Amedin

Amlodipine besylate.

Pharmacology: Pharmacodynamics: Amedin 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 Amedin is due to a direct relaxant effect on vascular smooth muscle. The precise mechanism by which Amedin relieves angina has not been fully determined but Amedin reduces total ischaemic burden by the following 2 actions: Amedin 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.
The mechanism of action of Amedin 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 (Prinzmetal's or variant angina). In patients with hypertension, once-daily dosing provides clinically significant reductions of blood pressure in both the supine and standing positions throughout the 24-hr interval. Due to the slow onset of action, acute hypotension is not a feature of Amedin administration. In patients with angina, once-daily administration of Amedin increases total exercise time, time to angina onset, and time to 1-mm ST segment depression and decreases both angina attack frequency and glyceryl trinitrate tablet consumption. Amedin 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. Haemodynamic studies and exercise based controlled clinical trials in New York heart association (NYHA) class II-IV heart failure patients have shown that Amedin did not lead to clinical deterioration as measured by exercise tolerance, left ventricular ejection fraction and clinical symptomatology. A placebo controlled study (PRAISE) designed to evaluate patients in NYHA class III-IV heart failure receiving digoxin, diuretics and ACE inhibitors has shown that Amedin did not lead to an increase in risk of mortality or combined mortality and morbidity with heart failure.
Pharmacokinetics: Absorption, Distribution, Plasma-Protein Binding: After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels between 6- to 12-hrs 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.
Biotransformation/Elimination: The terminal plasma elimination half-life is about 35-50 hrs and is consistent with once-daily dosing. Amlodipine is extensively metabolised by the liver to inactive metabolites with 10% of the parent compound and 60% of metabolites excreted in the urine.
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.

Hypertension; prophylaxis of chronic stable angina pectoris; Prinzmetal's (variant) angina.
In hypertensive patients, Amedin has been used in combination with a thiazide diuretic, α-blocker, β-adrenoceptor blocker or an angiotensin-converting enzyme (ACE) inhibitor.
For angina, Amedin may be used as monotherapy or in combination with other antianginal drugs in patients with angina that is refractory to nitrates and/or adequate doses of β-blockers.
Amedin is well tolerated in patients with heart failure and history of hypertension or ischaemic heart disease.

Adults: Hypertension and Angina: Initial Dose: 5 mg once daily which may be increased to a maximum dose of 10 mg depending on the individual response.
No dose adjustment of Amedin is required upon concomitant administration of thiazide diuretics, β-blockers, and ACE inhibitors.
Children: Not recommended.
Elderly: Used at similar doses in elderly or younger patients is equally well tolerated. Therefore, normal dosage regimens are recommended.
Hepatic Impairment: See as follows.
Renal Impairment: Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment, therefore normal dosage is recommended. Amlodipine is not dialysable.

In humans, experience with intentional overdose is limited. Gastric lavage may be worthwhile in some cases. Available data suggest that gross overdosage could result in excessive peripheral vasodilatation with subsequent marked and probably prolonged systemic hypotension. Clinically significant hypotension due to Amedin overdosage 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. IV calcium gluconate may be beneficial in reversing the effects of calcium channel blockade. Since Amedin is highly protein bound, dialysis is not likely to be of benefit.

Hypersensitivity to dihydropyridines.
Amedin should not be used in cardiogenic shock, clinically significant aortic stenosis, unstable angina (excluding Prinzmetal's angina).

As with all calcium antagonists, amlodipine's half-life is prolonged in patients with impaired liver function and dosage recommendations have not been established. Amedin should therefore be administered with caution in these patients. There are no data to support the use of Amedin alone, during or within 1 month of myocardial infarction. The safety and efficacy of Amedin in hypertensive crisis has not been established.
Effects on the Ability to Drive or Operate Machinery: Clinical experience with Amedin indicates that therapy is unlikely to impair a patient's ability to drive or use machinery.
Use in pregnancy & lactation: Although some dihydropyridine compounds have been found to be teratogenic in animals, data in rat and rabbit for amlodipine provide no evidence for a teratogenic effect. There is, however, no clinical experience with Amedin in pregnancy or lactation. Accordingly, Amedin should not be administered during pregnancy, or lactation, or to women of childbearing potential unless effective contraception is used.

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

The most commonly reported side effects of Amedin are headache, oedema, rash, fatigue, nausea, flushing and dizziness. Gingival hyperplasia has been reported after administration of Amedin.
The following adverse reactions have been reported rarely: Alopecia, pruritus, angioedema, palpitations, dyspnoea, abdominal pain, back pain, dyspepsia, muscle cramps, asthenia, somnolence, altered bowel habit, myalgia, arthralgia, peripheral neuropathy, pancreatitis, mood changes, dry mouth, increased urinary frequency, hypergylcaemia, impotence, increased sweating, syncope, thrombocytopenia, vasculitis and visual disturbances. In many instances, causal association is uncertain.
The following adverse reactions have been reported very rarely: Abnormal liver function tests, hepatitis, jaundice, erythema multiforme and gynaecomastia.
As with other calcium channel blockers, the following adverse events have been rarely reported and cannot be distinguished from the natural history of the underlying disease: Myocardial infarction, arrythmia (including ventricular tachycardia and atrial fibrillation) and chest pain.

Amedin has been safely administered with thiazide diuretics, α-blockers, β-blockers, ACE inhibitors, long-acting nitrates, sublingual glyceryl trinitrate, nonsteroidal anti-inflammatory drugs, antibiotics and oral hypoglycaemic drugs.
Pharmacokinetic studies with cyclosporin have demonstrated that amlodipine does not significantly alter the pharmacokinetics of cyclosporin. Special studies have indicated that the co-administration of Amedin with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers and that the co-administration of cimetidine did not alter the pharmacokinetics of amlodipine. In healthy male volunteers, the co-administration of Amedin does not significantly alter the effect of warfarin on prothrombin response time.
In vitro data from studies with human plasma indicate that amlodipine has no effect on protein binding of digoxin, phenytoin, warfarin or indomethacin.
Grapefruit juice may interact with Amedin to increase the plasma concentration. However, this increase is too small to significantly alter blood pressure or heart rate.

Store in a dry place below 25°C.
Shelf-Life: 3 years.

Calcium Antagonists / Anti-Anginal Drugs

C08CA01 - amlodipine ; Belongs to the class of dihydropyridine derivative selective calcium-channel blockers with mainly vascular effects. Used in the treatment of cardiovascular diseases.

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