III-IV heart failure receiving digoxin, diuretics and ACE inhibitors has shown that amlodipine did not lead to an increase in risk of mortality or combined mortality and morbidity with heart failure.

In a follow-up, long term, placebo controlled study of amlodipine in patients with NYHA III and IV heart failure without clinical symptoms or objective finding suggestive or underlying ischemic disease, on stable doses of ACE inhibitors, digitalis and diuretics, amlodipine had no effect on total cardiovascular mortality. In this same population amlodipine was associated with increased reports of pulmonary edema despite no significant difference in the incidence of worsening heart failure as compared to placebo.

The long-term effects of amlodipine on growth, puberty and general development have not been studied. The long-term efficacy of amlodipine on therapy in childhood to reduce cardiovascular morbidity and mortality in adulthood have also not been established.

Pharmacokinetic Properties:

Amlodipine is well absorbed following oral administration with peak plasma blood concentrations occurring after 6 12 hours. It has prolonged terminal elimination half-life of 35 to 50 hours and steady state plasma concentrations are not achieved until 7 to 8 days of administration.

Amlodipine is extensively metabolized; metabolites are mostly excreted in urine together with less than 10% of a dose as unchanged drug.

Amlodipine is reported to be about 97.5% bound to plasma protein.

Use in the elderly:

The time to reach peak plasma concentrations of amlodipine is similar in elderly and younger subjects. Amlodipine clearance tends to be decreased with resulting increases in AUC and elimination half-life in elderly patients. Increases in AUC and elimination half-life in patients with congestive heart failure were as expected for the patient age group studied.

Indication

Management of Hypertension.

Management of stable and vasopastic angina pectoris.

Dosage and Administration

For Adults:

For both hypertension and angina the usual initial dose is 5mg amlodipine once daily which may be increased to a maximum dose of 10mg depending on the individual patient's response.

No dose adjustment of amlodipine is required upon concomitant administration of thiazide diuretics, beta blockers, and angiotensin-converting enzyme inhibitors.

Use in the elderly: Amlodipine is used at similar doses in elderly or younger patients, is equally well tolerated. Therefore normal dosage regimens are recommended.

Patients with renal impairment: Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment, therefore the normal dosage is recommended. Amlodipine is not dialysable.

For Children and infants by age groups: Not recommended.

Contraindication

• Amlodipine is contraindicated in patients with known sensitivity to dihydropyridines, amlodipine or any of the excipients.
• Amlodipine should not be used in cardiogenic shock, clinically significant aortic stenosis, unstable angina (excluding Prinzmetal's angina)
• Pregnancy and lactation

Warning and Precautions

Use in patients with Heart Failure: In a long-term, placebo controlled study of amlodipine in patients with NYHA III and IV heart failure or non-ischemic etiology, amlodipine was associated with increased reports of pulmonary edema despite no significant difference in the incidence of worsening heart failure as compared to placebo.

Use in patients with impaired hepatic function: As with all calcium antagonists, amlodipine's half-life is prolonged in patients with impaired liver function and dosage recommendations have not been established. The drug should therefore be administered with caution in these patients.

There are no data to support the use of amlodipine alone, during or within one month of myocardial infarction.

The safety and efficacy of amlodipine in hypertensive crisis has not been established.

Pregnancy and Lactation

Although some dihydropyridine compounds have been found to be teratogenic in animals, data in the rat and rabbit for amlodipine provide no evidence for a teratogenic effect. There is, however, no clinical experience with the preparation in pregnancy or lactation. Accordingly, amlodipine should not be administered during pregnancy, or lactation, or to women of childbearing potential unless effective concentration is used.

Adverse Drug Reactions

The most commonly reported side effects of amlodipine are headache, edema, rash, fatigue, nausea, flushing, and dizziness.

Other reported side effects are:

Blood and lymphatic system disorders

Very rare: thrombocytopenia, leucocytopenia

Immune system disorders

Very rare: allergic reaction

Metabolic and nutrition disorders

Very rare: hyperglycemia

Psychiatric disorders

Uncommon: mood changes, insomnia

Nervous system disorders

Common: somnolence

Uncommon: tremor, taste pervesion, syncope, hypoaesthesia, paresthesia

Very rare: peripheral neuropathy

Eye disorders

Uncommon: visual disturbances

Ear and Labyrinth disorders

Uncommon: tinnitus

Cardiac disorders

Common: palpitations

Rare: syncope

Very rare: Myocardial infarction, arrhythmia, ventricular tachycardia and atrial fibrillation

Vascular disorders

Uncommon: hypotension

Very rare: vasculitis

Respiratory, thoracic and mediastinal disorders

Uncommon: Dyspnea, rhinitis

Very rare: coughing

Gastrointestinal disorders

Common: Abdominal pain

Uncommon: Vomiting, dyspnea, altered bowel habits, dry mouth

Very rare: Pancreatitis, gastritis, gingival hyperplasia

Hepato-biliary disorders

Very rare: Abnormal liver function tests, hepatitis, jaundice

Skin and subcutaneous tissue disorders

Uncommon: alopecia, pruritus, perpura, skin discoloration, increased sweating

Very rare: erythema multiforme, angioedema and urticaria

Musculoskeletal, connective tissue and bone disorders

Uncommon: Myalgia, arthralgia, muscle cramps and back pain

Renal and urinary disorders

Uncommon: Increased urinary frequency, micturition disorder, nocturia

Reproductive system and breast disorders

Uncommon: Impotence, gynecomastia

General disorders and administration site conditions

Uncommon: Chest pain, asthenia, pain, malaise, increase or decrease in weight

Drug Interactions

Amlodipine has been safely administered with thiazide diuretics, alpha blockers, beta blockers, angiotensin-converting enzyme inhibitors, long acting nitrates, sublingual glyceryl trinitrate, non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics and oral hypoglycemic drugs.

Special Studies: Effect of Other agents on amlodipine

Cimetidine: Co-administration of amlodipine with cimetidine did not alter the pharmacokinetics of amlodipine.

Grapefruit Juice: Co-administration of 240ml of grapefruit juice with a single oral dose of amlodipine 10mg in 20 healthy volunteers had no significant effect on the pharmacokinetics of amlodipine.

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

Special Studies: Effect of amlodipine on other agents

Atorvastatin: Co-administration of multiple 10mg doses of amlodipine with 80mg of atorvastatin resulted in no significant change in the steady state pharmacokinetics parameters of atorvastatin.

Digoxin: Co-administration of amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers.

Warfarin: In healthy male volunteers, the co-administration of amlodipine does not significantly alter the effect of warfarin on prothrombin response time. Co-administration of amlodipine with warfarin did not change the warfarin prothrombin response time.

Ciclosporin: Pharmacokinetics studies with ciclosporin have demostrated that amlodipine does not significantly alter the pharmacokinetics of ciclosporin.

Drug/Laboratory test Interactions: None known.

Known symptoms of overdosage and particular of its treatment:

There is no documented experience with amlodipine overdosage. Gastric lavage may be of benefit. Gross overdosage could result in excessive peripheral vasodilation, resulting in marked and probably prolonged systemic hypotension. Clinically significant hypotension due to amlodipine over-dosage requires active cardiovascular support. Intravenous calcium gluconate may be of benefit in reversing the effects of calcium channel blockade. Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit. TREATMENT IS SYMPTOMATIC AND SUPPORTIVE.

Storage Conditions:

Store at temperatures not exceeding 30^oC.