Fredun Amlodipine Besylate Tablets

Amlodipine Besylate Tablets USP 10 mg

For the use only of a Registered Medical Practitioner or a hospital ma Laboratory

 

Composition

Each uncoated tablet contains:

Amlodipine Besylate USP

Equivalent to Amlodipine 10mg

Excipients: q.s.

 

Pharmacological action

i) 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.

ii) The mechanism of the entihypertensive action of Amlodipine is due to a direct relaxant effect on vascular smooth muscle.

iii) The precise mechanism by which Amlodipine relieves and reduces total ischaemic burden by the following two actions:

1. It dilates peripheral arterioles and thus, reduces the total peripheral resistance (after load) 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 dilatation of the main coronary arteries and coronary arterioles, both in normal and ischaemic regions. This dilatation increases myocardial oxygen delivery in patients with coronary artery spasm.

 

Pharmacokinetic Data

Absorption, distribution, plasma protein binding

After oral administration of therapeutic doses, Amlodipine is well absorbed with peak blood levels between 6-12 hours post dose. Absolute bioavailability has been estimated to be between 64 and 80%. The volume of distribution is approximately 21 l/kg. In vitro studies have shown that approximately 97.5% of circulating Amlodipine is bound to plasma proteins. The bioavailability of Amlodipine is not affected by food intake.

 

Biotransformation/elimination

The terminal plasma elimination half life is about 35-50 hours and is consistent with once daily dosing. Amlodipine is extensively metabolized by the liver to inactive metabolites With 10% of the parent compound and 60% of metabolites excreted in the urine.

 

Use in children

A population PK study has been conducted in 74 hypertensive children aged from 12 months to 17 years (with 34 patients aged 6 to 12 years and 28 patients aged 13 to 17 years) receiving Amlodipine between 1.25 and 20 mg given either once or twice daily.

In children 6 to 12 years and in adolescents 13-17 years of age the typical oral clearance (CL/F) was 22.5 and 27.4 L/hr respectively in males and 16.4 and 21.3 L/hr respectively in females. Large variability in exposure between individuals was observed. Data reported in children below 6 years is limited.

 

Use in 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.

 

Patients with impaired hepatic function

Very limited clinical data are available regarding Amlodipine administration in patients with hepatic impairment. Patients with hepatic insufficiency have decreased clearance of Amlodipine resulting in a longer half-life and an increase in AUC of approximately 40-60%.

 

Therapeutic category

Calcium channel blocker.

 

Therapeutic Indications

For the relief and treatment of pain and inflammation in:

1. Hypertension

2. Chronic stable angina pectoris

3. Vasospaatic (Prinzmetal’s) angina

 

Posology and Method of Administration

Route of Administration

Oral

 

Adults

i) The usual initial dose is 5mg Amlodipine once daily which may be increased to a maximum dose of 10 mg depending on the individual patient’s response.

ii) In hypertensive patients, it has been used in combination with a thiazide diuretic, alpha blocker, beta blocker, or an angiotensin converting enzyme inhibitor. For angina, Amlodipine may be used as monotherapy or in combination with other anti-anginal medicinal products in patients with angina that is refractory to nitrates and/or to adequate doses of beta blockers.

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

 

Paediatric population (Children and adolescents with hypertension from 6-17 years age)

The recommended dose is 2.5 mg once daily as a starting dose, up-titrated to 5 mg once daily if blood pressure goal is not achieved after 4 weeks. Doses in excess of 5 mg daily have not been studied in paediatric patients.

 

Children under 6 years old

No data are available.

 

Elderly patients

Normal dosage regimens are recommended in the elderly, but increase of the dosage should take place with care.

 

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 dialyzable.

 

Patients with 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.

 

Contraindications

i) Hypersensitivity to dihydropyridine derivatives, Amlodipine or any of the excipients.

ii) Severe hypotension.

iii) Shock (including cardiogenic shock).

iv) Obstruction of the outflow tract of the left ventricle (e.g. high grade sonic stenosis).

v) Haemodynamically unstable heart failure after acute myocardial infarction.

 

Warning and Precautions

Use in patients with Heart Failure

Amlodipine was associated with increased reports of pulmonary oedema 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.

 

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, it should not be administered during pregnancy, or lactation, or to women of childbearing potential unless effective contraception is used.

 

Adverse effects

i) 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.

ii) Other reactions occurred sporadically and cannot be distinguished from medications or concurrent disease states such as myocardial infarction and angina.

iii) It has not been associated with clinically significant changes in routine laboratory tests like serum potassium, serum glucose, total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or creatinine.

 

Drug interactions

Effects of other medicinal products on Amlodipine

 

CYP3A4 inhibitors

Concomitant use of Amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungal, and macrolides like erythromycin or Clarithromycin, verapamil or diltiazem) may give rise to significant increase in Amlodipine exposure. Clinical monitoring and dose adjustment may thus be required.

 

CYP3A4 Inducers

The concomitant use of CYP3A4 inducers (e.g., rifampicin, hypericum perforatun,) may give a lower plasma concentration of Amlodipine. It should be used with caution together.

Administration of Amlodipine with grapefruit or grapefruit juice is not recommended as bioavailability may be increased in some patients resulting in increased blood pressure lowering effects.

 

Dantrolene (infusion)

In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with hyperkalemia after administration of verapamil and dantrolene I.V. Due to risk of hyperkalemia, it is recommended that the co administration of calcium channel blockers such as Amlodipine be avoided in patients susceptible to malignant hyperthermia and in the management of malignant hyperthermia.

 

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.

 

Simvastatin

Co-administration of multiple doses of 10 mg of Amlodipine with 80 mg Simvastatin resulted in a 77% increase in exposure to Simvastatin compared to Simvastatin alone. Limit the dose of Simvastatin in patients on Amlodipine to 20 mg daily.

 

Overdosage

Symptoms

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

 

Treatment

i) Clinically significant hypotension due to Amlodipine over dosage 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.

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

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

iv) Since Amlodipine is highly protein-bound, dialysis is not likely to be of benefit.

 

Pharmaceutical information

Storage conditions

Store below 30o Protect from direct sunlight, heat and moisture.

Keep all medicines out of reach of children.

 

Shelf Life

36 months.

 

Pack size

Blister pack of 10 tablets

 

Description of the product

White coloured, circular, flat, beveled, uncoated tablet with break line on one side and other side plain.

 

Manufactured by

Fredun Pharmaceuticals Ltd.

14,15,16, Zorabian Industrial Complex,

Veoor, Palghar (E) -401 404. INDIA

 

Manufactured for

PREFERRED DRUGS NIGERIA LTD.

20 Erhuvwa Club Street,

Asaba Delta State, Nigeria

 

Preferred Groups LLC, Maryland U.S.A.

www.preferred-drugs.com