For treatment of overdosage, standard measures including monitoring of cardiac and respiratory functions should be implemented. The patient should be positioned to avoid cerebral anoxia. Frequent blood pressure determinations are essential. Vasopressors are clinically indicated for patients exhibiting profound hypotension.
Intravenous calcium gluconate may help reverse the effects of calcium entry blockade. Nicardipine hydrochloride is a calcium ion influx inhibitor slow channel blocker or calcium channel blocker.
Nicardipine hydrochloride for intravenous administration contains 2. It is soluble in methanol, sparingly soluble in ethanol, slightly soluble in acetone, chloroform and water. It has a molecular weight of Nicardipine hydrochloride injection is available as a sterile, non-pyrogenic, clear, yellow solution in 10 mL vials for intravenous infusion after dilution. Each mL contains 2. Sodium hydroxide, NF, may have been added to adjust pH to 3.
Nicardipine Hydrochloride in 0. Each mL contains 0. Hydrochloric acid may have been added to adjust pH. Nicardipine inhibits the transmembrane influx of calcium ions into cardiac muscle and smooth muscle without changing serum calcium concentrations. 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.
The effects of nicardipine are more selective to vascular smooth muscle than cardiac muscle. In animal models, nicardipine produced relaxation of coronary vascular smooth muscle at drug levels which cause little or no negative inotropic effect. Nicardipine produces significant decreases in systemic vascular resistance. In a study of intra-arterially administered nicardipine, the degree of vasodilation and the resultant decrease in blood pressure were more prominent in hypertensive patients than in normotensive volunteers.
Administration of nicardipine to normotensive volunteers at dosages of 0. An increase in heart rate is a normal response to vasodilation and decrease in blood pressure; in some patients these increases in heart rate may be pronounced.
Hemodynamic studies following intravenous dosing in patients with coronary artery disease and normal or moderately abnormal left ventricular function have shown significant increases in ejection fraction and cardiac output with no significant change, or a small decrease, in left ventricular end-diastolic pressure LVEDP. There is evidence that nicardipine increases blood flow.
Coronary dilatation induced by nicardipine improves perfusion and aerobic metabolism in areas with chronic ischemia, resulting in reduced lactate production and augmented oxygen consumption. In patients with coronary artery disease, nicardipine, administered after beta-blockade, significantly improved systolic and diastolic left ventricular function. In congestive heart failure patients with impaired left ventricular function, nicardipine increased cardiac output both at rest and during exercise.
Decreases in left ventricular end-diastolic pressure were also observed. However, in some patients with severe left ventricular dysfunction, it may have a negative inotropic effect and could lead to worsened failure.
Nicardipine has been shown to improve systolic shortening in both normal and hypokinetic segments of myocardial muscle. Radionuclide angiography has confirmed that wall motion remained improved during increased oxygen demand.
Occasional patients have developed increased angina upon receiving nicardipine capsules. Whether this represents coronary steal in these patients, or is the result of increased heart rate and decreased diastolic pressure, is not clear.
In patients with coronary artery disease, nicardipine improves left ventricular diastolic distensibility during the early filling phase, probably due to a faster rate of myocardial relaxation in previously underperfused areas.
There is little or no effect on normal myocardium, suggesting the improvement is mainly by indirect mechanisms such as afterload reduction and reduced ischemia. Nicardipine has no negative effect on myocardial relaxation at therapeutic doses. The clinical benefits of these properties have not yet been demonstrated. In general, no detrimental effects on the cardiac conduction system have been seen with nicardipine. During acute electrophysiologic studies, it increased heart rate and prolonged the corrected QT interval to a minor degree.
It did not affect sinus node recovery or SA conduction times. The relative and effective refractory periods of the His-Purkinje system were slightly shortened. Because nicardipine is extensively metabolized by the liver, plasma concentrations are influenced by changes in hepatic function. In a clinical study with nicardipine capsules in patients with severe liver disease, plasma concentrations were elevated and the half-life was prolonged [see Warnings and Precautions 5.
Similar results were obtained in patients with hepatic disease when nicardipine hydrochloride was administered for 24 hours at 0. When nicardipine was given to mild-to-moderate hypertensive patients with moderate degrees of renal impairment, significant reduction in glomerular filtration rate GFR and effective renal plasma flow RPF were observed.
No significant differences in liver blood flow were observed in these patients. A significantly lower systemic clearance and higher area under the curve AUC were observed. When nicardipine capsules 20 or 30 mg TID were given to hypertensive patients with impaired renal function, mean plasma concentrations, AUC, and C max were approximately two-fold higher than in healthy controls. There was a transient increase in electrolyte excretion, including sodium [see Warnings and Precautions 5.
Acute bolus administration of nicardipine hydrochloride injection 2. In healthy patients undergoing abdominal surgery, nicardipine hydrochloride injection 10 mg over 20 minutes increased GFR with no change in RPF when compared with placebo.
In two well-controlled studies of patients with obstructive airway disease treated with nicardipine capsules, no evidence of increased bronchospasm was seen. In one of the studies, nicardipine capsules improved forced expiratory volume 1 second FEV 1 and forced vital capacity FVC in comparison with metoprolol. Adverse reactions reported in a limited number of patients with asthma, reactive airway disease, or obstructive airway disease were similar to reactions in other patients treated with nicardipine capsules.
A rapid dose-related increase in nicardipine plasma concentrations is seen during the first two hours after the start of an infusion of nicardipine. Plasma concentrations increase at a much slower rate after the first few hours, and approach steady state at 24 to 48 hours.
The effects of nicardipine on blood pressure significantly correlate with plasma concentrations. Total plasma clearance Cl is 0. The pharmacokinetics of nicardipine is linear over the dosage range of 0. Inhibition of these enzymes may result in increased plasma levels of certain drugs, including cyclosporine and tacrolimus [ see Drug Interactions 7. The altered pharmacokinetics may necessitate dosage adjustment of the affected drug or discontinuation of treatment.
None of the dose was recovered as unchanged nicardipine. One-month and three-month studies in the rat have suggested that these results are linked to a nicardipine-induced reduction in plasma thyroxine T4 levels with a consequent increase in plasma levels of thyroid stimulating hormone TSH. Chronic elevation of TSH is known to cause hyperstimulation of the thyroid.
In rats on an iodine deficient diet, nicardipine administration for one month was associated with thyroid hyperplasia that was prevented by T4 supplementation.
There was no evidence of a mutagenic potential of nicardipine in a battery of genotoxicity tests conducted on microbial indicator organisms, in micronucleus tests in mice and hamsters, or in a sister chromatid exchange study in hamsters. These doses in the rat and rabbit are equivalent to human intravenous doses of about 1. The total daily human dose delivered by a continuous intravenous infusion ranges from 1. However, dystocia, reduced birth weight, reduced neonatal survival and reduced neonatal weight gain were noted.
In patients with mild-to-moderate chronic stable essential hypertension, nicardipine hydrochloride injection 0. In other settings e. Higher infusion rates produced therapeutic responses more rapidly. The average maintenance dose was 8. Freezing does not adversely affect the product, but exposure to elevated temperatures should be avoided. In animal models, nicardipine hydrochloride produces relaxation of coronary vascular smooth muscle at drug levels that cause little or no negative inotropic effect.
Nicardipine hydrochloride is completely absorbed following oral doses administered as capsules. These decreases in plasma levels observed following a meal may be significant, but the clinical trials establishing the efficacy and safety of nicardipine hydrochloride capsules were done in patients without regard to the timing of meals. Thus, the results of these trials reflect the effects of meal-induced variability. The pharmacokinetics of nicardipine hydrochloride capsules are nonlinear due to saturable hepatic first pass metabolism.
Following oral administration, increasing doses result in a disproportionate increase in plasma levels. Hence, increasing the dose from 20 to 30 mg every 8 hours more than doubled C max and increasing the dose from 20 to 40 mg every 8 hours increased C max more than threefold. A similar disproportionate increase in AUC with dose was observed.
Considerable inter-subject variability in plasma levels was also observed. Post-absorption kinetics of nicardipine hydrochloride capsules are also non-linear, although there is a reproducible terminal plasma half-life that averaged 8.
Elimination over the first 8 hours after dosing is much faster with a half-life of 2 to 4 hours. Steady-state plasma levels are achieved after 2 to 3 days of tid dosing every 8 hours and are two-fold higher than after a single dose. Inhibition of these enzymes may result in increased plasma levels of certain drugs, including cyclosporine and tacrolimus see Drug Interactions.
The altered pharmacokinetics may necessitate dosage adjustment of the affected drug or discontinuation of treatment. Nicardipine hydrochloride plasma levels were higher in patients with mild renal impairment baseline serum creatinine concentration ranged from 1.
After mg nicardipine hydrochloride tid at steady-state, C max and AUC were approximately two-fold higher in these patients. Because nicardipine hydrochloride is extensively metabolized by the liver, the plasma levels of the drug are influenced by changes in hepatic function. Nicardipine hydrochloride plasma levels were higher in patients with severe liver disease hepatic cirrhosis confirmed by liver biopsy or presence of endoscopically-confirmed esophageal varices than in normal subjects.
After mg nicardipine hydrochloride capsules bid at steady-state, C max and AUC were 1. After 1 week of nicardipine hydrochloride capsules dosing at 20 mg three times a day, the C max , T max , AUC, terminal plasma half-life and the extent of protein binding of nicardipine hydrochloride observed in healthy elderly hypertensive patients did not differ significantly from those observed in young normal volunteers.
In man, nicardipine hydrochloride produces a significant decrease in systemic vascular resistance. The degree of vasodilation and the resultant hypotensive effects are more prominent in hypertensive patients. In hypertensive patients, nicardipine reduces the blood pressure at rest and during isometric and dynamic exercise. In normotensive patients, a small decrease of about 9 mm Hg in systolic and 7 mm Hg in diastolic blood pressure may accompany this fall in peripheral resistance.
The pharmacokinetics of nicardipine hydrochloride injection are linear over the dosage range of 0. Rapid dose-related increases in nicardipine plasma concentrations are seen during the first two hours after the start of an infusion of nicardipine hydrochloride injection. Plasma concentrations increase at a much slower rate after the first few hours, and approach steady state at 24 to 48 hours.
The effects of nicardipine on blood pressure significantly correlate with plasma concentrations. Nicardipine hydrochloride injection has been shown to be rapidly and extensively metabolized by the liver.
None of the dose was recovered as unchanged nicardipine. Nicardipine does not induce or inhibit its own metabolism and does not induce or inhibit hepatic microsomal enzymes.
Nicardipine hydrochloride injection produces significant decreases in systemic vascular resistance. In a study of intra-arterially administered nicardipine hydrochloride injection, the degree of vasodilation and the resultant decrease in blood pressure were more prominent in hypertensive patients than in normotensive volunteers.
Administration of nicardipine hydrochloride injection to normotensive volunteers at dosages of 0. An increase in heart rate is a normal response to vasodilation and decrease in blood pressure; in some patients these increases in heart rate may be pronounced. Hemodynamic studies following intravenous dosing in patients with coronary artery disease and normal or moderately abnormal left ventricular function have shown significant increases in ejection fraction and cardiac output with no significant change, or a small decrease, in left ventricular end-diastolic pressure LVEDP.
There is evidence that nicardipine increases blood flow. Coronary dilatation induced by nicardipine hydrochloride injection improves perfusion and aerobic metabolism in areas with chronic ischemia, resulting in reduced lactate production and augmented oxygen consumption. In patients with coronary artery disease, nicardipine hydrochloride injection, administered after beta-blockade, significantly improved systolic and diastolic left ventricular function.
In congestive heart failure patients with impaired left ventricular function, nicardipine hydrochloride injection increased cardiac output both at rest and during exercise.
Decreases in left ventricular end-diastolic pressure were also observed. However, in some patients with severe left ventricular dysfunction, it may have a negative inotropic effect and could lead to worsened failure. Nicardipine hydrochloride injection has been shown to improve systolic shortening in both normal and hypokinetic segments of myocardial muscle.
Radionuclide angiography has confirmed that wall motion remained improved during increased oxygen demand. Occasional patients have developed increased angina upon receiving nicardipine capsules. Whether this represents coronary steal in these patients, or is the result of increased heart rate and decreased diastolic pressure, is not clear.
In patients with coronary artery disease, nicardipine hydrochloride injection improves left ventricular diastolic distensibility during the early filling phase, probably due to a faster rate of myocardial relaxation in previously under perfused areas. There is little or no effect on normal myocardium, suggesting the improvement is mainly by indirect mechanisms such as afterload reduction and reduced ischemia.
Nicardipine hydrochloride injection has no negative effect on myocardial relaxation at therapeutic doses. In general, no detrimental effects on the cardiac conduction system have been seen with nicardipine hydrochloride injection. During acute electrophysiologic studies, it increased heart rate and prolonged the corrected QT interval to a minor degree. It did not affect sinus node recovery or SA conduction times.
The relative and effective refractory periods of the His-Purkinje system were slightly shortened. When nicardipine hydrochloride injection was given to mild to moderate hypertensive patients with moderate degrees of renal impairment, significant reduction in glomerular filtration rate GFR and effective renal plasma flow RPF was observed.
No significant differences in liver blood flow were observed in these patients. A significantly lower systemic clearance and higher area under the curve AUC were observed. When nicardipine capsules 20 mg or 30 mg TID were given to hypertensive patients with impaired renal function, mean plasma concentrations, AUC, and C max were approximately two-fold higher than in healthy controls. Acute bolus administration of nicardipine hydrochloride injection 2.
In healthy patients undergoing abdominal surgery, nicardipine hydrochloride injection 10 mg over 20 minutes increased GFR with no change in RPF when compared with placebo. In two well-controlled studies of patients with obstructive airway disease treated with nicardipine capsules, no evidence of increased bronchospasm was seen.
In one of the studies, nicardipine capsules improved forced expiratory volume 1 second FEV 1 and forced vital capacity FVC in comparison with metoprolol. Adverse experiences reported in a limited number of patients with asthma, reactive airway disease, or obstructive airway disease are similar to all patients treated with nicardipine capsules. In patients with mild -to -moderate chronic stable essential hypertension, nicardipine hydrochloride injection 0.
In other settings e. Higher infusion rates produced therapeutic responses more rapidly. Nicardipine hydrochloride injection is indicated for the short-term treatment of hypertension when oral therapy is not feasible or not desirable. Nicardipine hydrochloride injection is contraindicated in patients with known hypersensitivity to the drug.
Nicardipine hydrochloride injection is also contraindicated in patients with advanced aortic stenosis because part of the effect of nicardipine hydrochloride injection is secondary to reduced afterload.
Reduction of diastolic pressure in these patients may worsen rather than improve myocardial oxygen balance. Several overdosages with orally administered nicardipine have been reported.
One adult patient allegedly ingested mg of nicardipine [standard immediate release capsules], and another patient, mg of the sustained release formulation of nicardipine. Symptoms included marked hypotension, bradycardia, palpitations, flushing, drowsiness, confusion and slurred speech. All symptoms resolved without sequelae.
An overdosage occurred in a one year old child who ingested half of the powder in a 30 mg nicardipine standard capsule.
0コメント