Label: NIFEDIPINE tablet, extended release

System Components and Performance

Nifedipine extended-release tablet is designed for once-a-day oral administration. The extended-release tablet uses two release-rate controlling mechanisms: a primary polymer matrix core composed of drug with excipients and a secondary enteric coating surrounding the core. Upon swallowing, water is taken up through the enteric coating membrane into the primary core matrix, and the enteric coating membrane will dissolve at rising gastrointestinal pH value, which in turn slowly releases the drug from the formulation.

Product meets USP dissolution test 15.

Mechanism of Action

Pharmacokinetics and Metabolism

Nifedipine is completely absorbed after oral administration. Plasma drug concentrations rise at a gradual, controlled rate after a nifedipine extended-release tablets 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 tablets. At steady-state, the bioavailability of the 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 gastrointestinal 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 (92–98%). Protein binding may be greatly reduced in patients with renal or hepatic impairment.

Following intravenous administration, clearance of nifedipine was decreased by 33% in elderly healthy subjects relative to young healthy subjects.

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.

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.

I.Vasospastic Angina

Nifedipine extended-release 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. Nifedipine extended-release 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)

Nifedipine extended-release 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

Nifedipine extended-release tablets are indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including nifedipine extended-release tablets.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program's Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.

Nifedipine extended-release tablets may be used alone or in combination with other antihypertensive agents.

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 extended-release tablets. 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 a gastrointestinal obstruction identified from post-marketing reports of nifedipine extended-release tablets include alteration in gastrointestinal anatomy (e.g., severe gastrointestinal narrowing, colon cancer, small bowel obstruction, bowel resection, gastric bypass, vertical banded gastroplasty, colostomy, diverticulitis, diverticulosis, and inflammatory bowel disease), hypomotility disorders (e.g., constipation, gastroesophageal reflux disease, ileus, obesity, hypothyroidism, and diabetes) and concomitant medications (e.g., H 2-histamine blockers, opiates, nonsteroidal anti-inflammatory drugs, laxatives, anticholinergic agents, levothyroxine, and neuromuscular blocking agents).

Gastrointestinal Ulcers

Cases of tablet adherence to the gastrointestinal wall with ulceration have been reported, some requiring hospitalization and intervention.

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:

Nifedipine extended-release tablets should be swallowed whole. Do not chew, divide or crush tablets.

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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:

Beta-adrenergic blocking agents: (see   INDICATIONS AND USAGEand 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 co-administered 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.

Nifedipine is metabolized by CYP3A4. Co-administration of nifedipine with phenytoin, an inducer of CYP3A4, lowers the systemic exposure to nifedipine by approximately 70%. Avoid co-administration of nifedipine with phenytoin or any known CYP3A4 inducer or consider an alternative antihypertensive therapy.

CYP3A inhibitors such as fluconazole, itraconazole, clarithromycin, erythromycin, nefazodone, fluoxetine, saquinavir, indinavir, and nelfinavir may result in increased exposure to nifedipine when co-administered. Careful monitoring and dose adjustment may be necessary; consider initiating nifedipine at the lowest dose available if given concomitantly with these medications.

Other Interactions:

Grapefruit Juice: Co-administration of nifedipine with grapefruit juice resulted in approximately a doubling in nifedipine AUC and Cmax with no change in half-life. The increased plasma concentrations most likely result from inhibition of CYP 3A4 related first-pass metabolism. Avoid ingestion of grapefruit and grapefruit juice should be avoided while taking nifedipine.

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 5 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 vivomutagenicity studies were negative.

Pregnancy:

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 (5 to 50 times) than the maximum recommended human dose of 120 mg/day. On a mg/m 2basis, 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/m 2basis.

There are no adequate and well-controlled studies in pregnant women. Nifedipine extended-release tablets should be used during pregnancy only if the potential benefit justifies the potential risk.

Lactation:

Nifedipine is transferred through breast milk. Nifedipine extended-release tablets should be used during breast-feeding only if the potential benefit justifies the potential risk.

Pediatric Use:

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use:

Age appears to have a significant effect on the pharmacokinetics of nifedipine. The clearance is decreased resulting in a higher AUC in the elderly. These changes are not due to changes in renal function (see CLINICAL PHARMACOLOGY, Pharmacokinetics).

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 PRECAUTIONS, Drug Interactions, for information on co-administration of nifedipine with beta blockers or long-acting nitrates.