NICARDIPINE: 2,317 Adverse Event Reports & Safety Profile

CARDENE I.V. (nicardipine hydrochloride) is a calcium ion influx inhibitor (slow channel blocker or calcium channel blocker). CARDENE I.V. for intravenous administration contains 20 mg (0.1 mg/mL) of nicardipine hydrochloride per 200 mL in either dextrose or sodium chloride or 40 mg (0.2 mg/mL) of nicardipine hydrochloride per 200 mL in sodium chloride. Nicardipine hydrochloride is a dihydropyridine derivative with 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 has the following structure: Nicardipine hydrochloride is a greenish-yellow, odorless, crystalline powder that melts at about 169 o 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. CARDENE I.V. is available as a ready-to-use sterile, non-pyrogenic, clear, colorless to yellow, iso-osmotic solution for intravenous administration in a 200 mL GALAXY container with 20 mg (0.1 mg/mL) or 40 mg (0.2 mg/mL) nicardipine hydrochloride in either dextrose or sodium chloride.

Nicardipine

Hydrochloride in 4.8% Dextrose Injection 20 mg in 200 mL (0.1 mg/mL) Each mL contains 0.1 mg nicardipine hydrochloride, 48 mg dextrose hydrous, USP, 0.0192 mg citric acid, anhydrous, USP, and 1.92 mg sorbitol, NF. Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH to 3.7 to 4.7.

Nicardipine

Hydrochloride in 0.86% Sodium Chloride Injection 20 mg in 200 mL (0.1 mg/mL) Each mL contains 0.1 mg nicardipine hydrochloride, 8.6 mg sodium chloride, USP, 0.0192 mg citric acid, anhydrous, USP, and 1.92 mg sorbitol, NF. Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH to 3.7 to 4.7.

Nicardipine

Hydrochloride in 0.83% Sodium Chloride Injection 40 mg in 200 mL (0.2 mg/mL) Each mL contains 0.2 mg nicardipine hydrochloride, 8.3 mg sodium chloride, USP, 0.0384 mg citric acid, anhydrous, USP, and 3.84 mg sorbitol, NF. Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH to 3.7 to 4.7. The GALAXY container is fabricated from multilayered plastic. Solutions are in contact with the polyethylene layer of the container and can leach out certain chemical components of the plastic in very small amounts within the expiration period. The suitability and safety of the plastic have been confirmed in tests in animals according to the USP biological tests for plastic containers, as well as by tissue culture toxicity studies.

Cardene Structural

Formula

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 hydrochloride it is important to be aware of the relatively large peak to trough differences in blood pressure effect (See DOSAGE AND ADMINISTRATION ).

AND ADMINISTRATION

• For Intravenous Use. (2.1)
• No further dilution is required. (2.3)
• When substituting for oral nicardipine therapy, use the intravenous infusion rate from the table below (2.1): Oral Nicardipine Dose Equivalent I.V. Infusion rate (0.1 mg/mL) Equivalent I.V.

Infusion

Rate (0.2 mg/mL) 20 mg q8h 0.5 mg/hr = 5 mL/hr 0.5 mg/hr = 2.5 mL/hr 30 mg q8h 1.2 mg/hr = 12 mL/hr 1.2 mg/hr = 6 mL/hr 40 mg q8h 2.2 mg/hr = 22 mL/hr 2.2 mg/hr = 11 mL/hr

• In a patient not receiving oral nicardipine, initiate therapy at 5 mg/hr. Increase the infusion rate by 2.5 mg/hr every 5 minutes (for rapid titration) to 15 minutes (for gradual titration) up to a maximum of 15 mg/hr until desired blood pressure reduction is achieved. (2.1)

Conversion

Table (mg/hr) Equivalent I.V.

Infusion

Rate (0.1 mg/mL) Equivalent I.V.

Infusion

Rate (0.2 mg/mL) 5 mg/hr 50 mL/hr 25 mL/hr 2.5 mg/hr 25 mL/hr 12.5 mL/hr 15 mg/hr 150 mL/hr 75 mL/hr

• If unacceptable hypotension or tachycardia occurs, discontinue the infusion. When blood pressure and heart rate stabilize, restart the infusion at low doses such as 3 to 5 mg/hr. (2.2)

2.1 Recommended Dosing Nicardipine hydrochloride in sodium chloride injection is intended for intravenous use. Titrate dose to achieve the desired blood pressure reduction. Individualize dosage depending on the blood pressure to be obtained and the response of the patient. Dosage as a Substitute for Oral Nicardipine Therapy The intravenous infusion rate required to produce an average plasma concentration equivalent to a given oral dose at steady state is shown in the following table: Oral Nicardipine Dose Equivalent I.V.

Infusion Rate

20 mg in 200 mL (0.1 mg/mL) Equivalent I.V.

Infusion Rate

40 mg in 200mL (0.2 mg/mL) 20 mg q8h 0.5 mg/hr = 5 mL/hr 0.5 mg/hr = 2.5 mL/hr 30 mg q8h 1.2 mg/hr = 12 mL/hr 1.2 mg/hr = 6 mL/hr 40 mg q8h 2.2 mg/hr = 22 mL/hr 2.2 mg/hr = 11 mL/hr Dosage for Initiation of Therapy in a Patient Not Receiving Oral Nicardipine Nicardipine hydrochloride in sodium chloride injection 20 mg in 200 mL (0.1 mg/mL): Initiate therapy at 50 mL/hr (5 mg/hr). If desired blood pressure reduction is not achieved at this dose, the infusion rate may be increased by 25 mL/hr (2.5 mg/hr) every 5 minutes (for rapid titration) to 15 minutes (for gradual titration) up to a maximum of 150 mL/hr (15 mg/hr), until desired blood pressure reduction is achieved. Following achievement of the blood pressure goal utilizing rapid titration, decrease the infusion rate to 30 mL/hr (3 mg/hr). Nicardipine hydrochloride in sodium chloride injection 40 mg in 200 mL (0.2 mg/mL): Initiate therapy at 25 mL/hr (5 mg/hr). If desired blood pressure reduction is not achieved at this dose, the infusion rate may be increased by 12.5 mL/hr (2.5 mg/hr) every 5 minutes (for rapid titration) to 15 minutes (for gradual titration) up to a maximum of 75 mL/hr (15 mg/hr), until desired blood pressure reduction is achieved. Following achievement of the blood pressure goal utilizing rapid titration, decrease the infusion rate to 15 mL/hr (3 mg/hr).

Drug

Discontinuation and Transition to an Oral Antihypertensive Agent Discontinuation of infusion is followed by a 50% offset of action in about 30 minutes. If treatment includes transfer to an oral antihypertensive agent other than oral nicardipine, initiate therapy upon discontinuation of nicardipine hydrochloride in sodium chloride injection. If oral nicardipine is to be used, administer the first dose 1 hour prior to discontinuation of the infusion.

Special Populations Titrate

Nicardipine hydrochloride in sodium chloride injection slowly in patients with heart failure or impaired hepatic or renal function [see Warnings and Precautions (5.2, 5.3 and 5.4)]

2.2 Monitoring The time course of blood pressure decrease is dependent on the initial rate of infusion and the frequency of dosage adjustment. With constant infusion, blood pressure begins to fall within minutes. It reaches about 50% of its ultimate decrease in about 45 minutes. Monitor blood pressure and heart rate continually during infusion and avoid too rapid or excessive blood pressure drop during treatment. If there is concern of impending hypotension or tachycardia, the infusion should be discontinued. Then, when blood pressure has stabilized, infusion of Nicardipine hydrochloride in sodium chloride injection may be restarted at low doses such as 30 to 50 mL/hr (3 to 5 mg/hr) for 20 mg in 200 mL or 15 to 25 mL/hr (3 to 5 mg/hr) for 40 mg in 200 mL and adjusted to maintain desired blood pressure.

2.3 Instructions for Administration Administer Nicardipine hydrochloride in sodium chloride injection by a central line or through a large peripheral vein. Change the infusion site every 12 hours if administered via peripheral vein <span class="opacity-50 text-xs">[see Warnings and Precautions (5.5)]</span>. Nicardipine hydrochloride in sodium chloride injection is available as a single-dose, ready-to-use, iso-osmotic solution for intravenous administration. No further dilution is required.

Inspect

Nicardipine hydrochloride in sodium chloride injection visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Check the container for minute leaks prior to use by squeezing the bag firmly; ensure that the seal is intact. If leaks are found, discard solution as sterility may be impaired. Nicardipine hydrochloride in sodium chloride injection is normally a clear, colorless to yellow solution. Do not combine Nicardipine hydrochloride in sodium chloride injection with any product in the same intravenous line or premixed container. Do not add supplementary medication to the bag. Protect from light until ready to use. Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before the administration of the fluid from the secondary container is complete. Preparation for administration 1 Suspend container from eyelet support. 2 Remove protector from outlet port at bottom of container. 3 Attach administration set. Refer to complete directions accompanying set. 4 Discard unused portion.

4 CONTRAINDICATIONS

• Do not use in patients with advanced aortic stenosis (4.1).

4.1 Advanced Aortic Stenosis Nicardipine hydrochloride in sodium chloride injection is contraindicated in patients with advanced aortic stenosis because part of the effect of Nicardipine hydrochloride in sodium chloride injection is secondary to reduced afterload. Reduction of diastolic pressure in these patients may worsen rather than improve myocardial oxygen balance.

ADVERSE REACTIONS In multiple-dose US and foreign controlled short-term (up to 3 months) studies 1910 patients received nicardipine hydrochloride capsules 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 hydrochloride capsules.

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 hydrochloride capsules (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 that were recorded in a different category). Where the frequency of adverse effects for nicardipine hydrochloride capsules 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)

Adverse

Experience NICARDIPINE HYDROCHLORIDE CAPSULES (n=520) PLACEBO (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 (0)

Increased Angina

5.6 (3.5) 4.2 (1.9)

Palpitations

3.3 (0.4) 0.0 (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 (0)

Rash

1.2 (0.2) 0.3 (0)

Tachycardia

1.2 (0.2) 0.6 (0)

Myalgia

1.0 (0) 0.0 (0)

Other Edema

1.0 (0) 0.0 (0)

Paresthesia

1.0 (0.2) 0.3 (0)

Sustained Tachycardia

0.8 (0.6) 0.0 (0)

Syncope

0.8 (0.2) 0.0 (0)

Constipation

0.6 (0.2) 0.6 (0)

Dyspnea

0.6 (0) 0.0 (0) Abnormal ECG 0.6 (0.6) 0.0 (0)

Malaise

0.6 (0) 0.0 (0)

Nervousness

0.6 (0) 0.3 (0)

Tremor

0.6 (0) 0.0 (0) In addition, adverse events were observed that 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 hydrochloride capsules 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 hydrochloride capsules (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 hydrochloride capsules 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)

Adverse

Experience NICARDIPINE HYDROCHLORIDE CAPSULES (n=1390) PLACEBO (n=211)

Flushing

9.7 (2.1) 2.8 (0)

Headache

8.2 (2.6) 4.7 (0)

Pedal Edema

8.0 (1.8) 0.9 (0)

Asthenia

4.2 (1.7) 0.5 (0)

Palpitations

4.1 (1.0) 0.0 (0)

Dizziness

4.0 (1.8) 0.0 (0)

Tachycardia

3.4 (1.2) 0.5 (0)

Nausea

2.2 (0.9) 0.9 (0)

Somnolence

1.1 (0.1) 0.0 (0)

Dyspepsia

0.8 (0.3) 0.5 (0)

Insomnia

0.6 (0.1) 0.0 (0)

Malaise

0.6 (0.1) 0.0 (0)

Other Edema

0.6 (0.3) 1.4 (0)

Abnormal Dreams

0.4 (0) 0.0 (0)

Dry Mouth

0.4 (0.1) 0.0 (0)

Nocturia

0.4 (0) 0.0 (0)

Rash

0.4 (0.4) 0.0 (0)

Vomiting

0.4 (0.4) 0.0 (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 To report SUSPECTED ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc. at 1-855-204-1431 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

WARNINGS AND PRECAUTIONS To reduce the possibility of venous thrombosis, phlebitis, and vascular impairment, do not use small veins, such as those on the dorsum of the hand or wrist. Avoid intraarterial administration or extravasation ( 5.7 ). To minimize the risk of peripheral venous irritation, change the site of infusion of nicardipine every 12 hours ( 5.7 ). Nicardipine is not a beta-blocker and therefore gives no protection against the dangers of abrupt beta-blocker withdrawal. Withdraw beta-blockers gradually ( 5.8 ). Closely monitor response in patients with angina ( 5.3 ), congestive heart failure ( 5.4 ), impaired hepatic function ( 5.5 ), portal hypertension ( 5.5 ), and renal impairment ( 5.6 ) and pheochromocytoma ( 5.9 ).

5 WARNINGS AND PRECAUTIONS

5.1 Excessive Pharmacologic Effects In administrating nicardipine, close monitoring of blood pressure and heart rate is required. Nicardipine may occasionally produce symptomatic hypotension or tachycardia. Avoid systemic hypotension when administering the drug to patients who have sustained an acute cerebral infarction or hemorrhage.

5.2 Rapid Decreases in Blood Pressure No clinical events have been reported suggestive of a too rapid decrease in blood pressure with nicardipine. However, as with any antihypertensive agent, blood pressure lowering should be accomplished over as long a time as is compatible with the patient&apos;s clinical status.

5.3 Use in Patients with Angina Increases in frequency, duration, or severity of angina have been seen in chronic oral therapy with nicardipine capsules. Induction or exacerbation of angina has been seen in less than 1% of coronary artery disease patients treated with nicardipine. The mechanism of this effect has not been established.

5.4 Use in Patients with Congestive Heart Failure Nicardipine reduced afterload without impairing myocardial contractility in preliminary hemodynamic studies of CHF patients. However, in vitro and in some patients, a negative inotropic effect has been observed. Therefore, monitor vital signs carefully when using nicardipine, particularly in combination with a beta-blocker, in patients with CHF or significant left ventricular dysfunction.

5.5 Use in Patients with Impaired Hepatic Function Since nicardipine is metabolized in the liver, consider lower dosages and closely monitor response. Nicardipine administered intravenously increased hepatic venous pressure gradient by 4 mmHg in cirrhotic patients at high doses (5 mg/20 min) in one study. Use caution in patients with portal hypertension.

5.6 Use in Patients with Impaired Renal Function When nicardipine was given to mild-to-moderate hypertensive patients with moderate renal impairment, a significantly lower systemic clearance and higher AUC was observed. These results are consistent with those seen after oral administration of nicardipine. Careful dose titration is advised when treating patients with more than mild renal impairment.

5.7 Intravenous Infusion Site To reduce the possibility of venous thrombosis, phlebitis, local irritation, swelling, extravasation, and the rare occurrence of vascular impairment, administer drug through large peripheral veins or central veins rather than arteries or small peripheral veins, such as those on the dorsum of the hand or wrist. To minimize the risk of peripheral venous irritation, consider changing the site of the drug infusion every 12 hours.

5.8 Beta-Blocker Withdrawal Nicardipine is not a beta-blocker and therefore gives no protection against the dangers of abrupt beta-blocker withdrawal. Withdraw beta-blockers gradually.

5.9 Use in Patients with Pheochromocytoma Only limited clinical experience exists in use of nicardipine for patients with hypertension from pheochromocytoma.

PRECAUTIONS General Blood Pressure Because nicardipine hydrochloride capsules decrease peripheral resistance, careful monitoring of blood pressure during the initial administration and titration of nicardipine hydrochloride capsules are suggested. Nicardipine hydrochloride capsules 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 hydrochloride capsules are subject to first pass metabolism, the drug should be used with caution in patients having impaired liver function or reduced hepatic blood flow. Patients with severe liver disease developed elevated blood levels (fourfold increase in AUC) and prolonged half-life (19 hours) of nicardipine (see DOSAGE AND ADMINISTRATION ). Use in Patients With Impaired Renal Function: When nicardipine hydrochloride capsules 20 mg or 30 mg tid was given to hypertensive patients with mild renal impairment, mean plasma concentrations, AUC and C max were approximately twofold 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 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 though 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. 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 1 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 1 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 hydrochloride capsules should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

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

Pediatric Use

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

Geriatric Use

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 capsules concentrations in elderly hypertensive subjects were similar to plasma concentrations in healthy young adult subjects when nicardipine hydrochloride capsules were administered at doses of 10, 20, 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.

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. 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 1 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 1 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

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.

Nursing Mothers

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

Pediatric Use

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

Geriatric Use

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 capsules concentrations in elderly hypertensive subjects were similar to plasma concentrations in healthy young adult subjects when nicardipine hydrochloride capsules were administered at doses of 10, 20, 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.