WARNINGS
Increased Angina in Patients With Angina
In short-term, placebo-controlled angina trials with CARDENE (an
immediate release oral dosage form of nicardipine), about 7% of patients
on CARDENE (compared with 4% of patients on placebo) have developed
increased frequency, duration or severity of angina. Comparisons with
beta-blockers also show a greater frequency of increased angina, 4% vs
1%. The mechanism of this effect has not been established.
Use in Patients With Congestive Heart Failure
Although preliminary hemodynamic studies in patients with congestive
heart failure have shown that CARDENE 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
CARDENE 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
Because CARDENE decreases peripheral resistance,
careful monitoring of blood pressure during the initial administration
and titration of CARDENE is suggested. CARDENE, 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.
Blood Pressure:
Since the liver is the
major site of biotransformation and since CARDENE is subject to first-pass
metabolism, CARDENE 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 CARDENE.
Use in Patients With Impaired Hepatic Function:
When 45-mg CARDENE
SR bid was given to hypertensive patients with moderate renal
impairment, mean AUC and C values were approximately 2-fold to
3-fold higher than in patients with mild renal impairment. Doses in these
patients must be adjusted. Mean AUC and C values were similar in
patients 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-receptor
blockers have been frequently administered concomitantly with
CARDENE. The combination is well tolerated.
Beta-Blockers:
Cimetidine increases CARDENE plasma levels. Patients
receiving the two drugs concomitantly should be carefully monitored.
Cimetidine:
Some calcium blockers may increase the concentration of
digitalis preparations in the blood. CARDENE usually does not alter
the plasma levels of digoxin; however, serum digoxin levels should be
evaluated after concomitant therapy with CARDENE is initiated.
Digoxin:
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 CARDENE, an increased volume of circulating fluids
might be required if such an interaction were to occur.
Fentanyl Anesthesia:
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.
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 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
maximum recommended daily 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 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. CARDENE SR 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 effectiveness in pediatric patients have not been
established.
Geriatric use
Pharmacokinetic parameters did not differ significantly between elderly
hypertensive subjects (mean age: 70 years) and younger hypertensive
subjects (mean age: 44 years) after 1 week of treatment with CARDENE
SR (see).
CLINICAL PHARMACOLOGY: Geriatric Pharmacokinetics
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.
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