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Coumadin - Clinical Pharmacology

[Warfarin Sodium Tablets, USP]



Excretion:

The terminal half-life of warfarin after a single dose is approximately one week; however, the effective half-life ranges from 20 to 60 hours, with a mean of about 40 hours. The clearance of R-warfarin is generally half that of S-warfarin, thus as the volumes of distribution are similar, the half-life of R-warfarin is longer than that of S-warfarin. The half-life of R-warfarin ranges from 37 to 89 hours, while that of S-warfarin ranges from 21 to 43 hours. Studies with radiolabeled drug have demonstrated that up to 92% of the orally administered dose is recov-ered in urine. Very little warfarin is excreted unchanged in urine. Urinary excretion is in the form of metabolites.

Elderly:

Patients 60 years or older appear to exhibit greater than expected prothrombin time (PT)/ International Normalized Ratio (INR) response to the anticoagulant effects of warfarin. The cause of the increased sensitivity to the anticoagulant effects of warfarin in this age group is unknown. This increased anticoagulant effect from war-farin may be due to a combination of pharmacokinetic and pharmacodynamic factors. Racemic warfarin clearance may be unchanged or reduced with increasing age.

Limited information suggests there is no difference in the clear-ance of S-warfarin in the elderly versus young subjects. However, there may be a slight decrease in the clearance of R-warfarin in the elderly as compared to the young. Therefore, as patient age increases, a lower dose of war-farin is usually required to produce a therapeutic level of anticoagulation.

Asians:

Asian patients may require lower initiation and maintenance doses of warfarin. One non-controlled study conducted in 151 Chinese outpatients reported a mean daily warfarin requirement of 3.3 1.4 mg to achieve an INR of 2 to 2.5. These patients were stabilized on warfarin for various indications. Patient age was the most important determinant of warfarin requirement in Chinese patients with a progressively lower warfarin requirement with increasing age.