Nicardipine hydrochloride 30 MG Oral Capsule
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 hydrochloride capsules 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 hydrochloride capsules 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 hydrochloride capsules are 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.
DRUG INTERACTIONS
Drug Interactions Beta-Blockers In controlled clinical studies, adrenergic beta-receptor blockers have been frequently administered concomitantly with nicardipine hydrochloride capsules.
The combination is well tolerated.
Cimetidine Cimetidine increases nicardipine hydrochloride capsules 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 hydrochloride capsules usually do not alter the plasma levels of digoxin; however, serum digoxin levels should be evaluated after concomitant therapy with nicardipine hydrochloride capsules are initiated.
Maalox ® Coadministration of Maalox TC had no effect on nicardipine hydrochloride capsules 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 hydrochloride capsules, an increased volume of circulating fluids might be required if such an interaction were to occur.
Cyclosporine Concomitant administration of oral or intravenous nicardipine and cyclosporine results in elevated plasma cyclosporine levels through nicardipine inhibition of hepatic microsomal enzymes, including CYP3A4.
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.
When therapeutic concentrations of furosemide, propranolol, dipyridamole, warfarin, quinidine or naproxen were added to human plasma ( in vitro ), the plasma protein binding of nicardipine hydrochloride capsules were not altered.
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.
DESCRIPTION
Nicardipine hydrochloride capsules for oral administration each contain 20 mg or 30 mg of nicardipine hydrochloride.
Nicardipine hydrochloride capsules are a calcium ion influx inhibitor (slow channel blocker or calcium channel blocker).
Nicardipine hydrochloride is a dihydropyridine structure with the IUPAC (International Union of Pure and Applied Chemistry) chemical name 2-(Benzylmethylamino)ethyl methyl 1,4-dihydro-2,6-dimethyl-4-( m -nitrophenyl)-3,5-pyridinedicarboxylate monohydrochloride, and it has the following structure: nicardipine hydrochloride Nicardipine hydrochloride, USP is a yellow, odorless, crystalline powder that melts at about 169°C.
It is freely soluble in chloroform, methanol and glacial acetic acid, sparingly soluble in anhydrous ethanol, slightly soluble in n-butanol, water, 0.01 M potassium dihydrogen phosphate, acetone and dioxane, very slightly soluble in ethyl acetate, and practically insoluble in benzene, ether and hexane.
It has a molecular weight of 515.99.
Nicardipine hydrochloride capsules are available in hard-shell gelatin capsules containing 20 mg or 30 mg of nicardipine hydrochloride.
The 20 mg capsule strength is provided in a medium blue-green opaque cap and ivory opaque body, while the 30 mg capsule strength is provided in a bluish-green opaque cap and rich yellow body.
Each capsule contains the following inactive ingredients: colloidal silicon dioxide, gelatin, magnesium stearate, pregelatinized starch (corn), silicon dioxide, sodium lauryl sulfate, titanium dioxide and FD&C Green No.
3.
The 20 mg capsules also contain D&C Yellow No.
10.
The 30 mg capsules also contain yellow iron oxide.
The black imprinting ink contains the following: D&C Yellow No.
10 Aluminum Lake, FD&C Blue No.
1 Aluminum Lake, FD&C Blue No.
2 Aluminum Lake, FD&C Red No.
40 Aluminum Lake, pharmaceutical glaze, propylene glycol and synthetic black iron oxide.
Structural Formula
HOW SUPPLIED
Product: 68151-0093 NDC: 68151-0093-7 1 CAPSULE in a PACKAGE
GERIATRIC USE
Geriatric Use Pharmacokinetic parameters did not differ between elderly hypertensive patients (≥ 65 years) and healthy controls after 1 week of nicardipine hydrochloride capsules treatment at 20 mg tid.
Plasma nicardipine hydrochloride concentrations in elderly hypertensive patients were similar to plasma concentrations in healthy young adult subjects when nicardipine hydrochloride capsules were administered at doses of 10 mg, 20 mg and 30 mg tid, suggesting that the pharmacokinetics of nicardipine hydrochloride capsules 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.
MECHANISM OF ACTION
Mechanism of Action Nicardipine hydrochloride capsules are 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 hydrochloride capsules are more selective to vascular smooth muscle than cardiac muscle.
In animal models, nicardipine hydrochloride capsules produce relaxation of coronary vascular smooth muscle at drug levels that cause little or no negative inotropic effect.
INDICATIONS AND USAGE
I.
Stable Angina Nicardipine hydrochloride capsules are indicated for the management of patients with chronic stable angina (effort-associated angina).
Nicardipine hydrochloride capsules may be used alone or in combination with beta-blockers.
II.
Hypertension Nicardipine hydrochloride capsules are indicated for the treatment of hypertension.
Nicardipine hydrochloride capsules 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 (see DOSAGE AND ADMINISTRATION ).
PEDIATRIC USE
Pediatric Use Safety and efficacy in patients under the age of 18 have not been established.
PREGNANCY
Pregnancy Teratogenic Effects 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 hydrochloride capsules should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
NUSRING MOTHERS
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.
DOSAGE AND ADMINISTRATION
Angina The dose should be individually titrated for each patient beginning with 20 mg three times daily.
Doses in the range of 20 mg to 40 mg three times a day have been shown to be effective.
At least 3 days should be allowed before increasing the nicardipine hydrochloride capsules 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 hydrochloride capsules therapy.
2.
Prophylactic Nitrate Therapy: Nicardipine hydrochloride capsules may be safely coadministered with short- and long-acting nitrates.
3.
Beta-blockers : Nicardipine hydrochloride capsules may be safely coadministered with beta-blockers (see Drug Interactions ).
Hypertension The dose of nicardipine hydrochloride capsules should be individually adjusted according to the blood pressure response beginning with 20 mg three times daily.
The effective doses in clinical trials have ranged from 20 mg to 40 mg three 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 CLINICAL PHARMACOLOGY: Effects in Hypertension ).
At least 3 days should be allowed before increasing the nicardipine hydrochloride capsules dose to ensure achievement of steady-state plasma drug concentrations.
Concomitant Use With Other Antihypertensive Agents 1.
Diuretics : Nicardipine hydrochloride capsules may be safely coadministered with thiazide diuretics.
2.
Beta-blockers : Nicardipine hydrochloride capsules may be safely coadministered with beta-blockers (see Drug Interactions ).
Special Patient Populations Renal Insufficiency Although there is no evidence that nicardipine hydrochloride capsules impair renal function, careful dose titration beginning with 20 mg tid is advised (see PRECAUTIONS ).
Hepatic Insufficiency Nicardipine hydrochloride capsules 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 hydrochloride capsules dosage in patients with congestive heart failure (see WARNINGS ).