Nicardipine Hydrochloride

• CARDENE I.V. is a calcium channel blocker indicated for the short-term treatment of hypertension in adults when oral therapy is not feasible. ( 1.1 )

1.1 Hypertension CARDENE I.V. (nicardipine hydrochloride) is indicated in adults 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) ].

Injection: 200 mL nicardipine (0.1 mg/mL) in either dextrose (4.8%) or sodium chloride (0.86%) as a clear, colorless solution, ready-to-use, iso-osmotic solution in a single-dose GALAXY container Injection: 200 mL nicardipine (0.2 mg/mL) in sodium chloride (0.83%) as a clear, colorless solution, ready-to-use, iso-osmotic solution in a single-dose GALAXY container Injection: 200 mL nicardipine (0.1 mg/mL) in either dextrose (4.8%) or sodium chloride (0.86%) in a single-dose, ready-to-use, iso-osmotic solution in a GALAXY container ( 3 ) Injection: 200 mL nicardipine (0.2 mg/mL) in sodium-chloride (0.83%) in a single-dose, ready-to-use, iso-osmotic solution in a GALAXY container ( 3 )

• Do not use in patients with advanced aortic stenosis ( 4.1 ).

4.1 Advanced Aortic Stenosis CARDENE I.V. is contraindicated in patients with advanced aortic stenosis because part of the effect of CARDENE I.V. is secondary to reduced afterload. Reduction of diastolic pressure in these patients may worsen rather than improve myocardial oxygen balance.

• Closely monitor response in patients with angina, heart failure, impaired hepatic function, or renal impairment. ( 5.1 , 5.2 , 5.3 , 5.4 )
• 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. Exercise extreme care to avoid intra-arterial administration or extravasation. ( 5.5 )
• To minimize the risk of peripheral venous irritation, change the site of infusion of CARDENE I.V. every 12 hours. ( 5.5 )

5.1 Exacerbation of Angina Increases in frequency, duration, or severity of angina have been seen in chronic therapy with oral nicardipine. Induction or exacerbation of angina has been seen in less than 1% of coronary artery disease patients treated with CARDENE I.V. The mechanism of this effect has not been established.

5.2 Exacerbation of Heart Failure Titrate slowly when using CARDENE I.V., particularly in combination with a beta-blocker, in patients with heart failure or significant left ventricular dysfunction because of possible negative inotropic effects.

5.3 Increased effect with Impaired Hepatic Function Since nicardipine is metabolized in the liver, consider lower dosages and closely monitor responses in patients with impaired liver function or reduced hepatic blood flow.

5.4 Prolonged effect with Impaired Renal Function When CARDENE I.V. was given to mild to moderate hypertensive patients with moderate renal impairment, a significantly lower systemic clearance and higher area under the curve (AUC) was observed. These results are consistent with those seen after oral administration of nicardipine. Titrate gradually in patients with renal impairment.

5.5 Local Irritation To reduce the possibility of venous thrombosis, phlebitis, local irritation, swelling, extravasation, and the 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, change the site of the drug infusion every 12 hours.

Most common adverse reactions: are headache (15%), hypotension (6%), tachycardia (4%) and nausea/vomiting (5%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare Corporation at 1-866-888-2472 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 CARDENE I.V. 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 CARDENE I.V. than placebo. Adverse Event Cardene I.V. (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 CARDENE I.V.: 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 CARDENE I.V. ( 7.3 , 7.4 )

7.1 Beta-Blockers In most patients, CARDENE I.V. can safely be used concomitantly with beta blockers. However, titrate slowly when using CARDENE I.V. 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 CARDENE I.V. 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 CARDENE I.V. 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.

• Pregnancy: Based on animal data may cause embryofetal harm. ( 8.1 )

8.1 Pregnancy Risk Summary Available data from published literature (clinical trials and case series) over decades of use of intravenous nicardipine during pregnancy have not identified a drug-associated risk of major birth defects or miscarriage. However, nicardipine is predominantly used in pregnancy after 20 gestational weeks. Use of nicardipine in women with preeclampsia or pre-term labor is associated with maternal and fetal/neonatal adverse events. Maternal adverse events included pulmonary edema, dyspnea, hypoxia, hypotension, reflex tachycardia, postpartum hemorrhage, tocolysis, headache, nausea, dizziness, flushing, and phlebitis at site of injection. Fetal/neonatal adverse events included transient fetal heart rate decelerations, hypotension and acidosis (pH<7.25) (see Clinical Considerations). In animal reproductive and developmental toxicity studies in which nicardipine was administered intravenously to pregnant rats and rabbits during organogenesis, increased embryolethality, but no teratogenicity occurred at a dose 0.27 times and 0.05 times the maximum recommended human dose (MRHD) in rats and rabbits, respectively. No embryotoxicity occurred in offspring of pregnant rats administered oral doses of nicardipine 8 times the oral MRHD, but did occur in offspring of pregnant rabbits with oral doses at 24 times the oral MRHD (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects is 2% to 4% and miscarriage is 15% to 20% of clinically recognized pregnancies. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and stillbirth. Pregnant women with hypertension should be carefully monitored and managed accordingly. Maternal Adverse Reactions Hypotension, reflex tachycardia, postpartum hemorrhage, tocolysis, headache, nausea, dizziness, and flushing have been reported in pregnant women who were treated with intravenous nicardipine for hypertension during pregnancy. Adverse events in women treated with intravenous nicardipine during pre-term labor include pulmonary edema, dyspnea, hypoxia, hypotension, tachycardia, headache, and phlebitis at site of injection. Manage the patient accordingly. Fetal/Neonatal Adverse Reactions Nicardipine crosses the placenta. Transient fetal heart rate decelerations have been reported. Hypotension and acidosis (pH<7.25) have also been reported in neonates. The relationship to the use of nicardipine is not clear. If fetal heart rate decelerations, or neonatal hypotension or acidosis occur, manage accordingly. Data Animal Data In embryofetal toxicity studies, no embryotoxicity or teratogenicity was seen when nicardipine was administered intravenously to pregnant rats and rabbits during organogenesis at doses up to 0.14 times the MRHD based on body surface area (mg/m2) (5 mg/kg/day in rats) and 0.03 times the MRHD based on body surface area (mg/m2) (0.5 mg/kg/day in rabbits). Embryolethality, but no teratogenicity was seen at 0.27 times the MRHD based on body surface area (mg/m2) (10 mg/kg/day) in rats and at 0.05 times the MRHD based on body surface are (mg/m2) (1 mg/kg/day) in rabbits. In other animal studies, pregnant Japanese White rabbits received oral nicardipine during organogenesis, at doses 8 and 24 times the oral MRHD based on body surface area (mg/m2) (50 and 150 mg/kg/day). Embryolethality occurred at the high dose along with signs of maternal toxicity (marked maternal weight gain suppression). New Zealand albino rabbits received oral nicardipine during organogenesis, at doses up to 16 times the oral MRHD based on body surface area (mg/m2) (100 mg/kg/day). While significant maternal mortality occurred, no adverse effects on the fetus were observed. Pregnant rats received oral nicardipine from day 6 through day 15 of gestation at doses up to 8 times the oral MRHD based on body surface area (mg/m2) (100 mg/kg/day). There was no evidence of embryolethality or teratogenicity; however, dystocia, reduced birth weights, reduced neonatal survival, and reduced neonatal weight gain were noted.

8.2 Lactation Risk Summary Nicardipine is present in human milk in low amounts. In two published clinical studies in which 18 infants were exposed to nicardipine through breast milk in the postpartum period, the calculated daily infant dose was less than 0.3 mcg. In one study, there were no adverse neonatal outcomes attributed to maternal treatment with nicardipine in breastfed infants (see Data). There are no available data on the effect of nicardipine on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CARDENE I.V. and any potential adverse effects on the breastfed infant from CARDENE I.V. or from the underlying maternal condition. Data In a study of 11 women who received oral nicardipine 4 to 14 days postpartum, 4 women received immediate-release nicardipine 40 to 80 mg daily, 6 received sustained-release nicardipine 100 to 150 mg daily, and one received intravenous nicardipine 120 mg daily. The peak milk concentration was 7.3 mcg/L (range 1.9-18.8), and the mean milk concentration was 4.4 mcg/L (range 1.3-13.8). 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 preeclampsia, 34 milk samples were obtained at unspecified times and nicardipine was undetectable (<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 < 0.3 mcg daily or between 0.015 to 0.004% of the therapeutic dose in a 1 kg infant.

8.4 Pediatric Use The safety and effectiveness of CARDENE I.V. have not been established in pediatric patients.

8.5 Geriatric Use The steady-state pharmacokinetics of nicardipine are similar in elderly hypertensive patients (>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, use low initial doses in elderly patients, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

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.