1.1 Hypertension

Nicardipine hydrochloride injection 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)] .

2.1 Recommended Dosing

Nicardipine hydrochloride injection is intended for intravenous use. 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.

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 30-50 mL/hr (3 - 5 mg/hr) and adjusted to maintain desired blood pressure.

2.3 Instructions for Administration

Administer nicardipine hydrochloride injection 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)].

Nicardipine hydrochloride injection is available as a single-dose vial, -

Inspect Nicardipine hydrochloride injection visually for particulate matter and discoloration prior to administration, whenever solution and container permit. 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. Nicardipine hydrochloride injection is normally a clear, colorless to yellow solution.

Do not combine Nicardipine hydrochloride 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.

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.

5.1 Exacerbation of Angina

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

5.2 Exacerbation of Heart Failure

Titrate slowly when using nicardipine hydrochloride injection, 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 Effects with Impaired Renal Function

When nicardipine hydrochloride injection 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.

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 reactions where the rate is > 3% more common on nicardipine hydrochloride injection than placebo.

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).

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 [seeWarnings 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 VitroInteraction

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

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. Consider the possibility of infant exposure when using nicardipine in nursing mothers.

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 pre-eclampsia, 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

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 (> 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.

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.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Rats treated with nicardipine in the diet (at concentrations calculated to provide daily dosage levels of 5, 15, or 45 mg/kg/day) for two years showed a dose-dependent increase in thyroid hyperplasia and neoplasia (follicular adenoma/carcinoma). One- and three-month studies in the rat have suggested that these results are linked to a nicardipine-induced reduction in plasma thyroxine (T4) levels with a consequent increase in plasma levels of thyroid stimulating hormone (TSH). Chronic elevation of TSH is known to cause hyperstimulation of the thyroid.

In rats on an iodine deficient diet, nicardipine administration for one month was associated with thyroid hyperplasia that was prevented by T4 supplementation. Mice treated with nicardipine in the diet (at concentrations calculated to provide daily dosage levels of up to 100 mg/kg/day) for up to 18 months showed no evidence of neoplasia of any tissue and no evidence of thyroid changes.

There was no evidence of thyroid pathology in dogs treated with up to 25 mg nicardipine/kg/day for one year and no evidence of effects of nicardipine on thyroid function (plasma T4 and TSH) in man.

There was no evidence of a mutagenic potential of nicardipine in a battery of genotoxicity tests conducted on microbial indicator organisms, in micronucleus tests in mice and hamsters, or in a sister chromatid exchange study in hamsters.

No impairment of fertility was seen in male or female rats administered nicardipine at oral doses as high as 100 mg/kg/day (human equivalent dose about 16 mg/kg/day, 8 times the maximum recommended oral dose).

13.3 Reproductive and Developmental Toxicology

Embryotoxicity, but no teratogenicity, was seen at intravenous doses of 10 mg nicardipine/kg/day in rats and 1 mg/kg/day in rabbits. These doses in the rat and rabbit are equivalent to human IV doses of about 1.6 mg/kg/day and 0.32 mg/kg/day respectively. (The total daily human dose delivered by a continuous IV infusion ranges from 1.2 to 6 mg/kg/day, depending on duration at different infusion rates ranging from 3 to 15 mg/hr as individual patients are titrated for optimal results.) Nicardipine was also embryotoxic when administered orally to pregnant Japanese White rabbits, during organogenesis, at 150 mg/kg/day (a dose associated with marked body weight gain suppression in the treated doe), but not at 50 mg/kg/day (human equivalent dose about 16 mg/kg/day or about 8 times the maximum recommended human oral dose). No adverse effects on the fetus were observed when New Zealand albino rabbits were treated orally, during organogenesis, with up to 100 mg nicardipine/kg/day (a dose associated with significant mortality in the treated doe). In pregnant rats administered nicardipine orally at doses of up to 100 mg/kg/day (human equivalent dose about 16 mg/kg/day) there was no evidence of embryotoxicity or teratogenicity. However, dystocia, reduced birth weight, reduced neonatal survival and reduced neonatal weight gain were noted.

16.1 How Supplied

Nicardipine Hydrochloride Injection, USP 25 mg/10 mL (2.5 mg/mL) is a Clear yellow colour solution available in single dose vial and supplied as:

Ten Single dose vials (NDC 72819-149-06) are placed in a carton (NDC 72819-149-07)

16.2 Storage and Handling

Store at 20° to 25°C (68° to 77°F), refer to USP Controlled Room Temperature.

Protect from freezing. Avoid excessive heat. Protect from light,

store in carton until ready to use. Discard unused portion.

Manufactured by:
RK Pharma Inc,
401 North Middletown Road,
Building 215/215A,
Pearl River, NY-10965, U.S.A

Distributed by:
Archis Pharma LLC,
15 Corporate PI S Ste 108
Piscataway, NJ 08854, U.S.A

Revised: 05/2023
NCH: PI-NCH-02