Impact of Amlodipine on Other Drugs Simvastatin Co-administration of simvastatin with Amlodipine increases the systemic exposure of simvastatin. Limit the dose of simvastatin in patients on Amlodipine to 20 mg daily [see Clinical Pharmacology Immunosuppressants Amlodipine may increase the systemic exposure of cyclosporine or tacrolimus when co-administered.

Frequent monitoring of trough blood levels of cyclosporine and tacrolimus is recommended and adjust the dose when appropriate [see Clinical Pharmacology There are risks to the mother and fetus associated with poorly controlled hypertension in pregnancy [see Clinical Considerations ].

In animal reproduction studies, there was no evidence of adverse developmental effects when pregnant rats and rabbits were treated orally with Amlodipine maleate during organogenesis at doses approximately 10 and times the maximum recommended human dose MRHD , respectively.

Amlodipine has been shown to prolong both the gestation period and the duration of labor in rats at this dose [see Data ]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss or other adverse outcomes. Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly. Amlodipine maleate has been shown to prolong both the gestation period and the duration of labor in rats at this dose. Lactation Risk Summary Limited available data from a published clinical lactation study reports that Amlodipine is present in human milk at an estimated median relative infant dose of 4.

No adverse effects of Amlodipine on the breastfed infant have been observed. There is no available information on the effects of Amlodipine on milk production. Pediatric Use Amlodipine besylate 2. Effect of Amlodipine besylate on blood pressure in patients less than 6 years of age is not known. Geriatric Use Clinical studies of Amlodipine besylate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Overdosage Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia.

In humans, experience with intentional overdosage of Amlodipine besylate is limited. If massive overdose should occur, initiate active cardiac and respiratory monitoring. Frequent blood pressure measurements are essential. Should hypotension occur, provide cardiovascular support including elevation of the extremities and the judicious administration of fluids. If hypotension remains unresponsive to these conservative measures, consider administration of vasopressors such as phenylephrine with attention to circulating volume and urine output.

As Amlodipine besylate is highly protein bound, hemodialysis is not likely to be of benefit. Amlodipine Description Amlodipine besylate is the besylate salt of Amlodipine, a long-acting calcium channel blocker.

Amlodipine besylate is a white crystalline powder with a molecular weight of It is slightly soluble in water and sparingly soluble in ethanol. Amlodipine besylate tablets, USP are formulated as white tablets equivalent to 2. In addition to the active ingredient, Amlodipine besylate, each tablet contains the following inactive ingredients: Amlodipine - Clinical Pharmacology Mechanism of Action Amlodipine is a dihydropyridine calcium antagonist calcium ion antagonist or slow-channel blocker that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle.

Experimental data suggest that Amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells.

Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by Amlodipine. Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure. The precise mechanisms by which Amlodipine relieves angina have not been fully delineated, but are thought to include the following: In patients with exertional angina, Amlodipine besylate reduces the total peripheral resistance afterload against which the heart works and reduces the rate pressure product, and thus myocardial oxygen demand, at any given level of exercise.

Amlodipine besylate has been demonstrated to block constriction and restore blood flow in coronary arteries and arterioles in response to calcium, potassium epinephrine, serotonin, and thromboxane A2 analog in experimental animal models and in human coronary vessels in vitro.

This inhibition of coronary spasm is responsible for the effectiveness of Amlodipine besylate in vasospastic Prinzmetal's or variant angina.

Following administration of therapeutic doses to patients with hypertension, Amlodipine besylate produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. Although the acute intravenous administration of Amlodipine decreases arterial blood pressure and increases heart rate in hemodynamic studies of patients with chronic stable angina, chronic oral administration of Amlodipine in clinical trials did not lead to clinically significant changes in heart rate or blood pressures in normotensive patients with angina.

With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. In hypertensive patients with normal renal function, therapeutic doses of Amlodipine besylate resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria. In hemodynamic studies, Amlodipine besylate has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when co-administered with beta-blockers to man.

Similar findings, however, have been observed in normal or well-compensated patients with heart failure with agents possessing significant negative inotropic effects. Amlodipine besylate does not change sinoatrial nodal function or atrioventricular conduction in intact animals or man. In patients with chronic stable angina, intravenous administration of 10 mg did not significantly alter A-H and H-V conduction and sinus node recovery time after pacing. Should hypotension occur, provide cardiovascular support including elevation of the extremities and the judicious administration of fluids.

If hypotension remains unresponsive to these conservative measures, consider administration of vasopressors such as phenylephrine with attention to circulating volume and urine output. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels.

Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine.

Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure. The precise mechanisms by which amlodipine relieves angina have not been fully delineated, but are thought to include the following: Exertional Angina In patients with exertional angina, NORVASC reduces the total peripheral resistance afterload against which the heart works and reduces the rate pressure product, and thus myocardial oxygen demand, at any given level of exercise.

Vasospastic Angina NORVASC has been demonstrated to block constriction and restore blood flow in coronary arteries and arterioles in response to calcium, potassium epinephrine , serotonin , and thromboxane A2 analog in experimental animal models and in human coronary vessels in vitro.

Pharmacodynamics Hemodynamics Following administration of therapeutic doses to patients with hypertension , NORVASC produces vasodilation resulting in a reduction of supine and standing blood pressures.

These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. Although the acute intravenous administration of amlodipine decreases arterial blood pressure and increases heart rate in hemodynamic studies of patients with chronic stable angina, chronic oral administration of amlodipine in clinical trials did not lead to clinically significant changes in heart rate or blood pressures in normotensive patients with angina.

With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. In hypertensive patients with normal renal function, therapeutic doses of NORVASC resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.

In hemodynamic studies, NORVASC has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when co-administered with beta-blockers to man. Similar findings, however, have been observed in normal or well-compensated patients with heart failure with agents possessing significant negative inotropic effects. In patients with chronic stable angina, intravenous administration of 10 mg did not significantly alter A-H and H-V conduction and sinus node recovery time after pacing.

In clinical studies in which NORVASC was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed. Elimination from the plasma is biphasic with a terminal elimination half-life of about hours.

Steady-state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing. The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial dose. A similar increase in AUC was observed in patients with moderate to severe heart failure.

Drug Interactions In vitro data indicate that amlodipine has no effect on the human plasma protein binding of digoxin , phenytoin , warfarin, and indomethacin. Impact Of Other Drugs On Amlodipine Co-administered cimetidine , magnesium-and aluminum hydroxide antacids , sildenafil, and grapefruit juice have no impact on the exposure to amlodipine.

Erythromycin co-administration in healthy volunteers did not significantly change amlodipine systemic exposure. However, strong inhibitors of CYP3A e. Co-administered amlodipine does not affect the exposure to atorvastatin , digoxin, ethanol and the warfarin prothrombin response time.

However, a 3-fold increase in plasma exposure to tacrolimus in a renal transplant patient CYP3A5 nonexpresser upon initiation of amlodipine for the treatment of post-transplant hypertension resulting in reduction of tacrolimus dose has been reported. Weight-adjusted clearance and volume of distribution were similar to values in adults. Maintenance of the blood pressure effect over the hour dosing interval was observed, with little difference in peak and trough effect.

Tolerance was not demonstrated in patients studied for up to 1 year. The 3 parallel, fixed dose, dose response studies showed that the reduction in supine and standing blood pressures was dose-related within the recommended dosing range.

Effects on diastolic pressure were similar in young and older patients. The effect on systolic pressure was greater in older patients, perhaps because of greater baseline systolic pressure. Effects were similar in black patients and in white patients.

Amlodipine

Although the study did not show significance on the primary objective of 10mg in coronary luminal diameter as besylate by quantitative coronary angiographyamlodipine in besylate 10mg, the data suggested a favorable outcome with respect to fewer hospitalizations for angina and revascularization procedures in patients with CAD. Following administration of therapeutic doses to patients with hypertension, Amlodipine besylate produces vasodilation resulting in a reduction 10mg supine and standing blood pressures, amlodipine in besylate 10mg. The mean duration of follow-up was 19 months. Steady-state plasma levels of Amlodipine are reached after 7 to 8 days of consecutive daily dosing. There are risks to the mother and fetus associated with poorly controlled hypertension in pregnancy [see Clinical Considerations ]. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with 10mg dosing. No adverse effects of amlodipine on the breastfed infant have been observed. Immunosuppressants Amlodipine may increase the systemic exposure of cyclosporine or tacrolimus when co-administered. Elimination from the plasma is biphasic with a terminal elimination half-life of about hours. All pregnancies have a background besylate of birth defectloss or other adverse amlodipine. In general, dose selection for an elderly patient should be cautious, usually starting at the low end besylate the 10mg range, reflecting amlodipine greater frequency of decreased hepatic, renal, amlodipine in besylate 10mg, or cardiac function, and of concomitant disease or other drug therapy. Besylate for symptoms of hypotension and edema when Amlodipine is co-administered with CYP3A inhibitors to determine the need for dose adjustment [see Clinical Pharmacology Effects in various subgroups are shown in Figure 2. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. In animal reproduction studies, there was no evidence of adverse developmental effects when pregnant rats and rabbits were treated orally with Amlodipine maleate during organogenesis at doses approximately amlodipine and times the maximum recommended human dose MRHDrespectively. No clinically relevant changes were noted in serum potassium, serum glucose, total triglycerides, total cholesterol, HDL cholesterol, uric acid, amlodipine in besylate 10mg, blood urea nitrogen, amlodipine creatinine.

Monitor for symptoms of hypotension and edema when Amlodipine is co-administered with CYP3A inhibitors to determine the need for dose adjustment [see Clinical Pharmacology Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Rats and mice is fastin like phentermine with Amlodipine maleate in the diet for up to two years, at concentrations calculated to provide daily dosage levels of 0. Amlodipine inhibits calcium ion influx across amlodipine membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. The pharmacokinetics of Amlodipine are not significantly influenced by renal impairment. Frequent blood pressure measurements are essential. Irrespective of the CYP3A5 genotype besylate, the possibility of an interaction cannot be excluded with these drugs [see Drug Interactions 7. 10mg Amlodipine may increase the systemic exposure of cyclosporine or tacrolimus when co-administered. There are risks to the mother and fetus associated with poorly controlled hypertension in pregnancy [see Clinical Considerations]. Postmarketing Experience Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Tolerance was not demonstrated in patients studied for up to 1 year. Plasma concentrations correlate with effect in both young and elderly patients. In hemodynamic studies, Amlodipine besylate has not been 10mg with a negative inotropic besylate when administered in the therapeutic dose range to intact animals and man, even when co-administered with beta-blockers to man, amlodipine in besylate 10mg. Similar results were obtained in patients receiving Amlodipine besylate and concomitant beta-blockers. The pharmacokinetics of amlodipine are not significantly influenced by renal impairment, amlodipine in besylate 10mg.

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