NICARDIPINE HYDROCHLORIDE

Nicardipine hydrochloride, USP is a calcium ion influx inhibitor (slow channel blocker or calcium channel blocker). Nicardipine hydrochloride for intravenous administration contains 2.5 mg/mL of nicardipine hydrochloride, USP. 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, USP is a yellow to pale yellow, odorless, crystalline powder that has a melting point range of 165-170◦ C. It is soluble in methanol, sparingly soluble in ethanol, slightly soluble in acetone, chloroform and water. It has a molecular weight of 515.99. Nicardipine hydrochloride injection, USP is available as a sterile, non-pyrogenic, clear, yellow solution in 10 mL vials for intravenous infusion after dilution. Each mL contains 2.5 mg nicardipine hydrochloride, 0.305 mg benzoic acid, USP and 7.5 mg sodium chloride, USP, in Water for Injection, USP. Sodium hydroxide, NF, (q.s.) may have been added to adjust pH to 3.2 to 4.2. Nicardipine Hydrochloride in 0.9% Sodium Chloride Injection is available as a single-use, ready-to-use, iso-osmotic, clear, yellow solution for intravenous administration in a 200 mL single dose container. Each mL contains 0.1 mg or 0.2 mg nicardipine hydrochloride in 9 mg Sodium Chloride, USP. Hydrochloric acid (q.s.) may have been added to adjust pH to 3 to 5. Chemical Structure

Nicardipine hydrochloride injection, USP is a calcium channel blocker indicated for the short-term treatment of hypertension when oral therapy is not feasible. 1.1 Hypertension Nicardipine hydrochloride injection, USP is indicated for the short-term treatment of hypertension when oral therapy is not feasible or desirable. For prolonged control of blood pressure, transfer patients to oral medication as soon as their clinical condition permits [see Dosage and Administration (2.6) ].

Individualize dosage based upon the severity of hypertension and response of the patient during dosing (2.1 ). Single dose vials must be diluted before use ( 2.2 ). When substituting for oral nicardipine therapy, use the intravenous infusion rate as follows ( 2.3 ): Oral Nicardipine Dose Equivalent Intravenous Infusion Rate 20 mg every 8 hours 0.5 mg/hr 30 mg every 8 hours 1.2 mg/hr 40 mg every 8 hours 2.2 mg/hr In a drug-free patient, initiate therapy at 5 mg/hr. Increase the infusion rate by 2.5 mg/hr to a maximum of 15 mg/hr until desired blood pressure reduction is achieved. For a gradual blood pressure reduction the rate can be increased every 15 minutes, for a rapid reduction, every 5 minutes ( 2.4 ). If hypotension or tachycardia ensues, discontinue the infusion. After stabilized, patient can be restarted at low doses such as 3 mg/hr to 5 mg/hr ( 2.5 ). 2.1 General Information Individualize dosing based on the severity of hypertension and the response of the patient during dosing. Monitor blood pressure and heart rate both during and after the infusion to avoid tachycardia or too rapid or excessive reduction in either systolic or diastolic blood pressure. Administer Nicardipine Hydrochloride by slow continuous infusion by a central line or through a large peripheral vein. Change the infusion site every 12 hours if administered via peripheral vein [see Intravenous Infusion Site (5.7) ] . 2.2 Inspection and Preparation Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use the solution if particulate matter, precipitate, or crystallization is present, or if the container appears damaged. Single Dose Vials Dilution Single dose vials must be diluted before infusion. Each vial (25 mg) must 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. Compatability Nicardipine hydrochloride injection has been found compatible and stable in 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 is not compatible with Sodium Bicarbonate (5%) Injection, USP or Lactated Ringer’s Injection, USP. Single Dose Containers Dilution is not required for Nicardipine Hydrochloride in 0.9% Sodium Chloride Injection. 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. Do not combine Nicardipine Hydrochloride in 0.9% 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. Discard Unused Portion 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. 2.3 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 Intravenous Infusion Rate 20 mg every 8 hours 0.5 mg/hr 30 mg every 8 hours 1.2 mg/hr 40 mg every 8 hours 2.2 mg/hr 2.4 Dosage for Initiation of Therapy in a Drug-Free Patient The time course of blood pressure decrease is dependent on the initial rate of infusion and the frequency of dosage adjustment. Nicardipine hydrochloride injection is administered by slow continuous infusion at a concentration of 0.1 mg/mL. With constant infusion, blood pressure begins to fall within minutes. It reaches about 50% of its ultimate decrease in about 45 minutes. When treating acute hypertensive episodes in patients with chronic hypertension, discontinuation of infusion is followed by a 50% offset of action in 30 minutes plus/minus 7 minutes but plasma levels of drug and gradually decreasing antihypertensive effects exist for many hours. Titration For a gradual reduction in blood pressure, initiate therapy at a rate of 5 mg/hr. If desired blood pressure reduction is not achieved at this dose, increase the infusion rate by 2.5 mg/hr every 15 minutes up to a maximum of 15 mg/hr, until desired blood pressure reduction is achieved. For more rapid blood pressure reduction, titrate every 5 minutes. Maintenance Adjust the rate of infusion as needed to maintain desired response. 2.5 Conditions Requiring Infusion Adjustment Hypotension or Tachycardia: In case of hypotension or tachycardia, discontinue infusion. When blood pressure and heart rate stabilize, restart infusion at low doses such as 30 mL/hr to 50 mL/hr (3 mg/hr to 5 mg/hr) and titrate to maintain desired blood pressure. Infusion Site Changes: Change infusion site every 12 hours if administered via peripheral vein. Impaired Cardiac, Hepatic, or Renal Function: Monitor closely when titrating nicardipine hydrochloride injection in patients with congestive heart failure or impaired hepatic or renal function [see Warnings and Precautions (5.4 , 5.5 and 5.6) ]. 2.6 Transfer to Oral Antihypertensive Agents If treatment includes transfer to an oral antihypertensive agent other than nicardipine capsules, initiate oral therapy upon discontinuation of nicardipine hydrochloride injection. When switching to a three times a day regimen of nicardipine capsules, administer the first dose 1 hour prior to discontinuation of the infusion.

Do not use in patients with advanced aortic stenosis ( 4.1 ). 4.1 Advanced Aortic Stenosis Do not use nicardipine in patients with advanced aortic stenosis because of the afterload reduction effect of nicardipine. Reduction of diastolic pressure in these patients may worsen rather than improve myocardial oxygen balance.

Most common adverse reactions are headache (13%), hypotension (5%), tachycardia (4%) and nausea/vomiting (4%). To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Adverse Reactions Observed in Clinical Trials 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. Two hundred forty-four patients participated in two multicenter, double-blind, placebo-controlled trials of nicardipine. Adverse experiences were generally not serious and most were expected consequences of vasodilation. Adverse reactions occasionally required dosage adjustment. Therapy was discontinued in approximately 12% of patients, mainly due to hypotension, headache, and tachycardia. Adverse reactions that occurred more often on nicardipine than on placebo by at least 2% were headache (13%) and nausea/vomiting (4%). The following adverse reactions have been reported in clinical trials or in the literature during 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.

Cimetidine increases nicardipine plasma levels ( 7.3 ). Nicardipine may increase cyclosporine and tacrolimus plasma levels. Frequent monitoring of trough blood levels of cyclosporine and tacrolimus is recommended when co-administering nicardipine. ( 7.5 , 7.6 ). 7.1 Antihypertensive Agents Since nicardipine hydrochloride injection may be administered to patients already being treated with other medications, including other antihypertensive agents, careful monitoring of these patients is necessary to detect and to treat promptly any undesired effects from concomitant administration. 7.2 Beta-Blockers In most patients, nicardipine hydrochloride injection can safely be used concomitantly with beta-blockers. However, monitor response carefully when combining nicardipine hydrochloride injection with a beta-blocker in the treatment of congestive heart failure patients [see Warnings and Precautions (5.4) ] . 7.3 Cimetidine Cimetidine has been shown to increase nicardipine plasma concentrations with oral nicardipine administration. Carefully monitor patients receiving the two drugs concomitantly. Data with other histamine-2 antagonists are not available. 7.4 Digoxin Studies have shown that oral nicardipine usually does not alter digoxin plasma concentrations. 7.5 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. Monitor closely plasma concentrations of cyclosporine during nicardipine hydrochloride injection administration, and adjust the dose of cyclosporine accordingly. 7.6 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 administration, and adjust the dose of tacrolimus accordingly. 7.7 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 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Freezing does not adversely affect the product, but exposure to elevated temperatures should be avoided. Protect from light. Store vials in carton until used.