Amlodipine besylate
Calcium antagonist
Composition
Each tablet contains Amlodipine besylate 7 mg equivalent to Amlodipine 5 mg
Mechanism of Actions
Pharmacodynamic Properties
Amlodipine is a calcium ion-influx inhibitor (slow channel blocker or calcium ion antagonist) and inhibits the trans-membrane influx of calcium ions into cardiac and vascular smooth muscle.
The mechanism of the anti-hypertensive 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 the total ischemic burden by the following two actions:
- Amlodipine 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.
- The mechanism of action of Amlodipine also probably involves dilatation of the main coronary arteries and coronary arterioles, both in normal and ischemic regions. This dilatation increases myocardial oxygen delivery in patients with coronary artery spasm (Prinzmetal's or variant angina).
In patients with angina, once-daily administration of Amlodipine increase total exercise time, time to angina onset, and time to 1 mm ST segment depression and decreases bath angina attack frequency and nitroglycerin tablet consumption.
In vitro studies have shown that approximately 97.5% of circulating Amlodipine is bound to plasma proteins. Amlodipine has not been associated with any adverse metabolic effect or change in plasma lipids and is suitable for use in patients with asthma, diabetes, and gout.
Pharmacokinetic studies with cyclosporin have demonstrated that Amlodipine does not significantly alter the pharmacokinetics of cyclosporin.
Hemodynamic studies and exercise-based controlled clinical trial 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 (PRAISE) designed to evaluate patients in NYHA Class II-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 in patients with heart failure. In the same study, in a group of patients without clinical signs or symptoms suggestive of underlying ischemic disease, a clinically and statistically significant reductions in mortality and combined mortality and morbidity was observed with Amlodipine.
Pharmacokinetic Properties
Absorption
After oral administration of therapeutic doses, Amlodipine is well absorbed with peak blood levels between 612 hours post-dose. Absolute bio-availability has been estimated to be between 64% and 80%. The volume of distribution is approximately 21 l/kg. Absorption of Amlodipine is unaffected by consumption of food.
Bio-transformation/ Elimination
The terminal plasma elimination half life is about 35-50 hours and is consistent with once-daily dosing. Steady state plasma levels are reached after 7-8 days consecutive dosing. Amlodipine is extensively metabolized by the liver to inactive metabolites with 10 % of the parent compound and 60% of the metabolites excreted in the urine.
Indications
Amlodipine is indicated for treatment of hypertension and can be used as the sole agent to control blood pressure in the majority of patients. Patients not adequately control led on a single anti-hypertensive agent may benefit from the addition of Amlodipine which has been used in combination with a thiazide diuretic, beta adrenoceptor blocking agent or an angiotensin-converting enzyme inhibitors.
Amlodipine is indicated for the first-line treatment of myocardial ischemia, whether due to fixed obstruction (stable angina) and/or vasospasm/ vasoconstriction (Prinzmetal's or variant angina) of coronary vasculature. Amlodipine may be used where the clinical presentation suggests a possible vasospastic/vasoconstrictive component but where vasospasm/vasoconstriction has not been confirmed. Amlodipine may be used alone, as monotherapy, or in combination with other antianginal drugs in patients with angina that is refractory to nitrates and/or adequate doses of beta blockers.
Dosage and Administration
For both hypertension and angina the usual initial dose is 5 mg once daily which may be increased to a maximum dose of 10 mg depending on the individual patient's response and severity.
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 anti-hypertensive therapy.
Majority of hypertensive patients with 5 mg/day the dose may not necessarily be increased. For those who need higher dose, Amlodipine can be increased to 7.5 mg/day with maximum dose of 10 mg/ day.
The recommended dose for chronic stable or vasospastic angina is 5-10 mg, with the lower dose suggested in the elderly and in patients with hepatic insufficiency.
No dose adjustment of Amlodipine is required upon concomitant administration of thiazide diuretics, beta blockers, and angiotensin-converting enzyme inhibitors.
Use in children
No experience is available on use of Amlodipine in children.
Overdosage
In humans, experiences with intentional overdose is limited. Gastric lavage may be worthwhile in some cases, Available data suggest th at gross overdosage could result in excessive peripheral vasodilatation with subsequent market and probably prolonged systemic hypotension. Clinically significant hypotensi on due to Amlodipine 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. Intravenous calcium gluconate may be beneficial in reversing the effect of calcium channel blockade. Since Amlodipine is highly protein-bound, dialysis is not likely to be of benefit.
Warnings and Precautions
Use in patients with Impaired Hepatic Function
As with all calcium antagonists, Amlodipine 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.
Use in Renal Failure
Amlodipine is extensively metabolized to inactive metabolites with 10% excreted as unchanged drug in the urine. Changes in Amlodipine plasma concentrations are not correlated with degree of renal impairment. Amlodipine may be used in such patients at normal doses.Amlodipine is not dialyzable.
Use in patients with Congestive Heart failure
In general, calcium channel blockers should be used with caution in patients with heart failure.
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. Amlodipine, used at similar doses in elderly or younger patients, is equally well tolerated. Therefore, normal dosage regimens are recommended.
Pregnancy and Lactation
Safety of Amlodipine in human pregnancy or lactation have not been established. Amlodipine does not demonstrate toxicity in animal reproductive studies other than to delay parturition and prolong labor in rats at a dose level fifty times the maximum recommended dose in humans. Accordingly, use in pregnancy and lactation is only recommended when there is no safer alternative and when the disease itself carries greater risk for the mother and fetus.
Effect on ability to drive and use machines
Not applicable.
Adverse Reactions
Amlodipine is well tolerated. In placebo controlled clinical trials involving patients with hypertension or angina, the most commonly observed side effect were headache, edema, fatigue, somnolence, nausea, abdominal pain, flushing palpitations and dizziness. In these clinical trials no pattern of clinically significant laboratory test abnormalities related to Amlodipine has been observed.
Less commonly observed adverse effects in marketing experience include altered bowel habits, arthralgia, asthenia, dyspepsia, dyspnea, gingival hyperplasia, gynecomastia, impotence, increased urinary frequency, mood changes, muscle cramps, myalgia, pruritus, rash, visual disturbance, and rarely erythema multiforme.
Jaundice and hepatic enzyme elevations have been reported very infrequently (mostly consistent with cholestasis). Same cases severe enough to require hospitalization have been reported in association with use Amlodipine. In many instances, causal association is uncertain.
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, arrhythmia (including ventricular tachycardia and atrial fibrillation) and chest pain.
Contraindications
Amlodipine is contraindicated in patients with a known sensitivity to dihydropyridines.
Interactions
Interaction with Other Medicament's and Other Forms of Interaction
Amlodipine has been safely administered with thiazide diuretics, alpha blockers, beta blockers, angiotensin-converting enzyme inhibitors, long-acting nitrates, sub-lingual nitroglycerin, non steroidal anti inflammatory drugs, antibiotics and oral hypoglycemic drugs.
Studies have indicated that the co-administration of Amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers, and that co-administration of cimetidine did not alter the pharmacokinetics of Amlodipine.
In vitro data from studies with human plasma indicate that Amlodipine has no effect on protein binding of the drugs tested (digoxin, phenytoin, warfarin or indomethacin).
In healthy male volunteers, the co-administration of Amlodipine does not significantly alter the effect of warfarin on prothrombin response time.
Presentations
Box of 3 strips @ l0 tablets
Box of 10 strips @ 10 tablets
Storage
Store below 30°C.
Manufactured by
PT. Merck Tbk., Jakarta
Reg. No.: DKL 0715808010Al
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