amlodipine besylate

Amlodipine besylate is a dihydropyridine derivative, and has the following chemical name: 3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-l,4-dihydro-6-methyl-3,5pyridinedicarboxylate benzene sulphonate.
Amlodipine besylate is slightly soluble in water and sparingly soluble in ethanol and has a molecular weight of 567.1 (free base 408.9).

Amlodipine besylate is available as white, 5 mg and 10 mg emerald-shaped tablets containing 6.944 mg amlodipine besylate equivalent to 5 mg amlodipine and 13.888 mg amlodipine besylate equivalent to 10 mg amlodipine, respectively. Inert ingredients : sodium starch glycolate, mycrocrystalline cellulose, magnesium stearate, and dibasic calcium phosphate anhydrous.

Pharmacodynamic Properties
Amlodipine is a calcium ion influx inhibitor (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 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 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 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 hypertension, once daily dosing provides clinically 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 1 mm ST segment depression, and decreases bath angina attack frequency and nitroglycerine tablet consumption.

In vitro studies have shown that approximately 97.5% of circulating amlodipines is bound to plasma proteins.

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.

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 exercised 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 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 reduction in mortality and combined mortality and morbidity was observed with amlodipine.

Pharmacokinetic properties
After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels between 6-12 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 of consecutive 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.

Interaction with Other Medicaments and Other Forms of Interaction
Amlodipine has been safely administered with thiazide diuretics, alpha blockers, beta blockers, angiotensin - converting enzyme inhibitors, long-acting nitrates, sublingual nitroglycerine, 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 indomethaein).

In healthy male volunteers, the co-administration of amlodipine does not significantly alter the effect of warfarin on prothrombin response time.

Pregnancy and Lactation
Safety of amlodipine in human pregnancy or lactation has 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 is only recommended when there is no safer alternative and when the disease itself carries greater risk for the mother and fetus.

Effects on Ability to Drive and Use Machines
Not applicable.

Therapeutic indications
Amlodiplne 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 controlled on a single antihypertensive 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 inhibitor.
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 mono therapy, or in combination with other antianginal drugs in patients with angina that is refractory to nitrates and/or adequate doses of beta blockers.

Amlodipine is contraindicated in patients with a known sensitivity to dihydropyridines.

Special Warnings and Special Precaution for Use
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. NORVASK (5-10 mg per day) has been studied in a placebo - controlled trial of 1153 patients with NYHA Class III or IV heart failure on stable doses of ACE Inhibitor, digoxin and diuretics. Follow-up was at least 6 months, with a mean of about 14 months. There was no overall adverse effect on survival or cardiac morbidity (as defined by Life-threatening arrhythmia, acute myocardial infarction, or hospitalization for worsened heart failure). NORVASK has been compared to placebo in four 8-12 week studies of patients with NY HA Class II/III heart failure, involving a total of 697 patients. In these studies, there was no evidence of worsened heart failure based on measures of exercise tolerance, NYHA classification, symptoms, or LVEF.

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

Undesirable Effects
Amlodipine is well tolerated. In placebo controlled clinical trials involving patients with hypertension or angina, the most commonly observed side effects 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 side 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 arythema multiforme.

Jaundice and hepatic enzyme elevations have been reported very infrequently (mostly consistent with cholestasis). Some cases severe enough to require hospitalization have been reported in association with use of 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.

Posology and Method of Administration
For both hypertension and angina the usual initial dose is 5 mg amlodipine 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 dase 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.

In humans, experience with intentional overdose is limited. Gastric lavage may be worthwhile is some cases. Available data suggest that gross over dosage could result in excessive peripheral vasodilatation with subsequent marked and probably prolonged systemic hypotension. Clinically significant hypotension 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 effects of calcium channel blockage. Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit.

NORVASK® is available as 5 mg tablets, packed in boxes of 3 blisters @ 10 scored tablets. 

Reg No. DKL9219803410A1
NORVASK® is available as 10 mg tablets, packed in boxes of 3 blisters @ 10 scored tablets.
Reg. No. DKL9619803410B1.
NORVASK® for ASKES is available as 5 mg tablets, packed in boxes of 3 blisters @ 10 scored tablets. 

Reg. No. DKL9219803410Al


Prepared by PT. Pfizer Indonesia, PO. Box 2706 Jakarta 
Under the authority of PFIZER INC., New York, NY, U.S.A. 

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