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Nifedipine
Immediate Release Capsules and Extended Release Tablets Nifedipine is an antianginal drug belonging to a class of pharmacological agents, the calcium channel blockers. Nifedipine is 3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-,dimethyl ester, C17H18N2O6. Nifedipine is a yellow crystalline substance, practically insoluble in water but soluble in ethanol. It has a molecular weight of 346.3. Immediate Release Capsules Procardia capsules are formulated as soft gelatin capsules for oral administration each containing 10 mg or 20 mg nifedipine. Inert Ingredients in the Formulations Are: Glycerin; peppermint oil; polyethylene glycol; soft gelatin capsules (which contain yellow 6, and may contain red ferric oxide and other inert ingredients), and water. The 10 mg capsules also contain saccharin sodium. Extended Release Tablets Procardia XL is a trademark for nifedipine GITS. Nifedipine GITS (Gastrointestinal Therapeutic System) Tablet is formulated as a once-a-day controlled-release tablet for oral administration designed to deliver 30, 60, or 90 mg of nifedipine. Inert Ingredients in the Formulations Are: Cellulose acetate; hydroxypropyl cellulose; hydroxypropyl methylcellulose; magnesium stearate; polyethylene glycol; polyethylene oxide; red ferric oxide; sodium chloride; titanium dioxide. System Components and Performance: Procardia XL extended release tablet is similar in appearance to a conventional tablet. It consists, however, of a semipermeable membrane surrounding an osmotically active drug core. The core itself is divided into two layers: an "active" layer containing the drug, and a "push" layer containing pharmacologically inert (but osmotically active) components. As water from the gastrointestinal tract enters the tablet, pressure increases in the osmotic layer and "pushes" against the drug layer, releasing drug through the precision laser-drilled tablet orifice in the active layer. Procardia XL extended release
tablet is designed to provide
nifedipine at an approximately constant
rate over 24 hours. This controlled
rate of drug delivery into the
gastrointestinal
lumen is independent of pH
or gastrointestinal motility. Procardia XL depends for its action
on the existence of an osmotic gradient between the contents of the bi-layer
core and fluid
in the GI tract. Drug delivery is essentially constant
as long as the osmotic gradient remains constant, and then gradually falls
to zero. Upon swallowing, the biologically inert
components of the tablet remain
intact during GI transit and are
eliminated in the feces as an
insoluble shell.
Nifedipine is a calcium ion influx inhibitor (slow-channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac muscle and smooth muscle. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Nifedipine selectively inhibits calcium ion influx across the cell membrane of cardiac muscle and vascular smooth muscle without changing serum calcium concentrations. Mechanism of Action The precise means by which this inhibition relieves angina has not been fully determined, but includes at least the following two mechanisms. Relaxation and Prevention of Coronary Artery Spasm Nifedipine dilates the main coronary arteries and coronary arterioles, both in normal and ischemic regions, and is a potent inhibitor of coronary artery spasm, whether spontaneous or ergonovine-induced. This property increases myocardial oxygen delivery in patients with coronary artery spasm, and is responsible for the effectiveness of nifedipine in vasospastic (Prinzmetal's or variant) angina. Whether this effect plays any role in classical angina is not clear, but studies of exercise tolerance have not shown an increase in the maximum exercise rate-pressure product, a widely accepted measure of oxygen utilization. This suggests that, in general, relief of spasm or dilation of coronary arteries is not an important factor in classical angina. Reduction of Oxygen Utilization Nifedipine regularly reduces arterial pressure at rest and at a given level of exercise by dilating peripheral arterioles and reducing the total peripheral resistance (afterload) against which the heart works. This unloading of the heart reduces myocardial energy consumption and oxygen requirements, and probably accounts for the effectiveness of nifedipine in chronic stable angina. Electrophysiologic Effects Although, like other members of its class, nifedipine decreases sinoatrial node function and atrioventricular conduction in isolated myocardial preparations, such effects have not been seen in studies in intact animals or in man. In formal electrophysiologic studies, predominantly in patients with normal conduction systems, nifedipine has had no tendency to prolong atrioventricular conduction, prolong sinus node recovery time, or slow sinus rate. Additional Information for Immediate Release Capsules Hemodynamics: Like other slow-channel blockers, nifedipine exerts a negative inotropic effect on isolated myocardial tissue. This is rarely, if ever, seen in intact animals or man, probably because of reflex responses to its vasodilating effects. In man, Nifedipine causes decreased peripheral vascular resistance and a fall in systolic and diastolic pressure, usually modest (5-10mm Hg systolic), but sometimes larger. There is usually a small increase in heart rate, a reflex response to vasodilation. Measurements of cardiac function in patients with normal ventricular function have generally found a small increase in cardiac index without major effects on ejection fraction, left ventricular end diastolic pressure (LVEDP) or volume (LVEDV). In patients with impaired ventricular function, most acute studies have shown some increase in ejection fraction and reduction in left ventricular filling pressure. Pharmacokinetics and Metabolism: Nifedipine is rapidly and fully absorbed after oral administration. The drug is detectable in serum 10 minutes after oral administration, and peak blood levels occur in approximately 30 minutes. Bioavailability is proportional to dose from 10 to 30 mg; half-life does not change significantly with dose. There is little difference in relative bioavailability when nifedipine capsules are given orally and either swallowed whole, bitten and swallowed, or, bitten and held sublingually. However, biting through the capsule prior to swallowing does result in slightly earlier plasma concentrations (27 ng/ml 10 minutes after 10 mg) than if capsules are swallowed intact. It is highly bound by serum proteins. Nifedipine is extensively converted to inactive metabolites and approximately 80% of nifedipine and metabolites are eliminated via the kidneys. The half-life of nifedipine in plasma is approximately 2 hours. Since hepatic biotransformation is the predominant route for the disposition of nifedipine, the pharmacokinetics may be altered in patients with chronic liver disease. Patients with hepatic impairment (liver cirrhosis) have a longer disposition half-life and higher bioavailability of nifedipine than healthy volunteers. The degree of serum protein binding of nifedipine is high (92-98%). Protein binding may be greatly reduced in patients with renal or hepatic impairment. Additional Information for Extended Release Tablets Hypertension The mechanism by which nifedipine reduces arterial blood pressure involves peripheral arterial vasodilatation and the resulting reduction in peripheral vascular resistance. The increased peripheral vascular resistance that is an underlying cause of hypertension results from an increase in active tension in the vascular smooth muscle. Studies have demonstrated that the increase in active tension reflects an increase in cytosolic free calcium. Nifedipine is a peripheral arterial vasodilator which acts directly on vascular smooth muscle. The binding of nifedipine to voltage-dependent and possibly receptor-operated channels in vascular smooth muscle results in an inhibition of calcium influx through these channels. Stores of intracellular calcium in vascular smooth muscle are limited and thus dependent upon the influx of extracellular calcium for contraction to occur. The reduction in calcium influx by nifedipine causes arterial vasodilation and decreased peripheral vascular resistance which results in reduced arterial blood pressure. Pharmacokinetics and Metabolism Nifedipine is completely absorbed after oral administration. Plasma drug concentrations rise at a gradual, controlled rate after a nifedipine extended release tablet dose and reach a plateau at approximately 6 hours after the first dose. For subsequent doses, relatively constant plasma concentrations at the plateau are maintained with minimal fluctuations over the 24 hour dosing interval. About a four-fold higher fluctuation index (ratio of peak to trough plasma concentration) was observed with the conventional immediate release nifedipine capsule at tid dosing than once daily nifedipine extended release tablet. At steady-state the bioavailability of nifedipine extended release tablets is 86% relative to nifedipine capsules. Administration of the nifedipine extended release tablets in the presence of food slightly alters the early rate of drug absorption, but does not influence the extent of drug bioavailability. Markedly reduced GI retention time over prolonged periods (i.e., short bowel syndrome), however, may influence the pharmacokinetic profile of the drug which could potentially result in lower plasma concentration. Pharmacokinetics of nifedipine extended release tablets are linear over the dose range of 30-180 mg in that plasma drug concentrations are proportional to dose administered. There was no evidence of dose dumping either in the presence or absence of food for over 150 subjects in pharmacokinetic studies. Nifedipine is extensively metabolized to highly water-soluble, inactive metabolites accounting for 60-80% of the dose excreted in the urine. The elimination half-life of nifedipine is approximately 2 hours. Only traces (less than 0.1% of the dose) of unchanged form can be detected in the urine. The remainder is excreted in the feces in metabolized form, most likely as a result of biliary excretion. Thus, the pharmacokinetics of nifedipine are not significantly influenced by the degree of renal impairment. Patients in hemodialysis or chronic ambulatory peritoneal dialysis have not reported significantly altered pharmacokinetics of nifedipine. Since hepatic biotransformation is the predominant route for the disposition of nifedipine, the pharmacokinetics may be altered in patients with chronic liver disease. Patients with hepatic impairment (liver cirrhosis) have a longer disposition half-life and higher bioavailability of nifedipine than healthy volunteers. The degree of serum protein binding of nifedipine is high (92-98%). Protein binding may be greatly reduced in patients with renal or hepatic impairments. Hemodynamics Like other slow-channel blockers, nifedipine exerts a negative
inotropic effect on isolated myocardial
tissue. This is rarely, if ever, seen in intact animals or man, probably
because of reflex responses
to its vasodilating effects. In man, nifedipine decreases peripheral
vascular resistance
which leads to a fall in systolic
and diastolic pressures,
usually minimal in normotensive
volunteers (less than 5-10 mm Hg
systolic), but sometimes larger. With nifedipine extended release
tablets, these decreases in blood pressure are not accompanied by any
significant change in
heart rate. Hemodynamic studies
in patients with normal ventricular
function have generally found
a small increase in cardiac
index without major effects
on ejection fraction, left
ventricular end
diastolic pressure
(LVEDP) or volume (LVEDV).
In patients with impaired ventricular
function, most acute studies
have shown some increase in ejection
fraction and reduction
in left ventricular
filling pressure.
Vasospastic Angina Nifedipine is indicated for the management of vasospastic angina confirmed by any of the following criteria: 1) classical pattern of angina at rest accompanied by ST segment elevation, 2) angina or coronary artery spasm provoked by ergonovine, or 3) angiographically demonstrated coronary artery spasm. In those patients who have had angiography, the presence of significant fixed obstructive disease is not incompatible with the diagnosis of vasospastic angina, provided that the above criteria are satisfied. Nifedipine may also be used where the clinical presentation suggests a possible vasospastic component but where vasospasm has not been confirmed, e.g., where pain has a variable threshold on exertion (or, in the extended release tablets, in unstable angina where electrocardiographic findings are compatible with intermittent vasospasm), or when angina is refractory to nitrates and/or adequate doses of beta blockers. Chronic Stable Angina Classical Effort-Associated Angina: 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. In chronic stable angina (effort-associated angina) nifedipine has been effective in controlled trials of up to 8 weeks duration in reducing angina frequency and increasing exercise tolerance, but confirmation of sustained effectiveness and evaluation of long-term safety in these patients are incomplete. Controlled studies in small numbers of patients suggest concomitant use of nifedipine and beta-blocking agents may be beneficial 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.) Additional Information for Extended Release Tablets Hypertension: Nifedipine is also indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.
Immediate Release Capsules The dosage of nifedipine needed to suppress angina and that can be tolerated by the patient must be established by titration. Excessive doses can result in hypotension. Therapy should be initiated with the 10 mg capsule. The starting dose is one 10 mg capsule, swallowed whole, 3 times/day. The usual effective dose range is 10-20 mg 3 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 3 or 4 times daily may be effective. Doses above 120 mg daily are rarely necessary. More than 180 mg per day is not recommended. In most cases, nifedipine titration should proceed over a 7-14 day period so that the physician can assess the response to each dose level and monitor the blood pressure before proceeding to higher doses. If symptoms so warrant, titration may proceed more rapidly provided that the patient is assessed frequently. Based on the patient's physical activity level, attack frequency, and sublingual nitroglycerin consumption, the dose of nifedipine may be increased from 10 mg tid to 20 mg tid and then to 30 mg tid over a 3-day period. In hospitalized patients under close observation, the dose may be increased in 10 mg increments over 4- to 6-hour periods as required to control pain and arrhythmias due to ischemia. A single dose should rarely exceed 30 mg. No "rebound effect" has been observed upon discontinuation of nifedipine. However, if discontinuation of nifedipine is necessary, sound clinical practice suggests that the dosage should be decreased gradually with close physician supervision. Co-Administration With Other Antianginal Drugs: Sublingual nitroglycerin may be taken as required for the control of acute manifestations of angina, particularly during nifedipine titration. See DRUG INTERACTIONS for information on co-administration of nifedipine with beta blockers or long-acting nitrates. Extended Release Tablets Dosage must be adjusted according to each patient's needs. Therapy for either hypertension or angina should be initiated with 30 or 60 mg once daily. Nifedipine extended release tablets should be swallowed whole and should not be bitten or divided. In general, titration should proceed over a 7-14 day period so that the physician can fully assess the response to each dose level and monitor blood pressure before proceeding to higher doses. Since steady-state plasma levels are achieved on the second day of dosing, if symptoms so warrant, titration may proceed more rapidly provided the patient is assessed frequently. Titration to doses above 120 mg are not recommended. Angina patients controlled on nifedipine capsules alone or in combination with other antianginal medications may be safety switched to nifedipine extended release tablets at the nearest equivalent total daily dose (e.g., 30 mg tid of nifedipine capsules may be changed to 90 mg once daily of nifedipine extended release tablets). Subsequent titration to higher or lower doses may be necessary and should be initiated as clinically warranted. Experience with dose greater than 90 mg in patients with angina is limited. Therefore, doses greater than 90 mg should be used with caution and only when clinically warranted. No "rebound effect" has been observed upon discontinuation of nifedipine extended release tablets. However, if discontinuation of nifedipine is necessary, sound clinical practice suggests that the dosage should be decreased gradually with close physician supervision. Care should be taken when dispensing nifedipine to assure that the extended release dosage form has been prescribed. Co-administration With Other Antianginal Drugs: Sublingual nitroglycerin may be taken as required for the control of acute manifestations of angina, particularly during nifedipine titration. See DRUG INTERACTIONS for information on co-administration of nifedipine with beta blockers or long-acting nitrates. HOW SUPPLIED Procardia Immediate Release Capsules Procardia soft gelatin capsules are supplied as: 10 mg orange #260; 20 mg orange and light brown #261. Storage: The capsules should be protected from light and moisture and stored at controlled room temperature 15- 25°C (59-77°F) in the manufacturer's original container. Procardia XL Extended Release Tablets Procardia XL extended release tablets are supplied as 30 mg, 60 mg, and 90 mg round biconvex, rose-pink, film-coated tablets. Storage: Stored below 30°C (86°F) Protect from moisture and humidity.
Immediate Release Capsules In multiple-dose U.S. and foreign controlled studies in which adverse reactions were reported spontaneously, adverse effects were frequent but generally not serious and rarely required discontinuation of therapy or dosage adjustment. Most were expected consequences of the vasodilator effects of nifedipine. (See TABLE 1.)
Incidence Approximately 10%:
Incidence Approximately 5%:
Incidence 2% or Less:
Incidence Approximately 0.5%: Cardiovascular: Syncope (mostly with initial dosing and/or an increase in dose), erythromelalgia. Incidence Less Than 0.5%:
Several of these side effects appear to be dose related. Peripheral edema occurred in about one in 25 patients at doses less than 60 mg per day and in about 1 patient in 8 at 120 mg per day or more. Transient hypotension, generally of mild to moderate severity and seldom requiring discontinuation of therapy, occurred in 1 of 50 patients at less than 60 mg per day and in one of 20 patients at 120 mg per day or more. Very rarely, introduction of nifedipine therapy was associated with an increase in anginal pain, possibly due to associated hypotension. Transient unilateral loss of vision has also occurred. In addition, more serious adverse events were 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. Myocardial infarction occurred in about 4% of patients and congestive heart failure or pulmonary edema in about 2%. Ventricular arrhythmias or conduction disturbances each occurred in fewer than 0.5% of patients. In a subgroup of over 1000 patients receiving nifedipine with concomitant beta blocker therapy, the pattern and incidence of adverse experiences was not different from that of the entire group of nifedipine treated patients. (See PRECAUTIONS.) In a subgroup of approximately 250 patients with a diagnosis of congestive heart failure as well as angina pectoris (about 10% of the total patient population), dizziness or lightheadedness, peripheral edema, headache or flushing each occurred in 1 in 8 patients. Hypotension occurred in about 1 in 20 patients. Syncope occurred in approximately 1 patient in 250. Myocardial infarction or symptoms of congestive heart failure each occurred in about 1 patient in 15. Atrial or ventricular dysrhythmias each occurred in about one patient in 150. In post-marketing experience, there have been rare reports of exfoliative dermatitis caused by nifedipine. There have been rare reports of exfoliative or bullous skin adverse events (such as exfoliative dermatitis, erythema multiforme, Stevens-Johnson Syndrome, and toxic epidermal necrolysis) and photosensitivity reactions. Extended Release Tablets Over 1000 patients from both controlled and open trials with nifedipine extended release tablets in hypertension and angina were included in the evaluation of adverse experiences. All side effects reported during nifedipine extended release tablet therapy were tabulated independent of their causal relation to medication. The most common side effect reported with nifedipine was edema which was dose related and ranged in frequency from approximately 10% to about 30% at the highest dose studied (180 mg). Other common adverse experience reported in placebo-controlled trials include those shown in TABLE 2.
The following adverse reactions occurred with an incidence of less than 3.0%. With the exception of leg cramps, the incidence of these side effects was similar to that of placebo alone.
Other adverse reactions were reported sporadically with an incidence of 1.0% or less. These include:
Adverse experiences which occurred in less than 1 in 1000 patients cannot be distinguished from concurrent disease states or medications. The following adverse experiences, reported in less than 1% of patients, occurred under conditions (e.g., open trials, marketing experience) where a causal relationship is uncertain: gastrointestinal irritation, gastrointestinal bleeding, gynecomastia. There is also a large uncontrolled experience in over 2100 patients in the United States. Most of the patients had vasospastic or resistant angina pectoris, and about half had concomitant treatment with beta-adrenergic blocking agents. The relatively common adverse events were similar in nature to those seen with nifedipine. In addition, more serious adverse events were 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. Myocardial infarction occurred in about 4% of patients and congestive heart failure or pulmonary edema in about 2%. Ventricular arrhythmias or conduction disturbances each occurred in fewer than 0.5% of patients. In a subgroup of over 1000 patients receiving nifedipine with concomitant beta blocker therapy, the pattern and incidence of adverse experiences was not different from that of the entire group of nifedipine treated patients. (See PRECAUTIONS.) In a subgroup of approximately 250 patients with a diagnosis of congestive heart failure as well as angina, dizziness or lightheadedness, peripheral edema, headache or flushing each occurred in 1 in 8 patients. Hypotension occurred in about 1 in 20 patients. Syncope occurred in approximately 1 patient in 250. Myocardial infarction or symptoms of congestive heart failure each occurred in about 1 patient in 15. Atrial or ventricular dysrhythmias each occurred in about one patient in 150. In post-marketing experience, there have been rare reports of exfoliative dermatitis caused by nifedipine. There have been rare reports of exfoliative or bullous skin adverse events (such as exfoliative dermatitis, erythema multiforme, Stevens-Johnson Syndrome, and toxic epidermal necrolysis) and photosensitivity reactions.
Beta-adrenergic Blocking Agents: (See INDICATIONS AND USAGE and WARNINGS.) Experience in over 1400 patients in a non-comparative clinical trial has shown that concomitant administration of nifedipine and beta-blocking agents is usually well tolerated, but there have been occasional literature reports suggesting that the combination may increase the likelihood of congestive heart failure, severe hypotension or exacerbation of angina. 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. Digitalis: Immediate Release Capsules: Since there have been isolated reports of patients with elevated digoxin levels, and there is a possible interaction between digoxin and nifedipine, it is recommended that digoxin levels be monitored when initiating, adjusting, and discontinuing nifedipine to avoid possible over- or under-digitalization. Extended Release Tablets: Administration of nifedipine with digoxin increased digoxin levels in 9 of 12 normal volunteers. The average increase was 45%. Another investigator found no increase in digoxin levels in 13 patients with coronary artery disease. In an uncontrolled study of over 200 patients with congestive heart failure during which digoxin blood levels were not measured, digitalis toxicity was not observed. Since there have been isolated reports of patients with elevated digoxin levels, it is recommended that digoxin levels be monitored when initiating, adjusting, and discontinuing nifedipine to avoid possible over- or under-digitalization. Quinidine: Immediate Release Capsules: There have been rare reports of an interaction between quinidine and nifedipine (with a decreased plasma level of quinidine). Coumarin Anticoagulants: There have been rare reports of increased prothrombin time in patients taking coumarin anticoagulants to whom nifedipine was administered. However, the relationship to nifedipine therapy is uncertain. Cimetidine: A study in 6 healthy volunteers has shown a
significant increase in
peak nifedipine plasma levels
(80%) and area-under-the-curve (74%) after a 1 week course of cimetidine
at 1000 mg per day and nifedipine
at 40 mg per day. Ranitidine produced
smaller, non-significant increases. The effect
may be mediated by the known inhibition
of cimetidine on hepatic
cytochrome P-450, the enzyme
system probably responsible
for the first-pass metabolism of nifedipine. If nifedipine therapy is
initiated in a patient currently receiving cimetidine, cautious titration
is advised.
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.
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 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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