Nicardipine Hydrochloride

1 INDICATIONS & 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 & ADMINISTRATION • Individualize dosage based upon the severity of hypertension and response of the patient during dosing ( 2.1 ). • 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 in 0.9% sodium chloride injection 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 Containers Dilution is not required for nicardipine hydrochloride in 0.9% sodium chloride injection. Check the container for minute leaks prior to use; 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 in 0.9% sodium chloride 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 …

5 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 ). 5.1 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.

4 CONTRAINDICATIONS • 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.

7 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 ) 7.1 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 .

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.

6 ADVERSE REACTIONS Most common adverse reactions are headache (13%), hypotension (5%), tachycardia (4%) and nausea/vomiting (4%) ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Somerset Therapeutics, LLC at 1-800-417-9175 or 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.