CONTRAINDICATIONS
Known hypersensitivity reaction to nifedipine.
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 flow 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: 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.