Nicardipine

Nicardipine
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]; Turky Alkathery, M.D. [3]

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Overview

Nicardipine is a Calcium Channel Blocker that is FDA approved for the treatment of short-term treatment of hypertension when oral therapy is not feasible or not desirable. Common adverse reactions include Hypotension, Peripheral edema, Tachyarrhythmia, Nausea, Vomiting, Headache.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Hypertension

• Dosing information (capsule)

• The dose of nicardipine hydrochloride should be individually adjusted according to the blood pressure response.
• Initial dosage: 20 mg PO tid.

• Dosage range: 20 mg - 40 mg PO tid. The maximum blood pressure lowering effect occurs approximately 1 to 2 hours after dosing. To assess the adequacy of blood pressure response, the blood pressure should be measured at trough (8 hours after dosing). Because of the prominent peak effects of nicardipine, blood pressure should be measured 1 to 2 hours after dosing, particularly during initiation of therapy.

• At least 3 days should be allowed before increasing the nicardipine dose to ensure achievement of steady-state plasma drug concentrations.

• Dosing information (Injection)

• _{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:

This image is provided by the National Library of Medicine.

• _{Dosage for Initiation of Therapy in a Patient Not Receiving Oral Nicardipine}

• Initiate dosage: 25 mL/hr (5.0 mg/hr).

• If desired blood pressure reduction is not achieved at this dose, the infusion rate may be increased by 12.5 mL/hr (2.5 mg/hr) every 5 minutes (for rapid titration) to 15 minutes (for gradual titration) up to a maximum of 75 mL/hr (15.0 mg/hr), until desired blood pressure reduction is achieved.

• Following achievement of the blood pressure goal utilizing rapid titration, decrease the infusion rate to 15 mL/hr (3 mg/hr).

• _{Drug Discontinuation and Transition to an Oral Antihypertensive Agent}

• Discontinuation of infusion is followed by a 50% offset of action in about 30 minutes.
• If treatment includes transfer to an oral antihypertensive agent other than oral nicardipine, initiate therapy upon discontinuation of Nicardipine I.V.Injection.
• If oral nicardipine is to be used, administer the first dose 1 hour prior to discontinuation of the infusion.

• _{Special Populations}

• Titrate Nicardipine I.V. Injection slowly in patients with heart failure or impaired hepatic or renal function.

Angina

• Dosing information (Capsule only)

• Initial dosage: 20 mg PO tid.
• Dosage range: 20 mg to 40 mg PO tid. At least 3 days should be allowed before increasing the nicardipine hydrochloride dose to ensure achievement of steady-state plasma drug concentrations.

• Concomitant Use With Other Antianginal Agents

1.Sublingual NTG may be taken as required to abort acute anginal attacks during nicardipine therapy.

2.Prophylactic Nitrate Therapy–Nicardipine may be safely coadministered with short- and long-acting nitrates.

3.Beta-blockers.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Nicardipine in adult patients.

Non–Guideline-Supported Use

Electroconvulsive therapy

• Dosing information

• Not applicable

Migraine

• Dosing information

• 20 mg PO tid.
• 20 mg PO bid.

Subarachnoid hemorrhage - Vasospasm

• Dosing information

• 0.15 mg/kg/hr .
• 0.83 mg/mL.
• 2 mg in 10 mL Intrathecal.
• 4 mg bid.

Variant angina

• Dosing information

• Intracoronary： 0.4 mg.
• Intracoronary：40-160 mg/day.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

FDA Package Insert for Nicardipine contains no information regarding FDA-labeled indications and dosage information for children.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Nicardipine in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Nicardipine in pediatric patients.

Contraindications

Nicardipine I.V. Injection is contraindicated in patients with advanced aortic stenosis because part of the effect of Nicardipine I.V. Injection is secondary to reduced afterload. Reduction of diastolic pressure in these patients may worsen rather than improve myocardial oxygen balance. Nicardipine is contraindicated in patients with hypersensitivity to the drug.

Warnings

For Nicardipine capsule

Increased Angina in Patients With Angina

In short-term, placebo-controlled angina trials with Nicardipine (an immediate release oral dosage form of nicardipine), about 7% of patients on Nicardipine (compared with 4% of patients on placebo) have developed increased frequency, duration or severity of angina. Comparisons with beta-blockers also show a greater frequency of increased angina, 4% vs 1%. The mechanism of this effect has not been established.

Use in Patients With Congestive Heart Failure

Although preliminary hemodynamic studies in patients with congestive heart failure have shown that Nicardipine reduced afterload without impairing myocardial contractility, it has a negative inotropic effect in vitro and in some patients. Caution should be exercised when using the drug in congestive heart failure patients, particularly in combination with a beta-blocker.

Beta-Blocker Withdrawal

Nicardipine is not a beta-blocker and therefore gives no protection against the dangers of abrupt beta-blocker withdrawal; any such withdrawal should be by gradual reduction of the dose of beta-blocker, preferably over 8 to 10 days.

PRECAUTIONS

General

Blood Pressure: Because Nicardipine decreases peripheral resistance, careful monitoring of blood pressure during the initial administration and titration of Nicardipine is suggested. Nicardipine, like other calcium channel blockers, may occasionally produce symptomatic hypotension. Caution is advised to avoid systemic hypotension when administering the drug to patients who have sustained an acute cerebral infarction or hemorrhage.

Use in Patients With Impaired Hepatic Function: Since the liver is the major site of biotransformation and since Nicardipine is subject to first-pass metabolism, Nicardipine should be used with caution in patients having impaired liver function or reduced hepatic blood flow. Patients with severe liver disease developed elevated blood levels (fourfold increase in AUC) and prolonged half-life (19 hours) of Nicardipine.

Use in Patients With Impaired Renal Function: When 45-mg Nicardipine bid was given to hypertensive patients with moderate renal impairment, mean AUC and Cmax values were approximately 2-fold to 3-fold higher than in patients with mild renal impairment. Doses in these patients must be adjusted. Mean AUC and Cmax values were similar in patients with mildly impaired renal function and normal volunteers.

For Nicardipine injection

Excessive Pharmacodynamic Effects

In administering 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.

Use in Patients with 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 Nicardipine I.V. The mechanism of this effect has not been established.

Use in Patients with Heart Failure

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

Use in Patients 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.

Use in Patients with Impaired Renal Function

When Nicardipine 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.

Intravenous Infusion Site

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.

Adverse Reactions

Clinical Trials Experience

For Nicardipine capsule

In multiple-dose US and foreign controlled studies, 667 patients received Nicardipine . In these studies adverse events were elicited by non-directed and in some cases directed questioning; adverse events were generally not serious and about 9% of patients withdrew prematurely from the studies because of them.

Hypertension

The incidence rates of adverse events in hypertensive patients were derived from placebo-controlled clinical trials. Following are the rates of adverse events for Nicardipine (n=322) and placebo (n=140), respectively, that occurred in 0.6% of patients or more on Nicardipine . These represent events considered probably drug related by the investigator. Where the frequency of adverse events for Nicardipine and placebo is similar, causal relationship is uncertain. The only dose-related effect was pedal edema.

This image is provided by the National Library of Medicine.

Uncontrolled experience in over 300 patients with hypertension treated for up to 27.5 months with Nicardipine has shown no unexpected adverse events or increase in incidence of adverse events compared to the controlled clinical trials.

Rare Events

The following rare adverse events have been reported in clinical trials or the literature:

Body as a Whole: infection, allergic reaction.

Cardiovascular: hypotension, atypical chest pain, peripheral vascular disorder, ventricular extrasystoles, ventricular tachycardia and angina pectoris.

Digestive: sore throat, abnormal liver chemistries.

Musculoskeletal: arthralgia.

Nervous: hot flashes, vertigo, hyperkinesia,impotence, depression, confusion and anxiety.

Respiratory: rhinitis and sinusitis.

Special Senses: tinnitus, abnormal vision and blurred vision.

Angina

Data are available from only 91 patients with chronic stable angina pectoris who received Nicardipine 30 to 60 mg administered twice daily in open-label clinical trials. Fifty-eight of these patients were treated for at least 30 days. The four most frequently reported adverse events thought by the investigators to be probably related to the use of Nicardipine were vasodilatation (5.5%), pedal edema (4.4%), asthenia (4.4%), and dizziness (3.3%).

For Nicardipine injection

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 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 Nicardipine I.V. than placebo.

This image is provided by the National Library of Medicine.

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 and deep-vein thrombophlebitis.

Digestive: dyspepsia.

Hemic and Lymphatic:thrombocytopenia.

Metabolic and Nutritional: hypophosphatemia and peripheral edema.

Nervous: confusion and hypertonia

Respiratory: respiratory disorder

Special Senses: conjunctivitis, ear disorder and 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.

Postmarketing Experience

FDA Package Insert for Abcixmab contains no information regarding Adverse Reactions.

Drug Interactions

For Nicardipine injection

Beta-Blockers

In most patients, Nicardipine I.V. Injection can safely be used concomitantly with beta blockers. However, titrate slowly when using Nicardipine I.V. Injection in combination with a beta-blocker in heart failure patients.

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.

Cyclosporine

Concomitant administration of oral nicardipine and cyclosporine results in elevated plasma cyclosporine levels. Closely monitor plasma concentrations of cyclosporine during Nicardipine I.V. Injection administration, and reduce the dose of cyclosporine accordingly.

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

Pregnancy Category (FDA): C There are no adequate and well-controlled studies of nicardipine use in pregnant women. However, limited human data in pregnant women with preeclampsia or pre-term labor are available. In animal studies, no embryotoxicity occurred in rats with oral doses 8 times the maximum recommended human dose (MRHD) based on body surface area (mg/m2), but did occur in rabbits with oral doses at 24 times the maximum recommended human dose (MRHD) based on body surface area (mg/m2). Nicardipine I.V. should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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. Fetal safety results ranged from transient fetal heart rate decelerations to no adverse events. Neonatal safety data ranged from hypotension to no adverse events.

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. Neonatal adverse events include acidosis (pH<7.25).

In embryofetal toxicity studies, 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) (rats) and 0.03 times the MRHD based on body surface area (mg/m2) (0.5 mg/kg/day) (rabbits). No embryotoxicity or teratogenicity was seen at these doses. Embryotoxicity, 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 MRHD based on body surface area (mg/m2) (50 and 150 mg/kg/day). Embryotoxicity 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 MRHD based on body surface area (mg/m2) (100 mg nicardipine/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 MRHD based on body surface area (mg/m2) (100 mg/kg/day). There was no evidence of embryotoxicity or teratogenicity; however, dystocia, reduced birth weights, reduced neonatal survival, and reduced neonatal weight gain were noted.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nicardipine in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Nicardipine during labor and delivery.

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.

Pediatric Use

Safety and efficacy in patients under the age of 18 have not been established.

Geriatic 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.

Gender

There is no FDA guidance on the use of Nicardipine with respect to specific gender populations.

Race

There is no FDA guidance on the use of Nicardipine with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Nicardipine in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Nicardipine in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Nicardipine in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Nicardipine in patients who are immunocompromised.

Administration and Monitoring

Administration

Oral and intravenous

Instructions for Administration

Administer Nicardipine I.V. by a central line or through a large peripheral vein. Change the infusion site every 12 hours if administered via peripheral vein. Nicardipine I.V. Injection is available as a single-use, ready-to-use, iso-osmotic solution for intravenous administration. No further dilution is required. Inspect Nicardipine I.V. 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 I.V. Injection is normally a clear, colorless to yellow solution. Do not combine Nicardipine I.V. Injection with any product in the same intravenous line or 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.

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.

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, infusion of Nicardipine I.V. Injection may be restarted at low doses such as 15‑25 mL/hr (3.0 - 5.0 mg/hr) and adjusted to maintain desired blood pressure.

IV Compatibility

FDA Package Insert for Nicardipine contains no information regarding IV compatibility.

Overdosage

For Nicardipine capsule

Three overdosages with Nicardipine or Nicardipine have been reported. Two occurred in adults, 1 of whom ingested 600 mg of Nicardipine and the other 2160 mg of Nicardipine . Symptoms included marked hypotension,bradycardia, palpitations, flushing, drowsiness, confusion, and slurred speech. All symptoms resolved without sequelae. The third over-dosage occurred in a 1-year-old child who ingested half of the powder in a 30-mg Nicardipine capsule. The child remained asymptomatic.

Based on results obtained in laboratory animals, overdosage 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 overdose standard measures (for example, evacuation of gastric contents, elevation of extremities, attention to circulating fluid volume, and urine output) including monitoring of cardiac and respiratory functions should be implemented. The patient should be positioned so as 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.

For Nicardipine Injection

Several overdosages with orally administered nicardipine have been reported. One adult patient allegedly ingested 600 mg of immediate-release oral nicardipine, 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, implement standard measures including monitoring of cardiac and respiratory functions. Position the patient so as to avoid cerebral anoxia. Use vasopressors for patients exhibiting profound hypotension.

Pharmacology

Template:Px
Nicardipine
Systematic (IUPAC) name
2-[benzyl(methyl)amino]ethyl methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate
Identifiers
CAS number	55985-32-5
ATC code	C08CA04
PubChem	4474
DrugBank	DB00622
Chemical data
Formula	Template:OrganicBox atomTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox
Mol. mass	479.525 g/mol
SMILES	eMolecules & PubChem
Physical data
Melt. point	136-138 °C (-80 °F)
Pharmacokinetic data
Bioavailability	?
Protein binding	>95%
Metabolism	?
Half life	8.6 hours
Excretion	?
Therapeutic considerations
Pregnancy cat.	?
Legal status	Template:Unicode Prescription only
Routes	Oral, intravenous

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.

Structure

Cardene (nicardipine hydrochloride) is a calcium ion influx inhibitor (slow channel blocker or calcium channel blocker). Nicardipine I.V. Injection for intravenous administration contains 40 mg of nicardipine hydrochloride per 200 mL (0.2 mg/mL) in either dextrose or sodium chloride. 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:

This image is provided by the National Library of Medicine.

Nicardipine hydrochloride is a greenish-yellow, odorless, crystalline powder that melts at about 169°C. It is freely soluble in chloroform, methanol, and glacial acetic acid, sparingly soluble in anhydrous ethanol, slightly soluble in n-butanol, water, 0.01 M potassium dihydrogen phosphate, acetone, and dioxane, very slightly soluble in ethyl acetate, and practically insoluble in benzene, ether, and hexane. It has a molecular weight of 515.99.

Pharmacodynamics

Hemodynamics

Nicardipine I.V. produces significant decreases in systemic vascular resistance. In a study of intra-arterially administered Nicardipine I.V., the degree of vasodilation and the resultant decrease in blood pressure were more prominent in hypertensive patients than in normotensive volunteers. Administration of Nicardipine I.V. to normotensive volunteers at dosages of 0.25 to 3.0 mg/hr for eight hours produced changes of <5 mmHg in systolic blood pressure and <3 mmHg in diastolic blood pressure.

An increase in heart rate is a normal response to vasodilation and decrease in blood pressure; in some patients these increases in heart rate may be pronounced. In placebo-controlled trials, the mean increases in heart rate were 7 ± 1 bpm in postoperative patients and 8 ± 1 bpm in patients with severe hypertension at the end of the maintenance period.

Hemodynamic studies following intravenous dosing in patients with coronary artery disease and normal or moderately abnormal left ventricular function have shown significant increases in ejection fraction and cardiac output with no significant change, or a small decrease, in left ventricular end-diastolic pressure (LVEDP). There is evidence that Nicardipine increases blood flow. Coronary dilatation induced by Nicardipine I.V. improves perfusion and aerobic metabolism in areas with chronic ischemia, resulting in reduced lactate production and augmented oxygen consumption. In patients with coronary artery disease, Nicardipine I.V., administered after beta-blockade, significantly improved systolic and diastolic left ventricular function.

In congestive heart failure patients with impaired left ventricular function, Nicardipine I.V. increased cardiac output both at rest and during exercise. Decreases in left ventricular end-diastolic pressure were also observed. However, in some patients with severe left ventricular dysfunction, it may have a negative inotropic effect and could lead to worsened failure.

“Coronary steal” has not been observed during treatment with Nicardipine I.V. (Coronary steal is the detrimental redistribution of coronary blood flow in patients with coronary artery disease from underperfused areas toward better perfused areas.) Nicardipine I.V. has been shown to improve systolic shortening in both normal and hypokinetic segments of myocardial muscle. Radionuclide angiography has confirmed that wall motion remained improved during increased oxygen demand. (Occasional patients have developed increased angina upon receiving oral nicardipine. Whether this represents coronary steal in these patients, or is the result of increased heart rate and decreased diastolic pressure, is not clear.)

In patients with coronary artery disease, Nicardipine I.V. improves left ventricular diastolic distensibility during the early filling phase, probably due to a faster rate of myocardial relaxation in previously underperfused areas. There is little or no effect on normal myocardium, suggesting the improvement is mainly by indirect mechanisms such as afterload reduction and reduced ischemia. Nicardipine I.V. has no negative effect on myocardial relaxation at therapeutic doses. The clinical benefits of these properties have not yet been demonstrated.

Electrophysiologic Effects

In general, no detrimental effects on the cardiac conduction system have been seen with Nicardipine I.V. During acute electrophysiologic studies, it increased heart rate and prolonged the corrected QT interval to a minor degree. It did not affect sinus node recovery or SA conduction times. The PA, AH, and HV intervals* or the functional and effective refractory periods of the atrium were not prolonged. The relative and effective refractory periods of the His-Purkinje system were slightly shortened.

• PA = conduction time from high to low right atrium; AH = conduction time from low right atrium to His bundle deflection, or AV nodal conduction time; HV = conduction time through the His bundle and the bundle branch-Purkinje system.

Hepatic Function

Because the liver extensively metabolizes nicardipine, plasma concentrations are influenced by changes in hepatic function. In a clinical study with oral nicardipine in patients with severe liver disease, plasma concentrations were elevated and the half-life was prolonged. Similar results were obtained in patients with hepatic disease when Nicardipine I.V. (nicardipine hydrochloride) was administered for 24 hours at 0.6 mg/hr.

Renal Function

When Nicardipine I.V. was given to mild to moderate hypertensive patients with moderate degrees of renal impairment, significant reduction in glomerular filtration rate (GFR) and effective renal plasma flow (RPF) was observed. No significant differences in liver blood flow were observed in these patients. A significantly lower systemic clearance and higher area under the curve (AUC) were observed.

When oral nicardipine (20 mg or 30 mg TID) was given to hypertensive patients with impaired renal function, mean plasma concentrations, AUC, and Cmaxwere approximately two-fold higher than in healthy controls. There is a transient increase in electrolyte excretion, including sodium.

Acute bolus administration of Nicardipine I.V. (2.5 mg) in healthy volunteers decreased mean arterial pressure and renal vascular resistance; glomerular filtration rate (GFR), renal plasma flow (RPF), and the filtration fraction were unchanged. In healthy patients undergoing abdominal surgery, Nicardipine I.V. (10 mg over 20 minutes) increased GFR with no change in RPF when compared with placebo. In hypertensive type II diabetic patients with nephropathy, oral nicardipine (20 mg TID) did not change RPF and GFR, but reduced renal vascular resistance.

Pulmonary Function

In two well-controlled studies of patients with obstructive airway disease treated with oral nicardipine, no evidence of increased bronchospasm was seen. In one of the studies, oral nicardipine improved forced expiratory volume 1 second (FEV1) and forced vital capacity (FVC) in comparison with metoprolol. Adverse experiences reported in a limited number of patients with asthma, reactive airway disease, or obstructive airway disease are similar to all patients treated with oral nicardipine.

Pharmacokinetics

Distribution

Rapid dose-related increases in nicardipine plasma concentrations are seen during the first two hours after the start of an infusion of Nicardipine I.V. Plasma concentrations increase at a much slower rate after the first few hours, and approach steady state at 24 to 48 hours. The steady-state pharmacokinetics of nicardipine are similar in elderly hypertensive patients (>65 years) and young healthy adults. On termination of the infusion, nicardipine concentrations decrease rapidly, with at least a 50% decrease during the first two hours post-infusion. The effects of nicardipine on blood pressure significantly correlate with plasma concentrations. Nicardipine is highly protein bound (>95%) in human plasma over a wide concentration range.

Following infusion, nicardipine plasma concentrations decline tri-exponentially, with a rapid early distribution phase (α-half-life of 2.7 minutes), an intermediate phase (β-half-life of 44.8 minutes), and a slow terminal phase (γ-half-life of 14.4 hours) that can only be detected after long-term infusions. Total plasma clearance (Cl) is 0.4 L/hr•kg, and the apparent volume of distribution (Vd) using a non-compartment model is 8.3 L/kg. The pharmacokinetics of Nicardipine I.V. are linear over the dosage range of 0.5 to 40.0 mg/hr.

Metabolism and Excretion

Nicardipine I.V. has been shown to be rapidly and extensively metabolized by the liver. Nicardipine does not induce or inhibit its own metabolism and does not induce or inhibit hepatic microsomal enzymes.

After coadministration of a radioactive intravenous dose of Nicardipine I.V. with an oral 30 mg dose given every 8 hours, 49% of the radioactivity was recovered in the urine and 43% in the feces within 96 hours. None of the dose was recovered as unchanged nicardipine.

Nonclinical Toxicology

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).

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.

Clinical Studies

Effects In Hypertension

In patients with mild to moderate chronic stable essential hypertension, Nicardipine I.V. (0.5 to 4.0 mg/hr) produced dose-dependent decreases in blood pressure. At the end of a 48-hour infusion at 4.0 mg/hr, the decreases were 26.0 mmHg (17%) in systolic blood pressure and 20.7 mmHg (20%) in diastolic blood pressure. In other settings (e.g., patients with severe or postoperative hypertension), Nicardipine I.V. (5 to 15 mg/hr) produced dose-dependent decreases in blood pressure. Higher infusion rates produced therapeutic responses more rapidly. The mean time to therapeutic response for severe hypertension, defined as diastolic blood pressure ≤95 mmHg or ≥25 mmHg decrease and systolic blood pressure ≤160 mmHg, was 77 ± 5.2 minutes. The average maintenance dose was 8.0 mg/hr. The mean time to therapeutic response for postoperative hypertension, defined as ≥15% reduction in diastolic or systolic blood pressure, was 11.5 ± 0.8 minutes. The average maintenance dose was 3.0 mg/hr.Deep vein thrombosis

How Supplied

For Nicardipine capsule

Nicardipine hydrochloride capsules are available containing 20 mg or 30 mg of nicardipine hydrochloride, USP. The 20 mg capsule is a hard-shell gelatin capsule with a medium blue-green opaque cap and an ivory opaque body axially imprinted with MYLAN over 1020 in black ink on both the cap and the body. They are available as follows: NDC 0378-1020-77 bottles of 90 capsules NDC 0378-1020-05 bottles of 500 capsules The 30 mg capsule is a hard-shell gelatin capsule with a bluish green opaque cap and a rich yellow opaque body axially imprinted with MYLAN over 1430 in black ink on both the cap and the body. They are available as follows: NDC 0378-1430-77 bottles of 90 capsules NDC 0378-1430-05 bottles of 500 capsules

For Nicardipine Injection

Nicardipine I.V. Injection is supplied as a single-use, ready-to-use, iso-osmotic solution for intravenous administration in a 200 mL GALAXY container with 40 mg (0.2 mg/mL) nicardipine hydrochloride in either dextrose or sodium chloride.

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Storage

For Nicardipine capsule

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

For Nicardipine Injection

Store at controlled room temperature 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.

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Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Nicardipine Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Nicardipine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

• Cardene
• Cardene IV
• Cardene SR

Look-Alike Drug Names

Nicardipine - Nifedipine Nicardipine - Nimodipine

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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