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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, C 17 H 18 N 2 O 6 , 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. Nifedipine extended-release tablets are formulated as a once-a-day controlled-release tablet for oral administration to provide 30, 60, or 90 mg of nifedipine. Inert ingredients in the nifedipine extended-release tablet formulation are lactose monohydrate, microcrystalline cellulose, hypromellose, hydroxyethyl cellulose, ethylcellulose, sodium lauryl sulfate, magnesium stearate, methacrylic acid and methyl methacrylate copolymer, polyethylene glycol, talc, polyvinyl alcohol, titanium dioxide (30mg and 60mg), iron oxide yellow, iron oxide red, lecithin (soya) (30 mg and 90 mg), iron oxide black (30 mg and 90 mg). 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.

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 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.

ncentrations 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.

lly 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.

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.

INDICATIONS AND USAGE 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).

atients 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.

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. 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). Congestive Heart Failure Rarely, patients, usually receiving a beta blocker, have developed heart failure after beginning nifedipine.

ncomitant medications (e.g., H 2 -histamine blockers, opiates, nonsteroidal anti-inflammatory drugs, laxatives, anticholinergic agents, levothyroxine, and neuromuscular blocking agents). 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 Ulcers Cases of tablet adherence to the gastrointestinal wall with ulceration have been reported, some requiring hospitalization and intervention.

PRECAUTIONS General Hypotension: Because nifedipine decreases peripheral vascular resistance, careful monitoring of blood pressure during the initial administration and titration of nifedipine is suggested. Close observation is especially recommended for patients already taking medications that are known to lower blood pressure (see WARNINGS ). Peripheral Edema: 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. 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.

tients 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 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 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.

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 vivo mutagenicity 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 2 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/m 2 basis. 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 ).

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 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 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.

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 2 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/m 2 basis. 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.

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 ).

ADVERSE EXPERIENCES 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 tablets therapy were tabulated independent of their causal relation to medication. The most common side effect reported with nifedipine extended-release tablets 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 experiences reported in placebo-controlled trials include: Of these, only edema and headache were more common in nifedipine extended-release tablets patients than placebo patients. 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. Body as a Whole/Systemic: asthenia, flushing, pain Cardiovascular: palpitations Central Nervous System: insomnia, nervousness, paresthesia, somnolence Dermatologic: pruritus, rash Gastrointestinal: abdominal pain, diarrhea, dry mouth, dyspepsia, flatulence Musculoskeletal: arthralgia, leg cramps Respiratory: chest pain (nonspecific), dyspnea Urogenital: impotence, polyuria Other adverse reactions were reported sporadically with an incidence of 1.0% or less. These include: Body as a Whole/Systemic: face edema, fever, hot flashes, malaise, periorbital edema, rigors Cardiovascular: arrhythmia, hypotension, increased angina, tachycardia, syncope Central Nervous System: anxiety, ataxia, decreased libido, depression, hypertonia, hypoesthesia, migraine, paroniria, tremor, vertigo Dermatologic: alopecia, increased sweating, urticaria, purpura Gastrointestinal: eructation, gastroesophageal reflux, gum hyperplasia, melena, vomiting, weight increase Musculoskeletal: back pain, gout, myalgias Respiratory: coughing, epistaxis, upper respiratory tract infection, respiratory disorder, sinusitis Special Senses: abnormal lacrimation, abnormal vision, taste perversion, tinnitus Urogenital/Reproductive: breast pain, dysuria, hematuria, nocturia 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. Gastrointestinal obstruction resulting in hospitalization and surgery, including the need for bezoar removal, has occurred in association with nifedipine extended-release tablets, even in patients with no prior history of gastrointestinal disease (see WARNINGS ). Cases of tablet adherence to the gastrointestinal wall with ulceration have been reported, some requiring hospitalization and intervention. In multiple-dose U.S. and foreign controlled studies with nifedipine capsules 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. There is also a large uncontrolled experience in over 2100 patients in the United States.

ns 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. 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 extended-release tablets. 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 capsules with concomitant beta blocker therapy, the pattern and incidence of adverse experiences was not different from that of the entire group of nifedipine capsules-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 one in eight patients. Hypotension occurred in about one in 20 patients. Syncope occurred in approximately one patient in 250. Myocardial infarction or symptoms of congestive heart failure each occurred in about one 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 erythema multiforme, Stevens-Johnson Syndrome, and toxic epidermal necrolysis) and photosensitivity reactions. Acute generalized exanthematous pustulosis also has been reported. To report SUSPECTED ADVERSE REACTIONS, please call Ingenus Pharmaceuticals, LLC toll-free at 1-877-748-1970 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

OVERDOSAGE Experience with nifedipine overdosage is limited. Generally, overdosage with nifedipine leading to pronounced hypotension calls for active cardiovascular support, including monitoring of cardiovascular and respiratory function, elevation of extremities, judicious use of calcium infusion, pressor agents, and fluids. Clearance of nifedipine would be expected to be prolonged in patients with impaired liver function. Since nifedipine is highly protein-bound, dialysis is not likely to be of any benefit. There has been one reported case of massive overdosage with nifedipine extended-release tablets. The main effects of ingestion of approximately 4800 mg of nifedipine extended-release tablets in a young man attempting suicide as a result of cocaine-induced depression was initial dizziness, palpitations, flushing, and nervousness. Within several hours of ingestion, nausea, vomiting, and generalized edema developed. No significant hypotension was apparent at presentation, 18 hours post-ingestion. Electrolyte abnormalities consisted of a mild, transient elevation of serum creatinine, and modest elevations of LDH and CPK, but normal SGOT. Vital signs remained stable, no electrocardiographic abnormalities were noted, and renal function returned to normal within 24 to 48 hours with routine supportive measures alone. No prolonged sequelae were observed. The effect of a single 900 mg ingestion of nifedipine capsules in a depressed anginal patient also on tricyclic antidepressants was loss of consciousness within 30 minutes of ingestion, and profound hypotension, which responded to calcium infusion, pressor agents, and fluid replacement. A variety of ECG abnormalities were seen in this patient with a history of bundle branch block, including sinus bradycardia and varying degrees of AV block. These dictated the prophylactic placement of a temporary ventricular pacemaker, but otherwise resolved spontaneously. Significant hyperglycemia was seen initially in this patient, but plasma glucose levels rapidly normalized without further treatment. A young hypertensive patient with advanced renal failure ingested 280 mg of nifedipine capsules at one time, with resulting marked hypotension responding to calcium infusion and fluids. No AV conduction abnormalities, arrhythmias, or pronounced changes in heart rate were noted, nor was there any further deterioration in renal function.

DOSAGE AND ADMINISTRATION 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, titration may proceed more rapidly, if symptoms so warrant, 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 safely switched to nifedipine extended-release tablets at the nearest equivalent total daily dose (e.g., 30 mg t.i.d. 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 doses 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. Avoid co-administration of nifedipine with grapefruit juice (see CLINICAL PHARMACOLOGY and PRECAUTIONS : Other Interactions ). 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 extended-release tablets 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 PRECAUTIONS , Drug Interactions , for information on co-administration of nifedipine with beta blockers or long-acting nitrates.

HOW SUPPLIED Nifedipine extended-release tablets are supplied as 30 mg, 60 mg and 90 mg round, biconvex, film-coated tablets. The different strengths can be identified as follows: 30 mg: Yellow round biconvex coated tablets, debossed "30" on one side 60 mg: Light brown round biconvex coated tablets, debossed "60" on one side 90 mg: Brown round biconvex coated tablets, debossed "90" on one side Bottles of 30: 30 mg (NDC 50742-260-30) 60 mg (NDC 50742-261-30) 90 mg (NDC 50742-262-30) Bottles of 100: 30 mg (NDC 50742-260-01) 60 mg (NDC 50742-261-01) 90 mg (NDC 50742-262-01) Bottles of 300: 30 mg (NDC 50742-260-03) 60 mg (NDC 50742-261-03) 90 mg (NDC 50742-262-03) Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature.] Protect from moisture and humidity.

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, C 17 H 18 N 2 O 6 , 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. Nifedipine extended-release tablets are formulated as a once-a-day controlled-release tablet for oral administration to provide 30, 60, or 90 mg of nifedipine. Inert ingredients in the nifedipine extended-release tablet formulation are lactose monohydrate, microcrystalline cellulose, hypromellose, hydroxyethyl cellulose, ethylcellulose, sodium lauryl sulfate, magnesium stearate, methacrylic acid and methyl methacrylate copolymer, polyethylene glycol, talc, polyvinyl alcohol, titanium dioxide (30mg and 60mg), iron oxide yellow, iron oxide red, lecithin (soya) (30 mg and 90 mg), iron oxide black (30 mg and 90 mg). 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. 01

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 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.

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.

ns 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. 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 extended-release tablets. 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 capsules with concomitant beta blocker therapy, the pattern and incidence of adverse experiences was not different from that of the entire group of nifedipine capsules-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 one in eight patients. Hypotension occurred in about one in 20 patients. Syncope occurred in approximately one patient in 250. Myocardial infarction or symptoms of congestive heart failure each occurred in about one 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 erythema multiforme, Stevens-Johnson Syndrome, and toxic epidermal necrolysis) and photosensitivity reactions. Acute generalized exanthematous pustulosis also has been reported. To report SUSPECTED ADVERSE REACTIONS, please call Ingenus Pharmaceuticals, LLC toll-free at 1-877-748-1970 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 02 03

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, C 17 H 18 N 2 O 6 , 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. Nifedipine extended-release tablets are formulated as a once-a-day controlled-release tablet for oral administration to provide 30, 60, or 90 mg of nifedipine. Inert ingredients in the nifedipine extended-release tablet formulation are lactose monohydrate, microcrystalline cellulose, hypromellose, hydroxyethyl cellulose, ethylcellulose, sodium lauryl sulfate, magnesium stearate, methacrylic acid and methyl methacrylate copolymer, polyethylene glycol, talc, polyvinyl alcohol, titanium dioxide (30mg and 60mg), iron oxide yellow, iron oxide red, lecithin (soya) (30 mg and 90 mg), iron oxide black (30 mg and 90 mg). 01 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.

HOW SUPPLIED Nifedipine extended-release tablets are supplied as 90 mg round, biconvex, film-coated tablets. 90 mg: Brown round biconvex coated tablets, debossed "90" on one side NDC 60760-862-90 BOTTLES OF 90 Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature.] Protect from moisture and humidity.

DESCRIPTION Nifedipine, USP is an antianginal drug belonging to a class of pharmacological agents, the calcium channel blockers. Nifedipine is 1, 4-Dihydro-2, 6-dimethyl-4-(2-nitrophenyl)-3, 5-pyridinecarboxylic acid dimethyl ester, C 17 H 18 N 2 O 6 , and has the structural formula: Nifedipine, USP is a yellow crystalline substance, practically insoluble in water but soluble in ethanol. It has a molecular weight of 346.3. Nifedipine capsules are formulated as soft gelatin capsules for oral administration, each containing 10 mg or 20 mg nifedipine. Inactive Ingredients : Nifedipine capsules for oral administration contain the following inactive ingredients: glycerin, peppermint oil, polyethylene glycol and saccharin sodium. The 10 mg capsule shell contains ammonium hydroxide, gelatin, glycerin, iron oxide black, light mineral oil, methyl paraben, propylene glycol, propyl paraben, shellac glaze, sorbitol, titanium dioxide and water. The 20 mg capsule shell contains ammonium hydroxide, FD and C Red No. 40 aluminum lake, FD and C Yellow No. 6 aluminum lake, gelatin, glycerin, iron oxide black, light mineral oil, methyl paraben, propylene glycol, propyl paraben, shellac glaze, sorbitol, titanium dioxide and water. structure

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 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: 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 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. 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. Nifedipine is highly bound by serum proteins. Nifedipine is extensively converted to inactive metabolites and approximately 80 percent of nifedipine and metabolites are eliminated via the kidneys. The elimination half-life of nifedipine is approximately two 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 to 98%). Protein binding may be greatly reduced in patients with renal or hepatic impairment.

er 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 to 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 causes decreased peripheral vascular resistance and a fall in systolic and diastolic pressure, usually modest (5 to 10 mm 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. 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.

INDICATIONS AND USAGE I. 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 when angina is refractory to nitrates and/or adequate doses of beta blockers. II. 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 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 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 . )

WARNINGS Excessive Hypotension Although, in most patients, the hypotensive effect of nifedipine is modest and well tolerated, occasional patients have had excessive and poorly tolerated hypotension. These responses have usually occurred during initial titration or at the time of subsequent upward dosage adjustment. 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 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. 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. 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). Use in Essential Hypertension Nifedipine and other immediate-release nifedipine capsules have also been used for the long-term control of essential hypertension, although nifedipine capsules have not been approved for this purpose and 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. 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.

rawal 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 nifedipine. Congestive Heart Failure Rarely, patients, usually those receiving a beta blocker, have developed heart failure after beginning nifedipine. Patients with tight aortic stenosis may be at greater risk for such an event, as the unloading effect of nifedipine would be expected to be of less benefit to these patients, owing to their fixed impedance to flow across the aortic valve.

PRECAUTIONS General: Hypotension: Because nifedipine decreases peripheral vascular resistance, careful monitoring of blood pressure during the initial administration and titration of nifedipine is suggested. Close observation is especially recommended for patients already taking medications that are known to lower blood pressure. (See WARNINGS . ) Peripheral Edema: Mild to moderate peripheral edema, typically associated with arterial vasodilation and not due to left ventricular dysfunction, occurs in about one in ten 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. 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. Rare instances of allergic hepatitis have been reported. 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. Drug Interactions: Beta-adrenergic blocking agents: (See INDICATIONS AND USAGE and WARNINGS . ) Experience in over 1,400 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: Since there have been isolated reports of patients with elevated digoxin levels, and since 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. Quinidine: There have been rare reports of an interaction between quinidine and nifedipine (with a decreased plasma level of quinidine).

en digoxin and nifedipine, it is recommended that digoxin levels be monitored when initiating, adjusting, and discontinuing nifedipine to avoid possible over- or under-digitalization. Quinidine: 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 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 1,000 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 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 vivo mutagenicity studies were negative. Pregnancy: 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 (5 to 50 times) than the maximum recommended human dose of 120 mg/day.

etal 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 2 basis, some doses were higher and some were lower than the maximum recommended human dose but all were 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 2 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. Lactation: Nifedipine is transferred through breast milk. Nifedipine 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. Use in pediatric population is not recommended. 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 ).

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, typically associated with arterial vasodilation and not due to left ventricular dysfunction, occurs in about one in ten 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.

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. Rare instances of allergic hepatitis have been reported. 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.

Drug Interactions: Beta-adrenergic blocking agents: (See INDICATIONS AND USAGE and WARNINGS . ) Experience in over 1,400 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: Since there have been isolated reports of patients with elevated digoxin levels, and since 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. Quinidine: 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 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 1,000 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.

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 vivo mutagenicity studies were negative.

Pregnancy: 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 (5 to 50 times) than the maximum recommended human dose of 120 mg/day. On a mg/m 2 basis, some doses were higher and some were lower than the maximum recommended human dose but all were 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 2 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. Lactation: Nifedipine is transferred through breast milk. Nifedipine should be used during breast-feeding only if the potential benefit justifies the potential risk.

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 ).

ADVERSE REACTIONS In multiple-dose United States 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. Adverse Effect Nifedipine (%) (N=226) Placebo (%) (N=235) Dizziness, lightheadedness, giddiness 27 15 Flushing, heat sensation 25 8 Headache 23 20 Weakness 12 10 Nausea, heartburn 11 8 Muscle cramps, tremor 8 3 Peripheral edema 7 1 Nervousness, mood changes 7 4 Palpitation 7 5 Dyspnea, cough, wheezing 6 3 Nasal congestion, sore throat 6 8 There is also a large uncontrolled experience in over 2,100 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 most common adverse events were: Incidence Approximately 10% Cardiovascular: peripheral edema Central Nervous System: dizziness or lightheadedness Gastrointestinal: nausea Systemic: headache and flushing, weakness Incidence Approximately 5% Cardiovascular: transient hypotension Incidence 2% or Less Cardiovascular: palpitation Respiratory: nasal and chest congestion, shortness of breath Gastrointestinal: diarrhea, constipation, cramps, flatulence Musculoskeletal: inflammation, joint stiffness, muscle cramps Central Nervous System: shakiness, nervousness, jitteriness, sleep disturbances, blurred vision, difficulties in balance Other: dermatitis, pruritus, urticaria, fever, sweating, chills, sexual difficulties Incidence Approximately 0.5% Cardiovascular: syncope (mostly with initial dosing and/or an increase in dose), erythromelalgia Incidence Less Than 0.5% Hematologic: thrombocytopenia, anemia, leukopenia, purpura Gastrointestinal: allergic hepatitis Face and Throat: angioedema (mostly oropharyngeal edema with breathing difficulty in a few patients), gingival hyperplasia CNS: depression, paranoid syndrome Special Senses: transient blindness at the peak of plasma level, tinnitus Urogenital: nocturia, polyuria Other: arthritis with ANA (+), exfoliative dermatitis, gynecomastia Musculoskeletal: myalgia 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 one patient in eight at 120 mg per day or more. Transient hypotension, generally of mild to moderate severity and seldom requiring discontinuation of therapy, occurred in one 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.

sease 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 1,000 patients receiving nifedipine with concomitant beta blocker therapy, the pattern and incidence of adverse experiences were 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 one in eight patients. Hypotension occurred in about one in 20 patients. Syncope occurred in approximately one patient in 250. Myocardial infarction or symptoms of congestive heart failure each occurred in about one 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 erythema multiforme, Stevens-Johnson Syndrome, and toxic epidermal necrolysis) and photosensitivity reactions. Acute generalized exanthematous pustulosis also has been reported. To report SUSPECTED ADVERSE REACTIONS, contact Avet Pharmaceuticals Inc. at 1-866-901-DRUG (3784) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

<table width="100%"><col width="51%"/><col width="25%"/><col width="22%"/><tbody><tr><td align="center" valign="top" styleCode="Rrule Botrule Lrule Toprule "><paragraph><content styleCode="bold"> Adverse Effect</content> </paragraph></td><td align="center" valign="top" styleCode="Rrule Botrule Toprule "><paragraph><content styleCode="bold"> Nifedipine (%)</content> <content styleCode="bold"> (N=226)</content> </paragraph></td><td align="center" valign="top" styleCode="Rrule Botrule Toprule "><paragraph><content styleCode="bold"> Placebo (%)</content> <content styleCode="bold"> (N=235)</content> </paragraph></td></tr><tr><td valign="top" styleCode="Rrule Lrule Botrule "><paragraph> Dizziness, lightheadedness, giddiness </paragraph></td><td valign="top" styleCode="Rrule Botrule "><paragraph> 27 </paragraph></td><td valign="top" styleCode="Rrule Botrule "><paragraph> 15 </paragraph></td></tr><tr><td valign="top" styleCode="Rrule Lrule Botrule "><paragraph> Flushing, heat sensation </paragraph></td><td valign="top" styleCode="Rrule Botrule "><paragraph> 25 </paragraph></td><td valign="top" styleCode="Rrule Botrule "><paragraph> 8 </paragraph></td></tr><tr><td valign="top" styleCode="Rrule Lrule Botrule "><paragraph> Headache </paragraph></td><td valign="top" styleCode="Rrule Botrule "><paragraph> 23 </paragraph></td><td valign="top" styleCode="Rrule Botrule "><paragraph> 20 </paragraph></td></tr><tr><td valign="top" styleCode="Rrule Lrule Botrule "><paragraph> Weakness </paragraph></td><td valign="top" styleCode="Rrule Botrule "><paragraph> 12 </paragraph></td><td valign="top" styleCode="Rrule Botrule "><paragraph> 10 </paragraph></td></tr><tr><td valign="top" styleCode="Rrule Lrule Botrule "><paragraph> Nausea, heartburn </paragraph></td><td valign="top" styleCode="Rrule Botrule "><paragraph> 11 </paragraph></td><td valign="top" styleCode="Rrule Botrule "><paragraph> 8 </paragraph></td></tr><tr><td valign="top" styleCode="Rrule Lrule Botrule "><paragraph> Muscle cramps, tremor </paragraph></td><td valign="top" styleCode="Rrule Botrule "><paragraph> 8 </paragraph></td><td valign="top" styleCode="Rrule Botrule "><paragraph> 3 </paragraph></td></tr><tr><td valign="top" styleCode="Rrule Lrule Botrule "><paragraph> Peripheral edema </paragraph></td><td valign="top" styleCode="Rrule Botrule "><paragraph> 7 </paragraph></td><td valign="top" styleCode="Rrule Botrule "><paragraph> 1 </paragraph></td></tr><tr><td valign="top" styleCode="Rrule Lrule Botrule "><paragraph> Nervousness, mood changes </paragraph></td><td valign="top" styleCode="Rrule Botrule "><paragraph> 7 </paragraph></td><td valign="top" styleCode="Rrule Botrule "><paragraph> 4 </paragraph></td></tr><tr><td valign="top" styleCode="Rrule Lrule Botrule "><paragraph> Palpitation </paragraph></td><td valign="top" styleCode="Rrule Botrule "><paragraph> 7 </paragraph></td><td valign="top" styleCode="Rrule Botrule "><paragraph> 5 </paragraph></td></tr><tr><td valign="top" styleCode="Rrule Lrule Botrule "><paragraph> Dyspnea, cough, wheezing </paragraph></td><td valign="top" styleCode="Rrule Botrule "><paragraph> 6 </paragraph></td><td valign="top" styleCode="Rrule Botrule "><paragraph> 3 </paragraph></td></tr><tr><td valign="top" styleCode="Rrule Botrule Lrule "><paragraph> Nasal congestion, sore throat </paragraph></td><td valign="top" styleCode="Rrule Botrule "><paragraph> 6 </paragraph></td><td valign="top" styleCode="Rrule Botrule "><paragraph> 8 </paragraph></td></tr></tbody></table>

OVERDOSAGE Experience with nifedipine overdosage is limited. Generally, overdosage with nifedipine leading to pronounced hypotension calls for active cardiovascular support including monitoring of cardiovascular and respiratory function, elevation of extremities, and judicious use of calcium infusion, pressor agents, and fluids. Clearance of nifedipine would be expected to be prolonged in patients with impaired liver function. Since nifedipine is highly protein bound, dialysis is not likely to be of any benefit; however, plasmapheresis may be beneficial.

DOSAGE AND ADMINISTRATION 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 to 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 to 30 mg three or four 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 to 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 t.i.d. to 20 mg t.i.d. and then to 30 mg t.i.d. over a three-day period. In hospitalized patients under close observation, the dose may be increased in 10 mg increments over four- to six-hour periods as required to control pain and arrhythmias due to ischemia. A single dose should rarely exceed 30 mg. Avoid co-administration of nifedipine with grapefruit juice (see CLINICAL PHARMACOLOGY and PRECAUTIONS : Other Interactions ). 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 PRECAUTIONS , Drug Interactions , for information on co-administration of nifedipine with beta blockers or long-acting nitrates.

HOW SUPPLIED Nifedipine Capsules, USP are available as white opaque, oblong soft gelatin capsules containing 10 mg of nifedipine. Each capsule is imprinted with " HP 194" in black ink. They are supplied as follows: Overbagged with 10 soft gelatin capsules per bag, NDC 55154-0196-0 WARNING: This Unit Dose package is not child resistant and is Intended for Institutional Use Only. Keep this and all drugs out of the reach of children. The capsules should be protected from light and moisture and stored at Controlled Room Temperature 68° to 77°F (20° to 25°C); excursions permitted to 15° to 30°C (59° to 86°F), in the manufacturer's original container. Distributed by: Avet Pharmaceuticals Inc. East Brunswick, NJ 08816 1.866.901.DRUG (3784) Packaged and Distributed by: MAJOR® PHARMACEUTICALS Indianapolis, IN 46268 USA Refer to package label for Distributor's NDC Number Distributed By: Cardinal Health Dublin, OH 43017 L60837290426 51U000000140US07 Revised: 03/2022 logo

Rx only For Oral Use Distributed by: Oceanside Pharmaceuticals, a division of Bausch Health US, LLC Bridgewater, NJ 08807 USA Manufactured by: Bausch Health Companies Inc. Steinbach, MB R5G 1Z7, Canada © 2019 Bausch Health Companies Inc. or its affiliates 9495004 20002760 Rev. 10/2019

DESCRIPTION Nifedipine extended-release tablets are an extended-release tablet dosage form of the calcium channel blocker nifedipine. Nifedipine is 3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(2 - nitrophenyl)-, dimethyl ester. The molecular formula is C 17 H 18 N 2 O 6 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. Nifedipine extended-release tablets contain 30 mg of nifedipine for once-a-day oral administration. In addition, each tablet contains the following inactive ingredients: ethylcellulose, ferric oxide yellow, hydroxyethyl cellulose, hypromellose, lactose anhydrous, magnesium stearate, microcrystalline cellulose, polyacrylic dispersion (copolymer of ethyl acrylate and methyl methacrylate), polyethylene glycol, silicon dioxide, sodium lauryl sulfate, talc, and titanium dioxide. Nifedipine extended-release tablets meet USP Dissolution Test 4 (using first derivative UV spectrophotometry at 245 nm for sample analysis).

CLINICAL PHARMACOLOGY Nifedipine is a calcium ion influx inhibitor (slow-channel blocker or calcium ion antagonist) which inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. The contractile processes of vascular smooth muscle and cardiac 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 vascular smooth muscle and cardiac muscle without altering serum calcium concentrations. Mechanism of Action The mechanism by which nifedipine reduces arterial blood pressure involves peripheral arterial vasodilatation and, consequently, a reduction in peripheral vascular resistance. The increased peripheral vascular resistance, 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. The bioavailability of nifedipine as nifedipine extended-release tablet relative to immediate-release nifedipine is in the range of 84% to 89%. After ingestion of nifedipine extended-release tablets under fasting conditions, plasma concentrations peak at about 2.5 to 5 hours with a second small peak or shoulder evident at approximately 6 to 12 hours post dose. The elimination half-life of nifedipine administered as nifedipine extended-release tablet is approximately 7 hours in contrast to the known 2 hour elimination half-life of nifedipine administered as an immediate-release capsule. When nifedipine extended-release tablet is administered as multiples of 30 mg tablets over a dose range of 30 mg to 90 mg, the area under the curve (AUC) is dose proportional; however, the peak plasma concentration for the 90 mg dose given as 3 × 30 mg is 29% greater than predicted from the 30 mg and 60 mg doses. Two 30 mg nifedipine extended-release tablets may be interchanged with a 60 mg nifedipine extended-release tablet. Three 30 mg nifedipine extended-release tablets, however, result in substantially higher C max values than those after a single 90 mg nifedipine extended-release tablet. Three 30 mg tablets should, therefore, not be considered interchangeable with a 90 mg tablet. Once daily dosing of nifedipine extended-release tablets under fasting conditions results in decreased fluctuations in the plasma concentration of nifedipine when compared to t.i.d. dosing with immediate-release nifedipine capsules. The mean peak plasma concentration of nifedipine following a 90 mg nifedipine extended-release tablet, administered under fasting conditions, is approximately 115 ng/mL.

results in decreased fluctuations in the plasma concentration of nifedipine when compared to t.i.d. dosing with immediate-release nifedipine capsules. The mean peak plasma concentration of nifedipine following a 90 mg nifedipine extended-release tablet, administered under fasting conditions, is approximately 115 ng/mL. When nifedipine extended-release tablet is given immediately after a high fat meal in healthy volunteers, there is an average increase of 60% in the peak plasma nifedipine concentration, a prolongation in the time to peak concentration, but no significant change in the AUC. Plasma concentrations of nifedipine when nifedipine extended-release tablet is taken after a fatty meal result in slightly lower peaks compared to the same daily dose of the immediate-release formulation administered in three divided doses. This may be, in part, because nifedipine extended-release tablet is less bioavailable than the immediate-release formulation. Nifedipine is extensively metabolized to highly water soluble, inactive metabolites accounting for 60% to 80% of the dose excreted in the urine. Only traces (less than 0.1% of the dose) of the 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. Nifedipine is metabolized via the cytochrome P450 3A4 system. Drugs that are known to either inhibit or induce this enzyme system may alter the first pass or clearance of nifedipine. No studies have been performed with nifedipine extended-release tablets in patients with renal failure; however, significant alterations in the pharmacokinetics of nifedipine immediate-release capsules have not been reported in patients undergoing hemodialysis or chronic ambulatory peritoneal dialysis. Since the absorption of nifedipine from nifedipine extended-release tablets could be modified by renal disease, caution should be exercised in treating such patients. Because nifedipine is metabolized via the cytochrome P450 3A4 system, its pharmacokinetics may be altered in patients with chronic liver disease. Nifedipine extended-release tablets have not been studied in patients with hepatic disease; however, in patients with hepatic impairment (liver cirrhosis), nifedipine has a longer elimination half-life and higher bioavailability than in healthy volunteers. The degree of protein binding of nifedipine is high (92% to 98%). Protein binding may be greatly reduced in patients with renal or hepatic impairment. After administration of nifedipine extended-release tablets to healthy elderly men and women (age >60 years), the mean C max is 36% higher and the average plasma concentration is 70% greater than in younger patients. In healthy subjects, the elimination half-life of a different sustained-release nifedipine formulation was longer in elderly subjects (6.7 h) compared to young subjects (3.8 h) following oral administration. A decreased clearance was also observed in the elderly (348 mL/min) compared to young subjects (519 mL/min) following intravenous administration. Coadministration of nifedipine with grapefruit juice results in up to a 2-fold increase in AUC and C max due to inhibition of CYP3A related first-pass metabolism. Ingestion of grapefruit and grapefruit juice should be avoided while taking nifedipine. Clinical Studies Nifedipine extended-release tablets produced dose-related decreases in systolic and diastolic blood pressure as demonstrated in two double-blind, randomized, placebo-controlled trials in which over 350 patients were treated with nifedipine extended-release tablets, 30, 60 or 90 mg once daily for 6 weeks.

inical Studies Nifedipine extended-release tablets produced dose-related decreases in systolic and diastolic blood pressure as demonstrated in two double-blind, randomized, placebo-controlled trials in which over 350 patients were treated with nifedipine extended-release tablets, 30, 60 or 90 mg once daily for 6 weeks. In the first study, nifedipine extended-release tablet was given as monotherapy and in the second study, nifedipine extended-release tablet was added to a beta-blocker in patients not controlled on a beta-blocker alone. The mean trough (24 hours post-dose) blood pressure results from these studies are shown below: MEAN REDUCTIONS IN TROUGH SUPINE BLOOD PRESSURE (mmHg) SYSTOLIC/DIASTOLIC NIFEDIPINE EXTENDED-RELEASE DOSE N MEAN TROUGH REDUCTION STUDY 1 30 mg 60 5.3/2.9 60 mg 57 8.0/4.1 90 mg 55 12.5/8.1 STUDY 2 30 mg 58 7.6/3.8 60 mg 63 10.1/5.3 90 mg 62 10.2/5.8 The trough/peak ratios estimated from 24 hour blood pressure monitoring ranged from 41% to 78% for diastolic and 46% to 91% for systolic blood pressure. 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 mmHg 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 of the immediate-release nifedipine formulation 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 administered as the immediate-release capsule has had no tendency to prolong atrioventricular conduction or sinus node recovery time, or to slow sinus rate.

Mechanism of Action The mechanism by which nifedipine reduces arterial blood pressure involves peripheral arterial vasodilatation and, consequently, a reduction in peripheral vascular resistance. The increased peripheral vascular resistance, 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. The bioavailability of nifedipine as nifedipine extended-release tablet relative to immediate-release nifedipine is in the range of 84% to 89%. After ingestion of nifedipine extended-release tablets under fasting conditions, plasma concentrations peak at about 2.5 to 5 hours with a second small peak or shoulder evident at approximately 6 to 12 hours post dose. The elimination half-life of nifedipine administered as nifedipine extended-release tablet is approximately 7 hours in contrast to the known 2 hour elimination half-life of nifedipine administered as an immediate-release capsule. When nifedipine extended-release tablet is administered as multiples of 30 mg tablets over a dose range of 30 mg to 90 mg, the area under the curve (AUC) is dose proportional; however, the peak plasma concentration for the 90 mg dose given as 3 × 30 mg is 29% greater than predicted from the 30 mg and 60 mg doses. Two 30 mg nifedipine extended-release tablets may be interchanged with a 60 mg nifedipine extended-release tablet. Three 30 mg nifedipine extended-release tablets, however, result in substantially higher C max values than those after a single 90 mg nifedipine extended-release tablet. Three 30 mg tablets should, therefore, not be considered interchangeable with a 90 mg tablet. Once daily dosing of nifedipine extended-release tablets under fasting conditions results in decreased fluctuations in the plasma concentration of nifedipine when compared to t.i.d. dosing with immediate-release nifedipine capsules. The mean peak plasma concentration of nifedipine following a 90 mg nifedipine extended-release tablet, administered under fasting conditions, is approximately 115 ng/mL. When nifedipine extended-release tablet is given immediately after a high fat meal in healthy volunteers, there is an average increase of 60% in the peak plasma nifedipine concentration, a prolongation in the time to peak concentration, but no significant change in the AUC. Plasma concentrations of nifedipine when nifedipine extended-release tablet is taken after a fatty meal result in slightly lower peaks compared to the same daily dose of the immediate-release formulation administered in three divided doses. This may be, in part, because nifedipine extended-release tablet is less bioavailable than the immediate-release formulation. Nifedipine is extensively metabolized to highly water soluble, inactive metabolites accounting for 60% to 80% of the dose excreted in the urine. Only traces (less than 0.1% of the dose) of the 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. Nifedipine is metabolized via the cytochrome P450 3A4 system. Drugs that are known to either inhibit or induce this enzyme system may alter the first pass or clearance of nifedipine. No studies have been performed with nifedipine extended-release tablets in patients with renal failure; however, significant alterations in the pharmacokinetics of nifedipine immediate-release capsules have not been reported in patients undergoing hemodialysis or chronic ambulatory peritoneal dialysis. Since the absorption of nifedipine from nifedipine extended-release tablets could be modified by renal disease, caution should be exercised in treating such patients.

cokinetics of nifedipine immediate-release capsules have not been reported in patients undergoing hemodialysis or chronic ambulatory peritoneal dialysis. Since the absorption of nifedipine from nifedipine extended-release tablets could be modified by renal disease, caution should be exercised in treating such patients. Because nifedipine is metabolized via the cytochrome P450 3A4 system, its pharmacokinetics may be altered in patients with chronic liver disease. Nifedipine extended-release tablets have not been studied in patients with hepatic disease; however, in patients with hepatic impairment (liver cirrhosis), nifedipine has a longer elimination half-life and higher bioavailability than in healthy volunteers. The degree of protein binding of nifedipine is high (92% to 98%). Protein binding may be greatly reduced in patients with renal or hepatic impairment. After administration of nifedipine extended-release tablets to healthy elderly men and women (age >60 years), the mean C max is 36% higher and the average plasma concentration is 70% greater than in younger patients. In healthy subjects, the elimination half-life of a different sustained-release nifedipine formulation was longer in elderly subjects (6.7 h) compared to young subjects (3.8 h) following oral administration. A decreased clearance was also observed in the elderly (348 mL/min) compared to young subjects (519 mL/min) following intravenous administration. Coadministration of nifedipine with grapefruit juice results in up to a 2-fold increase in AUC and C max due to inhibition of CYP3A related first-pass metabolism. Ingestion of grapefruit and grapefruit juice should be avoided while taking nifedipine.

Clinical Studies Nifedipine extended-release tablets produced dose-related decreases in systolic and diastolic blood pressure as demonstrated in two double-blind, randomized, placebo-controlled trials in which over 350 patients were treated with nifedipine extended-release tablets, 30, 60 or 90 mg once daily for 6 weeks. In the first study, nifedipine extended-release tablet was given as monotherapy and in the second study, nifedipine extended-release tablet was added to a beta-blocker in patients not controlled on a beta-blocker alone. The mean trough (24 hours post-dose) blood pressure results from these studies are shown below: MEAN REDUCTIONS IN TROUGH SUPINE BLOOD PRESSURE (mmHg) SYSTOLIC/DIASTOLIC NIFEDIPINE EXTENDED-RELEASE DOSE N MEAN TROUGH REDUCTION STUDY 1 30 mg 60 5.3/2.9 60 mg 57 8.0/4.1 90 mg 55 12.5/8.1 STUDY 2 30 mg 58 7.6/3.8 60 mg 63 10.1/5.3 90 mg 62 10.2/5.8 The trough/peak ratios estimated from 24 hour blood pressure monitoring ranged from 41% to 78% for diastolic and 46% to 91% for systolic blood pressure.

<table ID="_RefID0EYFAC" width="100%"><caption>MEAN REDUCTIONS IN TROUGH SUPINE BLOOD PRESSURE (mmHg) </caption><col width="40%"/><col width="30%"/><col width="30%"/><tbody><tr><td styleCode="Botrule Toprule " valign="top"/><td align="center" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">SYSTOLIC/DIASTOLIC</content></paragraph></td><td styleCode="Botrule Toprule " valign="top"/></tr><tr><td align="center" styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">NIFEDIPINE EXTENDED-RELEASE</content> <content styleCode="bold">DOSE</content></paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">N</content></paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">MEAN TROUGH</content> <content styleCode="bold">REDUCTION</content></paragraph></td></tr><tr><td colspan="3" valign="top"><paragraph><content styleCode="bold">STUDY 1</content></paragraph></td></tr><tr><td align="center" valign="top"><paragraph>30 mg</paragraph></td><td align="center" valign="top"><paragraph>60</paragraph></td><td align="center" valign="top"><paragraph>5.3/2.9</paragraph></td></tr><tr><td align="center" valign="top"><paragraph>60 mg</paragraph></td><td align="center" valign="top"><paragraph>57</paragraph></td><td align="center" valign="top"><paragraph>8.0/4.1</paragraph></td></tr><tr><td align="center" styleCode="Botrule " valign="top"><paragraph>90 mg</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>55</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>12.5/8.1</paragraph></td></tr><tr><td colspan="3" valign="top"><paragraph><content styleCode="bold">STUDY 2</content></paragraph></td></tr><tr><td align="center" valign="top"><paragraph>30 mg</paragraph></td><td align="center" valign="top"><paragraph>58</paragraph></td><td align="center" valign="top"><paragraph>7.6/3.8</paragraph></td></tr><tr><td align="center" valign="top"><paragraph>60 mg</paragraph></td><td align="center" valign="top"><paragraph>63</paragraph></td><td align="center" valign="top"><paragraph>10.1/5.3</paragraph></td></tr><tr><td align="center" styleCode="Botrule " valign="top"><paragraph>90 mg</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>62</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>10.2/5.8</paragraph></td></tr></tbody></table>

CONTRAINDICATIONS Concomitant administration with strong P450 inducers, such as rifampin, are contraindicated since the efficacy of nifedipine tablets could be significantly reduced. (See PRECAUTIONS: Drug Interactions . ) Nifedipine must not be used in cases of cardiogenic shock. Nifedipine extended-release tablets are contraindicated in patients with a known hypersensitivity to any component of the tablet.

WARNINGS Excessive Hypotension Although in most patients the hypotensive effect of nifedipine is modest and well tolerated, occasional patients have had excessive and poorly tolerated hypotension. These responses have usually occurred during initial titration or at the time of subsequent upward dosage adjustment, and may be more likely in patients using concomitant beta-blockers. Severe hypotension and/or increased fluid volume requirements have been reported in patients who received immediate-release capsules together with a beta-blocking agent and 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 upon starting nifedipine or at the time of dosage increase. The mechanism of this effect is not established. Beta-Blocker Withdrawal When discontinuing a beta-blocker, it is important to taper its dose, if possible, rather than stopping 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 while receiving a beta-blocker) have developed heart failure after beginning nifedipine. Patients with tight aortic stenosis may be at greater risk for such an event, as the unloading effect of nifedipine would be expected to be of less benefit to these patients, owing to their fixed impedance to flow across the aortic valve.

PRECAUTIONS General Hypotension Because nifedipine decreases peripheral vascular resistance, careful monitoring of blood pressure during the initial administration and titration of nifedipine extended-release tablets 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 nifedipine extended-release tablets. The placebo subtracted rate is approximately 8% at 30 mg, 12% at 60 mg and 19% at 90 mg daily. This edema 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 hypertension is complicated by congestive heart failure, care should be taken to differentiate this peripheral edema from the effects of increasing left ventricular dysfunction. Use in Cirrhotic Patients Clearance of nifedipine is reduced and systemic exposure increased in patients with cirrhosis. It is unknown how systemic exposure may be altered in patients with moderate or severe liver impairment. Careful monitoring and dose reduction may be necessary; consider initiating therapy with the lowest dose available. Information for Patients Nifedipine extended-release tablets are an extended-release tablet and should be swallowed whole and taken on an empty stomach. It should not be administered with food. Do not chew, divide or crush tablets. 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 increase (<5%) in mean alkaline phosphatase was noted in patients treated with nifedipine extended-release tablets. This was an isolated finding and it rarely resulted in values which fell outside the normal range. Rare instances of allergic hepatitis have been reported with nifedipine treatment. In controlled studies, nifedipine extended-release tablets did not adversely affect serum uric acid, glucose, cholesterol or potassium. 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 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 or 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.

atients 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. Drug Interactions Nifedipine is mainly eliminated by metabolism and is a substrate of CYP3A. Inhibitors and inducers of CYP3A can impact the exposure to nifedipine and consequently its desirable and undesirable effects. In vitro and in vivo data indicate that nifedipine can inhibit the metabolism of drugs that are substrates of CYP3A, thereby increasing the exposure to other drugs. Nifedipine is a vasodilator, and coadministration of other drugs affecting blood pressure may result in pharmacodynamic interactions. CYP3A Inhibitors CYP3A inhibitors such as ketoconazole, fluconazole, itraconazole, clarithromycin, erythromycin (azithromycin, although structurally related to the class of macrolide antibiotic, is void of clinically relevant CYP3A inhibition), grapefruit, nefazodone, fluoxetine, saquinavir, indinavir, nelfinavir, and ritonavir may result in increased exposure to nifedipine when coadministered. Careful monitoring and dose adjustment may be necessary; consider initiating nifedipine at the lowest dose available if given concomitantly with these medications. Strong CYP3A Inducers Strong CYP3A inducers, such as rifampin, rifabutin, phenobarbital, phenytoin, carbamazepine, and St. John’s Wort reduce the bioavailability and efficacy of nifedipine; therefore nifedipine should not be used in combination with strong CYP3A inducers such as rifampin (see CONTRAINDICATIONS ). Cardiovascular Drugs Antiarrhythmics Quinidine: Quinidine is a substrate of CYP3A and has been shown to inhibit CYP3A in vitro . Coadministration of multiple doses of quinidine sulfate, 200 mg t.i.d., and nifedipine, 20 mg t.i.d., increased C max and AUC of nifedipine in healthy volunteers by factors of 2.30 and 1.37, respectively. The heart rate in the initial interval after drug administration was increased by up to 17.9 beats/minute. The exposure to quinidine was not importantly changed in the presence of nifedipine. Monitoring of heart rate and adjustment of the nifedipine dose, if necessary, are recommended when quinidine is added to a treatment with nifedipine. Flecainide: There has been too little experience with the coadministration of flecainide with nifedipine to recommend concomitant use. Calcium Channel Blockers Diltiazem: Pretreatment of healthy volunteers with 30 mg or 90 mg t.i.d. diltiazem p.o. increased the AUC of nifedipine after a single dose of 20 mg nifedipine by factors of 2.2 and 3.1, respectively. The corresponding C max values of nifedipine increased by factors of 2.0 and 1.7, respectively. Caution should be exercised when coadministering diltiazem and nifedipine and a reduction of the dose of nifedipine should be considered. Verapamil: Verapamil, a CYP3A inhibitor, can inhibit the metabolism of nifedipine and increase the exposure to nifedipine during concomitant therapy. Blood pressure should be monitored and reduction of the dose of nifedipine considered. ACE Inhibitors Benazepril: In healthy volunteers receiving single dose of 20 mg nifedipine ER and benazepril 10 mg, the plasma concentrations of benazeprilat and nifedipine in the presence and absence of each other were not statistically significantly different. A hypotensive effect was only seen after coadministration of the two drugs. The tachycardic effect of nifedipine was attenuated in the presence of benazepril. Angiotensin-II Blockers Irbesartan: In vitro studies show significant inhibition of the formation of oxidized irbesartan metabolites by nifedipine.

ly different. A hypotensive effect was only seen after coadministration of the two drugs. The tachycardic effect of nifedipine was attenuated in the presence of benazepril. Angiotensin-II Blockers Irbesartan: In vitro studies show significant inhibition of the formation of oxidized irbesartan metabolites by nifedipine. However, in clinical studies, concomitant nifedipine had no effect on irbesartan pharmacokinetics. Candesartan: No significant drug interaction has been reported in studies with candesartan cilexitil given together with nifedipine. Because candesartan is not significantly metabolized by the cytochrome P450 system and at therapeutic concentrations has no effect on cytochrome P450 enzymes, interactions with drugs that inhibit or are metabolized by those enzymes would not be expected. Beta-Blockers Nifedipine extended-release tablet was well tolerated when administered in combination with beta-blockers in 187 hypertensive patients in a placebo-controlled clinical trial. However, there have been occasional literature reports suggesting that the combination of nifedipine and beta-adrenergic blocking drugs may increase the likelihood of congestive heart failure, severe hypotension, or exacerbation of angina in patients with cardiovascular disease. Clinical monitoring is recommended, and a dose adjustment of nifedipine should be considered. Timolol: Hypotension is more likely to occur if dihydropryridine calcium antagonists such as nifedipine are coadministered with timolol. Central Alpha1-Blockers Doxazosin: Healthy volunteers participating in a multiple dose doxazosin-nifedipine interaction study received 2 mg doxazosin q.d. alone or combined with 20 mg nifedipine ER b.i.d. Coadministration of nifedipine resulted in a decrease in AUC and C max of doxazosin to 83% and 86% of the values in the absence of nifedipine, respectively. In the presence of doxazosin, AUC and C max of nifedipine were increased by factors of 1.13 and 1.23, respectively. Compared to nifedipine monotherapy, blood pressure was lower in the presence of doxazosin. Blood pressure should be monitored when doxazosin is coadministered with nifedipine and dose reduction of nifedipine considered. Digitalis Digoxin: The simultaneous administration of nifedipine and digoxin may lead to reduced clearance resulting in an increase in plasma concentration of digoxin. Since there have been isolated reports of patients with elevated digoxin levels and there is a possible interaction between digoxin and nifedipine extended-release tablet, it is recommended that digoxin levels be monitored when initiating, adjusting and discontinuing nifedipine extended-release tablet to avoid possible over- or under-digitalization. Antithrombotics Coumarins: 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. Platelet Aggregation Inhibitors Clopidogrel: No clinically significant pharmacodynamic interactions were observed when clopidogrel was coadministered with nifedipine. Tirofiban: Coadministration of nifedipine did not alter the exposure to tirofiban importantly. Other Diuretics, PDE5 inhibitors, alpha-methyldopa: Nifedipine may increase the blood pressure lowering effect of these concomitantly administered agents. Non-Cardiovascular Drugs Antifungal Drugs Ketoconazole, itraconazole and fluconazole are CYP3A inhibitors and can inhibit the metabolism of nifedipine and increase the exposure to nifedipine during concomitant therapy. Blood pressure should be monitored and a dose reduction of nifedipine considered.

dministered agents. Non-Cardiovascular Drugs Antifungal Drugs Ketoconazole, itraconazole and fluconazole are CYP3A inhibitors and can inhibit the metabolism of nifedipine and increase the exposure to nifedipine during concomitant therapy. Blood pressure should be monitored and a dose reduction of nifedipine considered. Antisecretory Drugs Omeprazole: In healthy volunteers receiving a single dose of 10 mg nifedipine, AUC and C max of nifedipine after pretreatment with omeprazole 20 mg q.d. for 8 days were 1.26 and 0.87 times those after pretreatment with placebo. Pretreatment with or coadministration of omeprazole did not impact the effect of nifedipine on blood pressure or heart rate. The impact of omeprazole on nifedipine is not likely to be of clinical relevance. Pantoprazole: In healthy volunteers the exposure to neither drug was changed significantly in the presence of the other drug. Ranitidine: Five studies in healthy volunteers investigated the impact of multiple ranitidine doses on the single or multiple dose pharmacokinetics of nifedipine. Two studies investigated the impact of coadministered ranitidine on blood pressure in hypertensive subjects on nifedipine. Coadministration of ranitidine did not have relevant effects on the exposure to nifedipine that affected the blood pressure or heart rate in normotensive or hypertensive subjects. Cimetidine: Five studies in healthy volunteers investigated the impact of multiple cimetidine doses on the single or multiple dose pharmacokinetics of nifedipine. Two studies investigated the impact of coadministered cimetidine on blood pressure in hypertensive subjects on nifedipine. In normotensive subjects receiving single doses of 10 mg or multiple doses of up to 20 mg nifedipine t.i.d. alone or together with cimetidine up to 1000 mg/day, the AUC values of nifedipine in the presence of cimetidine were between 1.52 and 2.01 times those in the absence of cimetidine. The C max values of nifedipine in the presence of cimetidine were increased by factors ranging between 1.60 and 2.02. The increase in exposure to nifedipine by cimetidine was accompanied by relevant changes in blood pressure or heart rate in normotensive subjects. Hypertensive subjects receiving 10 mg q.d. nifedipine alone or in combination with cimetidine 1000 mg q.d. also experienced relevant changes in blood pressure when cimetidine was added to nifedipine. The interaction between cimetidine and nifedipine is of clinical relevance and blood pressure should be monitored and a reduction of the dose of nifedipine considered. Cisapride: Simultaneous administration of cisapride and nifedipine may lead to increased plasma concentrations of nifedipine. Antibacterial Drugs Quinupristin/Dalfopristin: In vitro drug interaction studies have demonstrated that quinupristin/dalfopristin significantly inhibits the CYP3A metabolism of nifedipine. Concomitant administration of quinupristin/dalfopristin and nifedipine (repeated oral dose) in healthy volunteers increased AUC and C max for nifedipine by factors of 1.44 and 1.18, respectively, compared to nifedipine monotherapy. Upon coadministration of quinupristin/dalfopristin with nifedipine, blood pressure should be monitored and a reduction of the dose of nifedipine considered. Erythromycin: Erythromycin, a CYP3A inhibitor, can inhibit the metabolism of nifedipine and increase the exposure to nifedipine during concomitant therapy. Blood pressure should be monitored and a reduction of the dose of nifedipine considered.

e should be monitored and a reduction of the dose of nifedipine considered. Erythromycin: Erythromycin, a CYP3A inhibitor, can inhibit the metabolism of nifedipine and increase the exposure to nifedipine during concomitant therapy. Blood pressure should be monitored and a reduction of the dose of nifedipine considered. Antitubercular Drugs Rifampin: Strong CYP3A inducers, such as rifampin, rifapentin, and rifabutin reduce the bioavailability of nifedipine which may reduce the efficacy of nifedipine; therefore nifedipine should not be used in combination with strong CYP3A inducers such as rifampin (see CONTRAINDICATIONS ). The impact of multiple oral doses of 600 mg rifampin on the pharmacokinetics of nifedipine after a single oral dose of 20 mg nifedipine capsule was evaluated in a clinical study. Twelve healthy male volunteers received a single oral dose of 20 mg nifedipine capsule on study Day 1. Starting on study Day 2, the subjects received 600 mg rifampin once daily for 14 days. On study Day 15, a second single oral dose of 20 mg nifedipine capsule was administered together with the last dose of rifampin. Compared to study Day 1, 14 days pretreatment with rifampin reduced C max and AUC of concomitantly administered nifedipine on average by 95% and 97%, respectively. Antiviral Drugs Amprenavir, atanazavir, delavirine, fosamprinavir, indinavir, nelfinavir, and ritonavir, as CYP3A inhibitors, can inhibit the metabolism of nifedipine and increase the exposure to nifedipine. Caution is warranted and clinical monitoring of patients recommended. CNS Drugs Nefazodone, a CYP3A inhibitor, can inhibit the metabolism of nifedipine and increase the exposure to nifedipine during concomitant therapy. Blood pressure should be monitored and a reduction of the dose of nifedipine considered. Fluoxetine, a CYP3A inhibitor, can inhibit the metabolism of nifedipine and increase the exposure to nifedipine during concomitant therapy. Blood pressure should be monitored and a reduction of the dose of nifedipine considered. Valproic acid may increase the exposure to nifedipine during concomitant therapy. Blood pressure should be monitored and a dose reduction of nifedipine considered. Phenytoin, Phenobarbital, and Carbamazepine: Nifedipine is metabolized by CYP3A. Coadministration of nifedipine 10 mg capsule and 60 mg nifedipine coat-core tablet with phenytoin, an inducer of CYP3A, lowered the AUC and C max of nifedipine by approximately 70%. Phenobarbital and carbamazepine are also inducers of CYP3A. Alternative antihypertensive therapy should be considered in patients taking phenytoin, phenobarbital, and carbamazepine. Antiemetic Drugs Dolasetron: In patients taking dolasetron by the oral or intravenous route and nifedipine, no effect was shown on the clearance of hydrodolasetron. Immunosuppressive Drugs Tacrolimus: Tacrolimus has been shown to be metabolized via the CYP3A system. Nifedipine has been shown to inhibit the metabolism of tacrolimus in vitro . Transplant patients on tacrolimus and nifedipine required from 26% to 38% smaller doses than patients not receiving nifedipine. Nifedipine can increase the exposure to tacrolimus. When nifedipine is coadministered with tacrolimus the blood concentrations of tacrolimus should be monitored and a reduction of the dose of tacrolimus considered. Sirolimus: A single 60 mg dose of nifedipine and a single 10 mg dose of sirolimus oral solution were administered to 24 healthy volunteers. Clinically significant pharmacokinetic drug interactions were not observed. Glucose Lowering Drugs Pioglitazone: Coadministration of pioglitazone for 7 days with 30 mg nifedipine ER administered orally q.d.

dose of nifedipine and a single 10 mg dose of sirolimus oral solution were administered to 24 healthy volunteers. Clinically significant pharmacokinetic drug interactions were not observed. Glucose Lowering Drugs Pioglitazone: Coadministration of pioglitazone for 7 days with 30 mg nifedipine ER administered orally q.d. for 4 days to male and female volunteers resulted in least square mean (90% CI) values for unchanged nifedipine of 0.83 (0.73 to 0.95) for C max and 0.88 (0.80 to 0.96) for AUC relative to nifedipine monotherapy. In view of the high variability of nifedipine pharmacokinetics, the clinical significance of this finding is unknown. Rosiglitazone: Coadministration of rosiglitazone (4 mg b.i.d.) was shown to have no clinically relevant effect on the pharmacokinetics of nifedipine. Metformin: A single dose metformin-nifedipine interaction study in normal healthy volunteers demonstrated that coadministration of nifedipine increased plasma metformin C max and AUC by 20% and 9%, respectively, and increased the amount of metformin excreted in urine. T max and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Miglitol: No effect of miglitol was observed on the pharmacokinetics and pharmacodynamics of nifedipine. Repaglinide: Coadministration of 10 mg nifedipine with a single dose of 2 mg repaglinide (after 4 days nifedipine 10 mg t.i.d. and repaglinide 2 mg t.i.d.) resulted in unchanged AUC and C max values for both drugs. Acarbose: Nifedipine tends to produce hyperglycemia and may lead to loss of glucose control. If nifedipine is coadministered with acarbose, blood glucose levels should be monitored carefully and a dose adjustment of nifedipine considered. Drugs Interfering with Food Absorption Orlistat: In 17 normal-weight subjects receiving orlistat 120 mg t.i.d. for 6 days, orlistat did not alter the bioavailability of 60 mg nifedipine (extended-release tablets). Dietary Supplements Grapefruit Juice: In healthy volunteers, a single dose coadministration of 250 mL double strength grapefruit juice with 10 mg nifedipine increased AUC and C max by factors of 1.35 and 1.13, respectively. Ingestion of repeated doses of grapefruit juice (5 × 200 mL in 12 hours) after administration of 20 mg nifedipine ER increased AUC and C max of nifedipine by a factor of 2. Grapefruit juice should be avoided by patients on nifedipine. The intake of grapefruit juice should be stopped at least 3 days prior to initiating patients on nifedipine. Herbals St. John’s Wort: St. John’s Wort is an inducer of CYP3A and may decrease exposure to nifedipine. Alternative antihypertensive therapy should be considered in patients in whom St. John’s Wort therapy is necessary. CYP2D6 Probe Drug Debrisoquine: In healthy volunteers, pretreatment with nifedipine 20 mg t.i.d. for 5 days did not change the metabolic ratio of hydroxydebrisoquine to debrisoquine measured in urine after a single dose of 10 mg debrisoquine. Thus, it is improbable that nifedipine inhibits in vivo the metabolism of other drugs that are substrates of CYP2D6. 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.

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 Pregnancy Category C In rodents, rabbits, and monkeys, nifedipine has been shown to have a variety of embryotoxic, placentotoxic, teratogenic, and fetotoxic effects, including stunted fetuses (rats, mice, and rabbits), digital anomalies (rats and rabbits), rib deformities (mice), cleft palate (mice), small placentas and underdeveloped chorionic villi (monkeys), embryonic and fetal deaths (rats, mice, and rabbits), prolonged pregnancy (rats; not evaluated in other species), and decreased neonatal survival (rats; not evaluated in other species). On a mg/kg or mg/m 2 basis, some of the doses associated with these various effects are higher than the maximum recommended human dose and some are lower, but all are within an order of magnitude of it. The digital anomalies seen in nifedipine-exposed rabbit pups are strikingly similar to those seen in pups exposed to phenytoin, and these are in turn similar to the phalangeal deformities that are the most common malformation seen in human children with in utero exposure to phenytoin. From the clinical evidence available, a specific prenatal risk has not been identified. However, an increase in perinatal asphyxia, caesarean delivery, prematurity, and intrauterine growth retardation have been reported. Careful monitoring of blood pressure must be exercised in pregnant women, when administering nifedipine in combination with IV magnesium sulfate due to the possibility of an excessive fall in blood pressure which could harm the mother and fetus. There are no adequate and well-controlled studies in pregnant women. Nursing Mothers Nifedipine is excreted in human milk. Nursing mothers are advised not to breastfeed their babies when taking the drug. Pediatric Use The safety and effectiveness of nifedipine in pediatric patients have not been established. Geriatric Use Although small pharmacokinetic studies have identified an increased half-life and increased C max and AUC (see CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism ), clinical studies of nifedipine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Patients with Galactose Intolerance Since this medicinal product contains lactose, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

General Hypotension Because nifedipine decreases peripheral vascular resistance, careful monitoring of blood pressure during the initial administration and titration of nifedipine extended-release tablets is suggested. Close observation is especially recommended for patients already taking medications that are known to lower blood pressure (see WARNINGS ).

Information for Patients Nifedipine extended-release tablets are an extended-release tablet and should be swallowed whole and taken on an empty stomach. It should not be administered with food. Do not chew, divide or crush tablets.

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 increase (<5%) in mean alkaline phosphatase was noted in patients treated with nifedipine extended-release tablets. This was an isolated finding and it rarely resulted in values which fell outside the normal range. Rare instances of allergic hepatitis have been reported with nifedipine treatment. In controlled studies, nifedipine extended-release tablets did not adversely affect serum uric acid, glucose, cholesterol or potassium. 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 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 or 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.

Drug Interactions Nifedipine is mainly eliminated by metabolism and is a substrate of CYP3A. Inhibitors and inducers of CYP3A can impact the exposure to nifedipine and consequently its desirable and undesirable effects. In vitro and in vivo data indicate that nifedipine can inhibit the metabolism of drugs that are substrates of CYP3A, thereby increasing the exposure to other drugs. Nifedipine is a vasodilator, and coadministration of other drugs affecting blood pressure may result in pharmacodynamic interactions. CYP3A Inhibitors CYP3A inhibitors such as ketoconazole, fluconazole, itraconazole, clarithromycin, erythromycin (azithromycin, although structurally related to the class of macrolide antibiotic, is void of clinically relevant CYP3A inhibition), grapefruit, nefazodone, fluoxetine, saquinavir, indinavir, nelfinavir, and ritonavir may result in increased exposure to nifedipine when coadministered. Careful monitoring and dose adjustment may be necessary; consider initiating nifedipine at the lowest dose available if given concomitantly with these medications. Strong CYP3A Inducers Strong CYP3A inducers, such as rifampin, rifabutin, phenobarbital, phenytoin, carbamazepine, and St. John’s Wort reduce the bioavailability and efficacy of nifedipine; therefore nifedipine should not be used in combination with strong CYP3A inducers such as rifampin (see CONTRAINDICATIONS ). Cardiovascular Drugs Antiarrhythmics Quinidine: Quinidine is a substrate of CYP3A and has been shown to inhibit CYP3A in vitro . Coadministration of multiple doses of quinidine sulfate, 200 mg t.i.d., and nifedipine, 20 mg t.i.d., increased C max and AUC of nifedipine in healthy volunteers by factors of 2.30 and 1.37, respectively. The heart rate in the initial interval after drug administration was increased by up to 17.9 beats/minute. The exposure to quinidine was not importantly changed in the presence of nifedipine. Monitoring of heart rate and adjustment of the nifedipine dose, if necessary, are recommended when quinidine is added to a treatment with nifedipine. Flecainide: There has been too little experience with the coadministration of flecainide with nifedipine to recommend concomitant use. Calcium Channel Blockers Diltiazem: Pretreatment of healthy volunteers with 30 mg or 90 mg t.i.d. diltiazem p.o. increased the AUC of nifedipine after a single dose of 20 mg nifedipine by factors of 2.2 and 3.1, respectively. The corresponding C max values of nifedipine increased by factors of 2.0 and 1.7, respectively. Caution should be exercised when coadministering diltiazem and nifedipine and a reduction of the dose of nifedipine should be considered. Verapamil: Verapamil, a CYP3A inhibitor, can inhibit the metabolism of nifedipine and increase the exposure to nifedipine during concomitant therapy. Blood pressure should be monitored and reduction of the dose of nifedipine considered. ACE Inhibitors Benazepril: In healthy volunteers receiving single dose of 20 mg nifedipine ER and benazepril 10 mg, the plasma concentrations of benazeprilat and nifedipine in the presence and absence of each other were not statistically significantly different. A hypotensive effect was only seen after coadministration of the two drugs. The tachycardic effect of nifedipine was attenuated in the presence of benazepril. Angiotensin-II Blockers Irbesartan: In vitro studies show significant inhibition of the formation of oxidized irbesartan metabolites by nifedipine.

ly different. A hypotensive effect was only seen after coadministration of the two drugs. The tachycardic effect of nifedipine was attenuated in the presence of benazepril. Angiotensin-II Blockers Irbesartan: In vitro studies show significant inhibition of the formation of oxidized irbesartan metabolites by nifedipine. However, in clinical studies, concomitant nifedipine had no effect on irbesartan pharmacokinetics. Candesartan: No significant drug interaction has been reported in studies with candesartan cilexitil given together with nifedipine. Because candesartan is not significantly metabolized by the cytochrome P450 system and at therapeutic concentrations has no effect on cytochrome P450 enzymes, interactions with drugs that inhibit or are metabolized by those enzymes would not be expected. Beta-Blockers Nifedipine extended-release tablet was well tolerated when administered in combination with beta-blockers in 187 hypertensive patients in a placebo-controlled clinical trial. However, there have been occasional literature reports suggesting that the combination of nifedipine and beta-adrenergic blocking drugs may increase the likelihood of congestive heart failure, severe hypotension, or exacerbation of angina in patients with cardiovascular disease. Clinical monitoring is recommended, and a dose adjustment of nifedipine should be considered. Timolol: Hypotension is more likely to occur if dihydropryridine calcium antagonists such as nifedipine are coadministered with timolol. Central Alpha1-Blockers Doxazosin: Healthy volunteers participating in a multiple dose doxazosin-nifedipine interaction study received 2 mg doxazosin q.d. alone or combined with 20 mg nifedipine ER b.i.d. Coadministration of nifedipine resulted in a decrease in AUC and C max of doxazosin to 83% and 86% of the values in the absence of nifedipine, respectively. In the presence of doxazosin, AUC and C max of nifedipine were increased by factors of 1.13 and 1.23, respectively. Compared to nifedipine monotherapy, blood pressure was lower in the presence of doxazosin. Blood pressure should be monitored when doxazosin is coadministered with nifedipine and dose reduction of nifedipine considered. Digitalis Digoxin: The simultaneous administration of nifedipine and digoxin may lead to reduced clearance resulting in an increase in plasma concentration of digoxin. Since there have been isolated reports of patients with elevated digoxin levels and there is a possible interaction between digoxin and nifedipine extended-release tablet, it is recommended that digoxin levels be monitored when initiating, adjusting and discontinuing nifedipine extended-release tablet to avoid possible over- or under-digitalization. Antithrombotics Coumarins: 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. Platelet Aggregation Inhibitors Clopidogrel: No clinically significant pharmacodynamic interactions were observed when clopidogrel was coadministered with nifedipine. Tirofiban: Coadministration of nifedipine did not alter the exposure to tirofiban importantly. Other Diuretics, PDE5 inhibitors, alpha-methyldopa: Nifedipine may increase the blood pressure lowering effect of these concomitantly administered agents.

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 Pregnancy Category C In rodents, rabbits, and monkeys, nifedipine has been shown to have a variety of embryotoxic, placentotoxic, teratogenic, and fetotoxic effects, including stunted fetuses (rats, mice, and rabbits), digital anomalies (rats and rabbits), rib deformities (mice), cleft palate (mice), small placentas and underdeveloped chorionic villi (monkeys), embryonic and fetal deaths (rats, mice, and rabbits), prolonged pregnancy (rats; not evaluated in other species), and decreased neonatal survival (rats; not evaluated in other species). On a mg/kg or mg/m 2 basis, some of the doses associated with these various effects are higher than the maximum recommended human dose and some are lower, but all are within an order of magnitude of it. The digital anomalies seen in nifedipine-exposed rabbit pups are strikingly similar to those seen in pups exposed to phenytoin, and these are in turn similar to the phalangeal deformities that are the most common malformation seen in human children with in utero exposure to phenytoin. From the clinical evidence available, a specific prenatal risk has not been identified. However, an increase in perinatal asphyxia, caesarean delivery, prematurity, and intrauterine growth retardation have been reported. Careful monitoring of blood pressure must be exercised in pregnant women, when administering nifedipine in combination with IV magnesium sulfate due to the possibility of an excessive fall in blood pressure which could harm the mother and fetus. There are no adequate and well-controlled studies in pregnant women.

rted. Careful monitoring of blood pressure must be exercised in pregnant women, when administering nifedipine in combination with IV magnesium sulfate due to the possibility of an excessive fall in blood pressure which could harm the mother and fetus. There are no adequate and well-controlled studies in pregnant women. Pregnancy Category C In rodents, rabbits, and monkeys, nifedipine has been shown to have a variety of embryotoxic, placentotoxic, teratogenic, and fetotoxic effects, including stunted fetuses (rats, mice, and rabbits), digital anomalies (rats and rabbits), rib deformities (mice), cleft palate (mice), small placentas and underdeveloped chorionic villi (monkeys), embryonic and fetal deaths (rats, mice, and rabbits), prolonged pregnancy (rats; not evaluated in other species), and decreased neonatal survival (rats; not evaluated in other species). On a mg/kg or mg/m 2 basis, some of the doses associated with these various effects are higher than the maximum recommended human dose and some are lower, but all are within an order of magnitude of it. The digital anomalies seen in nifedipine-exposed rabbit pups are strikingly similar to those seen in pups exposed to phenytoin, and these are in turn similar to the phalangeal deformities that are the most common malformation seen in human children with in utero exposure to phenytoin. From the clinical evidence available, a specific prenatal risk has not been identified. However, an increase in perinatal asphyxia, caesarean delivery, prematurity, and intrauterine growth retardation have been reported. Careful monitoring of blood pressure must be exercised in pregnant women, when administering nifedipine in combination with IV magnesium sulfate due to the possibility of an excessive fall in blood pressure which could harm the mother and fetus. There are no adequate and well-controlled studies in pregnant women.

Geriatric Use Although small pharmacokinetic studies have identified an increased half-life and increased C max and AUC (see CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism ), clinical studies of nifedipine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

ADVERSE REACTIONS The incidence of adverse events during treatment with nifedipine extended-release tablets in doses up to 90 mg daily were derived from multi-center placebo-controlled clinical trials in 370 hypertensive patients. Atenolol 50 mg once daily was used concomitantly in 187 of the 370 patients on nifedipine extended-release tablets and in 64 of the 126 patients on placebo. All adverse events reported during nifedipine extended-release tablets therapy were tabulated independently of their causal relationship to medication. The most common adverse event reported with nifedipine extended-release tablets was peripheral edema. This was dose related, and the frequency was 18% on nifedipine extended-release tablets 30 mg daily, 22% on nifedipine extended-release tablets 60 mg daily, and 29% on nifedipine extended-release tablets 90 mg daily versus 10% on placebo. Other common adverse events reported in the above placebo-controlled trials include: Adverse Event NIFEDIPINE EXTENDED-RELEASE TABLETS (%) (n=370) PLACEBO (%) (n=126) Headache 19 13 Flushing/heat sensation 4 0 Dizziness 4 2 Fatigue/asthenia 4 4 Nausea 2 1 Constipation 1 0 Where the frequency of adverse events with nifedipine extended-release tablets and placebo is similar, causal relationship cannot be established.

NIFEDIPINE EXTENDED-RELEASE TABLETS (%) (n=370) PLACEBO (%) (n=126) Headache 19 13 Flushing/heat sensation 4 0 Dizziness 4 2 Fatigue/asthenia 4 4 Nausea 2 1 Constipation 1 0 Where the frequency of adverse events with nifedipine extended-release tablets and placebo is similar, causal relationship cannot be established. The following adverse events were reported with an incidence of 3% or less in daily doses up to 90 mg: Body as a Whole/Systemic: chest pain, leg pain Central Nervous System: paresthesia, vertigo Dermatologic: rash Gastrointestinal: constipation Musculoskeletal: leg cramps Respiratory: epistaxis, rhinitis Urogenital: impotence, urinary frequency Other adverse events reported with an incidence of less than 1% were: Body as a Whole/Systemic: allergic reaction, asthenia, cellulitis, substernal chest pain, chills, facial edema, lab test abnormal, malaise, neck pain, pelvic pain, pain, photosensitivity reaction Cardiovascular: atrial fibrillation, bradycardia, cardiac arrest, extrasystole, hypotension, migraine, palpitations, phlebitis, postural hypotension, tachycardia, cutaneous angiectases Central Nervous System: anxiety, confusion, decreased libido, depression, hypertonia, hypesthesia, insomnia, somnolence Dermatologic: angioedema, petechial rash, pruritus, sweating Gastrointestinal: abdominal pain, diarrhea, dry mouth, dysphagia, dyspepsia, eructation, esophagitis, flatulence, gastrointestinal disorder, gastrointestinal hemorrhage, GGT increased, gum disorder, gum hemorrhage, vomiting Hematologic: eosinophilia, lymphadenopathy Metabolic: gout, weight loss Musculoskeletal: arthralgia, arthritis, joint disorder, myalgia, myasthenia Respiratory: dyspnea, increased cough, rales, pharyngitis, stridor Special Senses: abnormal vision, amblyopia, conjunctivitis, diplopia, eye disorder, eye hemorrhage, tinnitus Urogenital/Reproductive: dysuria, kidney calculus, nocturia, breast engorgement, polyuria, urogenital disorder, erectile dysfunction (ED) The following adverse events have been reported rarely in patients given nifedipine in coat core or other formulations: allergenic hepatitis, alopecia, anaphylactic reaction, anemia, arthritis with ANA (+), depression, erythromelalgia, exfoliative dermatitis, fever, gingival hyperplasia, gynecomastia, hyperglycemia, jaundice, leukopenia, mood changes, muscle cramps, nervousness, paranoid syndrome, purpura, shakiness, sleep disturbances, Stevens-Johnson syndrome, syncope, taste perversion, thrombocytopenia, toxic epidermal necrolysis, transient blindness at the peak of plasma level, tremor, and urticaria. To report SUSPECTED ADVERSE REACTIONS, contact Oceanside Pharmaceuticals at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

<table width="100%"><col width="30%"/><col width="40%"/><col width="30%"/><thead><tr><th align="left" styleCode="Botrule Toprule " valign="top"><content styleCode="bold">Adverse Event</content></th><th align="left" styleCode="Botrule Toprule " valign="top"><content styleCode="bold">NIFEDIPINE</content> <content styleCode="bold">EXTENDED-RELEASE</content> <content styleCode="bold">TABLETS (%)</content> <content styleCode="bold">(n=370)</content></th><th align="left" styleCode="Botrule Toprule " valign="top"><content styleCode="bold">PLACEBO</content> <content styleCode="bold">(%)</content> <content styleCode="bold">(n=126)</content></th></tr></thead><tbody><tr><td styleCode="Toprule " valign="top"><paragraph>Headache</paragraph></td><td styleCode="Toprule " valign="top"><paragraph>19</paragraph></td><td styleCode="Toprule " valign="top"><paragraph>13</paragraph></td></tr><tr><td valign="top"><paragraph>Flushing/heat sensation</paragraph></td><td valign="top"><paragraph>4</paragraph></td><td valign="top"><paragraph>0</paragraph></td></tr><tr><td valign="top"><paragraph>Dizziness</paragraph></td><td valign="top"><paragraph>4</paragraph></td><td valign="top"><paragraph>2</paragraph></td></tr><tr><td valign="top"><paragraph>Fatigue/asthenia</paragraph></td><td valign="top"><paragraph>4</paragraph></td><td valign="top"><paragraph>4</paragraph></td></tr><tr><td valign="top"><paragraph>Nausea</paragraph></td><td valign="top"><paragraph>2</paragraph></td><td valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph>Constipation</paragraph></td><td styleCode="Botrule " valign="top"><paragraph>1</paragraph></td><td styleCode="Botrule " valign="top"><paragraph>0</paragraph></td></tr></tbody></table>

OVERDOSAGE Experience with nifedipine overdosage is limited. Symptoms associated with severe nifedipine overdosage include loss of consciousness, drop in blood pressure, heart rhythm disturbances, metabolic acidosis, hypoxia, cardiogenic shock with pulmonary edema. Generally, overdosage with nifedipine leading to pronounced hypotension calls for active cardiovascular support including monitoring of cardiovascular and respiratory function, elevation of extremities, judicious use of calcium infusion, pressor agents, and fluids. After oral ingestion, thorough gastric lavage is indicated, if necessary in combination with irrigation of the small intestine. In cases involving overdosage of a slow-release product like nifedipine, elimination must be as complete as possible, including from the small intestine, to prevent the subsequent absorption of the active substance. Additional liquid or volume must be administered with caution because of the risk of fluid overload. Clearance of nifedipine would be expected to be prolonged in patients with impaired liver function. Since nifedipine is highly protein bound, dialysis is not likely to be of any benefit; however, plasmapheresis may be beneficial. There has been one reported case of massive overdosage with tablets of another extended-release formulation of nifedipine. The main effects of ingestion of approximately 4800 mg of nifedipine in a young man attempting suicide as a result of cocaine-induced depression was initial dizziness, palpitations, flushing, and nervousness. Within several hours of ingestion, nausea, vomiting, and generalized edema developed. No significant hypotension was apparent at presentation, 18 hours post ingestion. Blood chemistry abnormalities consisted of a mild, transient elevation of serum creatinine and modest elevations of LDH and CPK, but normal SGOT. Vital signs remained stable, no electrocardiographic abnormalities were noted, and renal function returned to normal within 24 to 48 hours with routine supportive measures alone. No prolonged sequelae were observed. The effect of a single 900 mg ingestion of nifedipine capsules in a depressed anginal patient on tricyclic antidepressants was loss of consciousness within 30 minutes of ingestion, and profound hypotension, which responded to calcium infusion, pressor agents, and fluid replacement. A variety of ECG abnormalities were seen in this patient with a history of bundle branch block, including sinus bradycardia and varying degrees of AV block. These dictated the prophylactic placement of a temporary ventricular pacemaker, but otherwise resolved spontaneously. Significant hyperglycemia was seen initially in this patient, but plasma glucose levels rapidly normalized without further treatment. A young hypertensive patient with advanced renal failure ingested 280 mg of nifedipine capsules at one time, with resulting marked hypotension responding to calcium infusion and fluids. No AV conduction abnormalities, arrhythmias, or pronounced changes in heart rate were noted, nor was there any further deterioration in renal function. Bradycardiac heart rhythm disturbances may be treated symptomatically with β-sympathomimetics, and in life-threatening bradycardiac disturbances of heart rhythm temporary pacemaker therapy can be advisable.

DOSAGE AND ADMINISTRATION Dosage should be adjusted according to each patient’s needs. It is recommended that nifedipine extended-release tablet be administered orally once daily on an empty stomach. Nifedipine extended-release tablet is an extended-release dosage form and tablets should be swallowed whole, not bitten or divided. In general, titration should proceed over a 7 to 14 day period starting with 30 mg once daily. Upward titration should be based on therapeutic efficacy and safety. The usual maintenance dose is 30 mg to 60 mg once daily. Titration to doses above 90 mg daily is not recommended. If discontinuation of nifedipine extended-release tablets is necessary, sound clinical practice suggests that the dosage should be decreased gradually with close physician supervision. Coadministration of nifedipine with grapefruit juice is to be avoided (see CLINICAL PHARMACOLOGY and PRECAUTIONS ). Care should be taken when dispensing nifedipine extended-release tablets to assure that the extended-release dosage form has been prescribed.

HOW SUPPLIED Nifedipine Extended-Release Tablets, USP are supplied as 30 mg unscored, round film-coated tablets as follows: Strength Color Markings 30 mg Mustard yellow 30 mg unscored, round, film-coated tablets, engraved with "B" on one side and "30" on the other side. Nifedipine Extended-Release Tablets, USP are supplied in: Strength Quantity NDC Number 30 mg Bottles of 300 63629-9109-1 The tablets should be protected from light and moisture and stored at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Dispense in tight, light-resistant containers. Repackaged/Relabeled by: Bryant Ranch Prepack Burbank, CA 91504

<table width="100%"><tbody><tr><td align="center"><content styleCode="bold">Strength</content></td><td align="center"><content styleCode="bold">Color</content></td><td align="center"><content styleCode="bold"> Markings</content></td></tr><tr><td align="center"> 30 mg</td><td align="center"> Mustard yellow</td><td align="center"> 30 mg unscored, round, film-coated tablets, engraved with &quot;B&quot; on one side and &quot;30&quot; on the other side.</td></tr></tbody></table> <table width="100%"><tbody><tr><td align="center"><content styleCode="bold"> Strength</content></td><td align="center"><content styleCode="bold"> Quantity</content></td><td align="center"><content styleCode="bold"> NDC Number</content></td></tr><tr><td align="left"> 30 mg</td><td align="left"> Bottles of 300</td><td align="left"> 63629-9109-1</td></tr></tbody></table>

For Oral Use Patients with Galactose Intolerance Since this medicinal product contains lactose, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. Distributed by: Oceanside Pharmaceuticals, a division of Bausch Health US, LLC Bridgewater, NJ 08807 USA Manufactured by: Bausch Health Companies Inc. Steinbach, MB R5G 1Z7, Canada © 2025 Bausch Health Companies Inc. or its affiliates 9495305 20005956 Rev. 12/2025

DESCRIPTION Nifedipine extended-release tablets are an extended-release tablet dosage form of the calcium channel blocker nifedipine. Nifedipine is 3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(2 - nitrophenyl)- dimethyl ester, C 17 H 18 N 2 O 6 , 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. Nifedipine extended-release tablets contain 60 mg of nifedipine for once-a-day oral administration. In addition, each tablet contains the following inactive ingredients: ethylcellulose, ferric oxide yellow, hydroxyethyl cellulose, hypromellose, anhydrous lactose, magnesium stearate, microcrystalline cellulose, amino methacrylate copolymer, polyethylene glycol, colloidal silicon dioxide, sodium lauryl sulfate, talc, and titanium dioxide.

CLINICAL PHARMACOLOGY Nifedipine is a calcium ion influx inhibitor (slow-channel blocker or calcium ion antagonist) which inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. The contractile processes of vascular smooth muscle and cardiac 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 vascular smooth muscle and cardiac muscle without altering serum calcium concentrations. Mechanism of Action The mechanism by which nifedipine reduces arterial blood pressure involves peripheral arterial vasodilatation and, consequently, a reduction in peripheral vascular resistance. The increased peripheral vascular resistance, 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. The bioavailability of nifedipine as nifedipine extended-release tablet relative to immediate-release nifedipine is in the range of 84%-89%. After ingestion of nifedipine extended-release tablets under fasting conditions, plasma concentrations peak at about 2.5-5 hours with a second small peak or shoulder evident at approximately 6-12 hours post dose. The elimination half-life of nifedipine administered as nifedipine extended-release tablet is approximately 7 hours in contrast to the known 2 hour elimination half-life of nifedipine administered as an immediate release capsule. When nifedipine extended-release tablet is administered as multiples of 30 mg tablets over a dose range of 30 mg to 90 mg, the area under the curve (AUC) is dose proportional; however, the peak plasma concentration for the 90 mg dose given as 3 × 30 mg is 29% greater than predicted from the 30 mg and 60 mg doses. Two 30 mg nifedipine extended-release tablets may be interchanged with a 60 mg nifedipine extended-release tablet. Three 30 mg nifedipine extended-release tablets, however, result in substantially higher C max values than those after a single 90 mg nifedipine extended-release tablet. Three 30 mg tablets should, therefore, not be considered interchangeable with a 90 mg tablet. Once daily dosing of nifedipine extended-release tablets under fasting conditions results in decreased fluctuations in the plasma concentration of nifedipine when compared to t.i.d. dosing with immediate release nifedipine capsules. The mean peak plasma concentration of nifedipine following a 90 mg nifedipine extended-release tablet, administered under fasting conditions, is approximately 115 ng/mL.

results in decreased fluctuations in the plasma concentration of nifedipine when compared to t.i.d. dosing with immediate release nifedipine capsules. The mean peak plasma concentration of nifedipine following a 90 mg nifedipine extended-release tablet, administered under fasting conditions, is approximately 115 ng/mL. When nifedipine extended-release tablet is given immediately after a high fat meal in healthy volunteers, there is an average increase of 60% in the peak plasma nifedipine concentration, a prolongation in the time to peak concentration, but no significant change in the AUC. Plasma concentrations of nifedipine when nifedipine extended-release tablet is taken after a fatty meal result in slightly lower peaks compared to the same daily dose of the immediate release formulation administered in three divided doses. This may be, in part, because nifedipine extended-release tablet is less bioavailable than the immediate release formulation. Nifedipine is extensively metabolized to highly water soluble, inactive metabolites accounting for 60% to 80% of the dose excreted in the urine. Only traces (less than 0.1% of the dose) of the 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. Nifedipine is metabolized via the cytochrome P450 3A4 system. Drugs that are known to either inhibit or induce this enzyme system may alter the first pass or clearance of nifedipine. No studies have been performed with nifedipine extended-release tablets in patients with renal failure; however, significant alterations in the pharmacokinetics of nifedipine immediate release capsules have not been reported in patients undergoing hemodialysis or chronic ambulatory peritoneal dialysis. Since the absorption of nifedipine from nifedipine extended-release tablets could be modified by renal disease, caution should be exercised in treating such patients. Because nifedipine is metabolized via the cytochrome P450 3A4 system, its pharmacokinetics may be altered in patients with chronic liver disease. Nifedipine extended-release tablets have not been studied in patients with hepatic disease; however, in patients with hepatic impairment (liver cirrhosis) nifedipine has a longer elimination half-life and higher bioavailability than in healthy volunteers. The degree of protein binding of nifedipine is high (92%-98%). Protein binding may be greatly reduced in patients with renal or hepatic impairment. After administration of nifedipine extended-release tablets to healthy elderly men and women (age >60 years), the mean C max is 36% higher and the average plasma concentration is 70% greater than in younger patients. In healthy subjects, the elimination half-life of a different sustained-release nifedipine formulation was longer in elderly subjects (6.7 h) compared to young subjects (3.8 h) following oral administration. A decreased clearance was also observed in the elderly (348 mL/min) compared to young subjects (519 mL/min) following intravenous administration. Co-administration of nifedipine with grapefruit juice results in up to a 2-fold increase in AUC and C max due to inhibition of CYP3A related first-pass metabolism. Ingestion of grapefruit and grapefruit juice should be avoided while taking nifedipine. Clinical Studies Nifedipine extended-release tablets produced dose-related decreases in systolic and diastolic blood pressure as demonstrated in two double-blind, randomized, placebo-controlled trials in which over 350 patients were treated with nifedipine extended-release tablets, 30, 60 or 90 mg once daily for 6 weeks.

inical Studies Nifedipine extended-release tablets produced dose-related decreases in systolic and diastolic blood pressure as demonstrated in two double-blind, randomized, placebo-controlled trials in which over 350 patients were treated with nifedipine extended-release tablets, 30, 60 or 90 mg once daily for 6 weeks. In the first study, nifedipine extended-release tablet was given as monotherapy and in the second study, nifedipine extended-release tablet was added to a beta-blocker in patients not controlled on a beta-blocker alone. The mean trough (24 hours post-dose) blood pressure results from these studies are shown below: MEAN REDUCTIONS IN TROUGH SUPINE BLOOD PRESSURE (mmHg) SYSTOLIC/DIASTOLIC NIFEDIPINE EXTENDED-RELEASE, USP DOSE N MEAN TROUGH REDUCTION * STUDY 1 30 mg 60 5.3/2.9 60 mg 57 8.0/4.1 90 mg 55 12.5/8.1 STUDY 2 30 mg 58 7.6/3.8 60 mg 63 10.1/5.3 90 mg 62 10.2/5.8 * Placebo response subtracted. The trough/peak ratios estimated from 24 hour blood pressure monitoring ranged from 41%-78% for diastolic and 46%-91% for systolic blood pressure. 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 mmHg 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 of the immediate-release nifedipine formulation 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 administered as the immediate-release capsule has had no tendency to prolong atrioventricular conduction or sinus node recovery time, or to slow sinus rate.

Pharmacokinetics and Metabolism Nifedipine is completely absorbed after oral administration. The bioavailability of nifedipine as nifedipine extended-release tablet relative to immediate-release nifedipine is in the range of 84%-89%. After ingestion of nifedipine extended-release tablets under fasting conditions, plasma concentrations peak at about 2.5-5 hours with a second small peak or shoulder evident at approximately 6-12 hours post dose. The elimination half-life of nifedipine administered as nifedipine extended-release tablet is approximately 7 hours in contrast to the known 2 hour elimination half-life of nifedipine administered as an immediate release capsule. When nifedipine extended-release tablet is administered as multiples of 30 mg tablets over a dose range of 30 mg to 90 mg, the area under the curve (AUC) is dose proportional; however, the peak plasma concentration for the 90 mg dose given as 3 × 30 mg is 29% greater than predicted from the 30 mg and 60 mg doses. Two 30 mg nifedipine extended-release tablets may be interchanged with a 60 mg nifedipine extended-release tablet. Three 30 mg nifedipine extended-release tablets, however, result in substantially higher C max values than those after a single 90 mg nifedipine extended-release tablet. Three 30 mg tablets should, therefore, not be considered interchangeable with a 90 mg tablet. Once daily dosing of nifedipine extended-release tablets under fasting conditions results in decreased fluctuations in the plasma concentration of nifedipine when compared to t.i.d. dosing with immediate release nifedipine capsules. The mean peak plasma concentration of nifedipine following a 90 mg nifedipine extended-release tablet, administered under fasting conditions, is approximately 115 ng/mL. When nifedipine extended-release tablet is given immediately after a high fat meal in healthy volunteers, there is an average increase of 60% in the peak plasma nifedipine concentration, a prolongation in the time to peak concentration, but no significant change in the AUC. Plasma concentrations of nifedipine when nifedipine extended-release tablet is taken after a fatty meal result in slightly lower peaks compared to the same daily dose of the immediate release formulation administered in three divided doses. This may be, in part, because nifedipine extended-release tablet is less bioavailable than the immediate release formulation. Nifedipine is extensively metabolized to highly water soluble, inactive metabolites accounting for 60% to 80% of the dose excreted in the urine. Only traces (less than 0.1% of the dose) of the 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. Nifedipine is metabolized via the cytochrome P450 3A4 system. Drugs that are known to either inhibit or induce this enzyme system may alter the first pass or clearance of nifedipine. No studies have been performed with nifedipine extended-release tablets in patients with renal failure; however, significant alterations in the pharmacokinetics of nifedipine immediate release capsules have not been reported in patients undergoing hemodialysis or chronic ambulatory peritoneal dialysis. Since the absorption of nifedipine from nifedipine extended-release tablets could be modified by renal disease, caution should be exercised in treating such patients.

cokinetics of nifedipine immediate release capsules have not been reported in patients undergoing hemodialysis or chronic ambulatory peritoneal dialysis. Since the absorption of nifedipine from nifedipine extended-release tablets could be modified by renal disease, caution should be exercised in treating such patients. Because nifedipine is metabolized via the cytochrome P450 3A4 system, its pharmacokinetics may be altered in patients with chronic liver disease. Nifedipine extended-release tablets have not been studied in patients with hepatic disease; however, in patients with hepatic impairment (liver cirrhosis) nifedipine has a longer elimination half-life and higher bioavailability than in healthy volunteers. The degree of protein binding of nifedipine is high (92%-98%). Protein binding may be greatly reduced in patients with renal or hepatic impairment. After administration of nifedipine extended-release tablets to healthy elderly men and women (age >60 years), the mean C max is 36% higher and the average plasma concentration is 70% greater than in younger patients. In healthy subjects, the elimination half-life of a different sustained-release nifedipine formulation was longer in elderly subjects (6.7 h) compared to young subjects (3.8 h) following oral administration. A decreased clearance was also observed in the elderly (348 mL/min) compared to young subjects (519 mL/min) following intravenous administration. Co-administration of nifedipine with grapefruit juice results in up to a 2-fold increase in AUC and C max due to inhibition of CYP3A related first-pass metabolism. Ingestion of grapefruit and grapefruit juice should be avoided while taking nifedipine.

Clinical Studies Nifedipine extended-release tablets produced dose-related decreases in systolic and diastolic blood pressure as demonstrated in two double-blind, randomized, placebo-controlled trials in which over 350 patients were treated with nifedipine extended-release tablets, 30, 60 or 90 mg once daily for 6 weeks. In the first study, nifedipine extended-release tablet was given as monotherapy and in the second study, nifedipine extended-release tablet was added to a beta-blocker in patients not controlled on a beta-blocker alone. The mean trough (24 hours post-dose) blood pressure results from these studies are shown below: MEAN REDUCTIONS IN TROUGH SUPINE BLOOD PRESSURE (mmHg) SYSTOLIC/DIASTOLIC NIFEDIPINE EXTENDED-RELEASE, USP DOSE N MEAN TROUGH REDUCTION * STUDY 1 30 mg 60 5.3/2.9 60 mg 57 8.0/4.1 90 mg 55 12.5/8.1 STUDY 2 30 mg 58 7.6/3.8 60 mg 63 10.1/5.3 90 mg 62 10.2/5.8 * Placebo response subtracted. The trough/peak ratios estimated from 24 hour blood pressure monitoring ranged from 41%-78% for diastolic and 46%-91% for systolic blood pressure.

<table ID="_RefID0E1FAC" width="100%"><caption>MEAN REDUCTIONS IN TROUGH SUPINE BLOOD PRESSURE (mmHg)</caption><col width="39%"/><col width="30%"/><col width="29%"/><tbody><tr><td styleCode="Botrule Toprule " valign="top"/><td align="center" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">SYSTOLIC/DIASTOLIC</content></paragraph></td><td styleCode="Botrule Toprule " valign="top"/></tr><tr><td align="center" styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">NIFEDIPINE EXTENDED-RELEASE, USP DOSE</content></paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">N</content></paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">MEAN TROUGH</content> <content styleCode="bold">REDUCTION^*</content></paragraph></td></tr><tr><td colspan="3" valign="top"><paragraph><content styleCode="bold">STUDY 1</content></paragraph></td></tr><tr><td align="center" valign="top"><paragraph>30 mg</paragraph></td><td align="center" valign="top"><paragraph>60</paragraph></td><td align="center" valign="top"><paragraph>5.3/2.9</paragraph></td></tr><tr><td align="center" valign="top"><paragraph>60 mg</paragraph></td><td align="center" valign="top"><paragraph>57</paragraph></td><td align="center" valign="top"><paragraph>8.0/4.1</paragraph></td></tr><tr><td align="center" styleCode="Botrule " valign="top"><paragraph>90 mg</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>55</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>12.5/8.1</paragraph></td></tr><tr><td colspan="3" valign="top"><paragraph><content styleCode="bold">STUDY 2</content></paragraph></td></tr><tr><td align="center" valign="top"><paragraph>30 mg</paragraph></td><td align="center" valign="top"><paragraph>58</paragraph></td><td align="center" valign="top"><paragraph>7.6/3.8</paragraph></td></tr><tr><td align="center" valign="top"><paragraph>60 mg</paragraph></td><td align="center" valign="top"><paragraph>63</paragraph></td><td align="center" valign="top"><paragraph>10.1/5.3</paragraph></td></tr><tr><td align="center" styleCode="Botrule " valign="top"><paragraph>90 mg</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>62</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>10.2/5.8</paragraph></td></tr></tbody></table>

CONTRAINDICATIONS Concomitant administration with strong P450 inducers, such as rifampin, are contraindicated since the efficacy of nifedipine tablets could be significantly reduced. (See PRECAUTIONS, Drug Interactions. ) Nifedipine must not be used in cases of cardiogenic shock. Nifedipine extended-release tablets are contraindicated in patients with a known hypersensitivity to any component of the tablet.

WARNINGS Excessive Hypotension Although in most patients the hypotensive effect of nifedipine is modest and well tolerated, occasional patients have had excessive and poorly tolerated hypotension. These responses have usually occurred during initial titration or at the time of subsequent upward dosage adjustment, and may be more likely in patients using concomitant beta-blockers. Severe hypotension and/or increased fluid volume requirements have been reported in patients who received immediate-release capsules together with a beta-blocking agent and 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 upon starting nifedipine or at the time of dosage increase. The mechanism of this effect is not established. Beta-Blocker Withdrawal When discontinuing a beta-blocker it is important to taper its dose, if possible, rather than stopping 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 while receiving a beta-blocker) have developed heart failure after beginning nifedipine. Patients with tight aortic stenosis may be at greater risk for such an event, as the unloading effect of nifedipine would be expected to be of less benefit to these patients, owing to their fixed impedance to flow across the aortic valve.

PRECAUTIONS General Hypotension Because nifedipine decreases peripheral vascular resistance, careful monitoring of blood pressure during the initial administration and titration of nifedipine extended-release tablets 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 nifedipine extended-release tablets. The placebo subtracted rate is approximately 8% at 30 mg, 12% at 60 mg and 19% at 90 mg daily. This edema 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 hypertension is complicated by congestive heart failure, care should be taken to differentiate this peripheral edema from the effects of increasing left ventricular dysfunction. Use in Cirrhotic Patients Clearance of nifedipine is reduced and systemic exposure increased in patients with cirrhosis. It is unknown how systemic exposure may be altered in patients with moderate or severe liver impairment. Careful monitoring and dose reduction may be necessary; consider initiating therapy with the lowest dose available. Information for Patients Nifedipine extended-release tablets are an extended-release tablet and should be swallowed whole and taken on an empty stomach. It should not be administered with food. Do not chew, divide or crush tablets. 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 increase (<5%) in mean alkaline phosphatase was noted in patients treated with nifedipine extended-release tablets. This was an isolated finding and it rarely resulted in values which fell outside the normal range. Rare instances of allergic hepatitis have been reported with nifedipine treatment. In controlled studies, nifedipine extended-release tablets did not adversely affect serum uric acid, glucose, cholesterol or potassium. 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 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 or 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.

atients 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. Drug Interactions Nifedipine is mainly eliminated by metabolism and is a substrate of CYP3A. Inhibitors and inducers of CYP3A can impact the exposure to nifedipine and consequently its desirable and undesirable effects. In vitro and in vivo data indicate that nifedipine can inhibit the metabolism of drugs that are substrates of CYP3A, thereby increasing the exposure to other drugs. Nifedipine is a vasodilator, and co-administration of other drugs affecting blood pressure may result in pharmacodynamic interactions. CYP3A Inhibitors CYP3A inhibitors such as ketoconazole, fluconazole, itraconazole, clarithromycin, erythromycin (Azithromycin, although structurally related to the class of macrolide antibiotic is void of clinically relevant CYP3A4 inhibition), grapefruit, nefazodone, fluoxetine, saquinavir, indinavir, nelfinavir, and ritonavir 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. Strong CYP3A Inducers Strong CYP3A inducers, such as rifampin, rifabutin, phenobarbital, phenytoin, carbamazepine, and St. John’s Wort reduce the bioavailability and efficacy of nifedipine; therefore nifedipine should not be used in combination with strong CYP3A inducers such as rifampin (See CONTRAINDICATIONS ). Cardiovascular Drugs Antiarrhythmics Quinidine: Quinidine is a substrate of CYP3A and has been shown to inhibit CYP3A in vitro . Co-administration of multiple doses of quinidine sulfate, 200 mg t.i.d., and nifedipine, 20 mg t.i.d., increased C max and AUC of nifedipine in healthy volunteers by factors of 2.30 and 1.37, respectively. The heart rate in the initial interval after drug administration was increased by up to 17.9 beats/minute. The exposure to quinidine was not importantly changed in the presence of nifedipine. Monitoring of heart rate and adjustment of the nifedipine dose, if necessary, are recommended when quinidine is added to a treatment with nifedipine. Flecainide: There has been too little experience with the co-administration of Tambocor with nifedipine to recommend concomitant use. Calcium Channel Blockers Diltiazem: Pre-treatment of healthy volunteers with 30 mg or 90 mg t.i.d. diltiazem p.o. increased the AUC of nifedipine after a single dose of 20 mg nifedipine by factors of 2.2 and 3.1, respectively. The corresponding C max values of nifedipine increased by factors of 2.0 and 1.7, respectively. Caution should be exercised when co-administering diltiazem and nifedipine and a reduction of the dose of nifedipine should be considered. Verapamil: Verapamil, a CYP3A inhibitor, can inhibit the metabolism of nifedipine and increase the exposure to nifedipine during concomitant therapy. Blood pressure should be monitored and reduction of the dose of nifedipine considered. ACE Inhibitors Benazepril: In healthy volunteers receiving single dose of 20 mg nifedipine ER and benazepril 10 mg, the plasma concentrations of benazeprilat and nifedipine in the presence and absence of each other were not statistically significantly different. A hypotensive effect was only seen after co-administration of the two drugs. The tachycardic effect of nifedipine was attenuated in the presence of benazepril. Angiotensin-II Blockers Irbesartan: In vitro studies show significant inhibition of the formation of oxidized irbesartan metabolites by nifedipine.

y different. A hypotensive effect was only seen after co-administration of the two drugs. The tachycardic effect of nifedipine was attenuated in the presence of benazepril. Angiotensin-II Blockers Irbesartan: In vitro studies show significant inhibition of the formation of oxidized irbesartan metabolites by nifedipine. However, in clinical studies, concomitant nifedipine had no effect on irbesartan pharmacokinetics. Candesartan: No significant drug interaction has been reported in studies with candesartan cilexitil given together with nifedipine. Because candesartan is not significantly metabolized by the cytochrome P450 system and at therapeutic concentrations has no effect on cytochrome P450 enzymes, interactions with drugs that inhibit or are metabolized by those enzymes would not be expected. Beta-Blockers Nifedipine extended-release tablet was well tolerated when administered in combination with beta-blockers in 187 hypertensive patients in a placebo-controlled clinical trial. However, there have been occasional literature reports suggesting that the combination nifedipine and beta-adrenergic blocking drugs may increase the likelihood of congestive heart failure, severe hypotension or exacerbation of angina in patients with cardiovascular disease. Clinical monitoring is recommended and a dose adjustment of nifedipine should be considered. Timolol: Hypotension is more likely to occur if dihydropryridine calcium antagonists such as nifedipine are co-administered with timolol. Central Alpha1-Blockers Doxazosin: Healthy volunteers participating in a multiple dose doxazosin-nifedipine interaction study received 2 mg doxazosin q.d. alone or combined with 20 mg nifedipine ER b.i.d. Co-administration of nifedipine resulted in a decrease in AUC and C max of doxazosin to 83% and 86% of the values in the absence of nifedipine, respectively. In the presence of doxazosin, AUC and C max of nifedipine were increased by factors of 1.13 and 1.23, respectively. Compared to nifedipine monotherapy, blood pressure was lower in the presence of doxazosin. Blood pressure should be monitored when doxazosin is co-administered with nifedipine, and dose reduction of nifedipine considered. Digitalis Digoxin: The simultaneous administration of nifedipine and digoxin may lead to reduced clearance resulting in an increase in plasma concentrations of digoxin. Since there have been isolated reports of patients with elevated digoxin levels, and there is a possible interaction between digoxin and nifedipine extended-release tablet, it is recommended that digoxin levels be monitored when initiating, adjusting and discontinuing nifedipine extended-release tablet to avoid possible over- or under-digitalization. Antithrombotics Coumarins: 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. Platelet Aggregation Inhibitors Clopidogrel: No clinically significant pharmacodynamic interactions were observed when clopidogrel was co-administered with nifedipine. Tirofiban: Co-administration of nifedipine did not alter the exposure to tirofiban importantly. Other Diuretics, PDE5 inhibitors, alpha-methyldopa: Nifedipine may increase the blood pressure lowering effect of these concomitantly administered agents. Non-Cardiovascular Drugs Antifungal Drugs Ketoconazole, itraconazole and fluconazole are CYP3A inhibitors and can inhibit the metabolism of nifedipine and increase the exposure to nifedipine during concomitant therapy. Blood pressure should be monitored and a dose reduction of nifedipine considered.

dministered agents. Non-Cardiovascular Drugs Antifungal Drugs Ketoconazole, itraconazole and fluconazole are CYP3A inhibitors and can inhibit the metabolism of nifedipine and increase the exposure to nifedipine during concomitant therapy. Blood pressure should be monitored and a dose reduction of nifedipine considered. Antisecretory Drugs Omeprazole: In healthy volunteers receiving a single dose of 10 mg nifedipine, AUC and C max of nifedipine after pre-treatment with omeprazole 20 mg q.d. for 8 days were 1.26 and 0.87 times those after pre-treatment with placebo. Pre-treatment with or co-administration of omeprazole did not impact the effect of nifedipine on blood pressure or heart rate. The impact of omeprazole on nifedipine is not likely to be of clinical relevance. Pantoprazole: In healthy volunteers the exposure to neither drug was changed significantly in the presence of the other drug. Ranitidine: Five studies in healthy volunteers investigated the impact of multiple ranitidine doses on the single or multiple dose pharmacokinetics of nifedipine. Two studies investigated the impact of co-administered ranitidine on blood pressure in hypertensive subjects on nifedipine. Co-administration of ranitidine did not have relevant effects on the exposure to nifedipine that affected the blood pressure or heart rate in normotensive or hypertensive subjects. Cimetidine: Five studies in healthy volunteers investigated the impact of multiple cimetidine doses on the single or multiple dose pharmacokinetics of nifedipine. Two studies investigated the impact of co-administered cimetidine on blood pressure in hypertensive subjects on nifedipine. In normotensive subjects receiving single doses of 10 mg or multiple doses of up to 20 mg nifedipine t.i.d. alone or together with cimetidine up to 1000 mg/day, the AUC values of nifedipine in the presence of cimetidine were between 1.52 and 2.01 times those in the absence of cimetidine. The C max values of nifedipine in the presence of cimetidine were increased by factors ranging between 1.60 and 2.02. The increase in exposure to nifedipine by cimetidine was accompanied by relevant changes in blood pressure or heart rate in normotensive subjects. Hypertensive subjects receiving 10 mg q.d. nifedipine alone or in combination with cimetidine 1000 mg q.d. also experienced relevant changes in blood pressure when cimetidine was added to nifedipine. The interaction between cimetidine and nifedipine is of clinical relevance and blood pressure should be monitored and a reduction of the dose of nifedipine considered. Cisapride: Simultaneous administration of cisapride and nifedipine may lead to increased plasma concentrations of nifedipine. Antibacterial Drugs Quinupristin/Dalfopristin: In vitro drug interaction studies have demonstrated that quinupristin/dalfopristin significantly inhibits the CYP3A metabolism of nifedipine. Concomitant administration of quinupristin/dalfopristin and nifedipine (repeated oral dose) in healthy volunteers increased AUC and C max for nifedipine by factors of 1.44 and 1.18, respectively, compared to nifedipine monotherapy. Upon co-administration of quinupristin/dalfopristin with nifedipine, blood pressure should be monitored and a reduction of the dose of nifedipine considered. Erythromycin: Erythromycin, a CYP3A inhibitor, can inhibit the metabolism of nifedipine and increase the exposure to nifedipine during concomitant therapy. Blood pressure should be monitored and reduction of the dose of nifedipine considered.

ure should be monitored and a reduction of the dose of nifedipine considered. Erythromycin: Erythromycin, a CYP3A inhibitor, can inhibit the metabolism of nifedipine and increase the exposure to nifedipine during concomitant therapy. Blood pressure should be monitored and reduction of the dose of nifedipine considered. Antitubercular Drugs Rifampin: Strong CYP3A inducers, such as rifampin, rifapentin, and rifabutin reduce the bioavailability of nifedipine which may reduce the efficacy of nifedipine; therefore nifedipine should not be used in combination with strong CYP3A inducers such as rifampin (See CONTRAINDICATIONS ). The impact of multiple oral doses of 600 mg rifampin on the pharmacokinetics of nifedipine after a single oral dose of 20 mg nifedipine capsule was evaluated in a clinical study. Twelve healthy male volunteers received a single oral dose of 20 mg nifedipine capsule on study Day 1. Starting on study Day 2, the subjects received 600 mg rifampin once daily for 14 days. On study Day 15, a second single oral dose of 20 mg nifedipine capsule was administered together with the last dose of rifampin. Compared to study Day 1, 14 days pretreatment with rifampin reduced C max and AUC of concomitantly administered nifedipine on average by 95% and 97%, respectively. Antiviral Drugs Amprenavir, atanazavir, delavirine, fosamprinavir, indinavir, nelfinavir and ritonavir, as CYP3A inhibitors, can inhibit the metabolism of nifedipine and increase the exposure to nifedipine. Caution is warranted and clinical monitoring of patients recommended. CNS Drugs Nefazodone, a CYP3A inhibitor, can inhibit the metabolism of nifedipine and increase the exposure to nifedipine during concomitant therapy. Blood pressure should be monitored and a reduction of the dose of nifedipine considered. Fluoxetine, a CYP3A inhibitor, can inhibit the metabolism of nifedipine and increase the exposure to nifedipine during concomitant therapy. Blood pressure should be monitored and a reduction of the dose of nifedipine considered. Valproic acid may increase the exposure to nifedipine during concomitant therapy. Blood pressure should be monitored and a dose reduction of nifedipine considered. Phenytoin, Phenobarbital, and Carbamazepine: Nifedipine is metabolized by CYP3A. Co-administration of nifedipine 10 mg capsule and 60 mg nifedipine coat-core tablet with phenytoin, an inducer of CYP3A, lowered the AUC and C max of nifedipine by approximately 70%. Phenobarbital and carbamazepine are also inducers of CYP3A. Alternative antihypertensive therapy should be considered in patients taking phenytoin, phenobarbital, and carbamazepine. Antiemetic Drugs Dolasetron: In patients taking dolasetron by the oral or intravenous route and nifedipine, no effect was shown on the clearance of hydrodolasetron. Immunosuppressive Drugs Tacrolimus: Tacrolimus has been shown to be metabolized via the CYP3A system. Nifedipine has been shown to inhibit the metabolism of tacrolimus in vitro . Transplant patients on tacrolimus and nifedipine required from 26% to 38% smaller doses than patients not receiving nifedipine. Nifedipine can increase the exposure to tacrolimus. When nifedipine is co-administered with tacrolimus the blood concentrations of tacrolimus should be monitored and a reduction of the dose of tacrolimus considered. Sirolimus: A single 60 mg dose of nifedipine and a single 10 mg dose of sirolimus oral solution were administered to 24 healthy volunteers. Clinically significant pharmacokinetic drug interactions were not observed. Glucose Lowering Drugs Pioglitazone: Co-administration of pioglitazone for 7 days with 30 mg nifedipine ER administered orally q.d.

ose of nifedipine and a single 10 mg dose of sirolimus oral solution were administered to 24 healthy volunteers. Clinically significant pharmacokinetic drug interactions were not observed. Glucose Lowering Drugs Pioglitazone: Co-administration of pioglitazone for 7 days with 30 mg nifedipine ER administered orally q.d. for 4 days to male and female volunteers resulted in least square mean (90% CI) values for unchanged nifedipine of 0.83 (0.73-0.95) for C max and 0.88 (0.80-0.96) for AUC relative to nifedipine monotherapy. In view of the high variability of nifedipine pharmacokinetics, the clinical significance of this finding is unknown. Rosiglitazone: Co-administration of rosiglitazone (4 mg b.i.d.) was shown to have no clinically relevant effect on the pharmacokinetics of nifedipine. Metformin: A single dose metformin-nifedipine interaction study in normal healthy volunteers demonstrated that co-administration of nifedipine increased plasma metformin C max and AUC by 20% and 9%, respectively, and increased the amount of metformin excreted in urine. T max and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Miglitol: No effect of miglitol was observed on the pharmacokinetics and pharmacodynamics of nifedipine. Repaglinide: Co-administration of 10 mg nifedipine with a single dose of 2 mg repaglinide (after 4 days nifedipine 10 mg t.i.d. and repaglinide 2 mg t.i.d.) resulted in unchanged AUC and C max values for both drugs. Acarbose: Nifedipine tends to produce hyperglycemia and may lead to loss of glucose control. If nifedipine is co-administered with acarbose, blood glucose levels should be monitored carefully and a dose adjustment of nifedipine considered. Drugs Interfering with Food Absorption Orlistat: In 17 normal-weight subjects receiving orlistat 120 mg t.i.d. for 6 days, orlistat did not alter the bioavailability of 60 mg nifedipine (extended-release tablets). Dietary Supplements Grapefruit Juice: In healthy volunteers, a single dose co-administration of 250 mL double strength grapefruit juice with 10 mg nifedipine increased AUC and C max by factors of 1.35 and 1.13, respectively. Ingestion of repeated doses of grapefruit juice (5 × 200 mL in 12 hours) after administration of 20 mg nifedipine ER increased AUC and C max of nifedipine by a factor of 2. Grapefruit juice should be avoided by patients on nifedipine. The intake of grapefruit juice should be stopped at least 3 days prior to initiating patients on nifedipine. Herbals St. John’s Wort: St. John’s Wort is an inducer of CYP3A and may decrease exposure to nifedipine. Alternative antihypertensive therapy should be considered in patients in whom St. John’s Wort therapy is necessary. CYP2D6 Probe Drug Debrisoquine: In healthy volunteers, pre-treatment with nifedipine 20 mg t.i.d. for 5 days did not change the metabolic ratio of hydroxydebrisoquine to debrisoquine measured in urine after a single dose of 10 mg debrisoquine. Thus, it is improbable that nifedipine inhibits in vivo the metabolism of other drugs that are substrates of CYP2D6.

General Hypotension Because nifedipine decreases peripheral vascular resistance, careful monitoring of blood pressure during the initial administration and titration of nifedipine extended-release tablets is suggested. Close observation is especially recommended for patients already taking medications that are known to lower blood pressure (See WARNINGS ).

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 increase (<5%) in mean alkaline phosphatase was noted in patients treated with nifedipine extended-release tablets. This was an isolated finding and it rarely resulted in values which fell outside the normal range. Rare instances of allergic hepatitis have been reported with nifedipine treatment. In controlled studies, nifedipine extended-release tablets did not adversely affect serum uric acid, glucose, cholesterol or potassium. 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 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 or 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.

Drug Interactions Nifedipine is mainly eliminated by metabolism and is a substrate of CYP3A. Inhibitors and inducers of CYP3A can impact the exposure to nifedipine and consequently its desirable and undesirable effects. In vitro and in vivo data indicate that nifedipine can inhibit the metabolism of drugs that are substrates of CYP3A, thereby increasing the exposure to other drugs. Nifedipine is a vasodilator, and co-administration of other drugs affecting blood pressure may result in pharmacodynamic interactions. CYP3A Inhibitors CYP3A inhibitors such as ketoconazole, fluconazole, itraconazole, clarithromycin, erythromycin (Azithromycin, although structurally related to the class of macrolide antibiotic is void of clinically relevant CYP3A4 inhibition), grapefruit, nefazodone, fluoxetine, saquinavir, indinavir, nelfinavir, and ritonavir 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. Strong CYP3A Inducers Strong CYP3A inducers, such as rifampin, rifabutin, phenobarbital, phenytoin, carbamazepine, and St. John’s Wort reduce the bioavailability and efficacy of nifedipine; therefore nifedipine should not be used in combination with strong CYP3A inducers such as rifampin (See CONTRAINDICATIONS ). Cardiovascular Drugs Antiarrhythmics Quinidine: Quinidine is a substrate of CYP3A and has been shown to inhibit CYP3A in vitro . Co-administration of multiple doses of quinidine sulfate, 200 mg t.i.d., and nifedipine, 20 mg t.i.d., increased C max and AUC of nifedipine in healthy volunteers by factors of 2.30 and 1.37, respectively. The heart rate in the initial interval after drug administration was increased by up to 17.9 beats/minute. The exposure to quinidine was not importantly changed in the presence of nifedipine. Monitoring of heart rate and adjustment of the nifedipine dose, if necessary, are recommended when quinidine is added to a treatment with nifedipine. Flecainide: There has been too little experience with the co-administration of Tambocor with nifedipine to recommend concomitant use. Calcium Channel Blockers Diltiazem: Pre-treatment of healthy volunteers with 30 mg or 90 mg t.i.d. diltiazem p.o. increased the AUC of nifedipine after a single dose of 20 mg nifedipine by factors of 2.2 and 3.1, respectively. The corresponding C max values of nifedipine increased by factors of 2.0 and 1.7, respectively. Caution should be exercised when co-administering diltiazem and nifedipine and a reduction of the dose of nifedipine should be considered. Verapamil: Verapamil, a CYP3A inhibitor, can inhibit the metabolism of nifedipine and increase the exposure to nifedipine during concomitant therapy. Blood pressure should be monitored and reduction of the dose of nifedipine considered. ACE Inhibitors Benazepril: In healthy volunteers receiving single dose of 20 mg nifedipine ER and benazepril 10 mg, the plasma concentrations of benazeprilat and nifedipine in the presence and absence of each other were not statistically significantly different. A hypotensive effect was only seen after co-administration of the two drugs. The tachycardic effect of nifedipine was attenuated in the presence of benazepril. Angiotensin-II Blockers Irbesartan: In vitro studies show significant inhibition of the formation of oxidized irbesartan metabolites by nifedipine.

y different. A hypotensive effect was only seen after co-administration of the two drugs. The tachycardic effect of nifedipine was attenuated in the presence of benazepril. Angiotensin-II Blockers Irbesartan: In vitro studies show significant inhibition of the formation of oxidized irbesartan metabolites by nifedipine. However, in clinical studies, concomitant nifedipine had no effect on irbesartan pharmacokinetics. Candesartan: No significant drug interaction has been reported in studies with candesartan cilexitil given together with nifedipine. Because candesartan is not significantly metabolized by the cytochrome P450 system and at therapeutic concentrations has no effect on cytochrome P450 enzymes, interactions with drugs that inhibit or are metabolized by those enzymes would not be expected. Beta-Blockers Nifedipine extended-release tablet was well tolerated when administered in combination with beta-blockers in 187 hypertensive patients in a placebo-controlled clinical trial. However, there have been occasional literature reports suggesting that the combination nifedipine and beta-adrenergic blocking drugs may increase the likelihood of congestive heart failure, severe hypotension or exacerbation of angina in patients with cardiovascular disease. Clinical monitoring is recommended and a dose adjustment of nifedipine should be considered. Timolol: Hypotension is more likely to occur if dihydropryridine calcium antagonists such as nifedipine are co-administered with timolol. Central Alpha1-Blockers Doxazosin: Healthy volunteers participating in a multiple dose doxazosin-nifedipine interaction study received 2 mg doxazosin q.d. alone or combined with 20 mg nifedipine ER b.i.d. Co-administration of nifedipine resulted in a decrease in AUC and C max of doxazosin to 83% and 86% of the values in the absence of nifedipine, respectively. In the presence of doxazosin, AUC and C max of nifedipine were increased by factors of 1.13 and 1.23, respectively. Compared to nifedipine monotherapy, blood pressure was lower in the presence of doxazosin. Blood pressure should be monitored when doxazosin is co-administered with nifedipine, and dose reduction of nifedipine considered. Digitalis Digoxin: The simultaneous administration of nifedipine and digoxin may lead to reduced clearance resulting in an increase in plasma concentrations of digoxin. Since there have been isolated reports of patients with elevated digoxin levels, and there is a possible interaction between digoxin and nifedipine extended-release tablet, it is recommended that digoxin levels be monitored when initiating, adjusting and discontinuing nifedipine extended-release tablet to avoid possible over- or under-digitalization. Antithrombotics Coumarins: 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. Platelet Aggregation Inhibitors Clopidogrel: No clinically significant pharmacodynamic interactions were observed when clopidogrel was co-administered with nifedipine. Tirofiban: Co-administration of nifedipine did not alter the exposure to tirofiban importantly. Other Diuretics, PDE5 inhibitors, alpha-methyldopa: Nifedipine may increase the blood pressure lowering effect of these concomitantly administered agents.

Pregnancy Pregnancy Category C. In rodents, rabbits, and monkeys, nifedipine has been shown to have a variety of embryotoxic, placentotoxic, teratogenic and fetotoxic effects, including stunted fetuses (rats, mice and rabbits), digital anomalies (rats and rabbits), rib deformities (mice), cleft palate (mice), small placentas and underdeveloped chorionic villi (monkeys), embryonic and fetal deaths (rats, mice and rabbits), prolonged pregnancy (rats; not evaluated in other species), and decreased neonatal survival (rats; not evaluated in other species). On a mg/kg or mg/m 2 basis, some of the doses associated with these various effects are higher than the maximum recommended human dose and some are lower, but all are within an order of magnitude of it. The digital anomalies seen in nifedipine-exposed rabbit pups are strikingly similar to those seen in pups exposed to phenytoin, and these are in turn similar to the phalangeal deformities that are the most common malformation seen in human children with in utero exposure to phenytoin. From the clinical evidence available, a specific prenatal risk has not been identified. However, an increase in perinatal asphyxia, caesarean delivery, prematurity and intrauterine growth retardation have been reported. Careful monitoring of blood pressure must be exercised in pregnant women, when administering nifedipine in combination with IV magnesium sulfate due to the possibility of an excessive fall in blood pressure which could harm the mother and fetus. There are no adequate and well-controlled studies in pregnant women.

rted. Careful monitoring of blood pressure must be exercised in pregnant women, when administering nifedipine in combination with IV magnesium sulfate due to the possibility of an excessive fall in blood pressure which could harm the mother and fetus. There are no adequate and well-controlled studies in pregnant women. Pregnancy Pregnancy Category C. In rodents, rabbits, and monkeys, nifedipine has been shown to have a variety of embryotoxic, placentotoxic, teratogenic and fetotoxic effects, including stunted fetuses (rats, mice and rabbits), digital anomalies (rats and rabbits), rib deformities (mice), cleft palate (mice), small placentas and underdeveloped chorionic villi (monkeys), embryonic and fetal deaths (rats, mice and rabbits), prolonged pregnancy (rats; not evaluated in other species), and decreased neonatal survival (rats; not evaluated in other species). On a mg/kg or mg/m 2 basis, some of the doses associated with these various effects are higher than the maximum recommended human dose and some are lower, but all are within an order of magnitude of it. The digital anomalies seen in nifedipine-exposed rabbit pups are strikingly similar to those seen in pups exposed to phenytoin, and these are in turn similar to the phalangeal deformities that are the most common malformation seen in human children with in utero exposure to phenytoin. From the clinical evidence available, a specific prenatal risk has not been identified. However, an increase in perinatal asphyxia, caesarean delivery, prematurity and intrauterine growth retardation have been reported. Careful monitoring of blood pressure must be exercised in pregnant women, when administering nifedipine in combination with IV magnesium sulfate due to the possibility of an excessive fall in blood pressure which could harm the mother and fetus. There are no adequate and well-controlled studies in pregnant women.

rted. Careful monitoring of blood pressure must be exercised in pregnant women, when administering nifedipine in combination with IV magnesium sulfate due to the possibility of an excessive fall in blood pressure which could harm the mother and fetus. There are no adequate and well-controlled studies in pregnant women. Pregnancy Category C. In rodents, rabbits, and monkeys, nifedipine has been shown to have a variety of embryotoxic, placentotoxic, teratogenic and fetotoxic effects, including stunted fetuses (rats, mice and rabbits), digital anomalies (rats and rabbits), rib deformities (mice), cleft palate (mice), small placentas and underdeveloped chorionic villi (monkeys), embryonic and fetal deaths (rats, mice and rabbits), prolonged pregnancy (rats; not evaluated in other species), and decreased neonatal survival (rats; not evaluated in other species). On a mg/kg or mg/m 2 basis, some of the doses associated with these various effects are higher than the maximum recommended human dose and some are lower, but all are within an order of magnitude of it. The digital anomalies seen in nifedipine-exposed rabbit pups are strikingly similar to those seen in pups exposed to phenytoin, and these are in turn similar to the phalangeal deformities that are the most common malformation seen in human children with in utero exposure to phenytoin. From the clinical evidence available, a specific prenatal risk has not been identified. However, an increase in perinatal asphyxia, caesarean delivery, prematurity and intrauterine growth retardation have been reported. Careful monitoring of blood pressure must be exercised in pregnant women, when administering nifedipine in combination with IV magnesium sulfate due to the possibility of an excessive fall in blood pressure which could harm the mother and fetus. There are no adequate and well-controlled studies in pregnant women.

Geriatric Use Although small pharmacokinetic studies have identified an increased half-life and increased C max and AUC (See CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism ), clinical studies of nifedipine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

ADVERSE EXPERIENCES The incidence of adverse events during treatment with nifedipine extended-release tablets in doses up to 90 mg daily were derived from multi-center placebo-controlled clinical trials in 370 hypertensive patients. Atenolol 50 mg once daily was used concomitantly in 187 of the 370 patients on nifedipine extended-release tablets and in 64 of the 126 patients on placebo. All adverse events reported during nifedipine extended-release tablets therapy were tabulated independently of their causal relationship to medication. The most common adverse event reported with nifedipine extended-release tablets was peripheral edema. This was dose related, and the frequency was 18% on nifedipine extended-release tablets 30 mg daily, 22% on nifedipine extended-release tablets 60 mg daily, and 29% on nifedipine extended-release tablets 90 mg daily versus 10% on placebo. Other common adverse events reported in the above placebo-controlled trials include: Adverse Event NIFEDIPINE EXTENDED-RELEASE TABLETS (%) (n=370) PLACEBO (%) (n=126) Headache 19 13 Flushing/heat sensation 4 0 Dizziness 4 2 Fatigue/asthenia 4 4 Nausea 2 1 Constipation 1 0 Where the frequency of adverse events with nifedipine extended-release tablets and placebo is similar, causal relationship cannot be established.

NIFEDIPINE EXTENDED-RELEASE TABLETS (%) (n=370) PLACEBO (%) (n=126) Headache 19 13 Flushing/heat sensation 4 0 Dizziness 4 2 Fatigue/asthenia 4 4 Nausea 2 1 Constipation 1 0 Where the frequency of adverse events with nifedipine extended-release tablets and placebo is similar, causal relationship cannot be established. The following adverse events were reported with an incidence of 3% or less in daily doses up to 90 mg: Body as a Whole/Systemic: chest pain, leg pain Central Nervous System: paresthesia, vertigo Dermatologic: rash Gastrointestinal: constipation Musculoskeletal: leg cramps Respiratory: epistaxis, rhinitis Urogenital: impotence, urinary frequency Other adverse events reported with an incidence of less than 1.0% were: Body as a Whole/Systemic: allergic reaction, asthenia, cellulitis, substernal chest pain, chills, facial edema, lab test abnormal, malaise, neck pain, pelvic pain, pain, photosensitivity reaction Cardiovascular: atrial fibrillation, bradycardia, cardiac arrest, extrasystole, hypotension, migraine, palpitations, phlebitis, postural hypotension, tachycardia, cutaneous angiectases Central Nervous System: anxiety, confusion, decreased libido, depression, hypertonia, hypesthesia, insomnia, somnolence Dermatologic: angioedema, petechial rash, pruritus, sweating Gastrointestinal: abdominal pain, diarrhea, dry mouth, dysphagia, dyspepsia, eructation, esophagitis, flatulence, gastrointestinal disorder, gastrointestinal hemorrhage, GGT increased, gum disorder, gum hemorrhage, vomiting Hematologic: eosinophilia, lymphadenopathy Metabolic: gout, weight loss Musculoskeletal: arthralgia, arthritis, joint disorder, myalgia, myasthenia Respiratory: dyspnea, increased cough, rales, pharyngitis, stridor Special Senses: abnormal vision, amblyopia, conjunctivitis, diplopia, eye disorder, eye hemorrhage, tinnitus Urogenital/Reproductive: dysuria, kidney calculus, nocturia, breast engorgement, polyuria, urogenital disorder, erectile dysfunction (ED) The following adverse events have been reported rarely in patients given nifedipine in coat core or other formulations: allergenic hepatitis, alopecia, anaphylactic reaction, anemia, arthritis with ANA (+), depression, erythromelalgia, exfoliative dermatitis, fever, gingival hyperplasia, gynecomastia, hyperglycemia, jaundice, leukopenia, mood changes, muscle cramps, nervousness, paranoid syndrome, purpura, shakiness, sleep disturbances, Stevens-Johnson syndrome, syncope, taste perversion, thrombocytopenia, toxic epidermal necrolysis, transient blindness at the peak of plasma level, tremor and urticaria. To report SUSPECTED ADVERSE REACTIONS, contact Oceanside Pharmaceuticals at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

<table width="100%"><col width="30%"/><col width="39%"/><col width="29%"/><thead><tr><th align="left" styleCode="Botrule Toprule " valign="top"><content styleCode="bold">Adverse Event</content></th><th align="left" styleCode="Botrule Toprule " valign="top"><content styleCode="bold">NIFEDIPINE</content> <content styleCode="bold">EXTENDED-RELEASE</content> <content styleCode="bold">TABLETS (%)</content> <content styleCode="bold">(n=370)</content></th><th align="left" styleCode="Botrule Toprule " valign="top"><content styleCode="bold">PLACEBO</content> <content styleCode="bold">(%)</content> <content styleCode="bold">(n=126)</content></th></tr></thead><tbody><tr><td styleCode="Toprule " valign="top"><paragraph>Headache</paragraph></td><td styleCode="Toprule " valign="top"><paragraph>19</paragraph></td><td styleCode="Toprule " valign="top"><paragraph>13</paragraph></td></tr><tr><td valign="top"><paragraph>Flushing/heat sensation</paragraph></td><td valign="top"><paragraph>4</paragraph></td><td valign="top"><paragraph>0</paragraph></td></tr><tr><td valign="top"><paragraph>Dizziness</paragraph></td><td valign="top"><paragraph>4</paragraph></td><td valign="top"><paragraph>2</paragraph></td></tr><tr><td valign="top"><paragraph>Fatigue/asthenia</paragraph></td><td valign="top"><paragraph>4</paragraph></td><td valign="top"><paragraph>4</paragraph></td></tr><tr><td valign="top"><paragraph>Nausea</paragraph></td><td valign="top"><paragraph>2</paragraph></td><td valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph>Constipation</paragraph></td><td styleCode="Botrule " valign="top"><paragraph>1</paragraph></td><td styleCode="Botrule " valign="top"><paragraph>0</paragraph></td></tr></tbody></table>

OVERDOSAGE Experience with nifedipine overdosage is limited. Symptoms associated with severe nifedipine overdosage include loss of consciousness, drop in blood pressure, heart rhythm disturbances, metabolic acidosis, hypoxia, cardiogenic shock with pulmonary edema. Generally, overdosage with nifedipine leading to pronounced hypotension calls for active cardiovascular support including monitoring of cardiovascular and respiratory function, elevation of extremities, judicious use of calcium infusion, pressor agents and fluids. After oral ingestion, thorough gastric lavage is indicated, if necessary in combination with irrigation of the small intestine. In cases involving overdosage of a slow-release product like nifedipine, elimination must be as complete as possible, including from the small intestine, to prevent the subsequent absorption of the active substance. Additional liquid or volume must be administered with caution because of the risk of fluid overload. Clearance of nifedipine would be expected to be prolonged in patients with impaired liver function. Since nifedipine is highly protein bound, dialysis is not likely to be of any benefit; however, plasmapheresis may be beneficial. There has been one reported case of massive overdosage with tablets of another extended-release formulation of nifedipine. The main effects of ingestion of approximately 4800 mg of nifedipine in a young man attempting suicide as a result of cocaine-induced depression was initial dizziness, palpitations, flushing, and nervousness. Within several hours of ingestion, nausea, vomiting, and generalized edema developed. No significant hypotension was apparent at presentation, 18 hours post ingestion. Blood chemistry abnormalities consisted of a mild, transient elevation of serum creatinine and modest elevations of LDH and CPK, but normal SGOT. Vital signs remained stable, no electrocardiographic abnormalities were noted, and renal function returned to normal within 24 to 48 hours with routine supportive measures alone. No prolonged sequelae were observed. The effect of a single 900 mg ingestion of nifedipine capsules in a depressed anginal patient on tricyclic antidepressants was loss of consciousness within 30 minutes of ingestion, and profound hypotension, which responded to calcium infusion, pressor agents, and fluid replacement. A variety of ECG abnormalities were seen in this patient with a history of bundle branch block, including sinus bradycardia and varying degrees of AV block. These dictated the prophylactic placement of a temporary ventricular pacemaker, but otherwise resolved spontaneously. Significant hyperglycemia was seen initially in this patient, but plasma glucose levels rapidly normalized without further treatment. A young hypertensive patient with advanced renal failure ingested 280 mg of nifedipine capsules at one time, with resulting marked hypotension responding to calcium infusion and fluids. No AV conduction abnormalities, arrhythmias, or pronounced changes in heart rate were noted, nor was there any further deterioration in renal function. Bradycardiac heart rhythm disturbances may be treated symptomatically with β-sympathomimetics, and in life-threatening bradycardiac disturbances of heart rhythm temporary pacemaker therapy can be advisable.

DOSAGE AND ADMINISTRATION Dosage should be adjusted according to each patient’s needs. It is recommended that nifedipine extended-release tablet be administered orally once daily on an empty stomach. Nifedipine extended-release tablet is an extended-release dosage form and tablets should be swallowed whole, not bitten or divided. In general, titration should proceed over a 7-14 day period starting with 30 mg once daily. Upward titration should be based on therapeutic efficacy and safety. The usual maintenance dose is 30 mg to 60 mg once daily. Titration to doses above 90 mg daily is not recommended. If discontinuation of nifedipine extended-release tablets is necessary, sound clinical practice suggests that the dosage should be decreased gradually with close physician supervision. Co-administration of nifedipine with grapefruit juice is to be avoided (See CLINICAL PHARMACOLOGY and PRECAUTIONS ). Care should be taken when dispensing nifedipine extended-release tablets to assure that the extended-release dosage form has been prescribed.

HOW SUPPLIED Nifedipine Extended-Release Tablets, USP 60 mg Mustard yellow unscored, round, film-coated tablets, engraved with "B" on one side and "60" on the other side. NDC: 72162-2260-1: 100 Tablets in a BOTTLE The tablets should be protected from light and moisture and stored at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Dispense in tight, light-resistant containers. Repackaged/Relabeled by: Bryant Ranch Prepack Burbank, CA 91504

For Oral Use Patients with Galactose Intolerance Since this medicinal product contains lactose, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

DESCRIPTION Nifedipine extended-release tablets are an extended-release tablet dosage form of the calcium channel blocker nifedipine. The product is provided as a general matrix tablet with a polymer coating. Nifedipine is 3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)- dimethyl ester, C 17 H 18 N 2 O 6, 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. Nifedipine extended-release tablets contain 90 mg of nifedipine for once-a-day oral administration. In addition, each tablet contains the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, ethylcellulose, hydroxyethyl cellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, sodium lauryl sulfate, titanium dioxide, and triacetin. Contains FD&C Yellow No. 5 (tartrazine) as a color additive.

inical Studies Nifedipine extended-release tablets produced dose-related decreases in systolic and diastolic blood pressure as demonstrated in two double-blind, randomized, placebo-controlled trials in which over 350 patients were treated with nifedipine extended-release tablets, 30, 60 or 90 mg once daily for 6 weeks. In the first study, nifedipine extended-release tablet was given as monotherapy and in the second study, nifedipine extended-release tablet was added to a beta-blocker in patients not controlled on a beta-blocker alone. The mean trough (24 hours post-dose) blood pressure results from these studies are shown below: MEAN REDUCTIONS IN TROUGH SUPINE BLOOD PRESSURE (mmHg) SYSTOLIC/DIASTOLIC NIFEDIPINE EXTENDED- RELEASE, USP DOSE N MEAN TROUGH REDUCTION Placebo response subtracted. STUDY 1 30 mg 60 5.3/2.9 60 mg 57 8.0/4.1 90 mg 55 12.5/8.1 STUDY 2 30 mg 58 7.6/3.8 60 mg 63 10.1/5.3 90 mg 62 10.2/5.8 The trough/peak ratios estimated from 24 hour blood pressure monitoring ranged from 41%-78% for diastolic and 46%-91% for systolic blood pressure. 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 mmHg 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 of the immediate-release nifedipine formulation 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 administered as the immediate-release capsule has had no tendency to prolong atrioventricular conduction or sinus node recovery time, or to slow sinus rate.

Clinical Studies Nifedipine extended-release tablets produced dose-related decreases in systolic and diastolic blood pressure as demonstrated in two double-blind, randomized, placebo-controlled trials in which over 350 patients were treated with nifedipine extended-release tablets, 30, 60 or 90 mg once daily for 6 weeks. In the first study, nifedipine extended-release tablet was given as monotherapy and in the second study, nifedipine extended-release tablet was added to a beta-blocker in patients not controlled on a beta-blocker alone. The mean trough (24 hours post-dose) blood pressure results from these studies are shown below: MEAN REDUCTIONS IN TROUGH SUPINE BLOOD PRESSURE (mmHg) SYSTOLIC/DIASTOLIC NIFEDIPINE EXTENDED- RELEASE, USP DOSE N MEAN TROUGH REDUCTION Placebo response subtracted. STUDY 1 30 mg 60 5.3/2.9 60 mg 57 8.0/4.1 90 mg 55 12.5/8.1 STUDY 2 30 mg 58 7.6/3.8 60 mg 63 10.1/5.3 90 mg 62 10.2/5.8 The trough/peak ratios estimated from 24 hour blood pressure monitoring ranged from 41%-78% for diastolic and 46%-91% for systolic blood pressure.

<table ID="_RefID0EWFAC" width="100%"><caption>MEAN REDUCTIONS IN TROUGH SUPINE BLOOD PRESSURE (mmHg) SYSTOLIC/DIASTOLIC</caption><col width="39%"/><col width="29%"/><col width="30%"/><tbody><tr><td styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">NIFEDIPINE EXTENDED- RELEASE, USP DOSE</content></paragraph></td><td align="center" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">N</content></paragraph></td><td align="center" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">MEAN TROUGH</content> <content styleCode="bold">REDUCTION</content><footnote ID="_Ref221098948">Placebo response subtracted. </footnote></paragraph></td></tr><tr><td colspan="3" valign="top"><paragraph><content styleCode="bold">STUDY 1</content></paragraph></td></tr><tr><td align="center" valign="top"><paragraph>30 mg</paragraph></td><td align="center" valign="top"><paragraph>60</paragraph></td><td align="center" valign="top"><paragraph>5.3/2.9</paragraph></td></tr><tr><td align="center" valign="top"><paragraph>60 mg</paragraph></td><td align="center" valign="top"><paragraph>57</paragraph></td><td align="center" valign="top"><paragraph>8.0/4.1</paragraph></td></tr><tr><td align="center" styleCode="Botrule " valign="top"><paragraph>90 mg</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>55</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>12.5/8.1</paragraph></td></tr><tr><td colspan="3" valign="top"><paragraph><content styleCode="bold">STUDY 2</content></paragraph></td></tr><tr><td align="center" valign="top"><paragraph>30 mg</paragraph></td><td align="center" valign="top"><paragraph>58</paragraph></td><td align="center" valign="top"><paragraph>7.6/3.8</paragraph></td></tr><tr><td align="center" valign="top"><paragraph>60 mg</paragraph></td><td align="center" valign="top"><paragraph>63</paragraph></td><td align="center" valign="top"><paragraph>10.1/5.3</paragraph></td></tr><tr><td align="center" styleCode="Botrule " valign="top"><paragraph>90 mg</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>62</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>10.2/5.8</paragraph></td></tr></tbody></table>

General Hypotension Because nifedipine decreases peripheral vascular resistance, careful monitoring of blood pressure during the initial administration and titration of nifedipine extended-release tablets is suggested. Close observation is especially recommended for patients already taking medications that are known to lower blood pressure (See WARNINGS ).

HOW SUPPLIED Nifedipine Extended-Release Tablets, USP NDC: 72162-2261-1: 100 Tablets in a BOTTLE 90 mg Yellow unscored, round, film-coated tablets, engraved with "B" on one side and "90" on the other side. The tablets should be protected from light and moisture and stored at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Dispense in tight, light-resistant containers. Repackaged/Relabeled by: Bryant Ranch Prepack Burbank, CA 91504

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, C 17 H 18 N 2 O 6 , 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. PROCARDIA XL is a registered trademark for Nifedipine GITS. Nifedipine GITS (Gastrointestinal Therapeutic System) Tablet is formulated as a once-a-day controlled-release tablet for oral administration to provide 30, 60, or 90 mg of nifedipine. Each tablet contains 33 mg nifedipine to provide a 30 mg dose. Each tablet contains 66 mg nifedipine to provide a 60 mg dose. Each tablet contains 99 mg nifedipine to provide a 90 mg dose. Inert ingredients in the formulations are: cellulose acetate; hydroxypropyl cellulose; hypromellose; 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 gastrointestinal 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 gastrointestinal transit and are eliminated in the feces as an insoluble shell. Chemical Structure

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 PROCARDIA XL 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.

centrations rise at a gradual, controlled rate after a PROCARDIA XL 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 PROCARDIA ® capsule at t.i.d. dosing than with once daily PROCARDIA XL Extended Release Tablet. At steady-state, the bioavailability of the PROCARDIA XL Extended Release Tablet is 86% relative to PROCARDIA capsules. Administration of the PROCARDIA XL 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 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 PROCARDIA XL 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 PROCARDIA XL 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.

INDICATIONS AND USAGE I. Vasospastic Angina PROCARDIA XL 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. PROCARDIA XL 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) PROCARDIA XL 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 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 PROCARDIA XL is 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 PROCARDIA XL. 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.

acologic 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. PROCARDIA XL may be used alone or in combination with other antihypertensive agents.

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 PROCARDIA XL. 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.

rictures in association with the ingestion of PROCARDIA XL. 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 PROCARDIA XL (GITS tablet formulation) 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.

PRECAUTIONS General—Hypotension Because nifedipine decreases peripheral vascular resistance, careful monitoring of blood pressure during the initial administration and titration of nifedipine is suggested. Close observation is especially recommended for patients already taking medications that are known to lower blood pressure (see WARNINGS ). Peripheral Edema 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 PROCARDIA XL Extended Release Tablets should be swallowed whole. Do not chew, divide or crush tablets. Do not be concerned if you occasionally notice in your stool something that looks like a tablet. In PROCARDIA XL, 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. 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 PROCARDIA XL. 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, PROCARDIA XL did not adversely affect serum uric acid, glucose, or cholesterol. Serum potassium was unchanged in patients receiving PROCARDIA XL 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.

tients 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 USAGE and WARNINGS ) Experience in over 1400 patients with PROCARDIA 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.

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 vivo mutagenicity 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 2 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/m 2 basis. There are no adequate and well-controlled studies in pregnant women. PROCARDIA XL Extended Release Tablets should be used during pregnancy only if the potential benefit justifies the potential risk. Lactation Nifedipine is transferred through breast milk. PROCARDIA XL 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 ).

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 ).

Information for Patients PROCARDIA XL Extended Release Tablets should be swallowed whole. Do not chew, divide or crush tablets. Do not be concerned if you occasionally notice in your stool something that looks like a tablet. In PROCARDIA XL, 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.

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 PROCARDIA XL. 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, PROCARDIA XL did not adversely affect serum uric acid, glucose, or cholesterol. Serum potassium was unchanged in patients receiving PROCARDIA XL 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 USAGE and WARNINGS ) Experience in over 1400 patients with PROCARDIA 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 vivo mutagenicity 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 2 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/m 2 basis. There are no adequate and well-controlled studies in pregnant women. PROCARDIA XL Extended Release Tablets should be used during pregnancy only if the potential benefit justifies the potential risk. Lactation Nifedipine is transferred through breast milk. PROCARDIA XL should be used during breast-feeding only if the potential benefit justifies the potential risk.

ADVERSE EXPERIENCES Over 1000 patients from both controlled and open trials with PROCARDIA XL Extended Release Tablets in hypertension and angina were included in the evaluation of adverse experiences. All side effects reported during PROCARDIA XL Extended Release Tablet therapy were tabulated independent of their causal relation to medication. The most common side effect reported with PROCARDIA XL 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 experiences reported in placebo-controlled trials include: Adverse Effect PROCARDIA XL (%) (N=707) Placebo (%) (N=266) Headache 15.8 9.8 Fatigue 5.9 4.1 Dizziness 4.1 4.5 Constipation 3.3 2.3 Nausea 3.3 1.9 Of these, only edema and headache were more common in PROCARDIA XL patients than placebo patients. 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. Body as a Whole/Systemic: asthenia, flushing, pain Cardiovascular: palpitations Central Nervous System: insomnia, nervousness, paresthesia, somnolence Dermatologic: pruritus, rash Gastrointestinal: abdominal pain, diarrhea, dry mouth, dyspepsia, flatulence Musculoskeletal: arthralgia, leg cramps Respiratory: chest pain (nonspecific), dyspnea Urogenital: impotence, polyuria Other adverse reactions were reported sporadically with an incidence of 1.0% or less. These include: Body as a Whole/Systemic: face edema, fever, hot flashes, malaise, periorbital edema, rigors Cardiovascular: arrhythmia, hypotension, increased angina, tachycardia, syncope Central Nervous System: anxiety, ataxia, decreased libido, depression, hypertonia, hypoesthesia, migraine, paroniria, tremor, vertigo Dermatologic: alopecia, increased sweating, urticaria, purpura Gastrointestinal: eructation, gastroesophageal reflux, gum hyperplasia, melena, vomiting, weight increase Musculoskeletal: back pain, gout, myalgias Respiratory: coughing, epistaxis, upper respiratory tract infection, respiratory disorder, sinusitis Special Senses: abnormal lacrimation, abnormal vision, taste perversion, tinnitus Urogenital/Reproductive: breast pain, dysuria, hematuria, nocturia 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. Gastrointestinal obstruction resulting in hospitalization and surgery, including the need for bezoar removal, has occurred in association with PROCARDIA XL, even in patients with no prior history of gastrointestinal disease (see WARNINGS ). Cases of tablet adherence to the gastrointestinal wall with ulceration have been reported, some requiring hospitalization and intervention. In multiple-dose U.S. and foreign controlled studies with nifedipine capsules 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.

dose U.S. and foreign controlled studies with nifedipine capsules 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. Adverse Effect PROCARDIA CAPSULES (%) (N=226) Placebo (%) (N=235) Dizziness, lightheadedness, giddiness 27 15 Flushing, heat sensation 25 8 Headache 23 20 Weakness 12 10 Nausea, heartburn 11 8 Muscle cramps, tremor 8 3 Peripheral edema 7 1 Nervousness, mood changes 7 4 Palpitations 7 5 Dyspnea, cough, wheezing 6 3 Nasal congestion, sore throat 6 8 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 PROCARDIA XL. 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 PROCARDIA with concomitant beta blocker therapy, the pattern and incidence of adverse experiences was not different from that of the entire group of PROCARDIA-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 one in eight patients. Hypotension occurred in about one in 20 patients. Syncope occurred in approximately one patient in 250. Myocardial infarction or symptoms of congestive heart failure each occurred in about one 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 erythema multiforme, Stevens-Johnson Syndrome, and toxic epidermal necrolysis) and photosensitivity reactions. Acute generalized exanthematous pustulosis also has been reported.

<table width="80%"><col width="25%"/><col width="29%"/><col width="24%"/><thead><tr><th align="left" styleCode="Botrule Toprule " valign="bottom"><content styleCode="bold">Adverse Effect</content></th><th align="left" styleCode="Botrule Toprule " valign="middle"><content styleCode="bold"> PROCARDIA XL (%)</content> <content styleCode="bold">(N=707)</content></th><th align="center" styleCode="Botrule Toprule " valign="middle"><content styleCode="bold">Placebo (%)</content> <content styleCode="bold">(N=266)</content></th></tr></thead><tbody><tr><td styleCode="Toprule " valign="middle"><paragraph>Headache</paragraph></td><td align="center" styleCode="Toprule " valign="middle"><paragraph>15.8</paragraph></td><td align="center" styleCode="Toprule " valign="middle"><paragraph>9.8</paragraph></td></tr><tr><td valign="middle"><paragraph>Fatigue</paragraph></td><td align="center" valign="middle"><paragraph> 5.9</paragraph></td><td align="center" valign="middle"><paragraph>4.1</paragraph></td></tr><tr><td valign="middle"><paragraph>Dizziness</paragraph></td><td align="center" valign="middle"><paragraph> 4.1</paragraph></td><td align="center" valign="middle"><paragraph>4.5</paragraph></td></tr><tr><td valign="middle"><paragraph>Constipation</paragraph></td><td align="center" valign="middle"><paragraph> 3.3</paragraph></td><td align="center" valign="middle"><paragraph>2.3</paragraph></td></tr><tr><td styleCode="Botrule " valign="middle"><paragraph>Nausea</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph> 3.3</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>1.9</paragraph></td></tr></tbody></table>

"middle"><paragraph>2.3</paragraph></td></tr><tr><td styleCode="Botrule " valign="middle"><paragraph>Nausea</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph> 3.3</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>1.9</paragraph></td></tr></tbody></table> <table width="80%"><col width="27%"/><col width="31%"/><col width="21%"/><thead><tr><th align="left" styleCode="Botrule Toprule " valign="bottom"><content styleCode="bold">Adverse Effect</content></th><th align="center" styleCode="Botrule Toprule " valign="middle"><content styleCode="bold">PROCARDIA CAPSULES (%)</content> <content styleCode="bold">(N=226)</content></th><th align="center" styleCode="Botrule Toprule " valign="bottom"><content styleCode="bold">Placebo (%)</content> <content styleCode="bold">(N=235)</content></th></tr></thead><tbody><tr><td styleCode="Toprule " valign="middle"><paragraph>Dizziness, lightheadedness, giddiness</paragraph></td><td align="center" styleCode="Toprule " valign="bottom"><paragraph>27</paragraph></td><td align="center" styleCode="Toprule " valign="bottom"><paragraph>15</paragraph></td></tr><tr><td valign="middle"><paragraph>Flushing, heat sensation</paragraph></td><td align="center" valign="middle"><paragraph>25</paragraph></td><td align="center" valign="middle"><paragraph>8</paragraph></td></tr><tr><td valign="middle"><paragraph>Headache</paragraph></td><td align="center" valign="middle"><paragraph>23</paragraph></td><td align="center" valign="middle"><paragraph>20</paragraph></td></tr><tr><td valign="middle"><paragraph>Weakness</paragraph></td><td align="center" valign="middle"><paragraph>12</paragraph></td><td align="center" valign="middle"><paragraph>10</paragraph></td></tr><tr><td valign="middle"><paragraph>Nausea, heartburn</paragraph></td><td align="center" valign="middle"><paragraph>11</paragraph></td><td align="center" valign="middle"><paragraph> 8</paragraph></td></tr><tr><td valign="middle"><paragraph>Muscle cramps, tremor</paragraph></td><td align="center" valign="middle"><paragraph> 8</paragraph></td><td align="center" valign="middle"><paragraph> 3</paragraph></td></tr><tr><td valign="middle"><paragraph>Peripheral edema</paragraph></td><td align="center" valign="middle"><paragraph> 7</paragraph></td><td align="center" valign="middle"><paragraph> 1</paragraph></td></tr><tr><td valign="middle"><paragraph>Nervousness, mood changes</paragraph></td><td align="center" valign="middle"><paragraph> 7</paragraph></td><td align="center" valign="middle"><paragraph> 4</paragraph></td></tr><tr><td valign="middle"><paragraph>Palpitations</paragraph></td><td align="center" valign="middle"><paragraph> 7</paragraph></td><td align="center" valign="middle"><paragraph> 5</paragraph></td></tr><tr><td valign="middle"><paragraph>Dyspnea, cough, wheezing</paragraph></td><td align="center" valign="middle"><paragraph> 6</paragraph></td><td align="center" valign="middle"><paragraph> 3</paragraph></td></tr><tr><td styleCode="Botrule " valign="middle"><paragraph>Nasal congestion, sore throat</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph> 6</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph> 8</paragraph></td></tr></tbody></table>

OVERDOSAGE Experience with nifedipine overdosage is limited. Generally, overdosage with nifedipine leading to pronounced hypotension calls for active cardiovascular support, including monitoring of cardiovascular and respiratory function, elevation of extremities, judicious use of calcium infusion, pressor agents, and fluids. Clearance of nifedipine would be expected to be prolonged in patients with impaired liver function. Since nifedipine is highly protein-bound, dialysis is not likely to be of any benefit. There has been one reported case of massive overdosage with PROCARDIA XL Extended Release Tablets. The main effects of ingestion of approximately 4800 mg of PROCARDIA XL in a young man attempting suicide as a result of cocaine-induced depression was initial dizziness, palpitations, flushing, and nervousness. Within several hours of ingestion, nausea, vomiting, and generalized edema developed. No significant hypotension was apparent at presentation, 18 hours post-ingestion. Electrolyte abnormalities consisted of a mild, transient elevation of serum creatinine, and modest elevations of LDH and CPK, but normal SGOT. Vital signs remained stable, no electrocardiographic abnormalities were noted, and renal function returned to normal within 24 to 48 hours with routine supportive measures alone. No prolonged sequelae were observed. The effect of a single 900 mg ingestion of PROCARDIA capsules in a depressed anginal patient also on tricyclic antidepressants was loss of consciousness within 30 minutes of ingestion, and profound hypotension, which responded to calcium infusion, pressor agents, and fluid replacement. A variety of ECG abnormalities were seen in this patient with a history of bundle branch block, including sinus bradycardia and varying degrees of AV block. These dictated the prophylactic placement of a temporary ventricular pacemaker, but otherwise resolved spontaneously. Significant hyperglycemia was seen initially in this patient, but plasma glucose levels rapidly normalized without further treatment. A young hypertensive patient with advanced renal failure ingested 280 mg of PROCARDIA capsules at one time, with resulting marked hypotension responding to calcium infusion and fluids. No AV conduction abnormalities, arrhythmias, or pronounced changes in heart rate were noted, nor was there any further deterioration in renal function.

DOSAGE AND ADMINISTRATION 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. PROCARDIA XL 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, titration may proceed more rapidly, if symptoms so warrant, provided the patient is assessed frequently. Titration to doses above 120 mg are not recommended. Angina patients controlled on PROCARDIA capsules alone or in combination with other antianginal medications may be safely switched to PROCARDIA XL Extended Release Tablets at the nearest equivalent total daily dose (e.g., 30 mg t.i.d. of PROCARDIA capsules may be changed to 90 mg once daily of PROCARDIA XL Extended Release Tablets). Subsequent titration to higher or lower doses may be necessary and should be initiated as clinically warranted. Experience with doses 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. Avoid co-administration of nifedipine with grapefruit juice (see CLINICAL PHARMACOLOGY and PRECAUTIONS: Other Interactions ). No "rebound effect" has been observed upon discontinuation of PROCARDIA XL 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 PROCARDIA XL 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 PRECAUTIONS, Drug Interactions , for information on co-administration of nifedipine with beta blockers or long-acting nitrates.

HOW SUPPLIED PROCARDIA XL Extended Release Tablets are supplied to provide 30 mg, 60 mg and 90 mg round, biconvex, rose-pink, film-coated tablets in: Bottles of 100: 30 mg (NDC 0069-2650-66) 60 mg (NDC 0069-2660-66) 90 mg (NDC 0069-2670-66) Bottles of 300: 30 mg (NDC 0069-2650-72) 60 mg (NDC 0069-2660-72) Store below 86°F (30°C). Protect from moisture and humidity.

<table width="70%"><col width="27%"/><col width="14%"/><col width="27%"/><tbody><tr><td styleCode="Toprule " valign="middle"><paragraph>Bottles of 100:</paragraph></td><td styleCode="Toprule " valign="middle"><paragraph>30 mg</paragraph></td><td styleCode="Toprule " valign="middle"><paragraph>(NDC 0069-2650-66)</paragraph></td></tr><tr><td valign="middle"/><td valign="middle"><paragraph>60 mg</paragraph></td><td valign="middle"><paragraph>(NDC 0069-2660-66)</paragraph></td></tr><tr><td valign="middle"/><td valign="middle"><paragraph>90 mg</paragraph></td><td valign="middle"><paragraph>(NDC 0069-2670-66)</paragraph></td></tr><tr><td valign="middle"><paragraph>Bottles of 300:</paragraph></td><td valign="middle"><paragraph>30 mg</paragraph></td><td valign="middle"><paragraph>(NDC 0069-2650-72)</paragraph></td></tr><tr><td styleCode="Botrule " valign="middle"/><td styleCode="Botrule " valign="middle"><paragraph>60 mg</paragraph></td><td styleCode="Botrule " valign="middle"><paragraph>(NDC 0069-2660-72)</paragraph></td></tr></tbody></table>