Antianginal – Antihypertensive
Action And Clinical Pharmacology: Nicardipine is a calcium ion influx inhibitor (calcium entry blocker or calcium ion antagonist).
The therapeutic effect of this group of drugs is believed to be related to their specific cellular action of selectively inhibiting transmembrane influx of calcium ions into cardiac muscle and vascular smooth muscle. The contractile processes of these tissues are dependent upon the movement of extracellular calcium into the cells through specific ion channels. Nicardipine blocks transmembrane influx of calcium through the slow channel without affecting to any significant degree the transmembrane influx of sodium through the fast channel. This results in a reduction of free calcium ions available within cells of the above tissues. Nicardipine does not alter total serum calcium.
The precise mechanism by which nicardipine relieves angina has not been fully determined but it is believed to be brought about largely by its vasodilator action. In effort associated angina, it appears that the action of nicardipine is related to the reduction of myocardial oxygen demand. This is probably caused by a decrease in blood pressure brought about by the reduction of peripheral resistance.
The antihypertensive effect of nicardipine is believed to be brought about largely by its vasodilatory action on peripheral blood vessels with resultant decrease in peripheral vascular resistance.
In humans, nicardipine produces a significant decrease in systemic vascular resistance. In hypertensive patients, nicardipine reduces blood pressure at rest and during isometric and dynamic exercise. In normotensive patients, a small decrease in systolic and diastolic blood pressure may accompany the fall in peripheral resistance. An increase in heart rate may occur in response to the vasodilation and decrease in blood pressure, and in a few patients this heart rate increase may be pronounced.
In a study in patients with coronary artery disease, intracoronary administration of nicardipine caused no direct myocardial depression. Nicardipine does however have a negative inotropic effect in some patients with severe left ventricular dysfunction and could lead to worsened failure (see Warnings).
Nicardipine increased the heart rate when given i.v. during acute electrophysiological studies and prolonged the corrected QT interval to a minor degree. The sinus node recovery times and SA conduction times are not affected by the drug. The PA, AH and HVintervals and the functional and effective refractory periods of the atrium were not prolonged by nicardipine and the relative and effective refractory periods of the His-Purkinje system were slightly shortened after i.v. nicardipine.
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 bundle branch-Purkinje system.
Nicardipine is rapidly and completely absorbed following oral administration and is subject to extensive first pass effect giving absolute bioavailability of about 35%. Nicardipine is highly protein bound (>95%) in human plasma over a wide concentration range.
Nicardipine is metabolized extensively by the liver, less than 1% of intact drug is detected in the urine and none of the metabolites possess significant biological activity. Following a radioactive oral dose in solution, 60% of the radioactivity was recovered in the urine and 35% in feces. Most of the dose (>90%) was recovered within 48 hours of dosing.
Of the dihydropyridine calcium channel blockers studied, all undergo biotransformation by the cytochrome P450 system, mainly via the CYP 3A4 isoenzyme. There are no studies done to indicate that nicardipine is also metabolized via this pathway.
Plasma levels of nicardipine are detectable 20 minutes following an oral dose and maximal plasma levels are observed between 30 minutes and 2 hours (mean Tmax=1 hour). When given with a high fat meal, the mean Cmax and area under the concentration-time curve were reduced by 30 and 20%, respectively.
Following oral administration, increasing doses result in a disproportionate increase in plasma levels. Steady state Cmax value following 20, 30 and 40 mg (q8h) averaged 36, 88 and 133 ng/mL, respectively. Hence, increasing the dose from 20 to 30 mg (q8h) more than doubled Cmax and increasing the dose from 20 to 40 mg (q8h) increased Cmax more than 3-fold. A similar disproportionate increase in AUC with dose was observed. Steady state plasma levels are achieved after 2 to 3 days of dosing (at 20 or 30 mg q8h) and are 2- to 3-fold higher at steady state than after a single dose. No evidence of accumulation of nicardipine was observed with chronic dosing. However, considerable intersubject variability in plasma levels was observed. Postabsorption kinetics of nicardipine are also nonlinear although the terminal plasma half-life of nicardipine averaged 8.6 hours. The terminal half-life represents the elimination of less than 5% of the absorbed drug (measured by plasma concentrations). Elimination over the first 8 hours is much faster with a half-life of 2 to 4 hours.
The pharmacokinetics of nicardipine in elderly hypertensive patients are similar to those obtained in young normal adults. Pharmacokinetic parameters including the peak plasma concentration, time to peak plasma concentration, area under the concentration-time curve, terminal plasma half-life, and the extent of protein binding did not differ significantly between elderly hypertensive patients and healthy young volunteers after one week of nicardipine therapy (20 mg 3 times a day).
In patients with mild renal impairment (baseline serum creatinine concentration ranging from 1.2 to 5.5 mg/dL) nicardipine plasma levels were higher than in normal subjects. Cmax and AUC were approximately 2-fold higher in these patients.
Indications And Clinical Uses: Chronic Stable Angina: For the management of chronic stable angina (effort-associated angina) in patients who remain symptomatic despite adequate doses of beta-blockers and/or organic nitrates or who cannot tolerate those agents. Nicardipine may be tried in combination with beta adrenergic blocking drugs in chronic stable angina in patients with normal ventricular function. When such concomitant therapy is introduced, care must be taken to monitor blood pressure closely since hypotension can occur from the combined effects of drugs (see Warnings).
Hypertension: The treatment of mild to moderate essential hypertension. Nicardipine should normally be used in those patients in whom treatment with diuretics or beta-blockers has been associated with unacceptable adverse effects.
Nicardipine can be tried as initial agent in those patients in whom the use of diuretics and/or beta-blockers is contraindicated or in patients with medical conditions in which these drugs frequently cause serious adverse effects.
Combination of nicardipine with a diuretic or a beta-blocker has been found to be compatible and showed additive antihypertensive effect.
Safety of concurrent use of nicardipine with other antihypertensive agents has not been established and such use cannot be recommended at this time.
Contra-Indications: Patients with hypersensitivity to the drug.
Since a major part of the effect of nicardipine is secondary to reduced afterload, the drug should not be given to patients with advanced valvular aortic stenosis. Reduction of diastolic pressure in these patients may worsen rather than improve myocardial oxygen balance.
In patients with severe hypotension (less than 90 mmHg systolic).
Nicardipine is contraindicated in patients with acute myocardial infarction (see Warnings, Myocardial Infarction).
Manufacturers’ Warnings In Clinical States: Congestive Heart Failure: Because nicardipine has a negative inotropic effect in vitro and in some patients, it should be used with caution and under careful medical supervision in patients with congestive heart failure, particularly when used in combination with a beta-blocker (see Pharmacology).
Hypotension: 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 include measurements of blood pressure at peak effect (1 to 2 hours after dosing).
In patients with angina or arrhythmias using antihypertensive drugs, the additional hypotensive effect of nicardipine should be taken into consideration (see Indications).
Increased Angina: Approximately 5% of patients have developed increased frequency, duration or severity of angina on starting nicardipine or at the time of dosage increases, or during the course of treatment. The mechanism of this effect has not been established but could result from decreased coronary perfusion associated with decreased diastolic pressure and increased heart rate (see Adverse Effects).
Myocardial Infarction: Although there has not been a study of nicardipine in acute myocardial infarction reported, the use of nicardipine may have effects similar to those of the immediate-release formulation of the dihydropyridine, nifedipine, in acute myocardial infarction. Nicardipine should not be used within one week after myocardial infarction and not before the patient has stabilized.
Unstable Angina: Some clinical trials have shown that treatment with the immediate-release formulation of the dihydropyridine, nifedipine, in this setting increases the risk of myocardial infarction and recurrent ischemia.
Acute Reduction of Blood Pressure: Nicardipine should not be used for acute reduction of blood pressure. Strokes have occurred when immediate-release formulations of dihydropyridines were used in this setting.
Beta-blocker Withdrawal: Nicardipine gives no protection against the dangers of abrupt b-blocker withdrawal; any such withdrawal should be gradual reduction of the dose of beta-blockers.
Patients with Impaired Hepatic Function: 12 patients with severe liver disease given 20 mg of nicardipine b.i.d. for 6 days developed elevated blood levels (4 fold increase in AUC) and prolonged half-life (19 hours) of nicardipine. At this time there is insufficient data to recommend an appropriate dosing schedule in this group of patients. I.V. nicardipine at high doses (5 mg/20 minutes) has been reported to worsen portal vein hypertension and portal-systemic collateral blood flow index in cirrhotic patients.
Precautions: Peripheral Edema: Mild to moderate peripheral edema associated with arterial vasodilation has been reported to occur in patients treated with nicardipine (see Adverse Effects). Care should be taken to differentiate this peripheral edema from the effects of increasing left ventricular dysfunction.
Patients with Impaired Renal Function: Following a single dose or steady state treatment, patients with impaired renal function exhibited decreased nicardipine clearance, higher peak plasma concentrations and AUC which were approximately 2 fold that of healthy controls. Careful dose titration beginning with 20 mg nicardipine, thrice daily is advised when treating renally impaired patients. Medical supervision is recommended.
Pregnancy: The use of nicardipine has not been studied in pregnant women. Nicardipine should be used in pregnancy only if the potential benefit outweighs the potential risk to the fetus.
No adverse effects on mating, fertility or reproductive indices were found in rats. However, dystocia, reduced birth rate, reduced neonatal survival and reduced weight gains of pups were observed. Nicardipine was not teratogenic in rat or rabbit.
Lactation: Studies in rats reveal significant concentrations of nicardipine in maternal milk following oral administration. Nicardipine should not be given to nursing mothers.
Children: The safety of nicardipine in children has not been established.
Geriatrics: Pharmacokinetic parameters did not differ between elderly patients (65 years of age or older) and healthy adult subjects. However, since the elderly are less tolerant to side effects such as hypotension and dizziness, particular care in titration is advisable.
Interaction with Grapefruit Juice: Published data indicate that through inhibition of cytochrome P450, grapefruit juice can increase plasma levels and augment pharmacodynamic effects of dihydropyridine calcium channel blockers. Therefore, consumption of grapefruit juice prior to or during treatment with nicardipine should be avoided.
Drug Interactions: As with all drugs, care should be exercised when treating patients with multiple medications. Dihydropyridine calcium channel blockers undergo biotransformation by the cytochrome P450 system, mainly via the CYP 3A4 isoenzyme (see Pharmacology). Coadministration of nicardipine with other drugs which follow the same route of biotransformation may result in altered bioavailability. Dosages of similarly metabolized drugs, particularly those of low therapeutic ratio, and especially in patients with renal and/or hepatic impairment, may require adjustment when starting or stopping concomitantly administered nicardipine to maintain optimum therapeutic blood levels.
Drugs known to be inhibitors of the cytochrome P450 system include: azole antifungals, cimetidine, cyclosporine, erythromycin, quinidine, terfenadine, warfarin.
Drugs known to be inducers of the cytochrome P450 system include: phenobarbital, phenytoin, rifampin.
Drugs known to be biotransformed via P450 include: benzodiazepines, flecainide, imipramine, propafenone, theophylline.
Beta-blockers: When beta-adrenergic receptor blocking drugs are administered concomitantly with nicardipine, blood pressure and pulmonary signs and symptoms of congestive heart failure should be carefully monitored since the antihypertensive effect of beta-blockers may be augmented by nicardipine’s reduction in peripheral vascular resistance.
Short-and Long-Acting Nitrates: The combination of nicardipine with short- or long-acting nitrates did not result in any unusual or unknown side effects.
Other Antihypertensives: The concomitant use of antihypertensives such as, diuretics and beta-blockers, with nicardipine was well tolerated. At this time no data are available for other antihypertensive agents (see Indications).
Cimetidine: Cimetidine increases nicardipine plasma levels. Patients receiving these 2 drugs concomitantly should be carefully monitored.
Digoxin: Since some increase in serum digoxin levels has been observed following concomitant therapy with nicardipine, patients should be monitored for increased digoxin levels.
Fentanyl Anesthesia: Severe hypotension has been reported during fentanyl anesthesia with concomitant use of a beta-blocker and a calcium channel blocker. Although 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.
Carbamazepine: In healthy volunteers, concomitant administration with carbamazepine has been shown to result in increased plasma levels of carbamazepine (+28%) and reduced levels of nicardipine (-74%). Caution should be therefore exercised if these drugs are used concomitantly.
Adverse Reactions: Angina: Adverse effects were derived from multicenter, controlled clinical trials in 520 angina patients. Adverse effects (regardless of drug relationship) were reported in 56% of the patients on nicardipine and required discontinuation of treatment in 9%.
The most common (incidence of at least 1%) adverse effects were: headache (13%), asthenia (13%), dizziness (11%), pedal edema (8%), flushing (7%), palpitation (6%), dyspepsia (5%), nausea (4%), myalgia (3%), nervousness (3%), somnolence (3%), tachycardia (3%), dyspnea (3%), rash (2%), dry mouth (2%), infection (2%), constipation (2%), diarrhea (2%), gastrointestinal pain (2%), arthralgia (2%), paresthesia (2%), insomnia (1%), vomiting (1%).
In addition, the following events were reported in less than 1% of cases: Cardiovascular: sustained tachycardia, syncope, atrial fibrillation, myocardial infarction, cerebral ischemia, sudden death, ventricular and supraventricular tachycardia, hypotension, atypical chest pain, peripheral vascular disorder, postural hypotension, ventricular extrasystoles, AV block, sinus node dysfunction, bigeminy, hypertension, vasodilatation.
CNS: tremor, apathy, abnormal dreams, ataxia, confusion, depression, hot flashes, paresthesia, impotence.
Gastrointestinal: flatulence, sore throat, anorexia, eructation, hepatitis, gastroenteritis.
Dermatologic: burning sensation, pruritus, dermatitis, dry skin.
Musculoskeletal: arthritis, bursitis.
Respiratory: upper respiratory infection, bronchitis, increased cough, pharyngitis, rhinitis.
Special Senses: abnormal or blurred vision, tinnitus, taste perversion, conjunctivitis.
Other: malaise, edema, polyuria, increased sweating, chills, allergic reaction, increased urinary frequency, nocturia, urinary retention, gout.
Hypertension: In 1 390 hypertensive patients treated in controlled clinical studies, with nicardipine, adverse effects (regardless of drug relationship) were reported in 61% of patients and required discontinuation of therapy in 10%.
The most common (incidence of at least 1%) adverse effects were: headache (19%), pedal edema (12%), flushing (11%), dizziness (8%), asthenia (8%), palpitation (6%), tachycardia (4%), nausea (4%), upper respiratory infection (4%), somnolence (2%), insomnia (2%), dyspepsia (2%), vomiting (2%), myalgia (2%), arthralgia (2%), dry mouth (1%), nervousness (1%), back pain (1%), atypical chest pain (1%), angina pectoris (1%), increased urinary frequency (1%), nocturia (1%), gastrointestinal pain (1%), diarrhea (1%), paresthesia (1%), arthritis (1%), rhinitis (1%), increased cough (1%), sinusitis (1%), dyspnea (1%), rash (1%), pruritus (1%).
In addition the following events were reported in less than 1% of cases: Cardiovascular: hypotension, postural hypotension, extrasystoles, ventricular extrasystoles, ventricular and supraventricular tachycardia, migraine, peripheral vascular disorder, bigeminy, pericardial effusion, syncope.
CNS: abnormal dreams, tremor, vertigo, hyperkinesia, agitation, confusion, hostility, anxiety, depression, hot flashes, decreased libido, impotence, abnormal gait, amnesia.
Gastrointestinal: constipation, flatulence, anorexia, gastrointestinal fullness, sore throat, gastroenteritis, gastritis, cholecystitis, eructation.
Dermatologic: rash, pruritus, dry skin, eczema, urticaria.
Musculoskeletal: bursitis, myasthenia.
Respiratory: epistaxis, bronchitis.
Special Senses: abnormal or blurred vision, taste perversion or loss, parosmia, scleritis, conjunctivitis, tinnitus.
Genitourinary: polyuria, urinary urgency, dysuria.
Other: malaise, chills, edema, increased sweating, allergic reaction, fever, purpura, gout.
Laboratory Tests: In rare instances, mild to moderate transient elevations of alkaline phosphatase, AST, ALT, LDH, CPK and hypokalemia have been noted during nicardipine therapy.
Thrombocytopenia has been rarely reported in association with the use of nicardipine.
Isolated cases of angioedema have been reported. Angioedema may be accompanied by breathing difficulty.
The following adverse reactions, possibly drug related, were observed with either oral or i.v. nicardipine: increased angina, sustained tachycardia, syncope, ventricular tachycardia, supraventricular tachycardia, myocardial infarction, intracranial hemorrhage, atrioventricular block, sinus node dysfunction, gingival hyperplasia, erythema multiforme, Stevens-Johnson syndrome.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: Three cases of overdosage with nicardipine have been reported. Two occurred in adults, one of whom ingested 600 mg of nicardipine and the other 2 160 mg of nicardipine in a sustained release formulation. Symptoms included marked hypotension, bradycardia, palpitations, flushing, drowsiness, confusion and slurred speech. All symptoms resolved without sequelae. The second overdosage 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. 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. I.V. calcium gluconate may help reverse the effects of calcium entry blockade.
Dosage And Administration: Angina: The dose of nicardipine should be individually titrated for each patient beginning with 20 mg 3 times daily. Doses in the range of 20 to 40 mg 3 times daily have been shown to be effective. At least 3 days should be allowed before increasing the nicardipine dose to ensure achievement of steady state plasma drug concentration.
Hypertension: Therapy should be individualized for each patient according to the blood pressure response beginning with 20 mg 3 times daily. Doses of 20 to 40 mg 3 times a day have been effective in clinical trials. Because of the prominent difference in the peak and trough plasma levels of nicardipine, careful monitoring of blood pressure is required during initiation of therapy to ensure acceptable control of blood pressure during the entire dosing interval (see Warnings). At least 3 days should be allowed before increasing the nicardipine dose to ensure achievement of steady state plasma drug concentration.
Careful titration of nicardipine is advised when the drug is to be added to existing therapies with attention to the possibility of excessive blood pressure reduction (see Indications).
Special Patient Populations: Patients with Renal Insufficiency: In patients with renal impairment, careful dose titration beginning with 20 mg t.i.d. is advised. Medical supervision is recommended (see Precautions).
Hepatic Insufficiency: See Warnings.
Geriatrics: Particular care in titration is advisable (see Precautions).
Availability And Storage: 20 mg: Each hard, opaque white/white, gelatin capsule, imprinted ROCHE on the body and “CARDENE 20 mg” on the cap, with a blue band around the capsule, contains: nicardipine HCl 20 mg. Nonmedicinal ingredients: FD&C Blue No. 2, magnesium stearate, pregelatinized cornstarch and titanium dioxide. Alcohol-, gluten-, lactose-, sugar-, sulfites- and tartrazine-free. Bottles of 100.
30 mg: Each hard, opaque dark blue/opaque light blue, gelatin capsule, imprinted ROCHE on the body and “CARDENE 30 mg” on the cap, with a blue band around the capsule, contains: nicardipine HCl 30 mg. Nonmedicinal ingredients: FD&C Blue No. 2, magnesium stearate, pregelatinized cornstarch and titanium dioxide. Alcohol-, gluten-, lactose-, sugar-, sulfites- and tartrazine-free. Bottles of 100.
Store at room temperature and dispense in light-resistant containers.
CARDENE® Roche Nicardipine HCl Antianginal – Antihypertensive