ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. In multiple-dose US and foreign controlled studies, 667 patients receivedCARDENE SR. In these studies adverse events were elicited by non-directedand in some cases directed questioning; adverse events weregenerally not serious and about 9% of patients withdrew prematurelyfrom the studies because of them.. Hypertension. The incidence rates of adverse events in hypertensive patients werederived from placebo-controlled clinical trials. Following are the ratesof adverse events for CARDENE SR (n=322) and placebo (n=140),respectively, that occurred in 0.6% of patients or more on CARDENESR. These represent events considered probably drug related by theinvestigator. Where the frequency of adverse events for CARDENE SRand placebo is similar, causal relationship is uncertain. The only dose-relatedeffect was pedal edema.Percentage of Patients With Probably Drug Related Adverse Events in Placebo-Controlled StudiesAdverse EventCARDENE SR (n=322) Placebo (n=140) Headache6.27.1Pedal Edema5.91.4Vasodilatation4.71.4Palpitation2.81.4Nausea1.90.7Dizziness1.60.7Asthenia0.90.7Postural Hypotension0.90Increased UrinaryFrequency0.60Pain0.60Rash0.60Sweating Increased0.60Vomiting0.60Incidence (%) of Discontinuations Due to Any Adverse Event in Placebo-Controlled StudiesAdverse EventCARDENE SR (n=322) Placebo (n=140) Headache2.51.4Palpitation2.20.7Dizziness1.90.7Asthenia1.90Pedal Edema1.20Nausea1.20Rash0.90.7Diarrhea0.90Tachycardia0.90Blurred Vision0.60Chest Pain0.60Face Edema0.60Myocardial Infarct0.60Vasodilatation0.60Vomiting0.60Uncontrolled experience in over 300 patients with hypertension treatedfor up to 27.5 months with CARDENE SR has shown no unexpectedadverse events or increase in incidence of adverse events compared tothe controlled clinical trials.. Rare Events. The following rare adverse events have been reported in clinical trials orthe literature:infection, allergic reaction Body as Whole: hypotension, atypical chest pain, peripheral vasculardisorder, ventricular extrasystoles, ventricular tachycardia, anginapectoris Cardiovascular: sore throat, abnormal liver chemistries Digestive: arthralgia Musculoskeletal: hot flashes, vertigo, hyperkinesia, impotence, depression,confusion, anxiety Nervous: rhinitis, sinusitis Respiratory: tinnitus, abnormal vision, blurred vision Special Senses: Angina. Data are available from only 91 patients with chronic stable anginapectoris who received CARDENE SR 30 to 60 mg administered twicedaily in open-label clinical trials. Fifty-eight of these patients weretreated for at least 30 days. The four most frequently reported adverseevents thought by the investigators to be probably related to the useof CARDENE SR were vasodilatation (5.5%), pedal edema (4.4%),asthenia (4.4%), and dizziness (3.3%).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

Carcinogenesis, Mutagenesis, Impairment of Fertility. Rats treated with nicardipine in the diet (at concentrations calculated toprovide daily dosage levels of 5, 15 or 45 mg/kg/day) for years showed adose-dependent increase in thyroid hyperplasia and neoplasia (follicularadenoma/carcinoma). One- and 3-month studies in the rat have suggestedthat these results are linked to nicardipine-induced reduction in plasmathyroxine (T4) levels with consequent increase in plasma levels ofthyroid stimulating hormone (TSH). Chronic elevation of TSH is knownto cause hyperstimulation of the thyroid. In rats on an iodine deficientdiet, nicardipine administration for month was associated with thyroidhyperplasia that was prevented by T4 supplementation. Mice treatedwith nicardipine in the diet (at concentrations calculated to provide dailydosage levels of up to 100 mg/kg/day) for up to 18 months showed noevidence of neoplasia of any tissue and no evidence of thyroid changes.There was no evidence of thyroid pathology in dogs treated with up to 25mg nicardipine/kg/day for year and no evidence of effects of nicardipineon thyroid function (plasma T4 and TSH) in man.There was no evidence of mutagenic potential of nicardipine in abattery of genotoxicity tests conducted on microbial indicator organisms,in micronucleus tests in mice and hamsters, or in sister chromatidexchange study in hamsters.No impairment of fertility was seen in male or female rats administerednicardipine at oral doses as high as 100 mg/kg/day (50 times themaximum recommended daily dose in man, assuming patient weightof 60 kg).

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Mechanism of Action. Nicardipine is calcium entry blocker (slow channel blocker or calciumion antagonist) that inhibits the transmembrane influx of calcium ionsinto cardiac muscle and smooth muscle without changing serumcalcium concentrations. The contractile processes of cardiac muscleand vascular smooth muscle are dependent upon the movement ofextracellular calcium ions into these cells through specific ion channels.The effects of nicardipine are more selective to vascular smooth musclethan cardiac muscle. In animal models, nicardipine produces relaxationof coronary vascular smooth muscle at drug levels that cause little or nonegative inotropic effect.. Pharmacokinetics and Metabolism. Nicardipine is completely absorbed following oral doses administered ascapsules, and the systemic bioavailability is about 35% following 30-mg oral dose at steady-state. The pharmacokinetics of nicardipine arenonlinear due to saturable hepatic first-pass metabolism.Following oral administration of CARDENE SR, plasma levels aredetectable as early as 20 minutes and maximal plasma levels areachieved as broad peak generally between and hours. Theaverage terminal plasma half-life of nicardipine is 8.6 hours. Followingoral administration increasing doses result in disproportionate increasesin plasma levels. Steady-state values following 30-, 45- and 60-mgdoses every 12 hours averaged 13.4, 34.0, and 58.4 ng/mL, respectively.Hence, increasing the dose twofold increases maximum plasma levels4-fold to 5-fold. similar disproportionate increase is observed withAUC. In comparison with equivalent daily doses of CARDENE capsules,CARDENE SR shows significant reduction in . CARDENE SR alsohas somewhat lower bioavailability than CARDENE except at the highestdose. Minimum plasma levels produced by equivalent daily doses aresimilar. CARDENE SR thus exhibits significantly reduced fluctuation inplasma levels in comparison to CARDENE capsules. max max When CARDENE SR was administered with high-fat breakfast, meanC was 45% lower, AUC was 25% lower and trough levels were 75%higher than when CARDENE SR was given in the fasting state. Thus,taking CARDENE SR with the meal reduced the fluctuation in plasmalevels. Clinical trials establishing the safety and efficacy of CARDENESR were carried out in patients without regard to the timing of meals. max Nicardipine is highly protein bound (>95%) in human plasma over wideconcentration range.Nicardipine is metabolized extensively by the liver; less than 1% ofintact drug is detected in the urine. Following radioactive oral dose insolution, 60% of the radioactivity was recovered in the urine and 35% infeces. Most of the dose (over 90%) was recovered within 48 hours ofdosing. Nicardipine does not induce its own metabolism and does notinduce hepatic microsomal enzymes.Nicardipine plasma levels following administration of CARDENE SRin hypertensive patients with moderate renal impairment (creatinineclearance 10 to 55 mL/min) were significantly higher following single-oraldose and at steady-state than in hypertensive patients with mildlyimpaired renal function (creatinine clearance >55 mL/min). After 45-mgCARDENE SR bid at steady-state, and AUC were 2-fold to 3-foldhigher in the patients with moderate renal impairment. Plasma levelsin patients with mildly impaired renal function were similar to those innormal subjects. max In patients with severe renal impairment undergoing routine hemodialysis,plasma levels following single dose of CARDENE SR were notsignificantly different from those patients with mildly impaired renalfunction.Because nicardipine is extensively metabolized by the liver, the plasmalevels of the drug are influenced by changes in hepatic function. Followingadministration of CARDENE capsules, nicardipine plasma levels werehigher in patients with severe liver disease (hepatic cirrhosis confirmedby liver biopsy or presence of endoscopically-confirmed esophagealvarices) than in normal subjects. After 20-mg CARDENE bid at steady-state,C and AUC were 1.8-fold and 4-fold higher, and the terminalhalf-life was prolonged to 19 hours in these patients. CARDENE SR hasnot been studied in patients with severe liver disease. max Geriatric Pharmacokinetics. The pharmacokinetics of CARDENE SR in elderly hypertensive subjects(mean age 70 years) were compared to those in younger hypertensivesubjects (mean age 44 years). After single dose and after week ofdosing with CARDENE SR there were no significant differences in ,T AUC or clearance between the young and elderly subjects. In bothgroups of subjects, steady-state plasma levels were significantly higherthan following single dose. In the elderly subjects, disproportionalincrease in plasma levels with dose was observed similar to that observedin normal subjects. max max Hemodynamics. In man, nicardipine produces significant decrease in systemic vascularresistance. The degree of vasodilation and the resultant hypotensiveeffects are more prominent in hypertensive patients. In hypertensivepatients, nicardipine reduces the blood pressure at rest and duringisometric and dynamic exercise. In normotensive patients, smalldecrease of about mm Hg in systolic and mm Hg in diastolic bloodpressure may accompany this fall in peripheral resistance. An increasein heart rate may occur in response to the vasodilation and decrease inblood pressure, and in few patients this heart rate increase may bepronounced. In clinical studies mean heart rate at time of peak plasmalevels was usually increased by to 10 beats per minute compared toplacebo, with the greater increases at higher doses, while there was nodifference from placebo at the end of the dosing interval. Hemodynamicstudies following intravenous dosing in patients with coronary arterydisease and normal or moderately abnormal left ventricular function haveshown significant increases in ejection fraction and cardiac output withno significant change, or small decrease, in left ventricular end-diastolicpressure (LVEDP). Although there is evidence that nicardipine increasescoronary blood flow, there is no evidence that this property plays anyrole in its effectiveness in stable angina. In patients with coronary arterydisease, intracoronary administration of nicardipine caused no directmyocardial depression. CARDENE does, however, have negativeinotropic effect in some patients with severe left ventricular dysfunctionand could, in patients with very impaired function, lead to worsenedfailure.Coronary Steal, the detrimental redistribution of coronary blood flowin patients with coronary artery disease (diversion of blood from under-perfusedareas toward better perfused areas), has not been observedduring nicardipine treatment. On the contrary, nicardipine has beenshown to improve systolic shortening in normal and hypokinetic segmentsof myocardial muscle, and radionuclide angiography has confirmed thatwall motion remained improved during an increase in oxygen demand.Nonetheless, occasional patients have developed increased angina uponreceiving nicardipine. Whether this represents steal in those patients, oris the result of increased heart rate and decreased diastolic pressure, isnot clear.In patients with coronary artery disease nicardipine improves L.V. diastolicdistensibility during the early filling phase, probably due to faster rateof myocardial relaxation in previously under-perfused areas. There islittle or no effect on normal myocardium, suggesting the improvement ismainly by indirect mechanisms such as afterload reduction and reducedischemia. Nicardipine has no negative effect on myocardial relaxation attherapeutic doses. The clinical consequences of these properties are asyet undemonstrated.. Electrophysiologic Effects. In general, no detrimental effects on the cardiac conduction system wereseen with the use of CARDENE.Nicardipine increased the heart rate when given intravenously duringacute electrophysiologic studies and prolonged the corrected QT intervalto minor degree. The sinus node recovery times and SA conductiontimes were not affected by the drug. The PA, AH and HV intervals andthe functional and effective refractory periods of the atrium were notprolonged by nicardipine and the relative and effective refractory periodsof the His-Purkinje system were slightly shortened after intravenousnicardipine.. Renal Function. There is transient increase in electrolyte excretion, including sodium.CARDENE does not cause generalized fluid retention, as measured byweight changes.PA=conduction time from high to low right atrium, AH=conduction timefrom low right atrium to His bundle deflection or AV nodal conductiontime, HV=conduction time through the His bundle and the bundle branch-Purkinje system.. Effects in Hypertension. CARDENE SR produced decreases in both systolic and diastolicblood pressure throughout the dosing interval in clinical trials. Theantihypertensive efficacy of CARDENE SR administered twice daily hasbeen demonstrated using in-clinic blood pressure measures in placebo-controlledtrials involving patients with mild to moderate hypertensionand in trials using 12 or 24 hour ambulatory blood pressure monitoring.

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS. CARDENE is contraindicated in patients with hypersensitivity to thedrug.Because part of the effect of CARDENE is secondary to reducedafterload, the drug is also contraindicated in patients with advancedaortic stenosis. Reduction of diastolic pressure by any means in thesepatients may worsen rather than improve myocardial oxygen balance.

DESCRIPTION SECTION.

DESCRIPTION. CARDENE SR is sustained release formulation of CARDENE .CARDENE SR capsules for oral administration each contain 30 mg, 45mg or 60 mg of nicardipine hydrochloride. Nicardipine hydrochlorideis calcium ion influx inhibitor (slow channel blocker or calcium entryblocker). (R) (R) Nicardipine hydrochloride is dihydropyridine derivative with the 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 it hasthe following structure:Nicardipine hydrochloride is greenish-yellow, odorless, crystallinepowder that melts at about 169C. It is freely soluble in chloroform,methanol and glacial acetic acid, sparingly soluble in anhydrous ethanol,slightly soluble in n-butanol, water, 0.01 potassium dihydrogenphosphate, acetone and dioxane, very slightly soluble in ethyl acetate,and practically insoluble in benzene, ether and hexane. It has molecularweight of 515.99.CARDENE SR is available in hard gelatin capsules containing 30mg, 45 mg or 60 mg nicardipine hydrochloride. All strengths containa two component capsule fill. powder component containing 25%of total nicardipine hydrochloride dose contains pregelatinized starchand magnesium stearate as inactive ingredients. spherical granulecomponent containing 75% of total nicardipine hydrochloride dose alsocontains microcrystalline cellulose, starch, lactose and methacrylic acidcopolymer Type as inactive ingredients.The colorants used in the 30-mg capsules are titanium dioxide, FD&CRed No. 40 and red iron oxide, and the colorants used in the 45-mg and60-mg capsule are titanium dioxide and FD&C Blue No. 2.. nicardipine hydrochloride.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. The dose of CARDENE SR should be individually adjusted according tothe blood pressure response beginning with 30 mg two times daily. Theeffective doses in clinical trials have ranged from 30 mg to 60 mg twotimes daily. The maximum blood pressure lowering effect at steady-stateis sustained from hours until hours after dosing.When initiating therapy or upon increasing dose, blood pressure shouldbe measured to hours after the first dose or dose increase, as well asat the end of dosing interval.The total daily dose of immediate release nicardipine (CARDENE) maynot be useful guide to judging the effective dose of CARDENE SR.Patients currently receiving immediate release nicardipine may be titratedwith CARDENE SR starting at their current total daily dose of immediaterelease nicardipine and then reexamined to assess the adequacy of bloodpressure control.Concomitant Use With Other Antihypertensive Agents:: CARDENE may be safely coadministered with thiazidediuretics. Diuretics CARDENE may be safely coadministered with beta-blockers(see ). Beta-Blockers Drug Interactions : CARDENE may be safely coadministered with thiazidediuretics. Diuretics : CARDENE may be safely coadministered with beta-blockers(see ). Beta-Blockers Drug Interactions Special Patient Populations. Although there is no evidence that CARDENESR impairs renal function, careful dose titration beginning with 30-mgCARDENE SR bid is advised (see ). Renal Insufficiency: PRECAUTIONS CARDENE SR has not been studied in patientswith severe liver impairment (see ). Hepatic Insufficiency: PRECAUTIONS Caution is advised when titrating CARDENESR dosage in patients with congestive heart failure (see ). Congestive Heart Failure: WARNINGS.

DRUG INTERACTIONS SECTION.

Drug Interactions. In controlled clinical studies, adrenergic beta-receptorblockers have been frequently administered concomitantly withCARDENE. The combination is well tolerated. Beta-Blockers: Cimetidine increases CARDENE plasma levels. Patientsreceiving the two drugs concomitantly should be carefully monitored. Cimetidine: Some calcium blockers may increase the concentration ofdigitalis preparations in the blood. CARDENE usually does not alterthe plasma levels of digoxin; however, serum digoxin levels should beevaluated after concomitant therapy with CARDENE is initiated. Digoxin: Severe hypotension has been reported duringfentanyl anesthesia with concomitant use of beta-blocker and calciumchannel blocker. Even though such interactions were not seen duringclinical studies with CARDENE, an increased volume of circulating fluidsmight be required if such an interaction were to occur. Fentanyl Anesthesia: Concomitant administration of nicardipine and cyclosporineresults in elevated plasma cyclosporine levels. Plasma concentrationsof cyclosporine should therefore be closely monitored, and its dosagereduced accordingly, in patients treated with nicardipine. Cyclosporine: When therapeutic concentrations of furosemide, propranolol, dipyridamole,warfarin, quinidine or naproxen were added to human plasma (in vitro),the plasma protein binding of CARDENE was not altered.

GENERAL PRECAUTIONS SECTION.

General. Because CARDENE decreases peripheral resistance,careful monitoring of blood pressure during the initial administrationand titration of CARDENE is suggested. CARDENE, like other calciumchannel blockers, may occasionally produce symptomatic hypotension.Caution is advised to avoid systemic hypotension when administeringthe drug to patients who have sustained an acute cerebral infarction orhemorrhage. Blood Pressure: Since the liver is themajor site of biotransformation and since CARDENE is subject to first-passmetabolism, CARDENE should be used with caution in patientshaving impaired liver function or reduced hepatic blood flow. Patientswith severe liver disease developed elevated blood levels (fourfoldincrease in AUC) and prolonged half-life (19 hours) of CARDENE. Use in Patients With Impaired Hepatic Function: When 45-mg CARDENESR bid was given to hypertensive patients with moderate renalimpairment, mean AUC and values were approximately 2-fold to3-fold higher than in patients with mild renal impairment. Doses in thesepatients must be adjusted. Mean AUC and values were similar inpatients with mildly impaired renal function and normal volunteers (see and ). Use in Patients With Impaired Renal Function: max max CLINICAL PHARMACOLOGY DOSAGE AND ADMINISTRATION.

GERIATRIC USE SECTION.

Geriatric use. Pharmacokinetic parameters did not differ significantly between elderlyhypertensive subjects (mean age: 70 years) and younger hypertensivesubjects (mean age: 44 years) after week of treatment with CARDENESR (see ). CLINICAL PHARMACOLOGY: Geriatric Pharmacokinetics Clinical studies of nicardipine did not include sufficient numbers ofsubjects aged 65 and over to determine whether they respond differentlyfrom younger subjects. Other reported clinical experience has notidentified differences in responses between the elderly and youngerpatients. In general, dose selection for an elderly patient should becautious, usually starting at the low end of the dosing range, reflectingthe greater frequency of decreased hepatic, renal, or cardiac function,and of concomitant disease or other drug therapy.

HOW SUPPLIED SECTION.

HOW SUPPLIED. NDC:68151-0089-0 in PACKAGE of CAPSULE, EXTENDED RELEASES.

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. CARDENE SR is indicated for the treatment of hypertension. CARDENESR may be used alone or in combination with other anti-hypertensivedrugs.

MECHANISM OF ACTION SECTION.

Mechanism of Action. Nicardipine is calcium entry blocker (slow channel blocker or calciumion antagonist) that inhibits the transmembrane influx of calcium ionsinto cardiac muscle and smooth muscle without changing serumcalcium concentrations. The contractile processes of cardiac muscleand vascular smooth muscle are dependent upon the movement ofextracellular calcium ions into these cells through specific ion channels.The effects of nicardipine are more selective to vascular smooth musclethan cardiac muscle. In animal models, nicardipine produces relaxationof coronary vascular smooth muscle at drug levels that cause little or nonegative inotropic effect.

NURSING MOTHERS SECTION.

Nursing Mothers. Studies in rats have shown significant concentrations of nicardipinein maternal milk following oral administration. For this reason it isrecommended that women who wish to breastfeed should not take thisdrug.

OVERDOSAGE SECTION.

OVERDOSAGE. Three overdosages with CARDENE or CARDENE SR have beenreported. Two occurred in adults, of whom ingested 600 mg ofCARDENE and the other 2160 mg of CARDENE SR. Symptoms includedmarked hypotension, bradycardia, palpitations, flushing, drowsiness,confusion, and slurred speech. All symptoms resolved without sequelae.The third over-dosage occurred in 1-year-old child who ingested halfof the powder in 30-mg CARDENE capsule. The child remainedasymptomatic.Based on results obtained in laboratory animals, overdosage may causesystemic hypotension, bradycardia (following initial tachycardia) andprogressive atrioventricular conduction block. Reversible hepatic functionabnormalities and sporadic focal hepatic necrosis were noted in someanimal species receiving very large doses of nicardipine.standard measures (for example, evacuationof gastric contents, elevation of extremities, attention to circulating fluidvolume, and urine output) including monitoring of cardiac and respiratoryfunctions should be implemented. The patient should be positioned soas to avoid cerebral anoxia. Frequent blood pressure determinations areessential. Vasopressors are clinically indicated for patients exhibitingprofound hypotension. Intravenous calcium gluconate may help reversethe effects of calcium entry blockade. For treatment of overdose.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Nicardipine HCL 30 mg SR caps. Label Image.

PEDIATRIC USE SECTION.

Pediatric Use. Safety and effectiveness in pediatric patients have not beenestablished.

PHARMACOKINETICS SECTION.

Pharmacokinetics and Metabolism. Nicardipine is completely absorbed following oral doses administered ascapsules, and the systemic bioavailability is about 35% following 30-mg oral dose at steady-state. The pharmacokinetics of nicardipine arenonlinear due to saturable hepatic first-pass metabolism.Following oral administration of CARDENE SR, plasma levels aredetectable as early as 20 minutes and maximal plasma levels areachieved as broad peak generally between and hours. Theaverage terminal plasma half-life of nicardipine is 8.6 hours. Followingoral administration increasing doses result in disproportionate increasesin plasma levels. Steady-state values following 30-, 45- and 60-mgdoses every 12 hours averaged 13.4, 34.0, and 58.4 ng/mL, respectively.Hence, increasing the dose twofold increases maximum plasma levels4-fold to 5-fold. similar disproportionate increase is observed withAUC. In comparison with equivalent daily doses of CARDENE capsules,CARDENE SR shows significant reduction in . CARDENE SR alsohas somewhat lower bioavailability than CARDENE except at the highestdose. Minimum plasma levels produced by equivalent daily doses aresimilar. CARDENE SR thus exhibits significantly reduced fluctuation inplasma levels in comparison to CARDENE capsules. max max When CARDENE SR was administered with high-fat breakfast, meanC was 45% lower, AUC was 25% lower and trough levels were 75%higher than when CARDENE SR was given in the fasting state. Thus,taking CARDENE SR with the meal reduced the fluctuation in plasmalevels. Clinical trials establishing the safety and efficacy of CARDENESR were carried out in patients without regard to the timing of meals. max Nicardipine is highly protein bound (>95%) in human plasma over wideconcentration range.Nicardipine is metabolized extensively by the liver; less than 1% ofintact drug is detected in the urine. Following radioactive oral dose insolution, 60% of the radioactivity was recovered in the urine and 35% infeces. Most of the dose (over 90%) was recovered within 48 hours ofdosing. Nicardipine does not induce its own metabolism and does notinduce hepatic microsomal enzymes.Nicardipine plasma levels following administration of CARDENE SRin hypertensive patients with moderate renal impairment (creatinineclearance 10 to 55 mL/min) were significantly higher following single-oraldose and at steady-state than in hypertensive patients with mildlyimpaired renal function (creatinine clearance >55 mL/min). After 45-mgCARDENE SR bid at steady-state, and AUC were 2-fold to 3-foldhigher in the patients with moderate renal impairment. Plasma levelsin patients with mildly impaired renal function were similar to those innormal subjects. max In patients with severe renal impairment undergoing routine hemodialysis,plasma levels following single dose of CARDENE SR were notsignificantly different from those patients with mildly impaired renalfunction.Because nicardipine is extensively metabolized by the liver, the plasmalevels of the drug are influenced by changes in hepatic function. Followingadministration of CARDENE capsules, nicardipine plasma levels werehigher in patients with severe liver disease (hepatic cirrhosis confirmedby liver biopsy or presence of endoscopically-confirmed esophagealvarices) than in normal subjects. After 20-mg CARDENE bid at steady-state,C and AUC were 1.8-fold and 4-fold higher, and the terminalhalf-life was prolonged to 19 hours in these patients. CARDENE SR hasnot been studied in patients with severe liver disease. max.

PRECAUTIONS SECTION.

PRECAUTIONS. General. Because CARDENE decreases peripheral resistance,careful monitoring of blood pressure during the initial administrationand titration of CARDENE is suggested. CARDENE, like other calciumchannel blockers, may occasionally produce symptomatic hypotension.Caution is advised to avoid systemic hypotension when administeringthe drug to patients who have sustained an acute cerebral infarction orhemorrhage. Blood Pressure: Since the liver is themajor site of biotransformation and since CARDENE is subject to first-passmetabolism, CARDENE should be used with caution in patientshaving impaired liver function or reduced hepatic blood flow. Patientswith severe liver disease developed elevated blood levels (fourfoldincrease in AUC) and prolonged half-life (19 hours) of CARDENE. Use in Patients With Impaired Hepatic Function: When 45-mg CARDENESR bid was given to hypertensive patients with moderate renalimpairment, mean AUC and values were approximately 2-fold to3-fold higher than in patients with mild renal impairment. Doses in thesepatients must be adjusted. Mean AUC and values were similar inpatients with mildly impaired renal function and normal volunteers (see and ). Use in Patients With Impaired Renal Function: max max CLINICAL PHARMACOLOGY DOSAGE AND ADMINISTRATION Drug Interactions. In controlled clinical studies, adrenergic beta-receptorblockers have been frequently administered concomitantly withCARDENE. The combination is well tolerated. Beta-Blockers: Cimetidine increases CARDENE plasma levels. Patientsreceiving the two drugs concomitantly should be carefully monitored. Cimetidine: Some calcium blockers may increase the concentration ofdigitalis preparations in the blood. CARDENE usually does not alterthe plasma levels of digoxin; however, serum digoxin levels should beevaluated after concomitant therapy with CARDENE is initiated. Digoxin: Severe hypotension has been reported duringfentanyl anesthesia with concomitant use of beta-blocker and calciumchannel blocker. Even though such interactions were not seen duringclinical studies with CARDENE, an increased volume of circulating fluidsmight be required if such an interaction were to occur. Fentanyl Anesthesia: Concomitant administration of nicardipine and cyclosporineresults in elevated plasma cyclosporine levels. Plasma concentrationsof cyclosporine should therefore be closely monitored, and its dosagereduced accordingly, in patients treated with nicardipine. Cyclosporine: When therapeutic concentrations of furosemide, propranolol, dipyridamole,warfarin, quinidine or naproxen were added to human plasma (in vitro),the plasma protein binding of CARDENE was not altered.. Carcinogenesis, Mutagenesis, Impairment of Fertility. Rats treated with nicardipine in the diet (at concentrations calculated toprovide daily dosage levels of 5, 15 or 45 mg/kg/day) for years showed adose-dependent increase in thyroid hyperplasia and neoplasia (follicularadenoma/carcinoma). One- and 3-month studies in the rat have suggestedthat these results are linked to nicardipine-induced reduction in plasmathyroxine (T4) levels with consequent increase in plasma levels ofthyroid stimulating hormone (TSH). Chronic elevation of TSH is knownto cause hyperstimulation of the thyroid. In rats on an iodine deficientdiet, nicardipine administration for month was associated with thyroidhyperplasia that was prevented by T4 supplementation. Mice treatedwith nicardipine in the diet (at concentrations calculated to provide dailydosage levels of up to 100 mg/kg/day) for up to 18 months showed noevidence of neoplasia of any tissue and no evidence of thyroid changes.There was no evidence of thyroid pathology in dogs treated with up to 25mg nicardipine/kg/day for year and no evidence of effects of nicardipineon thyroid function (plasma T4 and TSH) in man.There was no evidence of mutagenic potential of nicardipine in abattery of genotoxicity tests conducted on microbial indicator organisms,in micronucleus tests in mice and hamsters, or in sister chromatidexchange study in hamsters.No impairment of fertility was seen in male or female rats administerednicardipine at oral doses as high as 100 mg/kg/day (50 times themaximum recommended daily dose in man, assuming patient weightof 60 kg).. Pregnancy. Pregnancy Category C. Nicardipine was embryocidal when administeredorally to pregnant Japanese White rabbits, during organogenesis,at 150 mg/kg/day (a dose associated with marked body weight gainsuppression in the treated doe) but not at 50 mg/kg/day (25 times themaximum recommended dose in man). No adverse effects on thefetus were observed when New Zealand albino rabbits were treated,during organogenesis, with up to 100 mg nicardipine/kg/day (a doseassociated with significant mortality in the treated doe). In pregnantrats administered nicardipine orally at up to 100 mg/kg/day (50 timesthe maximum recommended human dose) there was no evidence ofembryolethality or teratogenicity. However, dystocia, reduced birthweights, reduced neonatal survival and reduced neonatal weight gainwere noted. There are no adequate and well-controlled studies inpregnant women. CARDENE SR should be used during pregnancy onlyif the potential benefit justifies the potential risk to the fetus.. Nursing Mothers. Studies in rats have shown significant concentrations of nicardipinein maternal milk following oral administration. For this reason it isrecommended that women who wish to breastfeed should not take thisdrug.. Pediatric Use. Safety and effectiveness in pediatric patients have not beenestablished.. Geriatric use. Pharmacokinetic parameters did not differ significantly between elderlyhypertensive subjects (mean age: 70 years) and younger hypertensivesubjects (mean age: 44 years) after week of treatment with CARDENESR (see ). CLINICAL PHARMACOLOGY: Geriatric Pharmacokinetics Clinical studies of nicardipine did not include sufficient numbers ofsubjects aged 65 and over to determine whether they respond differentlyfrom younger subjects. Other reported clinical experience has notidentified differences in responses between the elderly and youngerpatients. In general, dose selection for an elderly patient should becautious, usually starting at the low end of the dosing range, reflectingthe greater frequency of decreased hepatic, renal, or cardiac function,and of concomitant disease or other drug therapy.

PREGNANCY SECTION.

Pregnancy. Pregnancy Category C. Nicardipine was embryocidal when administeredorally to pregnant Japanese White rabbits, during organogenesis,at 150 mg/kg/day (a dose associated with marked body weight gainsuppression in the treated doe) but not at 50 mg/kg/day (25 times themaximum recommended dose in man). No adverse effects on thefetus were observed when New Zealand albino rabbits were treated,during organogenesis, with up to 100 mg nicardipine/kg/day (a doseassociated with significant mortality in the treated doe). In pregnantrats administered nicardipine orally at up to 100 mg/kg/day (50 timesthe maximum recommended human dose) there was no evidence ofembryolethality or teratogenicity. However, dystocia, reduced birthweights, reduced neonatal survival and reduced neonatal weight gainwere noted. There are no adequate and well-controlled studies inpregnant women. CARDENE SR should be used during pregnancy onlyif the potential benefit justifies the potential risk to the fetus.

SPL UNCLASSIFIED SECTION.

Geriatric Pharmacokinetics. The pharmacokinetics of CARDENE SR in elderly hypertensive subjects(mean age 70 years) were compared to those in younger hypertensivesubjects (mean age 44 years). After single dose and after week ofdosing with CARDENE SR there were no significant differences in ,T AUC or clearance between the young and elderly subjects. In bothgroups of subjects, steady-state plasma levels were significantly higherthan following single dose. In the elderly subjects, disproportionalincrease in plasma levels with dose was observed similar to that observedin normal subjects. max max.

WARNINGS SECTION.

WARNINGS. Increased Angina in Patients With Angina. In short-term, placebo-controlled angina trials with CARDENE (animmediate release oral dosage form of nicardipine), about 7% of patientson CARDENE (compared with 4% of patients on placebo) have developedincreased frequency, duration or severity of angina. Comparisons withbeta-blockers also show greater frequency of increased angina, 4% vs1%. The mechanism of this effect has not been established.. Use in Patients With Congestive Heart Failure. Although preliminary hemodynamic studies in patients with congestiveheart failure have shown that CARDENE reduced afterload withoutimpairing myocardial contractility, it has negative inotropic effect invitro and in some patients. Caution should be exercised when using thedrug in congestive heart failure patients, particularly in combination witha beta-blocker.. Beta-Blocker Withdrawal. CARDENE is not beta-blocker and therefore gives no protection againstthe dangers of abrupt beta-blocker withdrawal; any such withdrawalshould be by gradual reduction of the dose of beta-blocker, preferablyover to 10 days.