AHFS Class:

• Dihydropyridines 24:28.08

Generic Name(s):

• niCARdipine Hydrochloride

Nicardipine hydrochloride is a 1,4-dihydropyridine-derivative calcium-channel blocking agent (calcium-channel blocker).

Hypertension

Nicardipine hydrochloride is used alone or in combination with other classes of antihypertensive agents in the management of hypertension.1,2,3,1200

Calcium-channel blockers (e.g., nicardipine) are considered one of several preferred antihypertensive drugs for initial management of hypertension according to current evidence-based hypertension guidelines; other preferred options include angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and thiazide diuretics.501,502,503,504,1200 While there may be individual differences with respect to recommendations for initial drug selection and use in specific patient populations, current evidence indicates that these antihypertensive drug classes all generally produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes.501,502,504,1200,1213 (See Uses: Hypertension, in Amlodipine 24:28.08.)

Calcium-channel blockers may be beneficial in the management of hypertension in patients with certain coexisting conditions such as ischemic heart disease (e.g., angina)523 and in geriatric patients, including those with isolated systolic hypertension.502,510 (See Uses: Hypertension, in Amlodipine 24:28.08.)

In the Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study, the long-term cardiovascular morbidity and mortality benefit of a long-acting dihydropyridine calcium-channel blocker (amlodipine), a thiazide-like diuretic (chlorthalidone), and an ACE inhibitor (lisinopril) were compared in a broad population of patients with hypertension at risk for coronary heart disease.92,93,100,101,102,103 Although these antihypertensive agents were comparably effective in providing important cardiovascular benefit, apparent differences in certain secondary outcomes were observed.92,93 Patients receiving the ACE inhibitor experienced higher risks of stroke, combined cardiovascular disease, GI bleeding, and angioedema, while those receiving the calcium-channel blocker were at higher risk of developing heart failure.102,103 The ALLHAT investigators suggested that the favorable cardiovascular outcome may be attributable, at least in part, to the greater antihypertensive effect of the calcium-channel blocker compared with that of the ACE inhibitor, especially in women and black patients.102,103 (See Clinical Benefit of Thiazides in Hypertension under Hypertension in Adults: Treatment Benefits, in Uses in the Thiazides General Statement 40:28.20.)

Most patients with hypertension, especially black patients, will require at least 2 antihypertensive drugs to achieve adequate blood pressure control.1200 Calcium-channel blockers may be particularly useful in the management of hypertension in black patients;100,101,501,504,1250,1251,1252,1253,1254,1255 these patients tend to have greater blood pressure response to calcium-channel blockers and thiazide diuretics than to other antihypertensive drug classes (e.g., ACE inhibitors, angiotensin II receptor antagonists).501,504,1200 However, the combination of an ACE inhibitor or an angiotensin II receptor antagonist with a calcium-channel blocker or thiazide diuretic produces similar blood pressure lowering in black patients as in other racial groups.1200 (See Race under Hypertension: Other Special Considerations for Antihypertensive Therapy, in Uses in Amlodipine 24:28.08.)

For additional information on the role of calcium-channel blockers in the management of hypertension, see Uses: Hypertension, in Amlodipine 24:28.08. For information on overall principles and expert recommendations for treatment of hypertension, see Uses: Hypertension in Adults, in the Thiazides General Statement 40:28.20. For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.

Hypertensive Crises

Nicardipine can be used IV in the management of hypertensive crises (e.g., emergencies).18,1200 Hypertensive emergencies are those rare situations requiring immediate blood pressure reduction, although not necessarily to normal ranges, in order to prevent or limit target organ damage.1200 Such emergencies may be associated with hypertensive encephalopathy, acute myocardial infarction (MI), intracerebral hemorrhage, acute left ventricular failure with pulmonary edema, eclampsia, dissecting aortic aneurysm, unstable angina pectoris, acute ischemic stroke, and acute renal failure.1200 Patients with hypertensive emergencies require hospitalization and are treated initially with an appropriate parenteral agent.542,1200 Experts state that IV nicardipine is contraindicated in patients with advanced aortic stenosis for the management of hypertensive emergencies.1200 Experts also state that IV nicardipine is one of the preferred agents for the management of hypertensive emergency in patients with certain comorbidities such as acute coronary syndrome, acute renal failure, eclampsia or pre-eclampsia, perioperative hypertension, or acute sympathetic discharge or catecholamine excess states (e.g., pheochromocytoma, postcarotid endarterectomy status).1200

Elevated blood pressure alone, in the absence of progressive target organ damage, rarely is a hypertensive crisis requiring emergency therapy.1200 Although IV nicardipine also has been used for the management of hypertensive urgencies,18,22,23 situations in which there is severe elevation in blood pressure without progressive target organ damage, such urgencies generally can be managed by intensification or reinstitution (e.g., following noncompliance) of the current antihypertensive regimen and treatment of anxiety if needed.502,1200 Experts state that there is no need for rapid reduction of blood pressure in the emergency department in such patients and hospitalization also is unnecessary.1200

Excessive falls in blood pressure should be avoided in any hypertensive crisis since they may precipitate renal, cerebral, or coronary ischemia.542,1200

IV nicardipine also has been used for rapid reduction of blood pressure in children and adolescents† with acute severe hypertension and life-threatening symptoms.1150

Angina

Nicardipine is used orally for the management of chronic stable angina pectoris.1,3,5,25 The drug has been used alone or in combination with other antianginal agents.1,25

For additional information on the role of calcium-channel blockers in the management of angina, see Uses in Diltiazem 24:28.92, Nifedipine 24:28.08, and Verapamil 24:28.92.

Administration

Nicardipine hydrochloride usually is administered orally,1,2,5 but may be administered by slow, continuous IV infusion when oral administration is not feasible or desired.18,22,23 For prolonged therapy, patients should be transferred to oral therapy as soon as their clinical condition permits.18 Some experts state that nicardipine hydrochloride may also be administered as a direct IV (“bolus”) injection† in children and adolescents with acute severe hypertension and life-threatening symptoms.1150

Oral Administration

Nicardipine hydrochloride usually is administered orally 3 times daily as conventional capsules1 or twice daily as extended-release capsules.2 While the extent of absorption and peak concentrations achieved have been decreased by 20-30% when nicardipine hydrochloride was administered orally as conventional capsules 1 or 3 hours after a high-fat meal and by 25 and 45%, respectively, when administered orally as extended-release capsules with a high-fat meal, and such reductions may be important,1,2,5 the manufacturer states that clinical trials establishing the safety and efficacy of the drug were performed without regard to meals.1,2 Thus, these trials reflect the clinical effects of meal-induced variability.1,2

Concomitant oral administration of 1,4-dihydropyridine derivative calcium-channel blocking agents with grapefruit juice usually should be avoided since potentially clinically important increases in hemodynamic effects can result.69,85,86,87 (See Drug Interactions: Grapefruit Juice, in Nifedipine 24:28.08 .)

IV Administration

For the short-term management of hypertension when oral therapy is not feasible or desirable, nicardipine hydrochloride may be administered by slow, continuous IV infusion.18,22,23 If nicardipine hydrochloride is administered via a peripheral vein, the infusion site should be changed every 12 hours to minimize the risk of venous irritation.18 Some experts state that nicardipine hydrochloride also may be administered as a direct IV (“bolus”) injection† in children and adolescents with acute severe hypertension and life-threatening symptoms.1150

The injection concentrate must be diluted to a concentration of 0.1 mg/mL with a compatible IV infusion solution prior to administration; IV infusions may be prepared using ampuls containing nicardipine hydrochloride 2.5 mg/mL.18 Alternatively, commercially available premixed solutions containing nicardipine hydrochloride in a concentration of 0.1 mg/mL in either 4.8% dextrose or 0.86% sodium chloride injection or a concentration of 0.2 mg/mL in either 5% dextrose or 0.83% sodium chloride injection may be used; further dilution is not required.600,601 Additives should not be introduced into the premixed injection container or infused simultaneously through the same IV line, and the containers should not be used in series connections.600,601 Solutions of nicardipine hydrochloride should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.18,600,601

Blood pressure must be monitored closely during and after completion of IV administration of nicardipine.18 Rapid or excessive reduction in systolic or diastolic blood pressure during IV therapy should be avoided.18 The rate of infusion should be adjusted according to the blood pressure response.18 The time course of blood pressure reduction depends on the initial rate of infusion and the frequency of dosage adjustment.18 With constant infusion in patients not currently receiving antihypertensive therapy, blood pressure begins to decrease within minutes.18 Blood pressure decreases to approximately 50% of its ultimate reduction in about 45 minutes and does not reach steady state for about 50 hours.18

Standardize 4 Safety

Standardized concentrations for IV nicardipine have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. 249,250Multidisciplinary expert panels were convened to determine recommended standard concentrations. 249,250Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. 249,250 For additional information on S4S (including updates that may be available), see [Web].249,250

Dosage

Dosage adjustment of nicardipine hydrochloride generally does not appear to be necessary for geriatric patients unless renal and/or hepatic impairment is present.1,2

Hypertension

Oral Dosage

As monotherapy for the management of hypertension, the usual initial adult oral dosage of nicardipine hydrochloride extended-release capsules is 30 mg twice daily and the usual maintenance dosage is 30-60 mg twice daily.2,1200 The manufacturer states that the effective antihypertensive dosage range in clinical studies in adults was 30-60 mg twice daily as extended-release capsules.2

Dosage of nicardipine hydrochloride extended-release capsules should be adjusted according to the patient's blood pressure response 2-4 hours after oral dosing as well as just prior to the next dose.2 Maximal blood pressure response generally is sustained from 2-6 hours after an oral dose at steady state.2 The possibility of symptomatic hypotension should be considered during nicardipine hydrochloride dosing, particularly when initiating therapy with the drug or with upward dosage titration.2 Avoidance of hypotension is especially important in patients who have sustained an acute cerebral infarction or hemorrhage.1

When switching from conventional to extended-release nicardipine hydrochloride capsules, the total daily dose as conventional capsules may not be a useful guide in judging the effective antihypertensive dose as extended-release capsules.2 However, therapy with extended-release capsules can be initiated with the currently effective total daily dosage of conventional capsules, but administered in 2 rather than 3 divided doses, and then dosage subsequently should be adjusted according to blood pressure response and patient tolerance.1

Experts generally recommend the use of extended-release nicardipine for the management of hypertension because of less frequent dosing, potentially smoother blood pressure control,500,1200 and concerns raised by experience with short-acting (conventional, immediate-release) nifedipine.35,36,37,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,61,72,73 If nicardipine hydrochloride as conventional capsules is used, the usual initial adult oral dosage is 20 mg 3 times daily.1,5 The manufacturers state that the effective antihypertensive dosage range in clinical studies in adults was 20-40 mg 3 times daily as conventional capsules.1 Dosage of the drug should be adjusted according to the patient's peak (approximately 1-2 hours after dosing) and trough (8 hours after dosing) blood pressure responses, but generally no more frequently than at 3-day intervals.1 The possibility of substantial differences between peak and trough blood pressure responses to nicardipine should be considered.1 Because of nicardipine's prominent peak antihypertensive effect and the risk of symptomatic hypotension, assessment of blood pressure response 1-2 hours after dosing is particularly important during initial titration.1 Avoidance of hypotension is especially important in patients who have sustained an acute cerebral infarction or hemorrhage.1

Blood Pressure Monitoring and Treatment Goals

Blood pressure should be monitored regularly (i.e., monthly) during therapy and dosage of the antihypertensive drug adjusted until blood pressure is controlled.1200 If an adequate blood pressure response is not achieved with calcium-channel blocker monotherapy, the dosage may be increased or another antihypertensive agent with demonstrated benefit and preferably with a complementary mechanism of action (e.g., angiotensin-converting enzyme [ACE] inhibitor, angiotensin II receptor antagonist, thiazide diuretic) may be added; if target blood pressure is still not achieved, a third drug may be added.1200,1216 (See Uses: Hypertension.) In patients who develop unacceptable adverse effects with nicardipine, the drug should be discontinued and another antihypertensive agent from a different pharmacologic class should be initiated.1200,1216

The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure.1200 However, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial.505,506,507,508,515,523,530,1201,1207,1209,1222 A 2017 multidisciplinary hypertension guideline from the American College of Cardiology (ACC), American Heart Association (AHA), and a number of other professional organizations generally recommends a blood pressure goal of less than 130/80 mm Hg in all adults regardless of comorbidities or level of atherosclerotic cardiovascular disease (ASCVD) risk.1200,1207 Many patients will require at least 2 drugs from different pharmacologic classes to achieve their blood pressure goal; the potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs also should be considered when deciding a patient's blood pressure treatment goal.1200,1220

For additional information on target levels of blood pressure and on monitoring therapy in the management of hypertension, see Blood Pressure Monitoring and Treatment Goals under Dosage: Hypertension, in Dosage and Administration in the Thiazides General Statement 40:28.20.

IV Dosage

For the short-term management of hypertension when oral therapy is not feasible or desirable, nicardipine hydrochloride may be administered as a slow, continuous IV infusion.18,22,23 For patients who were maintained on oral nicardipine therapy and are being switched temporarily to IV therapy, the manufacturer of parenteral nicardipine hydrochloride states that the infusion rates necessary to produce an average plasma concentration equivalent to steady-state oral dosages are as follow: 0.5 mg/hour for a conventional capsule dosage of 20 mg every 8 hours, 1.2 mg/hour for a conventional capsule dosage of 30 mg every 8 hours, and 2.2 mg/hour for a conventional capsule dosage of 40 mg every 8 hours.18

For gradual reduction in acute hypertensive episodes in patients with chronic hypertension who were not receiving oral nicardipine hydrochloride therapy, the IV infusion may be initiated at a rate of 5 mg/hour.18 If the desired blood pressure reduction is not achieved at this dosage, the infusion rate may be increased by 2.5 mg/hour every 15 minutes up to a maximum of 15 mg/hour, until the desired blood pressure reduction is achieved.18 For more rapid blood pressure reduction, the infusion may be initiated at a rate of 5 mg/hour and, if the desired blood pressure reduction is not achieved at this dosage, the infusion rate may be increased by 2.5 mg/hour every 5 minutes up to a maximum of 15 mg/hour, until the desired blood pressure reduction is achieved.18 Following achievement of the desired blood pressure, the infusion rate should be decreased to 3 mg/hour.18 The rate of infusion should be adjusted as necessary to maintain the desired blood pressure response.18 If there is concern about impending hypotension or tachycardia during the infusion, the infusion should be discontinued; once blood pressure has stabilized, the infusion may be restarted at low dosages (e.g., 3-5 mg/hour) and adjusted to maintain the desired blood pressure response.18 Avoidance of hypotension is especially important in patients who have sustained an acute cerebral infarction or hemorrhage.1

When nicardipine hydrochloride is used in the management of a hypertensive emergency in adults, the usual dosage of the drug as an IV infusion is 5-15 mg/hour, adjusted according to blood pressure response and tolerance.1200 Patients who have hypertensive crisis with a compelling indication (e.g., aortic dissection, severe preeclampsia, eclampsia, pheochromocytoma crisis) should have their systolic blood pressure reduced to less than 140 mm Hg during the first hour and, in patients with acute aortic dissection, to less than 120 mm Hg within the first 20 minutes.1200 The initial goal of such therapy in adults without a compelling indication is to reduce systolic blood pressure by no more than 25% within the first hour, followed by further blood pressure reduction if stable to 160/110 to 160/100 mm Hg within the next 2-6 hours, avoiding excessive declines in pressure that could precipitate renal, cerebral, or coronary ischemia.1200 If this blood pressure is well tolerated and the patient is clinically stable, further gradual reductions toward normal can be implemented in the next 24-48 hours.1200

For rapid reduction of blood pressure in children and adolescents† with severe hypertension and life-threatening symptoms, some experts recommend administration of nicardipine hydrochloride as a rapid IV (“bolus”) dose of 30 mcg/kg (up to 2 mg) or an IV infusion of 0.5-4 mcg/kg per minute.1150 These experts suggest that blood pressure should be reduced by no more than 25% of the planned reduction over the first 8 hours.1150 For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.

For prolonged control of blood pressure, patients should be transferred to oral therapy as soon as their clinical condition permits.18 When transferring to an oral antihypertensive agent other than nicardipine, therapy generally should be initiated upon discontinuance of IV nicardipine.18 If nicardipine hydrochloride conventional capsules are to be used, the first dose of a 3-times daily regimen should be administered 1 hour prior to discontinuance of the IV infusion.18

Angina

As monotherapy for the management of chronic stable angina, the usual initial adult oral dosage of nicardipine hydrochloride as conventional capsules is 20 mg 3 times daily.1,5 Subsequent dosage should be individualized according to patient tolerance and response, but adjustments generally should not be made more frequently than at 3-day intervals.1 The manufacturer states that the effective antianginal dosage range is 20-40 mg 3 times daily.1 Use of extended-release capsules of the drug for the management of angina currently is not recommended by the manufacturer.2

Dosage in Renal and Hepatic Impairment

The elimination of nicardipine, including on first pass through the liver, may be impaired substantially in patients with hepatic impairment or reduced hepatic blood flow regardless of whether the drug is administered orally or parenterally.1,2 Therefore, the drug should be used with caution and the dosing frequency of conventional capsules reduced from 3 times daily to twice daily for initiation and maintenance of nicardipine hydrochloride therapy in such patients.1 Reduced dosages also should be considered for such patients receiving nicardipine IV.18 In patients with severe liver disease, oral bioavailability may be increased up to fourfold and elimination half-life prolonged substantially (e.g., to 19 hours).1,2 The use of nicardipine hydrochloride extended-release capsules has not been studied in patients with severe hepatic impairment.2 Because high doses of IV nicardipine hydrochloride (e.g., 5 mg over 20 minutes) have been reported to increase the hepatic venous gradient pressure by 4 mm Hg in cirrhotic patients, the drug should be used IV with caution in patients with portal hypertension; therefore, careful IV dosage titration also is recommended for patients with impaired renal function.18

For the management of hypertension or chronic stable angina in patients with severely impaired hepatic function, nicardipine hydrochloride should be initiated at an oral dosage of 20 mg twice daily as conventional capsules.1 Subsequent dosage should be individualized based on clinical findings, but the manufacturer recommends that a twice-daily dosing schedule be maintained.1

Careful titration of nicardipine hydrochloride dosage also is recommended for patients with renal impairment.1,2,18 The manufacturer states that plasma concentrations achieved and oral bioavailability may be increased approximately twofold with conventional capsules in patients with mild impairment (serum creatinine concentration of 1.2-5.5 mg/dL) compared with healthy individuals and twofold to threefold with extended-release capsules in patients with moderate impairment (creatinine clearance of 10-55 mL/minute) compared with those with mild impairment (creatinine clearance exceeding 55 mL/minute).1 With extended-release capsules, plasma concentrations and oral bioavailability of the drug appear to be similar in patients with mild impairment compared with healthy individuals.2 In patients with moderate renal impairment receiving IV nicardipine, systemic clearance was substantially lower and area under the plasma concentration-time curve (AUC) was substantially higher.18

For the management of hypertension or chronic stable angina in patients with renal impairment, nicardipine hydrochloride therapy should be initiated orally at a dosage of 20 mg 3 times daily as conventional capsules1,5 or 30 mg twice daily as extended-release capsules.2 Subsequent dosage should be titrated carefully based on blood pressure response and patient tolerance.1,2

Nicardipine hydrochloride shares the toxic potentials of calcium-channel blocking agents.1,2,5,18,20 In therapeutic dosages, nicardipine hydrochloride usually is well tolerated and has a relatively low incidence of adverse effects.1,2,18,28 Most adverse effects are mild in severity1,2,3,18,28 and transient,5,20,27,33 occur within the first few weeks of initiating therapy,5,33 do not require drug discontinuance,1,2,18,27,33 and occasionally may be obviated with dosage adjustment.1,2,5,18,27 The most common adverse effects and those that most frequently result in drug discontinuance are cardiovascular and nervous system effects 1,2,3,5,18,25 related to the vasodilator effects of the drug (e.g., pedal edema, flushing, palpitations, headache).1,2,18,28,29,33 Adverse effects requiring discontinuance of nicardipine therapy have occurred in approximately 9-12% of patients; in patients receiving the drug IV, the development of hypotension, headache, and/or tachycardia were the most common reasons for discontinuance, whereas in patients receiving the drug orally, headache, flushing, pedal edema, dizziness, and asthenia were the most common.1,2,18,27 A relationship between adverse effects and peak responses to nicardipine was not observed during clinical trials of the immediate-release formulation of oral nicardipine, but the possibility that adverse effects associated with reductions in blood pressure (e.g., tachycardia, hypotension) could occur during the time of the approximate peak effect of the drug should be considered.1

Cardiovascular Effects

The most common adverse cardiovascular effect of oral nicardipine is pedal edema,1,2,3,5,19,20,25,27,28,33 which occurred in up to 8% of patients receiving the drug orally in controlled clinical trials.1,2 Pedal edema is dose related,1,2,33 appears to increase with age,33 and resulted in drug discontinuance in about 1-2% of patients in controlled clinical trials.1,2,19 Peripheral or facial edema1,2,18,29 occurred in up to 1% of patients receiving nicardipine in controlled clinical trials1,2,18 and rarely resulted in drug discontinuance.1,2 Increased frequency, duration, or severity of angina on initiation of oral nicardipine therapy or at the time of an increase in dosage1,2,3,5,18,25,33 occurred in 4-7% of patients receiving the drug for angina in clinical trials.1 Increased angina was dose related and resulted in discontinuance of the drug in 3.5% of patients.1 Induction or exacerbation of angina occurred in less than 1% of patients with coronary artery disease receiving IV nicardipine in clinical trials.18 The mechanism of this effect has not been established.1,2,18 Flushing1,3,5,20,23,25,27,28,29,33 occurred in 5.6-9.7% of patients receiving nicardipine in controlled clinical trials.1 Occasionally, flushing may disappear despite continued therapy27 or require drug discontinuance.1 Hypotension1,2,5,18,20,22,23,33 occurred in 5.6% of patients receiving IV nicardipine18 but only rarely in patients receiving oral nicardipine in controlled clinical trials.1,2 Hypotension occasionally has resulted in drug discontinuance.18,22,23 Vasodilation2,18,19,23,33 occurred in 4.7% of patients receiving oral nicardipine2 and in less than 1% of patients receiving the drug IV18 in controlled clinical trials. Postural hypotension1,2,18,19,23,27,33 occurred in about 1% of patients receiving oral nicardipine2 and 1.4% of patients receiving the drug IV in controlled clinical trials.18

Ventricular extrasystoles18 occurred in 1.4% of patients receiving IV nicardipine in controlled clinical trials.18 Tachycardia,1,2,18,20,22,23,25,33 which may be sustained,1,25 occurred in about 1% of patients receiving oral nicardipine1,2 and 3.5% of patients receiving the drug IV18 in controlled clinical trials. Abnormal ECG,1,18,19,22,23,25,33 which may include ST-segment depression18,22 or inverted T waves,18 occurred in 0.6-1.4% of patients receiving nicardipine in controlled clinical trials.1,18 Palpitations1,2,3,5,19,20,28,33 occurred in 2.2-4.1% of patients receiving oral nicardipine in controlled clinical trials.1,2 Tachycardia,1,19,22 abnormal ECG,1,22 and palpitations1,19 occasionally have resulted in drug discontinuance.1 Chest pain,1,2,18,19,23 syncope,1,18,23,25,33 and ventricular tachycardia,1,2,18,25,33 each occurred in less than 1% of patients receiving nicardipine in controlled clinical trials.1,2,18 Myocardial infarction (MI)1,2,5,20,33 (possibly secondary to disease progression)18,33 occurred in less than 1% of patients receiving oral nicardipine in controlled clinical trials.1,2 Extrasystoles,18 hemopericardium,18 hypertension,18 and supraventricular tachycardia18,33 each occurred in less than 1% of patients receiving IV nicardipine in controlled clinical trials.18 Chest pain, syncope, and MI each occasionally have resulted in drug discontinuance.1 Atrial fibrillation,1,25 pericarditis,1 exertional hypotension,1 atrioventricular heart block,1,18 cerebral ischemia,1 atypical chest pain,2 peripheral vascular disorder,1,2 ventricular extrasystoles,1,2,23 and deep-vein thrombophlebitis18 each have been reported rarely in patients receiving nicardipine. Sick sinus syndrome has been reported rarely with IV nicardipine,20 and sinus node dysfunction (possibly secondary to disease progression) has occurred in patients receiving oral nicardipine.18

Nervous System Effects

The most common adverse nervous system effect of nicardipine is headache,1,2,3,5,18,19,20,23,24,27,28,29,33 which occurred in 6-8% of patients receiving the drug orally1,2 and 14.6% of patients receiving the drug IV18 in controlled clinical trials. Headache was the most frequent adverse effect resulting in drug discontinuance in controlled clinical trials, with 2.6% of patients receiving the drug orally discontinuing therapy.1,2,18,19 Occasionally, headache may disappear despite continued therapy.20 Dizziness1,2,18,19,20,23,25,28,29,33 occurred in up to 7% of patients receiving nicardipine in controlled clinical trials1,2,18 and occasionally resulted in drug discontinuance.1,2,19 Other common adverse nervous system effects of nicardipine include asthenia,1,2,18,19,20,23,24,25,33 which occurred in 0.7-5.8% of patients,1,2,18 and paresthesia,1,18,23 which occurred in up to 1% of patients receiving the drug in controlled clinical trials.1 Other adverse nervous system effects reported with oral nicardipine include somnolence1,33 and myalgia,1,3 each of which occurred in approximately 1% of patients in controlled clinical trials.1 Asthenia, somnolence, and paresthesia each have occasionally resulted in drug discontinuance.1,2 Syncope,1 malaise,1 nervousness,1 tremor,1 insomnia,1 and abnormal dreams1 each occurred in less than 1% of patients receiving oral nicardipine in clinical trials.1 Hypoesthesia18,23 and intracranial hemorrhage18,23 each occurred in less than 1% of patients receiving IV nicardipine in controlled clinical trials.18 Syncope, insomnia, and malaise each rarely have resulted in drug discontinuance.1 Hot flashes,1,2 vertigo,1,2 hyperkinesia,1,2 impotence,1,2 mental depression,1,2 confusion,1,2,18 anxiety,1,2 fatigue,3,28 cerebrovascular accident,33 cerebral ischemia,33 and hypertonia18 each have been reported rarely.

GI Effects

Nausea1,2,3,19,28,33 is the most common adverse GI effect of nicardipine, occurring in approximately 2% of patients receiving the drug orally in controlled clinical trials.1,2 Nausea rarely has resulted in drug discontinuance.1,2 Nausea and/or vomiting18,22,23 occurred in approximately 5% of patients receiving IV nicardipine in controlled clinical trials.18 Vomiting1,2,19 occurred in less than 1% of patients receiving oral nicardipine and rarely has resulted in drug discontinuance.1,2 Dyspepsia,1,18 constipation,1 dry mouth,1 abdominal pain,18,23 and diarrhea2,28 each have been reported in less than 1% of patients receiving nicardipine in controlled clinical trials.1,2,18 Dyspepsia, constipation, dry mouth, and diarrhea each rarely have resulted in drug discontinuance.1,2 Sore throat,1,2 parotitis,21 taste disturbance,28 and cholecystitis33 each have been reported rarely with oral nicardipine.

Dermatologic and Local Effects

Rash1,2,28,33 occurred in up to 1.2% of patients receiving oral nicardipine and rarely resulted in drug discontinuance.1,2 Allergic reactions1,2 have been reported rarely with oral nicardipine.1,2 Local reactions at the site of injection18,23 occurred in 1.4% and local pain18,23 occurred in 0.7% of patients receiving IV nicardipine in controlled clinical trials.18 Increased sweating2,18,23 occurred in up to 1.4% of patients receiving the drug in controlled clinical trials.2,18 Pruritus has been reported rarely with oral nicardipine.28

Other Adverse Effects

Polyuria18,22,23 occurred in 1.4% of patients receiving IV nicardipine in controlled clinical trials18 and occasionally resulted in drug discontinuance.22 Dyspnea,1,2,5,23 hypokalemia,18,23 nocturia,1 increased urinary frequency,1,2,18 hematuria,18 and pain2 each occurred in less than 1% of patients receiving the drug in controlled clinical trials.1,2,18 Infection,1,2 abnormal hepatic function test results,1,2 increased plasma renin concentrations,3 hyperglycemia,19,34 arthralgia,1,2 rhinitis,1,2 sinusitis,1,2 respiratory disorder,18 tinnitus,1,2,18,32 otic disorder,18 abnormal or blurred vision,1,2 conjunctivitis,18 thrombocytopenia,18 hypophosphatemia,18 and urinary retention26 each have been reported rarely. Blurred vision rarely resulted in drug discontinuance.2

Precautions and Contraindications

Some findings concerning possible risks of calcium-channel blocking agents have raised concerns about the safety and efficacy of these agents (mainly conventional [short-acting] preparations of nifedipine).35,36,37,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,61,72,73 (See Cautions, in Nifedipine 24:28.08.) Findings of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), which compared long-term therapy with a dihydropyridine-derivative calcium-channel blocker, a thiazide-like diuretic, or an angiotensin-converting enzyme (ACE) inhibitor, however, have failed to support these findings.93,96,100,101 (See Clinical Benefit of Thiazides in Hypertension under Hypertension in Adults: Treatment Benefits, in Uses in the Thiazides General Statement 40:28.20.)

Nicardipine shares the toxic potentials of dihydropyridine calcium-channel blocking agents, and the usual precautions of these agents should be observed.1,2,18

Because nicardipine decreases peripheral vascular resistance and occasionally causes excessive and poorly tolerated hypotension, blood pressure should be monitored carefully, especially during initiation of therapy and titration or upward adjustment of dosage.1,2,18 Nicardipine should be used with caution in patients with acute cerebral infarction or hemorrhage, and systemic hypotension should be avoided in these patients.1,2,18 In addition, the frequency, duration, and severity of angina occasionally may increase during initiation of nicardipine hydrochloride therapy or upward adjustment of dosage.1,2,18

Nicardipine hydrochloride should be used with caution and dosage titrated carefully in patients with congestive heart failure, especially in those receiving concomitant β-adrenergic blocking agents, since nicardipine has a negative inotropic effect in vitro and in some patients and may precipitate or worsen heart failure.1,2,18 Peripheral edema occurring during the course of nicardipine therapy should be investigated, especially in patients with congestive heart failure, since it may indicate deterioration in left ventricular function induced by the drug.

Nicardipine is not a β-adrenergic blocking agent and offers no protection against abrupt withdrawal of β-adrenergic blocking agents.1,2,18 If nicardipine is initiated in patients currently receiving a β-adrenergic blocking agent with the intent to withdraw the β-blocker, withdrawal of the β-adrenergic blocking agent should be done by a gradual reduction in dosage, preferably over 8-10 days.1,2,18

Although IV nicardipine has not been associated with adverse effects secondary to an excessively rapid decrease in blood pressure, reduction of blood pressure should be accomplished over as long a time period as is compatible with the patient's clinical status.18

Because there is limited clinical experience regarding usage of IV nicardipine in patients with hypertension associated with pheochromocytoma, the drug should be used with caution in such patients.18

Since nicardipine is extensively metabolized in the liver, the drug should be used with caution and in reduced dosage in patients with hepatic impairment or reduced hepatic blood flow.1,2,18,24 Bioavailability and the elimination half-life of nicardipine are increased substantially in patients with severe hepatic impairment.1,2 In addition, IV nicardipine hydrochloride should be used with caution in patients with portal hypertension since the drug reportedly increases the hepatic venous pressure gradient by 4 mm Hg in patients with cirrhosis at high doses (5 mg administered over 20 minutes).18 Nicardipine hydrochloride also should be used with caution and dosage titrated carefully in patients with impaired renal function.1,2,18 (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Nicardipine is contraindicated in patients with known hypersensitivity to the drug.1,2,18 Nicardipine also is contraindicated in patients with advanced aortic stenosis, since reduction in diastolic pressure in these patients may worsen myocardial oxygen balance.1,2,18

Pediatric Precautions

Although safety and efficacy of oral or IV nicardipine hydrochloride remain to be established in children younger than 18 years of age,1,2,18 some experts have recommended IV pediatric dosages for severe hypertension based on clinical experience.1150 (See IV Dosage under Dosage: Hypertension, in Dosage and Administration.) For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.

Geriatric Precautions

Safety and efficacy of nicardipine in the management of hypertension in geriatric patients have been established.1,2,18,20 While safety and efficacy of nicardipine in the management of chronic stable angina pectoris in geriatric patients have not been established specifically, clinical trials have included patients 65 years of age or older.1,2,20 Based on clinical studies with nicardipine that included patients in this age group, special precautions generally do not appear necessary.1,2,18,20,27,28,29 While clinical experience generally has not revealed age-related differences in pharmacokinetics, response, or tolerance,1,2,18,20 drug dosage generally should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range.20,68 The frequencies of pedal edema may be higher in geriatric patients than in younger adults, while the frequencies of flushing and headache may be lower.20,33 The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly should be considered.62,63,64,65,66,67,68

Mutagenicity and Carcinogenicity

A dose-dependent increase in thyroid hyperplasia and neoplasia (follicular adenoma and follicular carcinoma) was observed in rats receiving nicardipine hydrochloride in dosages of 5, 15, or 45 mg/kg daily for 2 years.1,2,18 One- and three-month studies in rats suggest that these observations are associated with a nicardipine-induced reduction in plasma thyroxine concentrations and subsequent increase in plasma thyrotropin (thyroid-stimulating hormone, TSH) concentrations.1,2,18 Chronic elevation of TSH is known to cause hyperstimulation of the thyroid.1,2,18 Nicardipine administration for 1 month in rats receiving an iodine-deficient diet was associated with thyroid hyperplasia that was prevented with thyroxine supplementation.1,2,18 Mice receiving nicardipine hydrochloride dosages of 100 mg/kg daily for up to 18 months did not exhibit evidence of thyroid changes or neoplasia of any tissue.1,2,18 Dogs receiving nicardipine hydrochloride dosages of 25 mg/kg daily for up to 1 year did not exhibit evidence of thyroid pathology.1,2,18 There was no evidence of adverse effects of nicardipine on thyroid function (plasma thyroxine and TSH concentrations) in humans.1,2,18

Genotoxicity tests with nicardipine conducted on microbial indicator organisms, in micronucleus tests in mice and hamsters, and in a sister chromatid exchange study in hamsters did not reveal evidence of mutagenic potential.1,2,18

Pregnancy, Fertility, and Lactation

Pregnancy

Nicardipine hydrochloride has been shown to be embryocidal in pregnant Japanese white rabbits when given at an oral daily dose of 150 mg/kg (a dosage associated with marked body weight gain suppression in the treated doe) during organogenesis but not at a daily dose of 50 mg/kg (25 times the maximum recommended human dosage).1,2,18 There was no evidence of embryotoxicity or teratogenicity when nicardipine hydrochloride was administered IV at dosages up to 5 mg/kg daily in pregnant rats or up to 0.5 mg/kg daily in pregnant rabbits.18 Embryotoxicity was observed at IV dosages of 10 mg/kg daily in rats and 1 mg/kg daily in rabbits, but there was no evidence of teratogenicity at these dosages.18 No adverse effects on the fetus were observed when New Zealand albino rabbits received nicardipine hydrochloride dosages up to 100 mg/kg daily (a dose associated with mortality in the treated doe) during organogenesis.1,2,18 Pregnant rats receiving oral nicardipine hydrochloride at dosages up to 100 mg/kg daily (50 times the maximum recommended human dosage) did not exhibit evidence of embryolethality or teratogenicity but did exhibit evidence of dystocia, reduced birthweights, reduced neonatal survival, and reduced neonatal weight gain.1,2,18 There are no adequate and controlled studies to date using nicardipine in pregnant women.1,2,18 Oral and IV nicardipine have been used effectively for the management of hypertension and preeclampsia during the third trimester in a limited number of women and were well tolerated and apparently did not affect the fetus adversely.30,31 Nicardipine crosses the placenta, but fetal plasma concentrations are only approximately 10% of concurrent maternal plasma concentrations.31 Nicardipine should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.1,2,18

Fertility

Nicardipine hydrochloride administration to male and female rats in oral dosages up to 100 mg/kg daily (50 times the maximum recommended human dosage) did not result in impaired fertility.1,2,18

Lactation

Nicardipine is distributed into milk in high concentrations in rats.1,2,18 Because of the potential for serious adverse reactions to nicardipine in nursing infants, it is recommended that women who breastfeed not be given the drug.1,2,18

Nicardipine is a 1,4-dihydropyridine derivative, and the possibility that the drug may share the drug interaction potential of nifedipine, another 1,4-dihydropyridine derivative, should be considered and the usual precautions observed. (See Drug Interactions in Nifedipine 24:28.08.)

Description

Nicardipine is a 1,4-dihydropyridine-derivative calcium-channel blocking agent that is structurally related to amlodipine, felodipine, nifedipine, and nimodipine.1,2,3,4

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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