Canada - English - Health Canada
P R O D U C T M O N O G R A P H
Nifedipine Capsules USP
5 and 10 mg
AA PHARMA INC.
DATE OF PREPARATION:
1165 Creditstone Road, Unit # 1
June 16, 2010
P R O D U C T M O N O G R A P H
Nifedipine Capsules USP
5 and 10 mg
T H E R A P E U T I C C L A S S I F I C A T I O N
A n t i - a n g i n a l a g e n t
A C T I O N A N D C L I N I C A L P H A R M A C O L O G Y
NIFEDIPINE (nifedipine) is a calcium ion influx inhibitor (calcium entry blocker or calcium ion
antagonist). The anti-anginal effect of this group of drugs is believed to be related to their
specific cellular action of selectively inhibiting transmembrane influx of calcium ions into cardiac
muscle and vascular smooth muscle. The contractile processes of these tissues are dependent upon
the movement of extra-cellular calcium into the cells through specific ion channels. Nifedipine blocks
the transmembrane influx of calcium through the slow channels without affecting to any significant
degree the transmembrane influx of sodium through the fast channel. This results in a reduction of
free calcium ions available within cells of the above tissues. Nifedipine does not alter total serum
The specific mechanism by which nifedipine relieves angina has not been fully determined but it is
believed to be brought about largely by its vasodilatory action.
Nifedipine dilates the main coronary arteries and coronary arterioles both in normal and ischemic
regions and is a potent inhibitor of coronary artery spasm. This property increases myocardial oxygen
delivery and is responsible for the effectiveness of nifedipine in vasospastic angina.
Nifedipine, by its vasodilatory action on peripheral arterioles, reduces the total peripheral vascular
resistance. This reduces the workload of the heart and thus reduces the myocardial energy
consumption and oxygen requirements and probably accounts for the effectiveness of
nifedipine in chronic stable angina.
The negative inotropic effect of nifedipine is usually not of major clinical significance because the
drug's vasodilating properties evoke at therapeutic doses a baroreceptor-mediated reflex tachycardia
which tends to counterbalance this negative inotropic effect.
Although nifedipine causes a slight depression of sinoatrial node function and atrioventricular
conduction in isolated myocardial preparations, such effects have not been seen in studies in intact
animals or man. In formal electrophysiologic studies, predominantly in patients with normal
conduction systems, nifedipine has no tendency to prolong atrioventricular conduction or sinus node
recovery time, or to slow sinus rate.
In man, oral administration of 10 mg C
nifedipine resulted in more than 90% absorption of the drug.
Radioactivity was detectable in the serum 20 minutes after oral ingestion and peak serum levels were
reached in 1 to 2 hours. 70 to 80% of the activity was eliminated via the kidneys and the
remainder via the feces.
The bi-exponential analysis of the disappearance of nifedipine in the plasma yields an initial fast half-
) of 2.5 to 3 hours and a terminal slow half-life (t
of 5 hours.
Studies in man, dog and rat showed that nifedipine is almost completely metabolized in the
body. It is transformed into two pharmacologically inactive metabolites. The main metabolite is the
hydroxycarboxylic acid derivative which represents about 95%, the other is the
corresponding lactone, which represents about 5%. The acid form is mainly excreted in the urine.
Protein binding of circulating nifedipine exceeds 90%.
Nifedipine is metabolized by the cytochrome P450 enzyme system, predominantly via CYP 3A4, but
also by CYP 1A2 and CYP 2A6 isoenzymes.
Pharmacokinetic studies in patients with hepatic cirrhosis showed a clinically significant alteration in
the kinetics of nifedipine (prolonged elimination half life and decreased total clearance). In these
patients, there is a considerable risk of accumulation (see PRECAUTIONS).
Compounds found in grapefruit juice inhibit the cytochrome P450 system, especially isoenzyme CYP
3A4. In a grapefruit juice-nifedipine interaction study in healthy male volunteers, pharmacokinetics
of nifedipine showed significant alteration. Following administration of a single dose of nifedipine 10
mg with 250 mL of grapefruit juice, the mean value of nifedipine AUC increased by 34% and the
increased from 0.8 hours to 1.2 hours, as compared to water (see PRECAUTIONS – Interaction
with Grapefruit Juice).
A comparative bioavailability study was performed on Adalat 10 mg capsules vs. NIFEDIPINE 10
mg capsules using 24 (twenty-four) normal volunteers. A single dose of 20 mg was
administered. The results are as follows:
I N D I C A T I O N S A N D C L I N I C A L U S E
NIFEDIPINE (nifedipine) may be used in the management of angina resulting from coronary
NIFEDIPINE is indicated for the management of chronic stable angina (effort-associated
angina) without evidence of vasospasm in patients who remain symptomatic despite adequate
doses of beta blockers and/or organic nitrates or who cannot tolerate those agents.
NIFEDIPINE may be used in combination with beta blocking drugs in patients with chronic stable
angina, but available information is not sufficient to predict with confidence the effects of
concurrent treatment, especially in patients with compromised left ventricular function or cardiac
conduction abnormalities. When introducing such concomitant therapy care must be taken to
monitor blood pressure closely, since severe hypotension can occur from the combined effects of
the drugs (see WARNINGS).
C O N T R A I N D I C A T I O N S
NIFEDIPINE (nifedipine) is contraindicated in pregnancy, during lactation and in women of
potential. Fetal malformations and adverse effects on pregnancy have been reported in animals.
An increase in the number of fetal mortalities and resorptions occurred after the administration
of 30 and 100 mg/kg nifedipine to pregnant mice, rats and rabbits. Fetal malformations occurred
after the administration of 30 and 100 mg/kg nifedipine to pregnant mice and 100 mg/kg to
In patients with acute myocardial infarction (see WARNINGS – Patients with Myocardial
In patients with cardiovascular shock.
In patients with hypersensitivity to nifedipine.
In patients with severe hypotension.
W A R N I N G S
NIFEDIPINE (nifedipine) should be used with care in the following conditions:
Excessive Hypotension: Since nifedipine lowers peripheral vascular resistance and blood pressure,
nifedipine should be used cautiously in patients who are prone to develop hypotension. Occasional
patients have had excessive and poorly tolerated hypotension. Syncope has been reported (see
ADVERSE REACTIONS). These responses have usually occurred during initial titration or at the
time of subsequent upward dosage adjustment, and may be more likely in patients on concomitant
beta blockers. If excessive hypotension occurs, dosage should be lowered or the drug should be
discontinued (see CONTRAINDICATIONS).
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.
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.
Patients with Myocardial Infarction: NIFEDIPINE should not be used within one week after
myocardial infarction and not before the patient has stabilized. Randomized, placebo-controlled
clinical trials have indicated that nifedipine may increase the risk of reinfarction and worsen survival
in patients treated early after myocardial infarction.
Patients with Unstable Angina: Some clinical trials have shown that treatment with nifedipine in this
setting increases the risk of myocardial infarction and recurrent ischemia.
Hypertension: NIFEDIPINE should not be used for the management of essential hypertension.
Acute Reduction of blood Pressure: NIFEDIPINE should not be used for acute reduction of blood
pressure. Strokes have occurred when nifedipine was used in this setting.
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. 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
Patients with Heart Failure: There have been isolated reports of severe hypotension and lowering of
cardiac output following administration of nifedipine to patients with severe heart failure. Rarely,
patients usually receiving a beta blocker, have developed heart failure after beginning nifedipine
In patients with severe aortic stenosis, nifedipine will not produce its usual afterload-reducing
effects, and there is a possibility that an unopposed negative inotropic action of the drug may
produce heart failure if the end-diastolic pressure is raised.
Caution should therefore be exercised when using nifedipine in patients with these conditions.
P R E C A U T I O N S
Because NIFEDIPINE (nifedipine) is an arterial and arteriolar vasodilator, hypotension and a
compensatory increase in heart rate may occur. Thus, blood pressure and heart rate should be
monitored carefully during nifedipine therapy. Close observation is especially recommended for
patients who are prone to develop hypotension, those with a history of cerebrovascular insufficiency,
and those who are taking medications that are known to lower blood pressure (see WARNINGS).
Mild to moderate peripheral edema, typically associated with arterial vasodilation and not due to left
ventricular dysfunction, has been reported to occur in patients treated with nifedipine (see
ADVERSE REACTIONS). 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
Use in Elderly
Nifedipine should be administered cautiously to elderly patients, especially to those with a history of
hypotension or cerebral vascular insufficiency. (See DOSAGE AND ADMINISTRATION).
Use in Diabetic Patients
The use of nifedipine in diabetic patients may require adjustment of their control.
Use in Patients with Impaired Liver Function
Nifedipine should be used with caution in patients with impaired liver function (see CLINICAL
PHARMACOLOGY). A dose reduction, particularly in severe cases, may be required. The
response and metabolic effect should be monitored closely.
Interaction with Grapefruit Juice
Published data indicate that through inhibition of cytochrome P450, grapefruit juice can increase
plasma levels and augment pharmacodynamic effects of some dihydropyridine calcium channel
blockers, including nifedipine (see ACTION AND CLINICAL PHARMACOLOGY —
Pharmacokinetics). Therefore, consumption of grapefruit juice prior to or during treatment with
nifedipine should be avoided.
As with all drugs, care should be exercised when treating patients with multiple medications.
Dihydropyridine calcium channel blockers undergo biotransformation by the cytochrome P450
system, mainly via the CYP 3A4 isoenzyme. Coadministration of nifedipine with other drugs
which follow the same route of biotransformation may result in altered bioavailability. Dosages of
similarly metabolized drugs, particularly those of low therapeutic ratio, and especially in patients
with renal and/or hepatic impairment, may require adjustment when starting or stopping
concomitantly administered nifedipine to maintain optimum therapeutic blood levels.
Drugs known to be inhibitors of the cytochrome P450 system include azole antifungals, cimetidine,
cyclosporine, erythromycin, quinidine, terfenadine and warfarin.
Drugs known to be inducers of the cytochrome P450 system include phenobarbital, phenytoin and
Drugs known to be biotransformed via P450 include benzodiazepines, flecainide, imipramine,
propafenone and theophylline.
The antihypertensive effect of beta-blockers may be augmented by nifedipine's reduction of
peripheral vascular resistance. The concomitant administration of nifedipine with beta-adrenergic
blocking drugs warrants caution and careful monitoring of the blood pressure and pulmonary signs
and symptoms of congestive failure (see WARNINGS).
Long acting nitrates: Nifedipine may be safely co-administered with nitrates, but there have been
no controlled studies to evaluate the antianginal effectiveness of this combination.
Antihypertensives: Nifedipine may potentiate the effects of hypotensive agents.
Concomitant use of nifedipine with short-acting nitrates, furosemide and anticoagulants has shown
no interaction or unusual toxic effects.
Administration of nifedipine with digoxin may lead to reduced digoxin clearance, and therefore, an
increase in the plasma digoxin level. It is recommended that the digoxin levels be monitored when
initiating, adjusting and discontinuing nifedipine to avoid possible under- or over-dosing with
The addition of nifedipine to a stable quinidine regimen may reduce the quinidine concentration by
50%; an enhanced response to nifedipine may also occur. The addition of quinidine to a stable
nifedipine regimen may result in elevated nifedipine concentrations and a reduced response to
quinidine. Some patients have experienced elevated quinidine levels when nifedipine was
discontinued. Therefore, patients receiving concomitant therapy of nifedipine and quinidine, or
those who had their nifedipine discontinued while still receiving quinidine, should be closely
monitored, including determination of plasma levels of quinidine. Consideration should be
given to dosage adjustment.
Pharmacokinetic studies have shown that concurrent administration of cimetidine or ranitidine and
nifedipine results in significant increases in nifedipine plasma levels (ca. 80% with
cimetidine, and 70% with ranitidine). Patients receiving either of these drugs concomitantly with
nifedipine should be monitored carefully for the possible exacerbation of effects of nifedipine, such
as hypotension. Adjustment of nifedipine dosage may be necessary.
A D V E R S E R E A C T I O N S
A safety analysis from the world literature (controlled and open studies) was carried out in a
heterogeneous group of 7146 patients who were treated with nifedipine. Adverse effects were
reported in 27.9% of patients and required discontinuation of treatment in 5.5% of patients.
The most common adverse effects, which generally result from the vasodilating effects of
nifedipine were: headache (7.2%); dizziness, lightheadedness and giddiness (6.7%), nausea and
vomiting and gastrointestinal distress (6.7%); flushing and heat sensation (5.8%); peripheral edema
(3.7%) and hypotension (2.0%).
As a part of the above analysis, a more comprehensive safety evaluation (controlled and open
studies) was carried out in 3074 patients, some of whom were severely ill and were receiving a
variety of concomitant drugs, such as beta-blockers, nitrates, antiarrhythmics, cardiac
glycosides, diuretics and anti-platelet drugs, etc.
The following adverse effects divided by systems were reported in these 3074 patients:
Peripheral edema, fluid retention and swelling:
Flushing, heat sensation:
Palpitation and increased heart rate:
Rarely, and possibly due to tachycardia, nifedipine has been reported to have precipitated an angina
pectoris attack. In addition, more serious events were occasionally observed, not readily
distinguishable from the natural history of the disease in these patients. It remains possible,
however, that some or many of these events were drug related. These events include
myocardial infarction, congestive heart failure or pulmonary edema, and ventricular arrhythmias or
Central Nervous System
Dizziness, lightheadedness, giddiness:
Shakiness, nervousness and jitteriness:
Nausea and vomiting:
Abdominal discomfort and heartburn
Joint stiffness, muscle pain and cramps:
Shortness of breath, dyspnea:
Pruritus, dermatitis, urticaria and rash:
Fever, sweating and chills:
Two cases of hypersensitivity have been reported resulting in an allergic hepatitis which resolved
when the drug was discontinued. In one case, recurrence was observed on re-challenge.
Nifedipine has been reported to cause in a small number of patients gingival hyperplasia similar to
that caused by diphenylhydantoin. The lesions usually regressed on discontinuation of nifedipine.
However, on occasion, gingivectomy was necessary.
Isolated cases of angioedema have been reported. Angioedema may be accompanied by breathing
One case of anaphylactic reaction has been reported.
Gynecomastia has been observed rarely in older men on long-term therapy, but has so far always
regressed completely on discontinuation of the drug.
Rarely, mild to moderate transient elevations of enzymes such as alkaline phosphatase, CPK, LDH,
SGOT and SGPT have been noted after treatment with nifedipine. These laboratory abnormalities
have rarely been associated with clinical symptoms, however, cholestasis with or without jaundice
has been reported. Infrequent reversible elevations in BUN and serum creatinine have been
reported in patients with pre-existing chronic renal insufficiency taking nifedipine.
S Y M P T O M S A N D T R E A T M E N T O F O V E R D O S A G E
There are several well documented cases of nifedipine immediate-release overdosage. The
following symptoms are observed in cases of severe nifedipine intoxication: disturbance of
consciousness to the point of coma, a drop in blood pressure, tachycardia/bradycardia,
hyperglycemia, metabolic acidosis, hypoxia, cardiogenic shock with pulmonary oedema.
As far as treatment is concerned, elimination of the active substance and the restoration of
stable cardiovascular conditions have priority. After oral ingestion, thorough gastric lavage is
indicated, if necessary in combination with irrigation of the small intestine. Haemodialysis serves
no purpose, as nifedipine is not dialysable, but plasmapheresis is advisable (high plasma protein
binding, relatively low volume of distribution).
Clinically significant hypotension calls for active cardiovascular support including monitoring of
cardiac and respiratory function including elevation of extremities and attention to circulating fluid
volume and urine output.
Hypotension as a result of arterial vasodilation can also be treated with calcium (10 mL of 10%
calcium gluconate solution administered slowly via intravenous route and repeated if necessary).
As a result, the serum calcium can reach the upper normal range to slightly elevated levels. If an
insufficient increase in blood pressure is achieved with calcium, vasoconstricting
sympathomimetics such as dopamine or noradrenaline are additionally administered as a last resort
only in patients without cardiac arrhythmia or ischemic heart disease and when other safer measures
have failed. The dosage of these drugs is determined solely by the effect obtained. Additional liquid
or volume must be administered with caution because of the danger of overloading the heart.
Bradycardia and/or bradyarrhythmias have been observed in some cases of nifedipine overdosage.
Appropriate clinical measures, according to the nature and severity of the symptoms, should be
D O S A G E A N D A D M I N I S T R A T I O N
In all cases, dosage should be adjusted to individual patient requirements.
The starting dose of NIFEDIPINE (nifedipine) is one 10 mg capsule, swallowed whole, 3 times/day.
The usual effective dose range is 10-20 mg three times daily. Some patients, especially those with
evidence of coronary artery spasm, respond only to higher doses, more frequent administration, or
both. In such patients, doses of 20-30 mg three or four times daily may be effective. A maximum
daily dose of 120 mg may be used.
In general there should be an interval of at least three days between increases in dose in order to
adequately assess the response to a particular dose level. In hospitalized patients under close
observation the titration phase may proceed more rapidly.
Nifedipine should be administered cautiously to elderly patients and the dosage should be carefully
and gradually adjusted depending on patient tolerance and response (see PRECAUTIONS).
NIFEDIPINE 5 mg capsules provide for greater flexibility of dose titration, e.g. in elderly patients.
P H A R M A C E U T I C A L I N F O R M A T I O N
pyridine-dicarboxylic acid dimethyl ester
Description: Nifedipine is a pyridine dicarboxylic acid dimethylester. It is a fine yellowish powder,
practically insoluble in water but soluble in ethanol. It is light-sensitive, and when exposed, is
converted to a pharmacologically inactive pyridine derivative via an intramolecular
Stability and Storage Recommendations
The capsules should be stored between 15° and 25°C. Avoid freezing. Protect from light.
A V A I L A B I L I T Y O F D O S A G E F O R M S
NIFEDIPINE (nifedipine) 5 mg: each mustard-coloured, opaque, soft gelatin capsule, imprinted '5',
contains nifedipine 5 mg. Available in bottle of 100.
NIFEDIPINE (nifedipine) 10 mg: each mustard-coloured, opaque, soft gelatin capsule, imprinted
'10', contains nifedipine 10 mg. Available in bottle of 100.
P H A R M A C O L O G Y
Inhibition of Transmembrane ca+
Nifedipine has been shown in isolated preparations to restrict the transmembrane calcium ion influx
during excitation-contraction coupling in both cardiac and vascular smooth muscles.
In the cat papillary muscle under voltage clamp conditions, nifedipine at a concentration of 10
did not influence the fast Na
inward current, but depressed the slow Ca
inward current in a
dose-dependent manner without altering the kinetic control mechanism (gating mechanism).
In isolated rabbit's ear perfused with Tyrode solution, nifedipine has been shown to cause immediate
vasodilation, loss of vascular tone and irresponsiveness to increased in perfusion pressure.
However, subsequent neutralization of the drug effect could be achieved by an 8–fold increase in
the extracellular Ca
In a study employing the isolated guinea pig heart, nifedipine strongly increased coronary perfusion
even at low concentrations of 10
g/mL. There was also a dose-dependent decrease in
oxygen consumption, left ventricular systolic pressure, and the maximum rate of pressure increase
in the left ventricle (dp/dt). The basic effects on the isolated hearts are therefore an increase in
myocardial perfusion, negative inotropic effect, and a consequent decrease in oxygen consumption
of the cardiac muscle.
In dogs under opiate analgesia (thereby maintaining practically intact regulation of the
circulation), nifedipine administered sublingually at dosages of 10 - 1000 kg/kg caused a dose-
dependent increase in coronary flow, resulting in an increased oxygen supply to the heart. The
peripheral flow, measured in the femoral artery, also increased in a dose-dependent manner.
At low doses (10 - 31.5 µg/kg) the cardiac contractility, measured by left ventricular dp/dt, and the
end-diastolic pressure were reduced or unaffected, while at higher doses (100 - 1000 µg/kg) there
was an increase in dp/dt dependent on the increase in heart rate. Thus, low doses of nifedipine may
produce a negative inotropic effect, but higher doses produce greater peripheral vasodilation, and
the direct negative inotropic effect is modified by the baroreceptor-mediated reflex positive
inotropic response and tachycardia. In further hemodynamic investigations conducted in conscious
dogs with implanted aortic flow-probes, a reduction in total peripheral resistance was observed with
nifedipine doses of only 10 µg/kg sublingually, which did not appreciably lower the mean blood
pressure. However, a decrease in the mean blood pressure occurred when doses were raised to 31.5
or 100 µg/kg. In this higher dose range, there were significant decreases in peripheral resistance,
with concomitant increases in heart rate, stroke volume and cardiac output as a result of
compensatory mechanisms. The drop in peripheral resistance associated with the increase in
cardiac output results in a partial transformation of the pressure workload of the heart into a volume
workload which is considered to be less oxygen consuming. Lowering of the peripheral resistance
also indicates that nifedipine reduces the afterload.
In the isolated guinea–pig atria the prolongation of the functional refractory period by nifedipine
was not very pronounced, although there was a marked decrease in contractility. Even at high
concentrations nifedipine did not affect myocardial excitability.
In the conscious dog, nifedipine produced a moderate, dose-dependent PQ shortening. Only by
injection of large doses (up to 30 µg) of nifedipine into the posterior septal artery did a dose-
dependent increase in A-V conduction occur. The increase in blood flow through the posterior
septal artery required only 1/10 the dose necessary to affect A-V conduction.
These electrophysiologic properties of nifedipine explain in part the lack of antiarrhythmic activity
of the drug.
T O X I C O L O G Y
Acute Toxicity Studies
Dose Level (mg/kg)
623 – 1604
739 – 1354
831 – 1204
3726 – 4962
5294 – 7261
4576 - 5463
The oral LD
of nifedipine in albino mice was calculated to be 1000 mg/kg regardless of sex; in
rats 6200 mg/kg and 4300 mg/kg for males and females respectively.
In mice, most deaths occurred within 24 hours of dosing while in rats, deaths occurred between
days 2 and 9 post-dosing. In mice, principal signs of toxicity included ptosis, piloerection,
hunching of the back, dyspnea, abdominal distention, tremor and reduced motor activity. In rats,
principal signs of toxicity included darkening of the liver, spleen and/or G.I. tract, reddening of the
lungs, adrenals, thymus and/or intestines, G.I. tract distention and in some animals, ascites. In both
species, animals killed routinely at the end of the studies revealed no abnormalities upon necropsy.
Subacute Toxicity Studies
In rats, oral doses of 0.5 to 100 mg/kg/day nifedipine for 13 weeks did not induce significant
adverse effects. Similar results were obtained in dogs treated with 0.5 to 50 mg/kg/day
nifedipine for 13 weeks.
Chronic Toxicity and Carcinogenicity Studies
Nifedipine was administered orally to dogs at dosages of 2.5, 20 and 100 mg/kg/day for 52 weeks.
No indication of toxic damage caused by nifedipine was found.
In a 2–year study, nifedipine was administered orally to male and female rats in the diet at dosages
of 5-9, 29-39, and 156-210 mg/kg/day. In the lowest dose group, nifedipine was without toxic
effects. The higher dosage led to dose-dependent, significant weight losses. An increased mortality
was found in the 156-210 mg/kg dose group, especially in the females. The pathological-
anatomical examination of the dead animals showed a hypotonia or atonia of the musculature of the
small intestine. An increase in the weight of the adrenal glands of male rats was also observed in
this dose group. Histopathological examinations revealed no organ damage related to treatment.
At the end of the study, all rats were examined histopathologically with regards to tumorigenesis.
Although the animals in the highest dose group showed no uncommon tumor incidences, this group
was considered not suitable for comparison with the other treatment groups because of the high
mortality rate. No significant difference were found between the controls and the remaining two
treatment groups with respect to the frequency, nature and localisation of tumors.
In the Dominant Lethal test, the oral administration of nifedipine to mice at a dose of 100 mg/kg for
5 consecutive days did not affect fertility rate or post-implantation loss.
In the Micronucleus test, 2 doses of 50 mg/kg or 100 mg/kg nifedipine given orally to mice also did
not produce any mutagenic effect. Furthermore, the formation of erythrocytes was not impaired as
shown by the polychromatic: normochromatic erythrocyte ratio.
In the Ames' Salmonella/microsome test, nifedipine at doses of up to 12500 ug per plate did not
cause any bacterotoxic effects. Also, a dose-dependent and biologically relevant increase in the
number of mutants to a level double that of the negative control was not noted.
Pregnant mice, rats and rabbits were treated orally with 10, 30 and 100 mg/kg nifedipine from day
6 to day 15 of gestation. In the mouse, at doses of 30 and 100 mg/kg there was an increase in the
number of fetal resorptions. Fetal malformations in the form of cleft palate and rib deformities
occurred at all dose levels in a dose related fashion. (Cleft palate occurred in 5/218 controls, 13/190
at 10 mg/kg, 22/112 at 30 mg/kg and 3/3 at 100 mg/kg).
In the rat, the dose of 30 mg/kg was not toxic to pregnant dams, but caused reduced fetal
weight and increased fetal loss. The dose of 100 mg/kg produced malformations in the fetuses from
20% of the mother animals. In a total of 11 fetuses, 10 showed malformation of the front or hind
paws (ectrodactyly, oligodactyly and adactyly) and one developed a severe malformation of the
In the rabbit, there was a dose-dependent anorexia and weight loss in mothers during the dosing
period. At 30 and 100 mg/kg, reduced litter size and weight and increased fetal loss were evident.
Studies on pregnant rhesus monkeys with oral doses of 2 (1 animal) or 6 mg/kg/day (4 animals)
revealed no teratogenic effects. The placentas were poorly developed in dosed animals.
Pre- and post-natal studies on rats with daily doses of 3, 10, 30 and 100 mg/kg showed that
nifedipine caused significant prolongation of the gestation period at dosage of 10 mg/kg
upwards and a decrease in litter size. The post-natal development of the newborn animals was
impaired when doses of 30 mg/kg or more had been administered. All offspring in the 100
mg/kg group died.
B I B L I O G R A P H Y
Antman E, Muller J, Goldberg S, et al. Nifedipine therapy for coronary-artery spasm. N Eng J
Med 1980; 302: 1269-1273.
Ebner F, Dunschede HB. Haemodynamics, therapeutic mechanism of action and clinical
findings of Adalat use based on worldwide clinical trials. In: Jatene AD, Lichtlen PR, eds. New
therapy of ischemic heart disease. Third Int Adalat Symp. Amsterdam Excerpta Medica,1976;
Fleckenstein A. On the basic pharmacological mechanism of nifedipine and its relation to
therapeutic efficacy. In: Jatene AD, Lichtlen PR, eds. New therapy of ischemic heart disease.
Third Int Adalat Symp. Amsterdam Excerpta Mecida, 1976; 1-13.
Goldberg S, Reichek N, Wilson J, et al. Nifedipine in the treatment of Prinzmetal's (variant)
angina. Am J Cardiol 1979; 44: 804-810.
Gunther S, Green L, Muller JE, et al. Inappropriate coronary vasoconstriction in patients with
coronary artery disease: a role for nifedipine? Am J Cardiol 1979; 44: 793-797.
Heupler FA Jr., Proudfit WL. Nifedipine therapy for refractory coronary arterial spasm. Am J
Cardiol 1979; 44: 798-803.
Kenmure ACF, Scruton JH. A double–blind controlled trial of the anti–anginal efficacy of
nifedipine compared with propranolol. Br J Clin Pract 1979; 33: 49-51
Maseri AM, L'Abbate A, Chierchia S, et al. Significance of spasm in the pathogenesis of
ischemic heart disease. Am J Cardiol 1979; 44: 788-792.
Moskowitz RM, Piccini PA, Nacarelli GV, Zelis R. Nifedipine therapy for stable angina
pectoris: preliminary results of effects on angina frequency and treadmill exercise response. Am
J Cardiol 1979; 44: 811-816.
Mueller HS, Chahine RA. Interim report of multicenter double–blind placebo–controlled
studies of nifedipine in chronic stable angina. 1981; 71: 645-657.
Rowland E, Evans T, Krikler D. Effect of nifedipine on atrioventricular conduction as compared
with verapamil. Intracardiac electrophysiological study. Br Hert J 1979; 42: 124-127.
Sherman LG, Liang C–S. Nifedipine in chronic stable angina: a double-blind placebo-
controlled crossover trial. Am J Cardiol 1983; 51: 706-711.
Stone PH, Muller JE, Turi ZG, et al. Efficacy of nifedipine therapy in patients with refractory
angina pectoris: significance of the presence of coronary spasm. Am Heart J 1983; 106: 644-
Terry RW. Nifedipine therapy in angina pectoris: evaluation of safety and side effects. Am
Heart J 1982; 104: 681-689.
Adalat Summary Basis of Approval, FDA.