Nifediac (Tablet, Film Coated, Extended Release)

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Dosage should be adjusted according to each patient's needs. It is recommended that NifediacCC extended-release tablet be administered orally once daily on an empty stomach. NifediacCC 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 NifediacCC extended-release tablets are necessary, sound clinical practice suggests that the dosage should be decreased gradually with close physician supervision. Care should be taken when dispensing NifediacCC extended-release tablet to assure that the extended release dosage form has been prescribed. Co-administration of nifedipine with grapefruit juice is to be avoided .

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.<br/>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 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 peripheralvascular resistance which results in reduced arterial blood pressure.<br/>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 Cvalues 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. 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 hepatic biotransformation is the predominant route for the disposition of nifedipine, its pharmacokinetics may be altered in patients with chronic liver disease. Nifedipine extended-release tablet has 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 Cis 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, due to inhibition of CYP3A4 related first-pass metabolism.<br/>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 meantrough (24 hours post-dose) blood pressure results from these studies are shown below. 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.<br/>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.<br/>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.

Known hypersensitivity to nifedipine.

http://www4.wiwiss.fu-berlin.de/drugbank/resource/drugs/DB01115

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Nifedipine

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-releasetablets 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 tablet was peripheral edema. This was dose related and the frequency was 18% on nifedipine extended-release tablet 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: 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: cellulitis, chills, facial edema, neck pain, pelvic pain, pain Cardiovascular: atrial fibrillation, bradycardia, cardiac arrest, extrasystole, hypotension, palpitations, phlebitis, postural hypotension, tachycardia, cutaneous angiectases Central Nervous System: anxiety, confusion, decreased libido, depression, hypertonia, insomnia, somnolence Dermatologic: pruritus, sweating Gastrointestinal: abdominal pain, diarrhea, dry mouth, dyspepsia, esophagitis, flatulence, gastrointestinal hemorrhage, vomiting Hematologic: lymphadenopathy Metabolic: gout, weight loss Musculoskeletal: arthralgia, arthritis, myalgia Respiratory: dyspnea, increase cough, rales, pharyngitis Special Senses: abnormal vision, amblyopia, conjunctivitis, diplopia, tinnitus Urogenital/Reproductive: kidney calculus, nocturia, breast engorgement The following adverse events have been reported rarely in patients given nifedipine in other formulations: allergenic hepatitis, alopecia, anemia, arthritis with ANA (+), depression, erythromelalagia, exfoliative dermatitis, fever, gingival hyperplasia, gynecomastia, leukopenia, mood changes, muscle cramps, nervousness, paranoid syndrome, purpura, shakiness, sleep disturbances, syncope, taste perversion, thrombocytopenia, transient blindness at the peak plasma level, tremor and urticaria. 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.

http://www4.wiwiss.fu-berlin.de/dailymed/resource/organization/Teva_Pharmaceuticals_USA

Nifediac