Nicardipine Hydrochloride by is a Prescription medication manufactured, distributed, or labeled by Emcure Pharmaceuticals Ltd.. Drug facts, warnings, and ingredients follow.
C26 H29 N3 O6 HCl
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.
Following infusion, nicardipine plasma concentrations decline tri-exponentially, with a rapid early distribution phase ((alpha)-half-life of 2.7 minutes), an intermediate phase ((beta)-half-life of 44.8 minutes), and a slow terminal phase ((gamma)-half-life of 14.4 hours) that can only be detected after long-term infusions. Total plasma clearance (Cl) is 0.4 L/hr·kg, and the apparent volume of distribution (Vd ) using a non-compartment model is 8.3 L/kg. The pharmacokinetics of nicardipine hydrochloride injection are linear over the dosage range of 0.5 to 40 mg/hr.
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. On termination of the infusion, nicardipine concentrations decrease rapidly, with at least a 50% decrease during the first two hours post-infusion. The effects of nicardipine on blood pressure significantly correlate with plasma concentrations.
Nicardipine is highly protein bound (>95%) in human plasma over a wide concentration range.
Nicardipine hydrochloride injection has been shown to be rapidly and extensively metabolized by the liver. After coadministration of a radioactive intravenous dose of nicardipine hydrochloride injection with an oral 30 mg dose given every 8 hours, 49% of the radioactivity was recovered in the urine and 43% in the feces within 96 hours. 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.
The steady-state pharmacokinetics of nicardipine are similar in elderly hypertensive patients (>65 years) and young healthy adults.
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 0.25 to 3 mg/hr for eight hours produced changes of <5 mmHg in systolic blood pressure and <3 mmHg in diastolic blood pressure.
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. In placebo-controlled trials, the mean increases in heart rate were 7±1 bpm in postoperative patients and 8±1 bpm in patients with severe hypertension at the end of the maintenance period.
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.
"Coronary steal" has not been observed during treatment with nicardipine hydrochloride injection (Coronary steal is the detrimental redistribution of coronary blood flow in patients with coronary artery disease from underperfused areas toward better perfused areas.) 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.
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 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 PA, AH, and HV intervals* or the functional and effective refractory periods of the atrium were not prolonged. The relative and effective refractory periods of the His-Purkinje system were slightly shortened.
*PA=conduction time from high to low right atrium; AH=conduction time from low right atrium to His bundle deflection, or AV nodal conduction time; HV=conduction time through the His bundle and the bundle branch-Purkinje system.
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 Cmax were approximately two-fold higher than in healthy controls. There is a transient increase in electrolyte excretion, including sodium (see “PRECAUTIONS”).
Acute bolus administration of nicardipine hydrochloride injection (2.5 mg) in healthy volunteers decreased mean arterial pressure and renal vascular resistance; glomerular filtration rate (GFR), renal plasma flow (RPF), and the filtration fraction were unchanged. 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 hypertensive Type II diabetic patients with nephropathy, nicardipine capsules (20 mg TID) did not change RPF and GFR, but reduced renal vascular resistance.
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 (0.5. to 4 mg/hr) produced dose-dependent decreases in blood pressure, although only the decreases at 4 mg/hr were statistically different from placebo. At the end of a 48-hour infusion at 4 mg/hr, the decreases were 26 mmHg (17%) in systolic blood pressure and 20.7 mmHg (20%) in diastolic blood pressure.
In other settings (e.g., patients with severe or postoperative hypertension), nicardipine hydrochloride injection (5 to 15 mg/hr) produced dose-dependent decreases in blood pressure. Higher infusion rates produced therapeutic responses more rapidly. The mean time to therapeutic response for severe hypertension, defined as diastolic blood pressure ≤ 95 mmHg or ≥ 25 mmHg decrease and systolic blood pressure ≤ 160 mmHg, was 77 ±5.2 minutes. The average maintenance dose was 8 mg/hr. The mean time to therapeutic response for postoperative hypertension, defined as ≥ 15% reduction in diastolic or systolic blood pressure, was 11.5 ±0.8 minutes. The average maintenance dose was 3 mg/hr.
Nicardipine hydrochloride injection is indicated for the short-term treatment of hypertension when oral therapy is not feasible or not desirable.
For prolonged control of blood pressure, patients should be transferred to oral medication as soon as their clinical condition permits (see “ DOSAGE AND ADMINISTRATION”).
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.
Adverse Experience
| Nicardipine HCl (n=144)
| Placebo (n=100)
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Body as a Whole
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Headache | 14.6 | 2.0 |
Asthenia | 0.7 | 0.0 |
Abdominal pain | 0.7 | 0.0 |
Chest pain | 0.7 | 0.0 |
Cardiovascular
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Hypotension | 5.6 | 1.0 |
Tachycardia | 3.5 | 0.0 |
ECG abnormality | 1.4 | 0.0 |
Postural hypotension | 1.4 | 0.0 |
Ventricular extrasystoles | 1.4 | 0.0 |
Extrasystoles | 0.7 | 0.0 |
Hemopericardium | 0.7 | 0.0 |
Hypertension | 0.7 | 0.0 |
Supraventricular tachycardia | 0.7 | 0.0 |
Syncope | 0.7 | 0.0 |
Vasodilation | 0.7 | 0.0 |
Ventricular tachycardia | 0.7 | 0.0 |
Digestive
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Nausea/vomiting | 4.9 | 1.0 |
Injection Site
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Injection site reaction | 1.4 | 0.0 |
Injection site pain | 0.7 | 0.0 |
Metabolic and Nutritional
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Hypokalemia | 0.7 | 0.0 |
Nervous
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Dizziness | 1.4 | 0.0 |
Hypesthesia | 0.7 | 0.0 |
Intracranial hemorrhage | 0.7 | 0.0 |
Paresthesia | 0.7 | 0.0 |
Respiratory
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Dyspnea | 0.7 | 0.0 |
Skin and Appendages
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Sweating | 1.4 | 0.0 |
Urogenital
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Polyuria | 1.4 | 0.0 |
Hematuria | 0.7 | 0.0 |
Several overdosages with orally administered nicardipine have been reported. One adult patient allegedly ingested 600 mg of nicardipine [standard (immediate release) capsules], and another patient, 2160 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. The child remained asymptomatic.
Based on results obtained in laboratory animals, lethal overdose may cause systemic hypotension, bradycardia (following initial tachycardia) and progressive atrioventricular conduction block. Reversible hepatic function abnormalities and sporadic focal hepatic necrosis were noted in some animal species receiving very large doses of nicardipine.
For treatment of overdosage, standard measures including monitoring of cardiac and respiratory functions should be implemented. The patient should be positioned so as 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 injection is intended for intravenous use. DOSAGE MUST BE INDIVIDUALIZED depending upon the severity of hypertension and the response of the patient during dosing. Blood pressure should be monitored both during and after the infusion; too rapid or excessive reduction in either systolic or diastolic blood pressure during parenteral treatment should be avoided.
Preparation
WARNING: VIALS MUST BE DILUTED BEFORE IV INFUSION
Dilution: Nicardipine hydrochloride injection is administered by slow continuous infusion at a CONCENTRATION OF 0.1 mg/mL. Each vial (25 mg) should be diluted with 240 mL of compatible intravenous fluid (see below), resulting in 250 mL of solution at a concentration of 0.1 mg/mL.
Nicardipine hydrochloride injection has been found to be compatible and stable in glass or polyvinyl chloride containers for 24 hours at controlled room temperature with:
Dextrose (5%) Injection, USP
Dextrose (5%) and Sodium Chloride (0.45%) Injection, USP
Dextrose (5%) and Sodium Chloride (0.9%) Injection, USP
Dextrose (5%) with 40 mEq Potassium, USP
Sodium Chloride (0.45%) Injection, USP
Sodium Chloride (0.9%) Injection, USP
Nicardipine hydrochloride injection is NOT compatible with Sodium Bicarbonate (5%) Injection, USP, or Lactated Ringer's Injection, USP.
THE DILUTED SOLUTION IS STABLE FOR 24 HOURS AT ROOM TEMPERATURE.
Oral Nicardipine Dose | Equivalent I.V. Infusion Rate |
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20 mg q8h | 0.5 mg/hr |
30 mg q8h | 1.2 mg/hr |
40 mg q8h | 2.2 mg/hr |
NICARDIPINE HYDROCHLORIDE
nicardipine hydrochloride injection |
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Labeler - Emcure Pharmaceuticals Ltd. (916921919) |
Establishment | |||
Name | Address | ID/FEI | Business Operations |
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Emcure Pharmaceuticals Ltd. | 916921919 | MANUFACTURE, ANALYSIS |