Manufacturing Process
About 0.1 mol each of 4-hydroxycoumarin and benzalacetone are dissolved, in
any desired order, in about three times their combined weight of pyridine. The
solution is refluxed for about 24 hours, and then allowed to cool; after which
it is poured into about 15 volumes of water, and acidified to about pH 2 by the
addition of hydrochloric acid. An oil separates, and on cooling and standing
overnight solidifies. The solid product is recovered, as by filtration, and
recrystallized from ethanol, according to US Patent 2,427,578.
The base melts at about 161°C. It is a white crystalline solid, soluble in hot
ethyl alcohol and substantially insoluble in cold water; it dissolves in alkali
solutions with formation of the salt. The yield is about 40%.
Then, as described in US Patent 2,777,859, warfarin may be reacted with
NaOH to give a sodium salt solution. Crystalline warfarin sodium may be
prepared as described in US Patent 2,765,321.
Drug interactions
Potentially hazardous interactions with other drugs
There are many significant interactions with warfarin.
Prescribe with care with regard to the following:
Anticoagulant effect enhanced by: alcohol,
amiodarone, anabolic steroids, aspirin, aztreonam,
bicalutamide, cephalosporins, chloramphenicol,
cimetidine, ciprofloxacin, clopidogrel, cranberry
juice, danazol, danshen, dipyridamole, dronedarone,
disulfiram, entacapone, esomeprazole, exenatide,
ezetimibe, fibrates, fluconazole, flutamide, fluvastatin,
glucosamine, grapefruit juice, itraconazole,
ketoconazole, levamisole, levofloxacin, macrolides,
methylphenidate, metronidazole, miconazole,
mirtazepine, nalidixic acid, neomycin, norfloxacin,
NSAIDs, ofloxacin, omeprazole, pantoprazole,
paracetamol, penicillins, proguanil, propafenone,
ritonavir, rosuvastatin, saquinavir, SSRIs, simvastatin,
sulfinpyrazone, sulphonamides, tamoxifen, tegafur,
testosterone, tetracyclines, thyroid hormones,
tigecycline, toremifene, tramadol, trimethoprim,
valproate, venlafaxine, vitamin E and voriconazole.
Anticoagulant effect decreased by: acitretin,
atorvastatin, azathioprine, barbiturates,
carbamazepine, enteral feeds, eslicarbazepine,
enzalutamide, fosphenytoin, ginseng, griseofulvin,
oral contraceptives, phenobarbital, phenytoin,
primidone, rifamycins, St John’s wort (avoid
concomitant use), sucralfate, vitamin K.
Anticoagulant effects enhanced / reduced by: anion
exchange resins, atazanavir, corticosteroids, dietary
changes, disopyramide, efavirenz, fosamprenavir,
nevirapine, ritonavir, telaprevir, tricyclics, trazodone.
Analgesics: increased risk of bleeding with IV
diclofenac and ketorolac - avoid concomitant use.
Anticoagulants: increased risk of haemorrhage with
apixaban, dabigatran, edoxaban and rivaroxaban -
avoid concomitant use.
Antidiabetic agents: enhanced hypoglycaemic
effect with sulphonylureas; also possible changes to
anticoagulant effect.
Camomile: enhanced anticoagulation.
Ciclosporin: there have been a few reports of altered
anticoagulant effect; decreased ciclosporin levels have
been seen rarely.
Cytotoxics: increased risk of bleeding with erlotinib,
imatinib and regorafenib; enhanced effect with
capecitabine, etoposide, fluorouracil, ifosfamide,
gefitinib, gemcitabine, sorafenib and vemurafenib;
reduced effect with mercaptopurine and mitotane.
Melatonin: possibly enhanced INR.
