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Pharmacology: Pharmacodynamics: Nifedipine is a calcium antagonist of the 1,4-dihydropyridine type. Calcium antagonists reduce the transmembranal influx of calcium ions through the slow calcium channel into the cell. Nifedipine acts particularly on the cells of the myocardium and the smooth muscle cells of the coronary arteries and the peripheral resistance vessels.
Pharmacokinetics: Adalat LA tablets are formulated to provide nifedipine at an approximately constant rate over 24 hours. Nifedipine is released from the tablet at a zero-order rate by a membrane-controlled, osmotic push-pull process. The delivery rate is independent of gastrointestinal pH or motility. Upon swallowing, the biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the faeces as an insoluble shell.
Absorption: After oral administration nifedipine is almost completely absorbed. The systemic availability of orally administered nifedipine immediate release formulations (nifedipine capsules) is 45 - 56 % owing to a first pass effect. At steady-state the bioavailability of Adalat LA tablets ranges from 68 - 86% relative to nifedipine capsules. Administration in the presence of food slightly alters the early rate of absorption, but does not influence the extent of drug availability.
Distribution: Nifedipine is about 95 % bound to plasma protein (albumin). The distribution half-life after intravenous administration has been determined to be 5 to 6 minutes.
Biotransformation: After oral administration nifedipine is metabolized in the gut wall and in the liver, primarily by oxidative processes. These metabolites show no pharmacodynamic activity.
Nifedipine is excreted in the form of its metabolites predominantly via the kidneys, and about 5 - 15 % via the bile in the faeces. The unchanged substance is recovered only in traces (below 0.1 %) in the urine.
Elimination: The terminal elimination half-life is 1.7 to 3.4 h in conventional formulations (nifedipine capsules). The terminal half-life after Adalat LA does not represent a meaningful parameter as a plateau-like plasma concentration is maintained during release from the tablets and absorption.
In cases of impaired kidney function no substantial changes have been detected in comparison with healthy volunteers.
In a study comparing the pharmacokinetics of nifedipine in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment with those in patients with normal liver function, oral clearance of nifedipine was reduced by on average 48% (Child Pugh A) and 72% (Child Pugh B). As a result AUC and Cmax of nifedipine increased on average by 93% and 64% (Child Pugh A) and by 253% and 171% (Child Pugh B), respectively, compared to patients with normal hepatic function. The pharmacokinetics of nifedipine has not been investigated in patients with severe hepatic impairment (see Precautions).
Toxicology: Preclinical Safety Data: Preclinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity, genotoxicity and carcinogenic potential.
Reproduction toxicology: Nifedipine has been shown to produce teratogenic findings in rats, mice and rabbits, including digital anomalies, malformation of the extremities, cleft palates, cleft sternum and malformation of the ribs.
Digital anomalies and malformation of the extremities are possibly a result of compromised uterine blood flow, but have also been observed in animals treated with nifedipine solely after end of the organogenesis period.
Nifedipine administration was associated with a variety of embryotoxic, placentotoxic and fetotoxic effects, including stunted fetuses (rats, mice, rabbits), 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). All of the doses associated with the teratogenic, embryotoxic or fetotoxic effects in animals were maternally toxic at several times the recommended maximum dose for humans.
