Fluorouracil Warfarin

Capecitabine is used for the treatment of colorectal and breast cancers. It is contraindicated in patients with known hypersensitivity to capecitabine or any of its components or to 5-fluorouracil and in patients with known dihydropyrimidine dehydrogenase (DPD) deficiency. The use of capecitabine is restricted in patients with severe renal impairment. The drag can induce diarrhea, sometimes severe. Other side effects include anemia, hand-foot syndrome, hyperbilirubinemia, nausea, stomatitis, pyrexia, edema, constipation, dyspnea, neutropenia, back pain, and headache. Cardiotoxicity has been observed with capecitabine. A clinically important drag interaction between capecitabine and warfarin has been demonstrated. Care should be exercised when the drag is co-administered with CYP2X9 substrates. 

Interferes w/ DNA synth Dose Adults. Anaerobic Infxns 500 mg IV q6-8h Amebic dysentery 750 mg/d PO for 5-10 d Trichomoniasis 250 mg PO tid for 7 d or 2 g PO X 1 C. difficile 500 mg PO or IV qSh for 7-10 d (PO preferred IV only if pt NPO) Vaginosis 1 applicator-full intravag bid or 500 mg PO bid for 7 d Acne rosacea/skin Apply bid Peds. 30 mg/ kg PO/IV/d q6H, 4 g/d max-s-. Amebic dysentery 35-50 mg/kg/24 h PO in 3 -s- doses for 5-10 d Rx 7-10 d for C. difficile-, in hepatic impair Caution [B, M] Avoid EtOH Contra 1st tri of PRO Disp Tabs, caps, IV, topical lotion, intravag gel, cream SE Disulfiram-like Rxn dizziness, HA, GI upset, anorexia, urine discoloration Interactions t Effects W/ cimetidine T effects OF carbamazepine, fluorouracil, Li, warfarin -1- effects W/ barbiturates, cholestyramine, colestipol, phenytoin EMS t Effects of anticoagulants concurrent EtOH use can cause disulfiram-like Rxn (tach, N/V, sweating, flushing, headache, blurred vision, confusion) may cause a metallic taste and discolored urine OD May cause N/V/D, numbness in hands and feet, Szs, and loss of coordination symptomatic and supportive... 

Brown MC. Multisite mucous membrane bleeding due to a possible interaction between warfarin and 5-fluorouracil. Pharmacotherapy 1997 17(3) 631-3. 

Levamisole and 5-fluorouracil interact with warfarin to produce bleeding (58). The mechanism of this effect is unclear, but the reports are sufficiently clear to point to the need for careful monitoring when this drug combination is used. 

Clinically important, potentially hazardous interactions with acenocoumarol, alfuzosin, aminophylline, anisindione, anticoagulants, buprenorphine, butorphanol, caffeine, carmustine, dobazam, cocoa, dicumarol, dofetilide, duloxetine, epirubicin, eszopiclone, fentanyl, floxuridine, fluorouracil, galantamine, gliclazide, hydromorphone, itraconazole, ketoconazole, lidocaine, meptazinol, midazolam, mizolastine, modobemide, morphine, narcotic analgesics, oxprenolol, oxycodone, pentazocine, phenytoin, posaconazole, prednisone, propranolol, sufentanil, tolazoline, warfarin, xanthines, zaleplon, zofenopril, zolmitriptan, zolpidem... 

Clinically important, potentially hazardous interactions with alcohol, anisindione, anticoagulants, astemizole, dicumarol, disulfiram, fluorouracil, mycophenolate, warfarin... 

Capecitabine markedly increases warfarin levels and increases its anticoagulant effects. A number of case reports describe over-anticoagulation in patients taking warfarin with capecitabine. Similarly, case reports describe overanticoagulation in patients taking warfarin and fluorouracil, ftorafur or tegafur. 

In an early clinical study, 25 patients with colon cancer were given bolus fluorouracil 15 to 20 mg/kg weekly plus warfarin daily, titrated to maintain the prothrombin time in the 20 to 30% range, and modified weekly as necessary. Three patients developed blood loss from the gut, which was controlled by giving a transfusion and stopping the warfarin. This study did not report the required dose of warfarin, or how often it needed adjusting in these patients. ... 

Other cases of overanticoagulation have been reported with warfarin and fluorouracil-based regimens including CMF (cyclophosphamide, methotrexate and fluorouracil), - CMF plus vincristine and prednisone, fluorouracil, cisplatin and etoposide, and fluorouracil, cispla-tin and mitomycin."... 

Uncertain. However, in a pharmacokinetic study in rats, fluorouracil significantly reduced the total clearance of5-warfarin by inhibiting its metabolism. Data from the clinical study with the fluorouracil prodrug, capecitabine, suggests this interacts similarly. ... 

Fairly well-documented and established interactions of clinical importance. Prothrombin times should be regularly monitored in patients taking warfarin and other coumarins and requiring fluorouracil, capecitabine or other fluorouracil pro-drugs, anticipating the need to reduce the warfarin dose. Note that, from a disease perspective, when treating venous throm-... 

Chlebowski RT, Gota CH, Charm KK, Weiner JM, Block JB, Batemen JR. Clinical and phar-macokinetic effects of combined warfarin and 5-fluorouracil in advanced colon cancer. Cancer Res ( 9Z2) 42, 4827-30. 

Wajima T, Mukhopadhyay P. Possible interactions between warfarin and 5-fluorouracil. Am... 

Carabine J, Wang F. International normalized ratio fluctuation widi warfarin-fluorouracil erapy, AmJHeaUh-SystPharm (2002), 59,875. 

Davis DA, Fugate SE, Increasing warfarin dosage reductions associated widi concurrent warfarin and repeated cycles of 5-fluorouracil therapy. Pharmaco erapy (2005) 25, 442-7. 

Scarfe MA, Israel MK. Possible drug interaction between warfarin and combination of le-vamisole and fluorouracil, AnnPharmaco er( 994) 28,464-7. 

Aki Z, Kotiloglu G, Ozyilkan O. A patient with a prolonged prothrombin time due to an adverse interaction between 5-fluorouracil and warfarin. Am J Gastroenterol (20(X>) 95,1093-... 

Zhou Q, Chan E. Effect of 5-fluorouracil on the anticoagulant activity and the pharmaedd-netics of warfarin enantiomers in rats. EurJPharm Sci (2002) 17,73-80. 

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