How should a switch from fluindione treatment to warfarin treatment be made?/nA young woman had pul

Fråga: How should a switch from fluindione treatment to warfarin treatment be made?

A young woman had pulmonary embolism during a stay in France. She received fluindione (Previscar), 20 mg every other day and 15 mg every other day. Now she has returned to Sweden and will be switched to warfarin therapy.

Sammanfattning: Since no conclusion can be drawn about the individual dose requirement of warfarin from the dose of fluindione used, the most prudent strategy to make a switch to warfarin is to stop the fluindione treatment, give only dalteparin (Fragmin) for four days and then begin warfarin treatment as usual under concomitant dalteparin treatment until a therapeutic INR has been reached.

Svar: There is a previous Drugline document concerning fluindione, which is an orally administered indanedione anticoagulant. It is, like warfarin, a vitamin K antagonist inhibiting the synthesis of factors II, VII, IX and X (1). Apparently, fluindione is registered only in France. The dose required of fluindione to reach therapeutic INR values varies. The mean daily dose is 20-40 mg according to the French medical product agency. The half-life of fluindione is 31h and it takes three to four days to return to normal coagulation status after cessation of fluindione treatment (2).

Warfarin and fluindione should probably not be used together since little appears to be known about the metabolism of fluindione. In eight patients treated with fluindione, administration of methylprednisolone caused an increase in INR from 2.75 to 8. Plasma concentrations of fluindione were measured in three patients and also increased after methylprednisolone administration. Methylprednisolone alone did not affect INR in controls. Since methylprednisolone inhibits the cytochrome P450 (CYP450) enzyme system (3), the above mentioned study suggests that one or several CYP450 isoenzymes are involved in the metabolism of fluindione. S-warfarin is mainly metabolised by CYP450 2C9 and R-warfarin is primarily metabolised by CYP1A2 and 3A4 (4). Thus, there might be metabolic interactions between fluindione and warfarin.

Since no conclusion can be drawn about the individual dose requirement of warfarin from the dose of fluindione used, the most prudent strategy to make a switch to warfarin is to stop the fluindione treatment, give only dalteparin (Fragmin) for four days and then begin warfarin treatment as usual under concomitant dalteparin treatment until a therapeutic INR has been reached. 1 Drugline no 09499 (year 1992) 2 Antivitamines K. Agence Francaise de securite sanitaire des produits de sante. Decembre 2000. 3 Costedoat-Chalumeau N, Amoura Z, Aymard G, Sevin O, Wechsler B et al. Potentiation of Vitamin K antagonists by high-dose intravenous methylprednisolone. Ann Intern Med 2000;132:631-5. 4 Kaminsky LS, Zhang Z-Y. Human P450 metabolism of warfarin. Pharmacol Ther 1997;73:67-74.