The elimination half-life of nifedipine is approximately two hours. Nifedipine is extensively metabolized to highly water-soluble, inactive metabolites, accounting for 60 to 80% of the dose excreted in the urine. There was no evidence of dose dumping either in the presence or absence of food for over 150 subjects in pharmacokinetic studies. 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. 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. 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. At steady-state, the bioavailability of the PROCARDIA XL Extended Release Tablet is 86% relative to PROCARDIA capsules. dosing than with once daily PROCARDIA XL Extended Release Tablet. 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. For subsequent doses, relatively constant plasma concentrations at this plateau are maintained with minimal fluctuations over the 24-hour dosing interval. 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. Nifedipine is completely absorbed after oral administration. The reduction in calcium influx by nifedipine causes arterial vasodilation and decreased peripheral vascular resistance which results in reduced arterial blood pressure. Stores of intracellular calcium in vascular smooth muscle are limited and thus dependent upon the influx of extracellular calcium for contraction to occur. 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. Nifedipine is a peripheral arterial vasodilator which acts directly on vascular smooth muscle. Studies have demonstrated that the increase in active tension reflects an increase in cytosolic free calcium. The increased peripheral vascular resistance that is an underlying cause of hypertension results from an increase in active tension in the vascular smooth muscle. The mechanism by which nifedipine reduces arterial blood pressure involves peripheral arterial vasodilatation and the resulting reduction in peripheral vascular resistance. Upon swallowing, the biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the feces as an insoluble shell. Drug delivery is essentially constant as long as the osmotic gradient remains constant, and then gradually falls to zero. 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. This controlled rate of drug delivery into the gastrointestinal lumen is independent of pH or gastrointestinal motility. PROCARDIA XL Extended Release Tablet is designed to provide nifedipine at an approximately constant rate over 24 hours. 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. 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. It consists, however, of a semipermeable membrane surrounding an osmotically active drug core. PROCARDIA XL ® Extended Release Tablet is similar in appearance to a conventional tablet.
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