Included as part of the PRECAUTIONS section.
Excessive Pharmacodynamic Effects
In administering 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.
Use In Patients With Angina
Increases in frequency, duration, or severity of angina
have been seen in chronic therapy with oral nicardipine. Induction or
exacerbation of angina has been seen in less than 1% of coronary artery disease
patients treated with Cardene I.V. The mechanism of this effect has not been
Use In Patients With Heart Failure
Titrate slowly when using Cardene I.V. Premixed
Injection, particularly in combination with a beta-blocker, in patients with
heart failure or significant left ventricular dysfunction because of possible
negative inotropic effects.
Use In Patients With Impaired Hepatic Function
Since nicardipine is metabolized in the liver, consider
lower dosages and closely monitor responses in patients with impaired liver
function or reduced hepatic blood flow.
Use In Patients With Impaired Renal Function
When Cardene I.V. was given to mild to moderate
hypertensive patients with moderate renal impairment, a significantly lower
systemic clearance and higher area under the curve (AUC) was observed. These
results are consistent with those seen after oral administration of
nicardipine. Titrate gradually in patients with renal impairment.
Intravenous Infusion Site
To reduce the possibility of venous thrombosis,
phlebitis, local irritation, swelling, extravasation, and the 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, change the site of the drug infusion every 12 hours.
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 two years showed a dose-dependent increase in thyroid
hyperplasia and neoplasia (follicular adenoma/carcinoma). One- and three-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 (human
equivalent dose about 16 mg/kg/day, 8 times the maximum recommended oral dose).
Reproductive And Developmental Toxicology
Embryotoxicity, but no teratogenicity, was seen at
intravenous doses of 10 mg nicardipine/kg/day in rats and 1 mg/kg/day in
rabbits. These doses in the rat and rabbit are equivalent to human IV doses of
about 1.6 mg/kg/day and 0.32 mg/kg/day respectively. (The total daily human
dose delivered by a continuous IV infusion ranges from 1.2 to 6 mg/kg/day,
depending on duration at different infusion rates ranging from 3 to 15 mg/hr as
individual patients are titrated for optimal results.) Nicardipine was also
embryotoxic 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 (human equivalent dose
about 16 mg/kg/day or about 8 times the maximum recommended human oral dose).
No adverse effects on the fetus were observed when New Zealand albino rabbits
were treated orally, 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 doses of up to 100 mg/kg/day (human
equivalent dose about 16 mg/kg/day) there was no evidence of embryotoxicity or
teratogenicity. However, dystocia, reduced birth weight, reduced neonatal
survival and reduced neonatal weight gain were noted.
Use In Specific Populations
Pregnancy Category C
There are no adequate and well-controlled studies of
nicardipine use in pregnant women. However, limited human data in pregnant
women with preeclampsia or pre-term labor are available. In animal studies, no
embryotoxicity occurred in rats with oral doses 8 times the maximum recommended
human dose (MRHD) based on body surface area (mg/m²), but did occur in rabbits
with oral doses at 24 times the maximum recommended human dose (MRHD) based on
body surface area (mg/m²). Cardene I.V. should be used during pregnancy only if
the potential benefit justifies the potential risk to the fetus.
Hypotension, reflex tachycardia, postpartum hemorrhage,
tocolysis, headache, nausea, dizziness, and flushing have been reported in
pregnant women who were treated with intravenous nicardipine for hypertension
during pregnancy. Fetal safety results ranged from transient fetal heart rate
decelerations to no adverse events. Neonatal safety data ranged from
hypotension to no adverse events.
Adverse events in women treated with intravenous
nicardipine during pre-term labor include pulmonary edema, dyspnea, hypoxia,
hypotension, tachycardia, headache, and phlebitis at site of injection.
Neonatal adverse events include acidosis (pH<7.25).
In embryofetal toxicity studies, nicardipine was
administered intravenously to pregnant rats and rabbits during organogenesis at
doses up to 0.14 times the MRHD based on body surface area (mg/m²) (5
mg/kg/day) (rats) and 0.03 times the MRHD based on body surface area (mg/m²)
(0.5 mg/kg/day) (rabbits). No embryotoxicity or teratogenicity was seen at
these doses. Embryotoxicity, but no teratogenicity was seen at 0.27 times the
MRHD based on body surface area (mg/m²) (10 mg/kg/day) in rats and at 0.05
times the MRHD based on body surface are (mg/m²) (1 mg/kg/day) in rabbits.
In other animal studies, pregnant Japanese White rabbits
received oral nicardipine during organogenesis, at doses 8 and 24 times the
MRHD based on body surface area (mg/m²) (50 and 150 mg/kg/day). Embryotoxicity
occurred at the high dose along with signs of maternal toxicity (marked
maternal weight gain suppression). New Zealand albino rabbits received oral
nicardipine during organogenesis, at doses up to 16 times the MRHD based on
body surface area (mg/m²) (100 mg nicardipine/kg/day). While significant
maternal mortality occurred, no adverse effects on the fetus were observed.
Pregnant rats received oral nicardipine from day 6 through day 15 of gestation
at doses up to 8 times the MRHD based on body surface area (mg/m²) (100
mg/kg/day). There was no evidence of embryotoxicity or teratogenicity; however,
dystocia, reduced birth weights, reduced neonatal survival, and reduced
neonatal weight gain were noted.
Nicardipine is minimally excreted into human milk. Among
18 infants exposed to nicardipine through breast milk in the postpartum period,
calculated daily infant dose was less than 0.3 mcg and there were no adverse
events observed. Consider the possibility of infant exposure when using
nicardipine in nursing mothers.
In a study of 11 women who received oral nicardipine 4 to
14 days postpartum, 4 women received immediate-release nicardipine 40 to 80 mg
daily, 6 received sustained-release nicardipine 100 to 150 mg daily, and one
received intravenous nicardipine 120 mg daily. The peak milk concentration was
7.3 mcg/L (range 1.9-18.8), and the mean milk concentration was 4.4 mcg/L
(range 1.3-13.8). Infants received an average of 0.073% of the weight-adjusted
maternal oral dose and 0.14% of the weight-adjusted maternal intravenous dose.
In another study of seven women who received intravenous
nicardipine for an average of 1.9 days in the immediate postpartum period as
therapy for pre-eclampsia, 34 milk samples were obtained at unspecified times
and nicardipine was undetectable (<5 mcg/L) in 82% of the samples. Four
women who received 1 to 6.5 mg/hour of nicardipine had 6 milk samples with
detectable nicardipine levels (range 5.1 to 18.5 mcg/L). The highest
concentration of 18.5 mcg/L was found in a woman who received 5.5 mg/hour of
nicardipine. The estimated maximum dose in a breastfed infant was < 0.3 mcg
daily or between 0.015 to 0.004% of the therapeutic dose in a 1 kg infant.
Safety and efficacy in patients under the age of 18 have
not been established.
The steady-state pharmacokinetics of nicardipine are
similar in elderly hypertensive patients (>65 years) and young healthy
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, use low initial doses in elderly patients, reflecting the
greater frequency of decreased hepatic, renal or cardiac function, and of
concomitant disease or other drug therapy.