NICARDIPINE HYDROCHLORIDE

Nicardipine hydrochloride is a calcium ion influx inhibitor (slow channel blocker or calcium channel blocker). niCARdipine Hydrochloride Injection, USP for intravenous administration contains 2.5 mg of nicardipine hydrochloride. Nicardipine hydrochloride is a dihydropyridine derivative with IUPAC (International Union of Pure and Applied Chemistry) chemical name (±)-2-(benzyl-methyl amino) ethyl methyl 1,4-dihydro-2,6-dimethyl-4-( m -nitrophenyl)-3,5-pyridinedicarboxylate monohydrochloride and has the following structure: Nicardipine hydrochloride is a greenish-yellow, odorless, crystalline powder that melts at about 169°C. It is freely soluble in chloroform, methanol, and glacial acetic acid, sparingly soluble in anhydrous ethanol, slightly soluble in n-butanol, water, 0.01 M potassium dihydrogen phosphate, acetone, and dioxane, very slightly soluble in ethyl acetate, and practically insoluble in benzene, ether, and hexane. It has a molecular weight of 515.99. 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 nicardipine hydrochloride 2.5 mg in water for injection with sorbitol 48 mg, and edetate disodium 0.04 mg, buffered to pH 3.5 with citric acid monohydrate 0.525 mg and sodium hydroxide 0.09 mg. Additional citric acid and/or sodium hydroxide may have been added to adjust pH. Cardene Structure

niCARdipine hydrochloride injection is a calcium channel blocker indicated for the short-term treatment of hypertension when oral therapy is not feasible. ( 1.1 ) 1.1 Hypertension niCARdipine Hydrochloride Injection, USP is indicated for the short-term treatment of hypertension when oral therapy is not feasible or not desirable. For prolonged control of blood pressure, transfer patients to oral medication as soon as their clinical condition permits [see Dosage and Administration ( 2.1 )] .

For Intravenous Use. ( 2.1 ) 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 Intravenous Infusion Rate (0.1 mg/mL) 20 mg q8h 0.5 mg/hr = 5 mL/hr 30 mg q8h 1.2 mg/hr = 12 mL/hr 40 mg q8h 2.2 mg/hr = 22 mL/hr In a patient not receiving oral nicardipine, initiate therapy at 50 mL/hr (5 mg/hr) 0.1 mg/mL solution. Increase the infusion rate by 25 mL/hr every 5 minutes (for rapid titration) to 15 minutes (for gradual titration) up to a maximum of 150 mL/hr until desired blood pressure reduction is achieved. ( 2.1 ) If unacceptable hypotension or tachycardia occurs, discontinue the infusion. When blood pressure and heart rate stabilize, restart the infusion at low doses such as 30 to 50 mL/hr. ( 2.2 ) 2.1 Recommended Dosing niCARdipine Hydrochloride Injection, USP is intended for intravenous use. Vial must be diluted 0.1 mg/mL before use [see Dosage and Administration ( 2.3 )]. 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: Table 1: Oral Equivalent Dosage Oral Nicardipine Dose Equivalent Intravenous Infusion Rate (0.1 mg/mL) 20 mg q8h 0.5 mg/hr = 5 mL/hr 30 mg q8h 1.2 mg/hr = 12 mL/hr 40 mg q8h 2.2 mg/hr = 22 mL/hr Dosage for Initiation of Therapy in a Patient Not Receiving Oral Nicardipine 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). 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 injection. If oral nicardipine is to be used, administer the first dose 1 hour prior to discontinuation of the infusion. Specific Populations Titrate nicardipine hydrochloride 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, restart infusion of nicardipine hydrochloride injection at low doses such as 30 to 50 mL/hr (3 to 5 mg/hr) and adjust to maintain desired blood pressure. 2.3 Instructions for Administration Administer nicardipine hydrochloride 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 )] . Preparation for Administration Vials must be diluted before infusion. Inspection As with all parenteral drugs, nicardipine hydrochloride injection should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Nicardipine hydrochloride injection is normally clear, yellow in color. 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.

Do not use in patients with advanced aortic stenosis. ( 4.1 ). 4.1 Advanced Aortic Stenosis Nicardipine hydrochloride injection is 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.

Most common adverse reactions are headache (15%), hypotension (6%), tachycardia (4%) and nausea/vomiting (5%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact American Regent, Inc. at 1-800-734-9236, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Two hundred forty-four patients participated in two multicenter, double-blind, placebo-controlled trials of nicardipine hydrochloride injection. Adverse experiences were generally not serious and most were expected consequences of vasodilation. Adverse experiences occasionally required dosage adjustment. Therapy was discontinued in approximately 12% of patients, mainly due to hypotension, headache, and tachycardia. Table 2 shows percentage of patients with adverse reactions where the rate is >3% more common on nicardipine hydrochloride injection than placebo. Table 2: Adverse Reactions Adverse Event Nicardipine Hydrochloride Injection (n=144) Placebo (n=100) Body as a Whole Headache, n (%) 21 (15) 2 (2) Cardiovascular Hypotension, n (%) 8 (6) 1 (1) Tachycardia, n (%) 5 (4) 0 Digestive Nausea/vomiting, n (%) 7 (5) 1 (1) Other adverse events have been reported in clinical trials or in the literature in association with the use of intravenously administered nicardipine: Body as a Whole: fever, neck pain Cardiovascular: angina pectoris, atrioventricular block, ST segment depression, inverted T wave, deep-vein thrombophlebitis Digestive: dyspepsia Hemic and Lymphatic: thrombocytopenia Metabolic and Nutritional: hypophosphatemia, peripheral edema Nervous: confusion, hypertonia Respiratory: respiratory disorder Special Senses: conjunctivitis, ear disorder, tinnitus Urogenital: urinary frequency Sinus node dysfunction and myocardial infarction, which may be due to disease progression, have been seen in patients on chronic therapy with orally administered nicardipine. 6.2 Postmarketing Because adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or to establish a causal relationship to drug exposure. The following adverse reaction has been identified during post-approval use of nicardipine hydrochloride injection: decreased oxygen saturation (possible pulmonary shunting). 6.2 Postmarketing Because adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or to establish a causal relationship to drug exposure. The following adverse reaction has been identified during post-approval use of nicardipine hydrochloride injection: decreased oxygen saturation (possible pulmonary shunting).

Cimetidine increases oral nicardipine plasma levels. ( 7.2 ) Oral or intravenous nicardipine may increase cyclosporine and tacrolimus plasma levels. Frequent monitoring of trough blood levels of cyclosporine and tacrolimus is recommended when co-administering nicardipine hydrochloride injection. ( 7.3 , 7.4 ) 7.1 Beta-Blockers In most patients, nicardipine hydrochloride injection can safely be used concomitantly with beta-blockers. However, titrate slowly when using nicardipine hydrochloride injection in combination with a beta-blocker in heart failure patients [see Warnings and Precautions ( 5.2 )]. 7.2 Cimetidine Cimetidine has been shown to increase nicardipine plasma concentrations with oral nicardipine administration. Frequently monitor response in patients receiving both drugs. Data with other histamine-2 antagonists are not available. 7.3 Cyclosporine Concomitant administration of oral or intravenous nicardipine and cyclosporine results in elevated plasma cyclosporine levels through nicardipine inhibition of hepatic microsomal enzymes, including CYP3A4. Closely monitor plasma concentrations of cyclosporine during nicardipine hydrochloride injection administration, and reduce the dose of cyclosporine accordingly. 7.4 Tacrolimus Concomitant administration of intravenous nicardipine and tacrolimus may result in elevated plasma tacrolimus levels through nicardipine inhibition of hepatic microsomal enzymes, including CYP3A4. Closely monitor plasma concentrations of tacrolimus during nicardipine hydrochloride injection administration, and adjust the dose of tacrolimus accordingly. 7.5 In Vitro Interaction The plasma protein binding of nicardipine was not altered when therapeutic concentrations of furosemide, propranolol, dipyridamole, warfarin, quinidine, or naproxen were added to human plasma in vitro.

16.2 Storage and Handling Store at controlled room temperature 20° to 25°C (68° to 77°F), refer to USP Controlled Room Temperature. Freezing does not adversely affect the product, but avoid exposure to elevated temperatures. Protect from light. Store vials in carton until used. AMERICAN REGENT, INC. SHIRLEY, NY 11967 RQ1087-B