NICARDIPINE HYDROCHLORIDE capsule

Nicardipine Hydrochloride by

Drug Labeling and Warnings

Nicardipine Hydrochloride by is a Prescription medication manufactured, distributed, or labeled by Carilion Materials Management. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

Renal Function

There is a transient increase in electrolyte excretion, including sodium. Nicardipine does not cause generalized fluid retention, as measured by weight changes, although 7% to 8% of the patients experience pedal edema.

Effects In Angina Pectoris

In controlled clinical trials of up to 12-weeks duration in patients with chronic stable angina, nicardipine increased exercise tolerance and reduced nitroglycerin consumption and the frequency of anginal attacks. The antianginal efficacy of nicardipine hydrochloride (20 mg to 40 mg) has been demonstrated in four placebo-controlled studies involving 258 patients with chronic stable angina. In exercise tolerance testing, nicardipine significantly increased time to angina, total exercise duration and time to 1 mm ST segment depression. Included among these four studies was a dose-definition study in which dose related improvements in exercise tolerance at one and four hours post-dosing and reduced frequency of anginal attacks were seen at doses of 10 mg, 20 mg and 30 mg TID. Effectiveness at 10 mg TID was, however, marginal. In a fifth placebo-controlled study, the antianginal efficacy of nicardipine was demonstrated at 8 hours post-dose (trough). The sustained efficacy of nicardipine has been demonstrated over long-term dosing. Blood pressure fell in patients with angina by about 10/8 mmHg at peak blood levels and was little different from placebo at trough blood levels.

Effects In Hypertension

Nicardipine produced dose related decreases in both systolic and diastolic blood pressure in clinical trials. The antihypertensive efficacy of nicardipine administered 3 times daily has been demonstrated in three placebo-controlled studies involving 517 patients with mild to moderate hypertension. The blood pressure responses in the three studies were statistically significant from placebo at peak (1 hour post-dosing) and trough (8 hours post-dosing) although it is apparent that well over half of the antihypertensive effect is lost by the end of the dosing interval. The results from placebo controlled studies of nicardipine given 3 times daily are shown in the following table:

SYSTOLIC BP (mmHg)

Dose

Number of Patients

Mean Peak Response

Mean Trough Response

Trough/Peak

20 mg

50    
52    

-10.3
-17.6

-4.9
-7.9

48%
45%

30 mg

45    
44    

-14.5
-14.6

-7.2
-7.5

50%
51%

40 mg

50    
38    

-16.3
-15.9

9.5
6

58%
38%

DIASTOLIC BP (mmHg)

Dose

Number of Patients

Mean Peak Response

Mean Trough Response

Trough/Peak

20 mg

50    
52    

-10.6
 -9

-4.6
-2.9

43%
32%

30 mg

45    
44    

-12.8
-14.2

-4.9
-4.3

38%
30%

40 mg

50    
38    

-15.4
-14.8

-5.9
-3.7

38%
25%

The responses are shown as differences from the concurrent placebo control group. The large changes between peak and trough effects were not accompanied by observed side effects at peak response times. In a study using 24 hour intra-arterial blood pressure monitoring, the circadian variation in blood pressure remained unaltered, but the systolic and diastolic blood pressures were reduced throughout the whole 24 hours.

When added to beta-blocker therapy, nicardipine further lowers both systolic and diastolic blood pressure.

  • INDICATIONS AND USAGE

    I. Stable Angina

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

    II. Hypertension

    Nicardipine hydrochloride capsules are indicated for the treatment of hypertension. They may be used alone or in combination with other antihypertensive drugs. In administering nicardipine hydrochloride it is important to be aware of the relatively large peak to trough differences in blood pressure effect. (See DOSAGE AND ADMINISTRATION.)

  • CONTRAINDICATIONS

    Nicardipine hydrochloride 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.

  • WARNINGS

    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. (See ADVERSE REACTIONS.)

    Use in Patients with Congestive Heart Failure

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

    Beta-Blocker Withdrawal

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

  • PRECAUTIONS

    General

    Blood Pressure

    Because nicardipine decreases peripheral resistance, careful monitoring of blood pressure during the initial administration and titration of nicardipine is suggested. Nicardipine, like other calcium channel blockers, may occasionally produce symptomatic hypotension. Caution is advised to avoid systemic hypotension when administering the drug to patients who have sustained an acute cerebral infarction or hemorrhage. 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 (4-fold increase in AUC) and prolonged half-life (19 hours) of nicardipine. (See DOSAGE AND ADMINISTRATION.)

    Use in patients with impaired renal function

    When nicardipine hydrochloride 20 mg or 30 mg TID was given to hypertensive patients with mild renal impairment, mean plasma concentrations, AUC, and Cmax were approximately 2-fold higher in renally impaired patients than in healthy controls. Doses in these patients must be adjusted. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)

    Drug Interactions

    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.

    Aluminum and Magnesium Hydroxides

    Coadministration of an antacid containing 600 mg aluminum hydroxide and 300 mg magnesium hydroxide had no effect on nicardipine absorption.

    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.

    When therapeutic concentrations of furosemide, propranolol, dipyridamole, warfarin, quinidine, or naproxen were added to human plasma (in vitro), the plasma protein binding of nicardipine was not altered.

    Carcinogenesis, Mutagenesis, Impairment of Fertility

    Rats treated with nicardipine in the diet (at concentrations calculated to provide daily dosage levels of 5, 15 or 45 mg/kg/day) for 2 years showed a dose dependent increase in thyroid hyperplasia and neoplasia (follicular adenoma/carcinoma). One and 3 month studies in the rat have suggested that these results are linked to a nicardipine-induced reduction in plasma thyroxine (T4) levels with a consequent increase in plasma levels of thyroid stimulating hormone (TSH). Chronic elevation of TSH is known to cause hyperstimulation of the thyroid. In rats on an iodine deficient diet, nicardipine administration for one month was associated with thyroid hyperplasia that was prevented by T4 supplementation. Mice treated with nicardipine in the diet (at concentrations calculated to provide daily dosage levels of up to 100 mg/kg/day) for up to 18 months showed no evidence of neoplasia of any tissue and no evidence of thyroid changes. There was no evidence of thyroid pathology in dogs treated with up to 25 mg nicardipine/kg/day for one year and no evidence of effects of nicardipine on thyroid function (plasma T4 and TSH) in man.

    There was no evidence of a mutagenic potential of nicardipine in a battery of genotoxicity tests conducted on microbial indicator organisms, in micronucleus tests in mice and hamsters, or in a sister chromatid exchange study in hamsters.

    No impairment of fertility was seen in male or female rats administered nicardipine at oral doses as high as 100 mg/kg/day (50 times the 40 mg TID maximum recommended antianginal or antihypertensive dose in man, assuming a patient weight of 60 kg).

    Pregnancy

    Pregnancy Category C

    Nicardipine was embryocidal 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 embryolethality 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 breast-feed should not take this drug.

    Pediatric Use

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

    Geriatric Use

    Pharmacokinetic parameters did not differ between elderly hypertensive patients (≥ 65 years) and healthy controls after one week of nicardipine treatment at 20 mg TID. Plasma nicardipine concentrations in elderly hypertensive patients were similar to plasma concentrations in healthy young adult subjects when nicardipine hydrochloride was administered at doses of 10 mg, 20 mg and 30 mg TID, suggesting that the pharmacokinetics of nicardipine are similar in young and elderly hypertensive patients.

    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.

  • ADVERSE REACTIONS

    In multiple-dose U.S. and foreign controlled short-term (up to 3 months) studies 1,910 patients received nicardipine alone or in combination with other drugs. In these studies adverse events were reported spontaneously; adverse experiences were generally not serious but occasionally required dosage adjustment and about 10% of patients left the studies prematurely because of them. Peak responses were not observed to be associated with adverse effects during clinical trials, but physicians should be aware that adverse effects associated with decreases in blood pressure (tachycardia, hypotension, etc.) could occur around the time of the peak effect. Most adverse effects were expected consequences of the vasodilator effects of nicardipine.

    Angina

    The incidence rates of adverse effects in anginal patients were derived from multicenter, controlled clinical trials. Following are the rates of adverse effects for nicardipine (n = 520) and placebo (n = 310), respectively, that occurred in 0.4% of patients or more. These represent events considered probably drug-related by the investigator (except for certain cardiovascular events which were recorded in a different category). Where the frequency of adverse effects for nicardipine and placebo is similar, causal relationship is uncertain. The only dose related effects were pedal edema and increased angina.

    Percent of Patients with Adverse Effects in Controlled Studies (Incidence of discontinuations shown in parentheses)
     NICARDIPINEPLACEBO
    Adverse Experience(n = 520)(n = 310)

    Pedal Edema

    7.1 (0)   

    0.3 (0)

    Dizziness

    6.9 (1.2)

    0.6 (0)

    Headache

    6.4 (0.6)

    2.6 (0)

    Asthenia

    5.8 (0.4)

    2.6 (0)

    Flushing

    5.6 (0.4)

    1 (0)

    Increased Angina

    5.6 (3.5)

       4.2 (1.9)

    Palpitations

    3.3 (0.4)

    0 (0)

    Nausea

    1.9 (0)   

    0.3 (0)

    Dyspepsia

    1.5 (0.6)

       0.6 (0.3)

    Dry Mouth

    1.4 (0)   

    0.3 (0)

    Somnolence

    1.4 (0)   

    1 (0)

    Rash

    1.2 (0.2)

    0.3 (0)

    Tachycardia

    1.2 (0.2)

    0.6 (0)

    Myalgia

    1 (0)   

    0 (0)

    Other edema

    1 (0)   

    0 (0)

    Paresthesia

    1 (0.2)

    0.3 (0)

    Sustained Tachycardia

    0.8 (0.6)

    0 (0)

    Syncope

    0.8 (0.2)

    0 (0)

    Constipation

    0.6 (0.2)

    0.6 (0)

    Dyspnea

    0.6 (0)   

    0 (0)

    Abnormal ECG

    0.6 (0.6)

    0 (0)

    Malaise

    0.6 (0)   

    0 (0)

    Nervousness

    0.6 (0)   

    0.3 (0)

    Tremor

    0.6 (0)   

    0 (0)

    In addition, adverse events were observed which are not readily distinguishable from the natural history of the atherosclerotic vascular disease in these patients. Adverse events in this category each occurred in <0.4% of patients receiving nicardipine and included myocardial infarction, atrial fibrillation, exertional hypotension, pericarditis, heart block, cerebral ischemia and ventricular tachycardia. It is possible that some of these events were drug-related.

    Hypertension

    The incidence rates of adverse effects in hypertensive patients were derived from multicenter, controlled clinical trials. Following are the rates of adverse effects for nicardipine (n = 1390) and placebo (n = 211), respectively, that occurred in 0.4% of patients or more. These represent events considered probably drug-related by the investigator. Where the frequency of adverse effects for nicardipine and placebo is similar, causal relationship is uncertain. The only dose-related effect was pedal edema.

    Percent of Patients with Adverse Effects in Controlled Studies (Incidence of discontinuations shown in parentheses)
     NICARDIPINEPLACEBO
    Adverse Experience(n=1,390)(n=211)

    Flushing

    9.7 (2.1)

    2.8 (0)

    Headache

    8.2 (2.6)

    4.7 (0)

    Pedal Edema

    8 (1.8)

    0.9 (0)

    Asthenia

    4.2 (1.7)

    0.5 (0)

    Palpitations

    4.1 (1)

    0 (0)

    Dizziness

    4 (1.8)

    0 (0)

    Tachycardia

    3.4 (1.2)

    0.5 (0)

    Nausea

    2.2 (0.9)

    0.9 (0)

    Somnolence

    1.1 (0.1)

    0 (0)

    Dyspepsia

    0.8 (0.3)

    0.5 (0)

    Insomnia

    0.6 (0.1)

    0 (0)

    Malaise

    0.6 (0.1)

    0 (0)

    Other edema

    0.6 (0.3)

    1.4 (0)

    Abnormal dreams

    0.4 (0)   

    0 (0)

    Dry mouth

    0.4 (0.1)

    0 (0)

    Nocturia

    0.4 (0)   

    0 (0)

    Rash

    0.4 (0.4)

    0 (0)

    Vomiting

    0.4 (0.4)

    0 (0)

    Rare Events

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

    Body as a Whole: infection, allergic reaction

    Cardiovascular: hypotension, postural hypotension, atypical chest pain, peripheral vascular disorder, ventricular extrasystoles, ventricular tachycardia

    Digestive: sore throat, abnormal liver chemistries

    Musculoskeletal: arthralgia

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

    Respiratory: rhinitis, sinusitis

    Special Senses: tinnitus, abnormal vision, blurred vision

    Urogenital: increased urinary frequency

  • OVERDOSAGE

    Overdosage with a 600 mg single dose (15 to 30 times normal clinical dose) has been reported. Marked hypotension (blood pressure unobtainable) and bradycardia (heart rate 20 bpm in normal sinus rhythm) occurred, along with drowsiness, confusion and slurred speech. Supportive treatment with a vasopressor resulted in gradual improvement with normal vital signs approximately 9 hours post treatment.

    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.

  • DOSAGE AND ADMINISTRATION

    Angina

    The dose should be individually titrated for each patient beginning with 20 mg 3 times daily. Doses in the range of 20 mg to 40 mg 3 times a day have been shown to be effective. At least 3 days should be allowed before increasing the nicardipine hydrochloride dose to ensure achievement of steady-state plasma drug concentrations.

    Concomitant Use With Other Antianginal Agents

    • 1. Sublingual NTG may be taken as required to abort acute anginal attacks during nicardipine therapy.
    • 2. Prophylactic Nitrate Therapy–Nicardipine may be safely coadministered with short- and long-acting nitrates.
    • 3. Beta-blockers–(See PRECAUTIONS, Drug Interactions.)

    Hypertension

    The dose of nicardipine hydrochloride should be individually adjusted according to the blood pressure response beginning with 20 mg 3 times daily. The effective doses in clinical trials have ranged from 20 mg to 40 mg 3 times daily. The maximum blood pressure lowering effect occurs approximately 1 to 2 hours after dosing. To assess the adequacy of blood pressure response, the blood pressure should be measured at trough (8 hours after dosing). Because of the prominent peak effects of nicardipine, blood pressure should be measured 1 to 2 hours after dosing, particularly during initiation of therapy. (See PRECAUTIONS, Blood Pressure; INDICATIONS AND USAGE; CLINICAL PHARMACOLOGY, Effects in Hypertension.) At least 3 days should be allowed before increasing the nicardipine dose to ensure achievement of steady-state plasma drug concentrations.

    Concomitant Use With Other Antihypertensive Agents, Beta-blockers

    (See PRECAUTIONS, Drug Interactions.)

    Special Patient Populations

    Renal Insufficiency

    Although there is no evidence that nicardipine impairs renal function, careful dose titration beginning with 20 mg TID is advised. (See PRECAUTIONS.)

    Hepatic Insufficiency

    Nicardipine should be administered cautiously in patients with severely impaired hepatic function. A suggested starting dose of 20 mg twice a day is advised with individual titration based on clinical findings maintaining the twice a day schedule. (See PRECAUTIONS.)

    Congestive Heart Failure

    Caution is advised when titrating nicardipine dosage in patients with congestive heart failure. (See WARNINGS.)

  • HOW SUPPLIED

    Product: 68151-0092

    NDC: 68151-0092-7 1 CAPSULE in a PACKAGE

  • NICARDIPINE HYDROCHLORIDE CAPSULE

    Label Image
  • INGREDIENTS AND APPEARANCE
    NICARDIPINE HYDROCHLORIDE 
    nicardipine hydrochloride capsule
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 68151-0092(NDC:0378-1020)
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    NICARDIPINE HYDROCHLORIDE (UNII: K5BC5011K3) (NICARDIPINE - UNII:CZ5312222S) NICARDIPINE HYDROCHLORIDE20 mg
    Inactive Ingredients
    Ingredient NameStrength
    SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
    GELATIN (UNII: 2G86QN327L)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    STARCH, CORN (UNII: O8232NY3SJ)  
    PROPYLENE GLYCOL (UNII: 6DC9Q167V3)  
    SODIUM LAURYL SULFATE (UNII: 368GB5141J)  
    FERROSOFERRIC OXIDE (UNII: XM0M87F357)  
    FD&C BLUE NO. 2 (UNII: L06K8R7DQK)  
    FD&C RED NO. 40 (UNII: WZB9127XOA)  
    FD&C BLUE NO. 1 (UNII: H3R47K3TBD)  
    D&C YELLOW NO. 10 (UNII: 35SW5USQ3G)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    FD&C GREEN NO. 3 (UNII: 3P3ONR6O1S)  
    Product Characteristics
    ColorBLUE (medium blue-green opaque) , WHITE (ivory opaque) Scoreno score
    ShapeCAPSULESize14mm
    FlavorImprint Code MYLAN;1020
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 68151-0092-7 1 in 1 PACKAGE; Type 0: Not a Combination Product07/19/1996
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA07464207/19/1996
    Labeler - Carilion Materials Management (079239644)
    Establishment
    NameAddressID/FEIBusiness Operations
    Carilion Materials Management079239644REPACK(68151-0092)

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