Nicardipine Hydrochloride

Dosage Forms and strengths ( 3 ) 02/2024 Dosage Forms and Strengths ( 3 ) 08/2024

1 INDICATIONS AND USAGE Nicardipine hydrochloride in 0.9% sodium chloride injection is a calcium channel blocker indicated for the short-term treatment of hypertension when oral therapy is not feasible. 1.1 Hypertension Nicardipine hydrochloride in 0.9% sodium chloride injection 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 )] .

2 DOSAGE AND ADMINISTRATION 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 pressur …

3 DOSAGE FORMS AND STRENGTHS Nicardipine hydrochloride is a clear, yellow solution and is available in the following presentations: 25 mg nicardipine hydrochloride in 10 mL injection (2.5 mg/mL) in a single dose vial 20 mg nicardipine hydrochloride in 200 mL 0.9% sodium chloride injection (0.1 mg/mL) in a single dose container 40 mg nicardipine hydrochloride in 200 mL 0.9% sodium chloride injection (0.2 mg/mL) in a single dose container • 25 mg nicardipine hydrochloride in 10 mL injection (2.5 mg/mL) in a single dose vial • 20 mg nicardipine hydrochloride in 200 mL 0.9% sodium chloride injection (0.1 mg/mL) in a single dose container • 40 mg nicardipine hydrochloride in 200 mL 0.9% sodium chloride injection (0.2 mg/mL) in a single dose container

4 CONTRAINDICATIONS 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.

6 ADVERSE REACTIONS Most common adverse reactions are headache (15%), hypotension (6%), tachycardia (4%) and nausea/vomiting (5%). (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Lifestar Pharma LLC at 1-888-995-4337 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. The table below shows percentage of patients with adverse events where the rate is >3% more common on nicardipine hydrochloride injection than placebo. Adverse Event Nicardipine hydrochloride (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 Experience 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).

DRUG INTERACTIONS 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 DRUG INTERACTIONS 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.

USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm ( 8.1 ). Nursing Mothers: It is recommended that women who wish to breastfeed should not be given this drug ( 8.3 ). Safety and efficacy in patients under the age of 18 have not been established ( 8.4 ). Revised: 11/2025

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C. There are no adequate and well-controlled studies of nicardipine use in pregnant women. There are limited human data in pregnant women with pre-eclampsia and preterm labor. In animal reproduction and developmental toxicity studies, evidence of fetal harm was observed. Therefore use nicardipine during pregnancy only if the potential benefit justifies the potential risk to the fetus. In reproduction studies conducted in rats and rabbits, increased embryolethality occurred when nicardipine was administered intravenously at doses equivalent to human intravenous doses of 1.6 (rats) and 0.32 mg/kg/day (rabbits). Increased embryolethality was also observed when nicardipine was administered orally to pregnant rabbits at a dose equivalent to a human oral dose of about 48 mg/kg/day (a dose 24 times the maximum recommended human oral dose and one associated with marked maternal body weight gain suppression). At a lower oral dose, equivalent to a human dose of about 32 mg/kg/day (16 times the maximum recommended human oral dose), in a different strain of rabbit, there were no adverse effects on the fetus, though there was increased maternal mortality. There was no evidence of embryolethality or teratogenicity when pregnant rats were administered nicardipine orally at a dose equivalent to a human oral dose of about 16 mg/kg/day (8 times the MRHD); however, dystocia, reduced birth weight, reduced neonatal survival and reduced neonatal weight gain were reported [see Nonclinical Toxicology (13.3) ] . 8.3 Nursing Mothers Nicardipine is minimally excreted into human milk. Among 18 infants exposed to nicardipine through breast milk in the postpartum period, calculated daily infant dose was less than 0.3 mcg and there were no adverse events observed. It is recommended that women who wish to breastfeed should not be given this drug. In a study of 11 women who received oral nicardipine 4 days to 14 days postpartum, 4 women received immediate-release nicardipine 40 to 80 mg daily, 6 women received sustained-release nicardipine 100 mg to 150 mg daily, and one woman received intravenous nicardipine 120 mg daily. The peak milk concentration was 7.3 mcg/L (range 1.9 to 18.8), and the mean milk concentration was 4.4 mcg/L (range 1.3 to 13.8). Infants received an average of 0.073% of the weight-adjusted maternal oral dose and 0.14% of the weight-adjusted maternal intravenous dose. In another study of seven women who received intravenous nicardipine for an average of 1.9 days in the immediate postpartum period as therapy for pre-eclampsia, 34 milk samples were obtained at unspecified times and nicardipine was undetectable (less than 5 mcg/L) in 82% of the samples. Four women who received 1 to 6.5 mg/hour of nicardipine had 6 milk samples with detectable nicardipine levels (range 5.1 to 18.5 mcg/L). The highest concentration of 18.5 mcg/L was found in a woman who received 5.5 mg/hour of nicardipine. The estimated maximum dose in a breastfed infant was less than 0.3 mcg daily or 0.015% to 0.004% of the therapeutic dose in a 1 kg infant. 8.4 Pediatric Use Safety and efficacy in patients under the age of 18 have not been established. 8.5 Geriatric Use The steady-state pharmacokinetics of nicardipine are similar in elderly hypertensive patients (greater than 65 years) and young healthy adults. Clinical studies of nicardipine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selecti …

12.1 Mechanism of Action 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.

11 DESCRIPTION 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

10 OVERDOSAGE Several overdosages with orally administered nicardipine have been reported. One adult patient allegedly ingested 600 mg of nicardipine 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 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.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Nicardipine Hydrochloride Injection, USP is a clear, yellow solution and is available in packages as follows: NDC Strength Packaged 0143-9689-01 0143-9689-10 25 mg/10 mL (2.5 mg/mL) 1 single dose vial Carton of 10 single dose vials Nicardipine Hydrochloride in 0.9% Sodium Chloride Injection is a clear, yellow solution and is available in packages as follows: NDC Strength Packaged 0143-9634-01 0143-9634-10 20 mg in 200 mL (0.1 mg/mL) 1 single dose container Carton of 10 single dose containers 0143-9633-01 0143-9633-10 40 mg in 200 mL (0.2 mg/mL) 1 single dose container Carton of 10 single dose containers 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.

16.1 How Supplied Nicardipine Hydrochloride Injection, USP is a clear, yellow solution and is available in packages as follows: NDC Strength Packaged 0143-9689-01 0143-9689-10 25 mg/10 mL (2.5 mg/mL) 1 single dose vial Carton of 10 single dose vials Nicardipine Hydrochloride in 0.9% Sodium Chloride Injection is a clear, yellow solution and is available in packages as follows: NDC Strength Packaged 0143-9634-01 0143-9634-10 20 mg in 200 mL (0.1 mg/mL) 1 single dose container Carton of 10 single dose containers 0143-9633-01 0143-9633-10 40 mg in 200 mL (0.2 mg/mL) 1 single dose container Carton of 10 single dose containers