Nifedical (nifedipine 60 mg) Dailymed

Rx only

For Oral use

Description

Nifedipine is a drug belonging to a class of pharmacological agents known as the calcium channel blockers. Nifedipine is 3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-, dimethyl ester, C₁₇H₁₈N₂O₆, and has the structural formula:

Nifedipine is a yellow crystalline substance, practically insoluble in water but soluble in ethanol. It has a molecular weight of 346.3. Each extended-release tablet, formulated as a once-a-day controlled release tablet for oral administration, delivers 30 or 60 mg of nifedipine.

In addition, each extended-release tablet contains the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, ethylcellulose, hydroxyethyl cellulose, hypromellose, magnesium stearate, methacrylic acid copolymer type A, methacrylic acid copolymer type B, microcrystalline cellulose, polyethylene glycol, red ferric oxide, sodium lauryl sulfate, talc and titanium dioxide.

Nifedipine Extended-release Tablets meet USP Dissolution Test 3.

Clinical Pharmacology

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 altering serum calcium concentrations.

Mechanism of Action

A) Angina

The precise mechanisms by which inhibition of calcium influx relieves angina has not been fully determined, but includes at least the following two mechanisms:

1) 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.

2) 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 vascular 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.

B) 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 six hours after the first dose. For subsequent doses, relatively constant plasma concentrations at this 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 t.i.d. dosing than with once daily nifedipine extended-release tablet. At steady-state the bioavailability of the nifedipine extended-release tablet is 86% relative to nifedipine capsules. Administration of the nifedipine extended-release tablet 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 concentrations. Pharmacokinetics of nifedipine extended-release tablets are linear over the dose range of 30 to 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 to 80% of the dose excreted in the urine. The elimination half-life of nifedipine is approximately two 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 (90 to 98%). Protein binding may be greatly reduced in patients with renal or hepatic impairment.

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 to 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.

Electrophysiologic Effects

Although, like other members of its class, 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 in man. In formal electrophysiologic studies, predominantly in patients with normal conduction systems, nifedipine has had no tendency to prolong atrioventricular conduction or sinus node recovery time, or to slow sinus rate.

Indications And Usage

I. Vasospastic Angina

Nifedical XL^® tablets are 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. Nifedical XL^® tablets 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 unstable angina where electrocardiographic findings are compatible with intermittent vasospasm, or when angina is refractory to nitrates and/or adequate doses of beta-blockers.

II. Chronic Stable Angina (Classical Effort-Associated Angina)

Nifedical XL^® tablets are 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 eight weeks duration in reducing angina frequency and increasing exercise tolerance, but confirmation of sustained effectiveness and evaluation of long-term safety in these patients is 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).

III. Hypertension

Nifedical XL^® tablets are indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.

Contraindications

Known hypersensitivity reaction to nifedipine.

Warnings

Excessive Hypotension

Although in most angina 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 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.

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

It is important to taper beta-blockers if possible, rather than stopping them abruptly before beginning nifedipine. 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 on occasion has been reported to increase it.

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, owing to the fixed impedance to flow across the aortic valve in these patients.

Gastrointestinal Obstruction Requiring Surgery

There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of nifedipine. Bezoars can occur in very rare cases and may require surgical intervention.

Cases of serious gastrointestinal obstruction have been identified in patients with no known gastrointestinal disease, including the need for hospitalization and surgical intervention.

Risk factors for gastrointestinal obstruction identified from post-marketing reports of nifedipine extended-release tablets include alteration in gastrointestinal anatomy (severe gastrointestinal narrowing, colon cancer, small bowel obstruction, bowel resection, gastric bypass, vertical banded gastroplasty, and colostomy), hypomotility disorders (constipation, gastroesophageal reflux disease, ileus, obesity, hypothyroidism, and diabetes) and concomitant medications (H2-histamine blockers, nonsteroidal anti-inflammatory drugs, laxatives, anticholinergic agents, and levothyroxine).

Precautions

GENERAL PRECAUTIONS SECTION

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: 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.

INFORMATION FOR PATIENTS SECTION

Information for Patients: Nifedical XL^® tablets should be swallowed whole. Do not chew, divide or crush tablets.

LABORATORY TESTS SECTION

Laboratory Tests: 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. A small (5.4%) increase in mean alkaline phosphatase was noted in patients treated with nifedipine extended release tablets. 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 extended-release tablets did not adversely affect serum uric acid, glucose, or cholesterol. Serum potassium was unchanged in patients receiving nifedipine extended-release tablets in the absence of concomitant diuretic therapy, and slightly decreased in patients receiving concomitant diuretics.

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 preexisting chronic renal insufficiency. The relationship to nifedipine therapy is uncertain in most cases but probable in some.

DRUG INTERACTIONS SECTION

Drug Interactions: Beta-adrenergic blocking agents: (see INDICATIONS AND USAGE and WARNINGS). Experience in over 1400 patients with nifedipine capsules in a noncomparative 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 coadministered with nitrates, but there have been no controlled studies to evaluate the antianginal effectiveness of this combination.

Digitalis: Administration of nifedipine with digoxin increased digoxin levels in nine of twelve normal volunteers. The average increase was 45%. Another investigator found no increase in digoxin levels in thirteen patients with coronary artery disease. In an uncontrolled study of over two hundred 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.

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 six healthy volunteers has shown a significant increase in peak nifedipine plasma levels (80%) and area-under-the-curve (74%), after a one-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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION

Carcinogenesis, Mutagenesis, Impairment of Fertility: Nifedipine was administered orally to rats for two 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 SECTION

Pregnancy: Pregnancy Category C: Nifedipine has been shown to produce teratogenic findings in rats and rabbits, including digital anomalies similar to those reported to 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 to 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. Nifedical XL^® Extended-release tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

PEDIATRIC USE SECTION

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.