200 ML nicardipine hydrochloride 0.1 MG/ML Injection

INDICATIONS AND USAGE I. Stable Angina Nicardipine hydrochloride capsules are indicated for the management of patients with chronic stable angina (effort-associated angina). Nicardipine hydrochloride capsules may be used alone or in combination with beta-blockers. II. Hypertension Nicardipine hydrochloride capsules are indicated for the treatment of hypertension. Nicardipine hydrochloride capsules may be used alone or in combination with other antihypertensive drugs. In administering nicardipine hydrochloride it is important to be aware of the relatively large peak to trough differences in blood pressure effect (See DOSAGE AND ADMINISTRATION ).

DOSAGE AND ADMINISTRATION • For Intravenous Use. (2.1) • No further dilution is required. (2.3) • When substituting for oral nicardipine therapy, use the intravenous infusion rate from the table below (2.1): Oral Nicardipine Dose Equivalent I.V. Infusion rate (0.1 mg/mL) Equivalent I.V. Infusion Rate (0.2 mg/mL) 20 mg q8h 0.5 mg/hr = 5 mL/hr 0.5 mg/hr = 2.5 mL/hr 30 mg q8h 1.2 mg/hr = 12 mL/hr 1.2 mg/hr = 6 mL/hr 40 mg q8h 2.2 mg/hr = 22 mL/hr 2.2 mg/hr = 11 mL/hr • In a patient not receiving oral nicardipine, initiate therapy at 5 mg/hr. Increase the infusion rate by 2.5 mg/hr every 5 minutes (for rapid titration) to 15 minutes (for gradual titration) up to a maximum of 15 mg/hr until desired blood pressure reduction is achieved. (2.1) Conversion Table (mg/hr) Equivalent I.V. Infusion Rate (0.1 mg/mL) Equivalent I.V. Infusion Rate (0.2 mg/mL) 5 mg/hr 50 mL/hr 25 mL/hr 2.5 mg/hr 25 mL/hr 12.5 mL/hr 15 mg/hr 150 mL/hr 75 mL/hr • If unacceptable hypotension or tachycardia occurs, discontinue the infusion. When blood pressure and heart rate stabilize, restart the infusion at low doses such as 3 to 5 mg/hr. (2.2) 2.1 Recommended Dosing Nicardipine hydrochloride in sodium chloride injection is intended for intravenous use. Titrate dose to achieve the desired blood pressure reduction. Individualize dosage depending on the blood pressure to be obtained and the response of the patient. Dosage as a Substitute for Oral Nicardipine Therapy The intravenous infusion rate required to produce an average plasma concentration equivalent to a given oral dose at steady state is shown in the following table: Oral Nicardipine Dose Equivalent I.V. Infusion Rate 20 mg in 200 mL (0.1 mg/mL) Equivalent I.V. Infusion Rate 40 mg in 200mL (0.2 mg/mL) 20 mg q8h 0.5 mg/hr = 5 mL/hr 0.5 mg/hr = 2.5 mL/hr 30 mg q8h 1.2 mg/hr = 12 mL/hr 1.2 mg/hr = 6 mL/hr 40 mg q8h 2.2 mg/hr = 22 mL/hr 2.2 mg/hr = 11 mL/hr Dosage for Initiation of Therapy in a Patient Not Receiving Oral Nicardipine Nicardipine hydrochloride in sodium chloride injection 20 mg in 200 mL (0.1 mg/mL): Initiate therapy at 50 mL/hr (5 mg/hr). If desired blood pressure reduction is not achieved at this dose, the infusion rate may be increased by 25 mL/hr (2.5 mg/hr) every 5 minutes (for rapid titration) to 15 minutes (for gradual titration) up to a maximum of 150 mL/hr (15 mg/hr), until desired blood pressure reduction is achieved. Following achievement of the blood pressure goal utilizing rapid titration, decrease the infusion rate to 30 mL/hr (3 mg/hr). Nicardipine hydrochloride in sodium chloride injection 40 mg in 200 mL (0.2 mg/mL): Initiate therapy at 25 mL/hr (5 mg/hr). If desired blood pressure reduction is not achieved at this dose, the infusion rate may be increased by 12.5 mL/hr (2.5 mg/hr) every 5 minutes (for rapid titration) to 15 minutes (for gradual titration) up to a maximum of 75 mL/hr (15 mg/hr), until desired blood pressure reduction is achieved. Following achievement of the blood pressure goal utilizing rapid titration, decrease the infusion rate to 15 mL/hr (3 mg/hr). Drug Discontinuation and Transition to an Oral Antihypertensive Agent Discontinuation of infusion is followed by a 50% offset of action in about 30 minutes. If treatment includes transfer to an oral antihypertensive agent other than oral nicardipine, initiate therapy upon discontinuation of nicardipine hydrochloride in sodium chloride injection. If oral nicardipine is to be used, administer the first dose 1 hour prior to discontinuation of the infusion. Special Populations Titrate Nicardipine hydrochloride in sodium chloride injection slowly in patients with heart failure or impaired hepatic or renal function [see Warnings and Precautions (5.2, 5.3 and 5.4)] 2.2 Monitoring The time course of blood pressure decrease is dependent on the initial rate of infusion and the frequency of dosage adjustment. With constant infusion, blood pressure begins to fall within minutes. It reaches about 50% of its ultimate decrease in about 45 minutes. Monitor blood pressure and heart rate continually during infusion and avoid too rapid or excessive blood pressure drop during treatment. If there is concern of impending hypotension or tachycardia, the infusion should be discontinued. Then, when blood pressure has stabilized, infusion of Nicardipine hydrochloride in sodium chloride injection may be restarted at low doses such as 30 to 50 mL/hr (3 to 5 mg/hr) for 20 mg in 200 mL or 15 to 25 mL/hr (3 to 5 mg/hr) for 40 mg in 200 mL and adjusted to maintain desired blood pressure. 2.3 Instructions for Administration Administer Nicardipine hydrochloride in sodium chloride injection by a central line or through a large peripheral vein. Change the infusion site every 12 hours if administered via peripheral vein [see Warnings and Precautions (5.5)]. Nicardipine hydrochloride in sodium chloride injection is available as a single-dose, ready-to-use, iso-osmotic solution for intravenous administration. No further dilution is required. Inspect Nicardipine hydrochloride in sodium chloride injection visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Check the container for minute leaks prior to use by squeezing the bag firmly; ensure that the seal is intact. If leaks are found, discard solution as sterility may be impaired. Nicardipine hydrochloride in sodium chloride injection is normally a clear, colorless to yellow solution. Do not combine Nicardipine hydrochloride in sodium chloride injection with any product in the same intravenous line or premixed container. Do not add supplementary medication to the bag. Protect from light until ready to use. Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before the administration of the fluid from the secondary container is complete. Preparation for administration 1 Suspend container from eyelet support. 2 Remove protector from outlet port at bottom of container. 3 Attach administration set. Refer to complete directions accompanying set. 4 Discard unused portion.

WARNINGS AND PRECAUTIONS To reduce the possibility of venous thrombosis, phlebitis, and vascular impairment, do not use small veins, such as those on the dorsum of the hand or wrist. Avoid intraarterial administration or extravasation ( 5.7 ). To minimize the risk of peripheral venous irritation, change the site of infusion of nicardipine every 12 hours ( 5.7 ). Nicardipine is not a beta-blocker and therefore gives no protection against the dangers of abrupt beta-blocker withdrawal. Withdraw beta-blockers gradually ( 5.8 ). Closely monitor response in patients with angina ( 5.3 ), congestive heart failure ( 5.4 ), impaired hepatic function ( 5.5 ), portal hypertension ( 5.5 ), and renal impairment ( 5.6 ) and pheochromocytoma ( 5.9 ). 5 WARNINGS AND PRECAUTIONS 5.1 Excessive Pharmacologic Effects In administrating nicardipine, close monitoring of blood pressure and heart rate is required. Nicardipine may occasionally produce symptomatic hypotension or tachycardia. Avoid systemic hypotension when administering the drug to patients who have sustained an acute cerebral infarction or hemorrhage. 5.2 Rapid Decreases in Blood Pressure No clinical events have been reported suggestive of a too rapid decrease in blood pressure with nicardipine. However, as with any antihypertensive agent, blood pressure lowering should be accomplished over as long a time as is compatible with the patient's clinical status. 5.3 Use in Patients with Angina Increases in frequency, duration, or severity of angina have been seen in chronic oral therapy with nicardipine capsules. Induction or exacerbation of angina has been seen in less than 1% of coronary artery disease patients treated with nicardipine. The mechanism of this effect has not been established. 5.4 Use in Patients with Congestive Heart Failure Nicardipine reduced afterload without impairing myocardial contractility in preliminary hemodynamic studies of CHF patients. However, in vitro and in some patients, a negative inotropic effect has been observed. Therefore, monitor vital signs carefully when using nicardipine, particularly in combination with a beta-blocker, in patients with CHF or significant left ventricular dysfunction. 5.5 Use in Patients with Impaired Hepatic Function Since nicardipine is metabolized in the liver, consider lower dosages and closely monitor response. Nicardipine administered intravenously increased hepatic venous pressure gradient by 4 mmHg in cirrhotic patients at high doses (5 mg/20 min) in one study. Use caution in patients with portal hypertension. 5.6 Use in Patients with Impaired Renal Function When nicardipine was given to mild-to-moderate hypertensive patients with moderate renal impairment, a significantly lower systemic clearance and higher AUC was observed. These results are consistent with those seen after oral administration of nicardipine. Careful dose titration is advised when treating patients with more than mild renal impairment. 5.7 Intravenous Infusion Site To reduce the possibility of venous thrombosis, phlebitis, local irritation, swelling, extravasation, and the rare occurrence of vascular impairment, administer drug through large peripheral veins or central veins rather than arteries or small peripheral veins, such as those on the dorsum of the hand or wrist. To minimize the risk of peripheral venous irritation, consider changing the site of the drug infusion every 12 hours. 5.8 Beta-Blocker Withdrawal Nicardipine is not a beta-blocker and therefore gives no protection against the dangers of abrupt beta-blocker withdrawal. Withdraw beta-blockers gradually. 5.9 Use in Patients with Pheochromocytoma Only limited clinical experience exists in use of nicardipine for patients with hypertension from pheochromocytoma.

CONTRAINDICATIONS • Do not use in patients with advanced aortic stenosis (4.1). 4.1 Advanced Aortic Stenosis Nicardipine hydrochloride in sodium chloride injection is contraindicated in patients with advanced aortic stenosis because part of the effect of Nicardipine hydrochloride in sodium chloride injection is secondary to reduced afterload. Reduction of diastolic pressure in these patients may worsen rather than improve myocardial oxygen balance.

CLINICAL PHARMACOLOGY Mechanism of Action Nicardipine hydrochloride is a calcium entry blocker (slow channel blocker or calcium ion antagonist) that 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 hydrochloride are more selective to vascular smooth muscle than cardiac muscle. In animal models, nicardipine hydrochloride produces relaxation of coronary vascular smooth muscle at drug levels that cause little or no negative inotropic effect. Pharmacokinetics and Metabolism Nicardipine hydrochloride is completely absorbed following oral doses administered as capsules. Plasma levels are detectable as early as 20 minutes following an oral dose and maximal plasma levels are observed within 30 minutes to 2 hours (mean T max = 1 hour). While nicardipine hydrochloride is completely absorbed, it is subject to saturable first pass metabolism and the systemic bioavailability is about 35% following a 30-mg oral dose at steady-state. When nicardipine hydrochloride was administered 1 or 3 hours after a high-fat meal, the mean C max and mean AUC were lower (20% to 30%) than when nicardipine hydrochloride was given to fasting subjects. These decreases in plasma levels observed following a meal may be significant, but the clinical trials establishing the efficacy and safety of nicardipine hydrochloride 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 are nonlinear due to saturable hepatic first pass metabolism. Following oral administration, increasing doses result in a disproportionate increase in plasma levels. Steady-state C max values following 20-, 30-, and 40-mg doses every 8 hours averaged 36, 88, and 133 ng/mL, respectively. 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 are also non-linear, although there is a reproducible terminal plasma half-life that averaged 8.6 hours following 30- and 40-mg doses at steady-state (tid). The terminal half-life represents the elimination of less than 5% of the absorbed drug (measured by plasma concentrations). 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 twofold higher than after a single dose. Nicardipine hydrochloride is highly protein bound (>95%) in human plasma over a wide concentration range. Nicardipine hydrochloride is metabolized extensively by the hepatic cytochrome P450 enzymes, CYP2C8, 2D6, and 3A4; less than 1% of intact drug is detected in the urine. Following a radioactive oral dose in solution, 60% of the radioactivity was recovered in the urine and 35% in feces. Most of the dose (over 90%) was recovered within 48 hours of dosing. Nicardipine hydrochloride does not induce its own metabolism, however, nicardipine causes inhibition of certain cytochrome P450 enzymes (including CYP3A4, CYP2D6, CYP2C8, and CYP2C19). 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 1.2 to 5.5 mg/dL) than in normal subjects. After 30-mg nicardipine hydrochloride tid at steady- state, C max and AUC were approximately twofold 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 20-mg nicardipine hydrochloride bid at steady-state, C max and AUC were 1.8 and fourfold higher, and the terminal half-life was prolonged to 19 hours in these patients. Geriatric Pharmacokinetics The steady-state pharmacokinetics of nicardipine hydrochloride in elderly hypertensive patients (≥65 years) are similar to those obtained in young normal adults. After 1 week of nicardipine hydrochloride 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. Hemodynamics 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. An increase in heart rate may occur in response to the vasodilation and decrease in blood pressure, and in a few patients this heart rate increase may be pronounced. In clinical studies mean heart rate at time of peak plasma levels was usually increased by 5 to 10 beats per minute compared to placebo, with the greater increases at higher doses, while there was no difference from placebo at the end of the dosing interval. 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). Although there is evidence that nicardipine hydrochloride increases coronary blood flow, there is no evidence that this property plays any role in its effectiveness in stable angina. In patients with coronary artery disease, intracoronary administration of nicardipine caused no direct myocardial depression. Nicardipine hydrochloride does, however, have a negative inotropic effect in some patients with severe left ventricular dysfunction and could, in patients with very impaired function, lead to worsened failure. "Coronary Steal," the detrimental redistribution of coronary blood flow in patients with coronary artery disease (diversion of blood from underperfused areas toward better perfused areas), has not been observed during nicardipine treatment. On the contrary, nicardipine has been shown to improve systolic shortening in normal and hypokinetic segments of myocardial muscle, and radio-nuclide angiography has confirmed that wall motion remained improved during an increase in oxygen demand. Nonetheless, occasional patients have developed increased angina upon receiving nicardipine. Whether this represents steal in those patients, or is the result of increased heart rate and decreased diastolic pressure, is not clear. In patients with coronary artery disease nicardipine improves L.V. 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, s