A number of case reports describe an increase in effects ofwarfarin, accompanied by bleeding in some cases, caused by antineoplastic regimens containing carboplatin, chlormethine, cyclophosphamide, doxorubicin, etoposide, gefitinib, gemcitabine,ifosfamide with mesna, methotrexate, procarbazine, trastuzumab, vincristine or vindesine. A decrease in effects of warfarin has been seen with azathioprine, cyclophosphamide, mercaptopurine and mitotane, a decrease in effects of acenocoumarol has been seen with mercaptopurine, and a decrease in effectsof phenprocoumon have been seen with azathioprine.
A survey of 103 patients with antiphospholipid syndrome found that azathioprine appeared to increase warfarin requirements.(See reference number 1) A woman who was resistant to warfarin, needing 14 to 17mg daily while taking azathioprine, began to bleed (epistaxes, haematemesis) when azathioprine was stopped. She was restabilised on warfarin 5mg daily (See reference number 2). Reduced warfarin effects were seen in 2 other patients taking azathioprine,(See reference number 3,4) one of whom had a marked fall in serum warfarin levels during azathioprine treatment (See reference number 4). Two women with systemic lupus erythematosus taking phenprocoumon(See reference number 5) and a third taking warfarin(See reference number 6) had marked falls in their INRs during treatment with azathioprine, and another woman needed an almost fourfold increase in dose of warfarin when she was given azathioprine (See reference number 7).
A woman stabilised on warfarin required a gradual decrease in dose from 4mg to 2.5mg daily after starting gefitinib 250 mg/m(See reference number 2) daily for lung cancer. In contrast,a second patient did not have an increase in warfarin effect while taking gefitinib (See reference number 11).
A 63-year-old man needed a reduction in his weekly warfarin dosage from 59.23mg to 50.75mg in order to keep his INR at about 2.5 during 2 cycles of gemcitabine. When gemcitabine was stopped his warfarin dosage had to be increased again (See reference number 12). The manufacturers have information on 4 cases of suspected interactions between gemcitabine and warfarin,and one with phenprocoumon (reported by December 2000) (See reference number 13). Based on 724 reports of concurrent use of gemcitabine and anticoagulants,(See reference number 13)they suggest that incidence of suspected interaction is 0.8%.
A man well stabilised on warfarin had a marked reduction in his anticoagulant response on two occasions while taking mercaptopurine,but no changes occurred when he took busulfan, cyclophosphamide, cytarabine, hydroxycarbamide, mitobronitol, demecolcine or melphalan (See reference number 15). A woman needed a marked increase in her dosage of acenocoumarol,from 21 to 70mg weekly, when she was given mercaptopurine 100mg daily (See reference number 16). Another patient required about a 25 % increase in warfarin dose while taking mercaptopurine 100mg daily (See reference number 17).
The prothrombin times of an elderly man given warfarin increased by 50 to 100 % in middle of three cycles of treatment with ProMace-Mopp (cyclophosphamide, doxorubicin, etoposide, chlormethine, vincristine, procarbazine, methotrexate and prednisone), and he developed a subconjunctival haemorrhage during first cycle (See reference number 19).
Two women stabilised on warfarin developed nosebleeds after 10 and 8 weekly doses of trastuzumab,respectively, and were found to have INRs of 6 and 5.8,respectively (See reference number 20). However, manufacturer notes that in an analysis of clinical study data rate of bleeding events was similar for patients receiving or not receiving trastuzumab, with or without anticoagulants (See reference number 21).
Not well understood. Mercaptopurine possibly increases synthesis or activation of prothrombin (See reference number 22). Azathioprine is metabolised to mercaptopurine,and would therefore be expected to interact similarly.
The absence of problems in early small studies using warfarin as an adjunct to chemotherapy,(See reference number 23,24) and small number of reports describing difficulties, suggest that many of these interactions may be uncommon events. The concurrent use of these drugs need not be avoided but there is clearly a need to be aware that any antineoplastic regimen might increase response to anticoagulants. It would also be prudent to note that mercaptopurine and azathioprine may decrease anticoagulant response. The anticoagulant dosages may need adjustment. Note that,from a disease perspective, when treating venous thromboembolic disease in patients with cancer, warfarin is generally inferior (higher risk of major bleeds and recurrent thrombosis) to low-molecular-weight heparins (See reference number 25).
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