AMLODAC (Amlodipine Basilate Tablets)

AMLODAC (Amlodipine Basilate Tablets)

AMLODAC (Amlodipine Basilate Tablets)

Therapeutic group: Calcium channel blockers, selective calcium channel blockers with mainly vascular effects.

The mechanism of Action.

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

The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect on vascular smooth muscles. The precise mechanism by which amlodipine relieves angina has not been fully determined but amlodipine reduces total ischaemic 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 involves dilation of the main coronary arteries and coronary arterioles, both in normal and ischaemic regions. This dilation increases myocardial oxygen delivery in patients with coronary artery spasm (Prinzmetal’s or variant angina).

In patients with angina, once daily administration of amlodipine increases total exercise time, time to angina onset and time to 1mmST 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 suitable for use in patients with asthma, diabetes, and gout.

Therapeutic indications

  • Hypertension
  • Chronic stable angina pectoris
  • Vasospastic (Prinzmetal’s) angina

Recommended dose and method of administration

Adults: for both hypertension and angina the usual initial dose is 5mg Amlodipine Besilate tablet once daily which may be increased to a maximum dose of 10mg depending on the individual patient’s response. In hypertensive patients, Amlodipine Besilate tablets has been used in combination with a thiazide diuretic, alpha blocker, beta blocker, or an angiotensin converting enzyme inhibitor. For angina, Amlodipine Besilate tablets may be used as monotherapy or in combination with other antianginal medicinal products in patients with angina that is refractory to nitrates and/or to adequate doses of beta blockers.

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

Special population

Elderly: Amlodipine Besilate tablets used at similar doses in elderly or younger patients is equally well tolerated. Normal dosage regimens are recommended in the elderly, but increase of the dosage should take place with care.

Hepatic impairment: dosage recommendations have not been established in patients with mild to moderate hepatic impairment; therefore dose selection should be cautious and should start at the lower end of the dosing range. The pharmacokinetics of amlodipine have not been studied in severe hepatic impairment. Amlodipine should be initiated at the lowest dose and titrated slowly in patients with severe hepatic impairment.

Renal impairment: changes in amlodipine plasma concentrations are not correlated with degree of renal impairment, therefore the normal dosage is recommended. Amlodipine is not dialyzable.

Paediatric population

Children and adolescents with hypertension from 6 years to 17 years of age: The recommended antihypertensive oral dose in paediatric patients ages 6-17 years is 2.5mg once daily as a starting dose, up-titrated to 5mg once daily if blood pressure goal is not achieved after 4 weeks. Doses in excess of 5mg daily have not been studied in paediatric patients.

Children under 6 years old: No data are available.

Method of administration

Tablet for oral administration

Contraindications

Amlodipine is contraindicated in patients with:

  • Hypersensitivity to duhydropyridine derivatives, amlodipine or to any of the excipients
  • Severe hypotension
  • Shock (including cardiogenic shock)
  • Obstruction of the outflow trat of the left ventricle (e.g. high grade aortic stenosis)
  • Haemodynamically unstable heart failure after acutemyocardial infarction.
Special warnings and precautions for use

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

Patients with cardiac failure: patients with heart failure should be treated with caution. In a long-term, placebo controlled study in patients with severe heart failure (NYHA class iii and iv) the reported incidence of pulmonary oedema was higher in the amlodipine treated group than in the placebo group Calcium channel blockers. Amlodipine should be used with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.

Use in patients with impaired hepatic function: the half-life of amlodipine is prolonged and AUC values are higher in patients with impaired liver function; dosage recommendations have not been established. Amlodipine should therefore be initiated at the lower end of the dosing range and caution should be used, both on initial treatment and when increasing the dose. Slow dose titration and careful monitoring may be required in patients with severe hepatic impairment.

Use in elderly patients: In the elderly increase of the dosage should take place with care.

Use in renal failure: Amlodipine may be used in such patients at normal doses. Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment. Amlodipine is not dialyzable.

Interaction with other medicinal products and other forms of interactions    

CYP3A4 inhibitors: Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides like erythromycin or clarithromycin, verapamil or diltiazem) may give rise to significant increase in amlodipine exposure. The clinical translation of these PK variations may be more pronounced in the elderly. Clinical monitoring and dose adjustment may thus be required

Effects of Amlodipine on other medicinal products: The blood pressure lowering effects of amlodipine adds to the blood pressure-lowering effects of other medicinal products with antihypertensive properties.

In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin, warfarin or cyclosporine.

Fertility, pregnancy and lactation

Pregnancy: The safety of amlodipine in human pregnancy has not been established. In animal studies, reproductive toxicity was observed at high doses. Use in pregnancy is only recommended when there is no safer alternative and when the disease itself carries greater risk for the mother and foetus.

Breast-feeding: It is not known whether amlodipine is excreted in breast milk. A decision on whether to continue/ discontinue breast-feeding or to continue/discontinue therapy with Amlodipine should be made taking into account the benefit of breast-feeding to the child and the benefit of amlodipine therapy to the mother.

Fertility: Reversible biochemical changes in the head of spermatozoa have been reported in some patients treated by calcium channel blockers. Clinical data are insufficient regarding the potential effect of amlodipine on fertility. In one rat study, adverse effects were found on male fertility.

Overdose

In human experience with intentional overdose is limited.

Symptoms

Available data suggest that gross overdosage could result in excessive peripheral vasodilation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension up to and including shock with fatal outcome have been reported.

Treatment

Clinically significant hypotension due to amlodipine overdose calls for active cardiovascular support including frequent monitoring of cardiac and respiratory function, elevation of extremities and attention to circulating fluid volume and urine output.

A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade.

Gastric lavage may be worthwhile in some cases. In healthy volunteers the use of charcoal up to 2 hours after administration of amlodipine 10mg has been shown to reduce the absorption rate of amlodipine.

Since amlodipine is highly protein-bound, dialysis is not likely to benefit.

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