WARNINGS
Excessive Hypotension
Although, in most patients, the hypotensive effect of
nifedipine is modest and well tolerated, occasional patients
have had excessive and poorly tolerated hypotension. These
responses have usually occurred during initial titration
or at the time of subsequent upward dosage adjustment,
and with the extended release tablets, may be more likely
in patients on concomitant beta blockers.
Severe hypotension and/or increased fluid volume requirements
have been reported in patients receiving nifedipine together
with a beta blocking agent who underwent coronary artery
bypass surgery using high dose fentanyl anesthesia. The
interaction with high dose fentanyl appears to be due
to the combination of nifedipine and a beta blocker, but
the possibility that it may occur with nifedipine alone,
with low doses of fentanyl, in other surgical procedures,
or with other narcotic analgesics cannot be ruled out.
In nifedipine treated patients where surgery using high
dose fentanyl anesthesia is contemplated, the physician
should be aware of these potential problems and, if the
patient's condition permits, sufficient time (at least
36 hours) should be allowed for nifedipine to be washed
out of the body prior to surgery.
Additional Information for Immediate Release
Capsules: Although patients have rarely experienced
excessive hypotension on nifedipine alone, this may be
more common in patients on concomitant beta-blocker therapy.
Although not approved for this purpose, nifedipine and
other immediate-release nifedipine capsules have been
used (orally and sublingually) for acute reduction of
blood pressure. Several well-documented reports describe
cases of profound hypotension, myocardial infarction,
and death when immediate-release nifedipine was used in
this way. Nifedipine capsules should not be used for the
acute reduction of blood pressure.
Nifedipine and other immediate-release nifedipine capsules
have also been used for the long-term control of essential
hypertension, although no properly-controlled studies
have been conducted to define an appropriate dose or dose
interval for such treatment. Nifedipine capsules should
not be used for the control of essential hypertension.
Several well-controlled, randomized trials studied the
use of immediate-release nifedipine in patients who had
just sustained myocardial infarctions. In none of these
trials did immediate-release nifedipine appear to provide
any benefit. In some of the trials, patients who received
immediate-release nifedipine had significantly worse outcomes
than patients who received placebo. Nifedipine capsules
should not be administered within the first week or two
after myocardial infarction, and they should also be avoided
in the setting of acute coronary syndrome (when infarction
may be imminent).
The following information should be taken into account
in those patients who are being treated for hypertension
as well as angina:
Increased Angina and/or Myocardial Infarction
Rarely, patients, particularly those who have severe
obstructive coronary artery disease, have developed well
documented increased frequency, duration and/or severity
of angina or acute myocardial infarction on starting nifedipine
or at the time of dosage increase. The mechanism of this
effect is not established.
Beta Blocker Withdrawal
Patients recently withdrawn from beta blockers may develop
a withdrawal syndrome with increased angina, probably
related to increased sensitivity to catecholamines. Initiation
of nifedipine treatment will not prevent this occurrence
and might be expected to exacerbate it by provoking reflex
catecholamine release. Additional Information for Immediate
Release Capsules: There have been occasional reports of
increased angina in a setting of beta blocker withdrawal
and nifedipine initiation. It is important to taper beta
blockers if possible, rather than stopping them abruptly
before beginning nifedipine. Additional Information for
Extended Release Tablets: It is important to taper beta
blockers if possible, rather than stopping them abruptly
before beginning nifedipine.
Congestive Heart Failure
Rarely, patients, usually receiving a beta blocker, have
developed heart failure after beginning nifedipine. Patients
with tight aortic stenosis may be at greater risk for
such an event, as the unloading effect of nifedipine would
be expected to be of less benefit to these patients, owing
to their fixed impedance to wflow across the aortic valve.
PRECAUTIONS
General
Hypotension: Because nifedipine decreases
peripheral vascular resistance, careful monitoring of
blood pressure during the initial administration and titration
of nifedipine is suggested. Close observation is especially
recommended for patients already taking medications that
are known to lower blood pressure. (See
WARNINGS
.)
Peripheral Edema: Immediate Release
Capsules: Mild to moderate peripheral edema, typically
associated with arterial vasodilation and not due to left
ventricular dysfunction, occurs in about 1 in 10 patients
treated with nifedipine. This edema occurs primarily in
the lower extremities and usually responds to diuretic
therapy. With patients whose angina is complicated by
congestive heart failure, care should be taken to differentiate
this peripheral edema from the effects of increasing left
ventricular dysfunction. Extended Release Tablets: Mild
to moderate peripheral edema occurs in a dose dependent
manner with an incidence ranging from approximately 10%
to about 30% at the highest dose studied (180 mg). It
is a localized phenomenon thought to be associated with
vasodilation of dependent arterioles and small blood vessels
and not due to left ventricular dysfunction or generalized
fluid retention. With patients whose angina or hypertension
is complicated by congestive heart failure, care should
be taken to differentiate this peripheral edema from the
effects of increasing left ventricular dysfunction.
Additional Information for Extended Release Tablets:
Other: As with any other non-deformable material, caution
should be used when administering nifedipine in patients
with preexisting severe gastrointestinal narrowing (pathologic
or iatrogenic). There have been rare reports of obstructive
symptoms in patients with known strictures in association
with the ingestion of nifedipine.
Information for the Patient
Extended Release Tablets: Nifedipine
extended release tablets should be swallowed whole. Do
not chew, divide or crush tablets. Do not be concerned
if you occasionally notice in you stool something that
looks like a tablet. In nifedipine, the medication is
contained within a nonabsorbable shell that has been specially
designed to slowly release the drug for your body to absorb.
When this process is completed, the empty tablet is eliminated
from your body.
Adalat CC should be taken on an empty stomach. It should
not be administered with food.
Laboratory Tests
Nifedipine, like other calcium channel blockers, decreases
platelet aggregation in vitro. Limited clinical studies
have demonstrated a moderate but statistically significant
decrease in platelet aggregation and an increase in bleeding
time in some nifedipine patients. This is thought to be
a function of inhibition of calcium transport across the
platelet membrane. No clinical significance for these
findings has been demonstrated.
Positive direct Coombs test with/without hemolytic anemia
has been reported but a causal relationship between nifedipine
administration and positivity of this laboratory test,
including hemolysis, could not be determined.
Although nifedipine has been used safely in patients
with renal dysfunction and has been reported to exert
a beneficial effect, in certain cases, rare, reversible
elevations in BUN and serum creatinine have been reported
in patients with pre-existing chronic renal insufficiency.
The relationship to nifedipine therapy is uncertain in
most cases but probable in some.
Additional Information for Immediate Release
Capsules: Rare, usually transient, but occasionally
significant elevations of enzymes such as alkaline phosphatase,
CPK, LDH, SGOT, and SGPT have been noted. The relationship
to nifedipine therapy is uncertain in most cases, but
probable in some. These laboratory abnormalities have
rarely been associated with clinical symptoms, however,
cholestasis with or without jaundice has been reported.
Rare instances of allergic hepatitis have been reported.
Additional Information for Extended Release Tablets:
Rare, usually transient, but occasionally significant
elevations of enzymes such as alkaline phosphatase, CPK,
LDH, SGOT, and SGPT have been noted. The relationship
to nifedipine therapy is uncertain in most case, but probable
in some. These laboratory abnormalities have rarely been
associated with clinical symptoms; however, cholestasis
with or without jaundice has been reported. A small (5.4%)
increase in mean alkaline phosphatase was noted in patients
treated with nifedipine. This was an isolated finding
not associated with clinical symptoms and it rarely resulted
in values which fell outside the normal range. Rare instances
of allergic hepatitis have been reported. In controlled
studies, nifedipine did not adversely affect serum uric
acid, glucose, or cholesterol. Serum potassium was unchanged
in patients receiving nifedipine in the absence of concomitant
diuretic therapy, and slightly decreased in patients receiving
concomitant diuretics.
Carcinogenesis, Mutagenesis, and Impairment of
Fertility
Nifedipine was administered orally to rats for 2 years
and was not shown to be carcinogenic. When given to rats
prior to mating, nifedipine caused reduced fertility at
a dose approximately 30 times the maximum recommended
human dose. There is a literature report of reversible
reduction in the ability of human sperm obtained from
a limited number of infertile men taking recommended doses
of nifedipine to bind to and fertilize an ovum in vitro.
In vivo mutagenicity studies were negative.
Pregnancy Category C
Nifedipine has been shown to produce teratogenic findings
in rats and rabbits, including digital anomalies similar
to those reported for phenytoin. Digital anomalies have
been reported to occur with other members of the dihydropyridine
class and are possibly a result of compromised uterine
blood flow. Nifedipine administration was associated with
a variety of embryotoxic, placentotoxic, and fetotoxic
effects, including stunted fetuses (rats, mice, rabbits),
rib deformities (mice), cleft palate (mice), small placentas
and underdeveloped chorionic villi (monkeys), embryonic
and fetal deaths (rats, mice, rabbits), and prolonged
pregnancy/decreased neonatal survival (rats; not evaluated
in other species). On a mg/kg basis, all of the doses
associated with the teratogenic embryotoxic or fetotoxic
effects in animals were higher (3.5-42 times) than the
maximum recommended human dose of 120 mg/day. On a mg/m2
basis, some doses were higher and some were lower than
the maximum recommended human dose but all are within
an order of magnitude of it. The doses associated with
placentotoxic effects in monkeys were equivalent to or
lower than the maximum recommended human dose on a mg/m2
basis.
There are no adequate and well-controlled studies in
pregnant women. Nifedipine should be used during pregnancy
only if the potential benefit justifies the potential
risk to the fetus.
Pediatric Use
Safety and effectiveness in pediatric patients have not
been established. Immediate Release Capsules: Use in pediatric
population is not recommended.
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