Nicardipine

Nicardipine is an antihypertensive agent belonging to calcium channel blocker.

Nicardipine is a calcium channel blocker used for the short-term treatment of hypertension and chronic stable angina.

Rapidly and completely absorbed from the GI tract. Bioavailability of Nicardipine is Approximately 35%. Time to peak plasma concentration of Immediate-release capsule and sustained-release capsule of Nicardipine is about 30-120 min and 60-240 min respectively. Nicardipine is highly protein bound (>95%) in human plasma over a wide concentration range. Nicardipine is metabolized extensively by the hepatic cytochrome P450 enzymes, CYP2C8, 2D6, and 3A4; less than 1% of intact drug is detected in the urine. Following a radioactive oral dose in solution, 60% of the radioactivity was recovered in the urine and 35% in feces.

Nicardipine shows common side effects like Headache, upset stomach, dizziness or light-headedness, excessive tiredness, flushing, numbness, fast heartbeat, muscle cramps, constipation, heartburn, increased sweating, dry mouth, etc.

Nicardipine is available in the form of Oral capsule, Intravenous Infusions, and Injectable solution.

Nicardipine is available in India, US, Canada, Japan, China, Spain, Netherlands, Luxemburg, Frame and Germany.

Nicardipine belonging to the Calcium Channel Blocker, acts as an antihypertensive agent.

Nicardipine is a calcium entry blocker (slow channel blocker or calcium ion antagonist) that 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 produces relaxation of coronary vascular smooth muscle at drug levels that cause little or no negative inotropic effect.

The onset of action of Nicardipine occurs within 0.5- 2hours (by Oral capsule), 10-20 minutes (by IV),

The Duration of Action for Nicardipine in the body is approximately 8 hours (by Immediate release and IV), 8-12 hours (by extended).

The Tmax was found within 0.5-2 hours (by Immediate), 2-4 hours (by extended), following the administration of Nicardipine.

Nicardipine is available in the form of Oral capsule, Intravenous Infusions, and Injectable solution.

Nicardipine capsule is taken orally 2-3 times a day.

Nicardipine is used to treat high blood pressure and other heart complications. The medicine should be taken in conjunction with a proper diet and regular exercise. It is also used in managing chest pain.

Nicardipine is an antihypertensive agent belonging to calcium channel blocker.

Nicardipine inhibits calcium ion from entering the “slow channels” or select voltage-sensitive areas of vascular smooth muscle and myocardium during depolarization, producing a relaxation of coronary vascular smooth muscle and coronary vasodilation; increases myocardial oxygen delivery in patients with vasospastic angina.

Nicardipine is approved for use in the following clinical indications

• Hypertension:

Nicardipine is indicated for the treatment of hypertension. Nicardipine may be used alone or in combination with other antihypertensive drugs. In administering nicardipine it is important to be aware of the relatively large peak to trough differences in blood pressure effect.

• Stable Angina:

Nicardipine is indicated for the management of patients with chronic stable angina (effort-associated angina). Nicardipine may be used alone or in combination with beta-blockers.

Although not approved, there have been certain off-label indications. These include

• Acute aortic syndromes/acute aortic dissection
• Acute ischemic stroke, BP management with reperfusion therapy
• Intracerebral hemorrhage, acute, blood pressure management
• Subarachnoid hemorrhage, blood pressure management

• Hypertension

ORAL:

Immediate release:

Initial dose: 20 mg orally 3 times a day

Maintenance dose: 20 to 40 mg orally 3 times a day

Sustained release:

Initial dose: 30 mg orally twice a day

Maintenance dose: 30 to 60 mg orally twice a day

Substitution for immediate-release Nicardipine: Start at the current total daily dose of immediate-release Nicardipine and titrate as needed.

IV INFUSION:

Continuous IV infusion:

Initial: 5 mg/hour; titrate by 2.5 mg/hour at 5- to 15-minute intervals to achieve target blood pressure.

Maximum dose: 15 mg/hour.

Hypertensive emergency in pregnancy or postpartum (including acute-onset severe hypertension in preeclampsia/eclampsia) (off-label use) (alternative agent):

Continuous IV infusion:

Initial: 5 mg/hour; titrate by 0.5 to 1 mg/hour at 15-minute intervals to achieve target BP.

Maximum dose: 15 mg/hour.

Substitution for oral therapy (approximate equivalents):

20 mg every 8 hours oral, equivalent to 0.5 mg/hour IV infusion.

30 mg every 8 hours oral, equivalent to 1.2 mg/hour IV infusion.

40 mg every 8 hours oral, equivalent to 2.2 mg/hour IV infusion.

Conversion to oral antihypertensive agent: Initiate oral antihypertensive at the same time that IV nicardipine is discontinued; if transitioning to oral nicardipine, start oral nicardipine 1 hour prior to IV discontinuation.

• Angina Pectoris

ORAL:

Immediate release:

Initial dose: 20 mg orally 3 times a day

Maintenance dose: 20 to 40 mg orally 3 times a day

Sustained release:

Initial dose: 30 mg orally twice a day

Maintenance dose: 30 to 60 mg orally twice a day

Substitution for immediate-release Nicardipine: Start at the current total daily dose of immediate-release Nicardipine and titrate as needed.

• Acute aortic syndromes/acute aortic dissection (adjunctive agent) (off-label use)

Continuous IV infusion:

Initial: 5 mg/hour; titrate by 2.5 mg/hour at 5- to 15-minute intervals to achieve target blood pressure.

Maximum dose: 15 mg/hour. Invasive blood pressure monitoring, preferably via arterial line, in a critical care unit is recommended for appropriate dose titration.

• Acute ischemic stroke, BP management with reperfusion therapy (off-label use)

Continuous IV infusion:

Initial: 5 mg/hour; titrate by 2.5 mg/hour at 5- to 15-minute intervals.

Maximum dose: 15 mg/hour.

• Intracerebral hemorrhage, acute, blood pressure management (off-label use)

Continuous IV infusion:

Initial: 5 mg/hour; titrate by 2.5 mg/hour at 5- to 15-minute intervals to target systolic BP.

Maximum dose: 15 mg/hour.

• Subarachnoid hemorrhage, blood pressure management (off-label use)

Continuous IV infusion:

Initiate 5 mg/hour; titrate by 2.5 mg/hour at 5- to 15-minute intervals to goal target systolic BP or mean arterial pressure.

Maximum dose: 15 mg/hour.

Nicardipine is available in various strengths as 30 mg; 45 mg; 60 mg; 20 mg; 2.5 mg/mL; 0.2 mg/mL-NaCl 0.9%; 0.1 mg/mL-NaCl 0.9%; 20 mg/200 mL-NaCl 0.86%; 20 mg/200 mL-D4.8%; 40 mg/200 mL-NaCl 0.83%; 40 mg/200 mL-D5%; 0.2 mg/mL-NaCl 0.83%.

Nicardipine is available in the form of Oral capsule, Intravenous Infusions, and Injectable solution.

Avoid high-fat foods or high-fat meals, eating grapefruit and drinking grapefruit juice while taking Nicardipine.

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

• Increased Angina:

About 7% of patients in short-term, placebo-controlled angina trials have developed increased frequency, duration or severity of angina on starting NICARDIPINE or at the time of dosage increases, compared with 4% of patients on placebo. 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.

• 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. Because of prominent effects at the time of peak blood levels, initial titration should be performed with measurements of blood pressure at peak effect (1 to 2 hours after dosing) and just before the next dose.

• 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, the drug 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 Nicardipine 20 mg or 30 mg three times a day was given to hypertensive patients with mild renal impairment, mean plasma concentrations, AUC and Cmax were approximately twofold higher in renally impaired patients than in healthy controls. Doses in these patients must be adjusted.

Information not available.

Studies in rats have shown significant concentrations of Nicardipine in maternal milk following oral administration. For this reason, it is recommended that women who wish to breastfeed should not take this drug.

Pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Avoid high-fat foods or high-fat meals, eating grapefruit and drinking grapefruit juice while taking Nicardipine.

• Common Adverse effects

Flushing, Peripheral edema, Pedal edema, Headache, Hypotension, Exacerbation of angina, Asthenia, Nausea, Ventricular extrasystoles, Dizziness, Rash, Polyuria.

• Rare Adverse effects

Asthenia, Facial edema, Hypotension, Myalgia, Syncope, Tachycardia.

• Beta-Blockers:

In controlled clinical studies, adrenergic beta-receptor blockers have been frequently administered concomitantly with Nicardipine. The combination is well tolerated.

• Cimetidine:

Cimetidine increases Nicardipine plasma levels. Patients receiving the two drugs concomitantly should be carefully monitored.

• Digoxin:

Some calcium blockers may increase the concentration of digitalis preparations in the blood. Nicardipine usually does not alter the plasma levels of digoxin; however, serum digoxin levels should be evaluated after concomitant therapy with Nicardipine is initiated.

• Fentanyl Anesthesia:

Severe hypotension has been reported during fentanyl anesthesia with concomitant use of a beta-blocker and a calcium channel blocker. Even though such interactions were not seen during clinical studies with Nicardipine, an increased volume of circulating fluids might be required if such an interaction were to occur.

• Cyclosporine:

Concomitant administration of nicardipine and cyclosporine results in elevated plasma cyclosporine levels. Plasma concentrations of cyclosporine should therefore be closely monitored, and its dosage reduced accordingly, in patients treated with nicardipine.

• Tacrolimus:

Concomitant administration of oral or intravenous nicardipine and tacrolimus may result in elevated plasma tacrolimus levels through nicardipine inhibition of hepatic microsomal enzymes, including CYP3A4. Closely monitor plasma concentrations of tacrolimus during nicardipine administration and adjust the dose of tacrolimus accordingly.

The common side effect of Nicardipine include the following

• Common

Headache, upset stomach, dizziness or light-headedness, excessive tiredness, flushing, numbness, fast heartbeat, muscle cramps, constipation, heartburn, increased sweating, dry mouth.

• Rare

Swelling of the face, eyes, lips, tongue, arms, or legs, difficulty breathing or swallowing, Fainting, rash, increase in frequency or severity of chest pain (angina).

• Pregnancy

Pregnancy Category C

Nicardipine was embryonical 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 (25 times the maximum recommended antianginal or antihypertensive dose in man). No adverse effects on the fetus were observed when New Zealand albino rabbits were treated, 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 up to 100 mg/kg/day (50 times the maximum recommended human dose) there was no evidence of embryo lethality or teratogenicity. However, dystocia, reduced birth weights, reduced neonatal survival, and reduced neonatal weight gain were noted. There are no adequate and well-controlled studies in pregnant women. Nicardipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

• Nursing Mothers

Studies in rats have shown significant concentrations of Nicardipine in maternal milk following oral administration. For this reason, it is recommended that women who wish to breastfeed should not take this drug.

• Pediatric Use

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

• Geriatric Use

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, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Symptoms: 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.

Pharmacodynamic

Nicardipine, a dihydropyridine calcium-channel blocker, is used alone or with an angiotensin-converting enzyme inhibitor, to treat hypertension, chronic stable angina pectoris, and Prinzmetal's variant angina. Nicardipine is similar to other peripheral vasodilators. Nicardipine inhibits the influx of extra cellular calcium across the myocardial and vascular smooth muscle cell membranes possibly by deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum. The decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload

Pharmacokinetics

• Absorption

Rapidly and completely absorbed from the GI tract. Bioavailability of Nicardipine is Approximately 35%. Time to peak plasma concentration of Immediate-release capsule and sustained-release capsule of Nicardipine is about 30-120 min and 60-240 min respectively.

• Distribution

Nicardipine is highly protein bound (>95%) in human plasma over a wide concentration range.

• Metabolism and Excretion
  

Nicardipine is metabolized extensively by the hepatic cytochrome P450 enzymes, CYP2C8, 2D6, and 3A4; less than 1% of intact drug is detected in the urine. Following a radioactive oral dose in solution, 60% of the radioactivity was recovered in the urine and 35% in feces.

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022276s003lbl.pdf
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/019488s010lbl.pdf
• https://www.rxlist.com/cardene-drug.htm#indications
• https://www.uptodate.com/contents/nicardipine-drug-information?search=Nicardipine&source=panel_search_result&selectedTitle=1~83&usage_type=panel&kp_tab=drug_general&display_rank=1#F201141
• https://reference.medscape.com/drug/cardene-iv-nicardipine-342377#10
• https://www.drugs.com/dosage/nicardipine.html#Usual_Adult_Dose_for_Angina_Pectoris_Prophylaxis
• https://go.drugbank.com/drugs/DB00622
• https://www.mims.com/philippines/drug/info/nicardipine?mtype=generic