stable angina (classical effort-associated angina) nifedipine extended-release tablets are indicated for the management of chronic stable angina (effort-associated angina) without evidence of vasospasm in patients who remain symptomatic despite adequate doses of beta blockers and/or organic nitrates or who cannot tolerate those agents. in chronic stable angina (effort-associated angina), nifedipine has been effective in controlled trials of up to eight weeks duration in reducing angina frequency and increasing exercise tolerance, but confirmation of sustained effectiveness and evaluation of long-term safety in these patients is incomplete. controlled studies in small numbers of patients suggest concomitant use of nifedipine and beta-blocking agents may be beneficial in patients with chronic stable angina, but available information is not sufficient to predict with confidence the effects of concurrent treatment, especially in patients with compromised left ventricular function or cardiac conduction abnormalities. when introducing such concomitant therapy, care must be taken to monitor blood pressure closely, since severe hypotension can occur from the combined effects of the drugs. (see warnings ) iii. hypertension nifedipine extended-release tablets are indicated for the treatment of hypertension, to lower blood pressure. lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. these benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including nifedipine extended-release tablets. control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. many patients will require more than one drug to achieve blood pressure goals. for specific advice on goals and management, see published guidelines, such as those of the national high blood pressure education program’s joint national committee on prevention, detection, evaluation, and treatment of high blood pressure (jnc). numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. the largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmhg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). these considerations may guide selection of therapy. nifedipine extended-release tablets may be used alone or in combination with other antihypertensive agents.

, the physician should be aware of these potential problems and, if the patient’s condition permits, sufficient time (at least 36 hours) should be allowed for nifedipine to be washed out of the body prior to surgery. the following information should be taken into account in those patients who are being treated for hypertension as well as angina: increased angina and/or myocardial infarction rarely, patients, particularly those who have severe obstructive coronary artery disease, have developed well documented increased frequency, duration and/or severity of angina or acute myocardial infarction on starting nifedipine or at the time of dosage increase. the mechanism of this effect is not established. beta blocker withdrawal it is important to taper beta blockers if possible, rather than stopping them abruptly before beginning nifedipine. patients recently withdrawn from beta blockers may develop a withdrawal syndrome with increased angina, probably related to increased sensitivity to catecholamines. initiation of nifedipine treatment will not prevent this occurrence and on occasion has been reported to increase it. congestive heart failure rarely, patients, usually receiving a beta blocker, have developed heart failure after beginning nifedipine. patients with tight aortic stenosis may be at greater risk for such an event, as the unloading effect of nifedipine would be expected to be of less benefit, owing to the fixed impedance to flow across the aortic valve in these patients. gastrointestinal obstruction requiring surgery there have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of nifedipine extended-release tablets. bezoars can occur in very rare cases and may require surgical intervention. cases of serious gastrointestinal obstruction have been identified in patients with no known gastrointestinal disease, including the need for hospitalization and surgical intervention. risk factors for a gastrointestinal obstruction identified from post-marketing reports of nifedipine extended-release tablets (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., h2-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.

ly 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 coadministration 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. coadministration 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 coadministration of nifedipine with beta blockers or long-acting nitrates.

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. adverse effect nifedipine 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 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 with concomitant beta blocker therapy, the pattern and incidence of adverse experiences was not different from that of the entire group of nifedipine-treated patients. (see precautions ) in a subgroup of approximately 250 patients with a diagnosis of congestive heart failure as well as angina, dizziness or lightheadedness, peripheral edema, headache, or flushing each occurred in 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 twi pharmaceuticals, inc. at 1-844-518-2989 or fda at 1-800-fda-1088 or www.fda.gov/medwatch .

ced. 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. 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 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 decreases peripheral vascular resistance which leads to a fall in systolic and diastolic pressures, usually minimal in normotensive volunteers (less than 5 to 10 mm hg systolic), but sometimes larger. with nifedipine extended-release tablets, these decreases in blood pressure are not accompanied by any significant change in heart rate. hemodynamic studies in patients with normal ventricular function have generally found a small increase in cardiac index without major effects on ejection fraction, left ventricular end diastolic pressure (lvedp), or volume (lvedv). in patients with impaired ventricular function, most acute studies have shown some increase in ejection fraction and reduction in left ventricular filling pressure. electrophysiologic effects although, like other members of its class, nifedipine causes a slight depression of sinoatrial node function and atrioventricular conduction in isolated myocardial preparations, such effects have not been seen in studies in intact animals or in man. in formal electrophysiologic studies, predominantly in patients with normal conduction systems, nifedipine has had no tendency to prolong atrioventricular conduction or sinus node recovery time, or to slow sinus rate.

icals, inc. taoyuan city, 32063, taiwan la-3039-01 rev. 04/2021 marketed/packaged by: gsms, inc. camarillo, ca usa 93012