WARFARIN SODIUM
Chemistry - A coumarin derivative, warfarin sodium occurs as a slightly bitter tasting, white, amorphous or crystalline powder. It is very soluble in water and freely soluble in alcohol. Thecommercially available products contain a racemic mixture of the two optical isomers.
Uses, Indications - In veterinary medicine, warfarin is used primarily for the oral, long-termtreatment (or prevention of recurrence) of thrombotic conditions, usually in cats, dogs or horses.
After absorption, warfarin is highly bound to plasma proteins in humans, with approximately 99%of the drug bound. It is reported that there are wide species variations with regard to proteinbinding; horses have a higher free (unbound) fraction of the drug than do rats, sheep or swine.
Only free (unbound) warfarin is active. While other coumarin and indandione anticoagulants aredistributed in milk, in humans at least, warfarin does not enter milk.
Warfarin is principally metabolized in the liver to inactive metabolites which are excreted in theurine and in the bile (and then reabsorbed and excreted in the urine). The plasma half-life of warfarin may be several hours to several days, depending on the patient (and species?).
Warfarin is embryotoxic, can cause congenital malformations and is considered contraindicatedduring pregnancy. If anticoagulant therapy is required during pregnancy, most clinicians recommend using low-dose heparin.
Overdosage, Acute Toxicity - Acute overdosages of warfarin may result in life-threateninghemorrhage. In dogs and cats, single doses of 5 - 50 mg/kg have been associated with toxicity. Itmust be remembered that a lag time of 2-5 days may occur before signs and symptoms of toxicityoccur and animals must be monitored and treated accordingly.
Cumulative toxic doses of warfarin have been reported as 1 - 5 mg/kg for 5-15 days in dogs and 1mg/kg for 7 days in cats.
If overdosage is detected early, prevent absorption from the gut using standard protocols. Ifsymptoms are noted, they should be treated with blood products and vitamin K1 (phytonadione).
Refer to the phytonadione monograph for more information.
The following drugs may decrease the anticoagulant response of warfarin: barbiturates(phenobarbital, etc.), carbamazepine, corticosteroids, corticotropin, griseofulvin, mercaptopurine, estrogen-containing products, rifampin, spironolactone, sucralfate, and vitamin
K.Should concurrent use of any of the above drugs with warfarin be necessary, enhanced monitoringis required. It is also recommended to refer to other references on drug interactions for morespecific information.
Drug/Laboratory Interactions - Warfarin may cause falsely decreased theophylline values ifusing the Schack and Waxler ultraviolet method of assay.
Storage, Stability, Compatibility
Warfarin sodium tablets should be stored in tight, light-resistant containers at temperatures less than 40°C and, preferably, at room temperature. Warfarinsodium powder for injection should be protected from light and used immediately after reconstituting.Pharmacology - WARFARIN SODIUM
Warfarin acts indirectly as an anticoagulant (it has no direct anticoagulant effect)by interfering with the action of vitamin K1 in the synthesis of the coagulation factors II, VII, IX, and X. Sufficient amounts of vitamin K1 can override this effect.Uses, Indications - In veterinary medicine, warfarin is used primarily for the oral, long-termtreatment (or prevention of recurrence) of thrombotic conditions, usually in cats, dogs or horses.
Pharmacokinetics - WARFARIN SODIUM
Warfarin is rapidly and completely absorbed in humans after oral administration; absorption data for veterinary species were not located.After absorption, warfarin is highly bound to plasma proteins in humans, with approximately 99%of the drug bound. It is reported that there are wide species variations with regard to proteinbinding; horses have a higher free (unbound) fraction of the drug than do rats, sheep or swine.
Only free (unbound) warfarin is active. While other coumarin and indandione anticoagulants aredistributed in milk, in humans at least, warfarin does not enter milk.
Warfarin is principally metabolized in the liver to inactive metabolites which are excreted in theurine and in the bile (and then reabsorbed and excreted in the urine). The plasma half-life of warfarin may be several hours to several days, depending on the patient (and species?).
Contraindications, Precautions, Reproductive Safety
Warfarin is contraindicated in patientswith preexistent hemorrhagic tendencies or diseases, those undergoing or contemplating eye or CNS surgery, major regional lumbar block anesthesia, or surgery of large, open surfaces. It shouldnot be used in patients with active bleeding from the GI, respiratory or GU tract. Contraindicationsalso include aneurysm, acute nephritis, cerebrovascular hemorrhage, blood dyscrasias, uncontrolledor malignant hypertension, hepatic insufficiency, pericardial effusion and visceral carcinomas.Warfarin is embryotoxic, can cause congenital malformations and is considered contraindicatedduring pregnancy. If anticoagulant therapy is required during pregnancy, most clinicians recommend using low-dose heparin.
Adverse Effects, Warnings
The principal adverse effect of warfarin use is dose-related hemorrhage, which may be manifested by signs or symptoms of anemia, thrombocytopenia, weakness, hematomas and ecchymoses, epistaxis, hematemesis, hematuria, melena, hematochezia, hemathrosis, hemothorax, intracranial and/or pericardial hemorrhage, and death.Overdosage, Acute Toxicity - Acute overdosages of warfarin may result in life-threateninghemorrhage. In dogs and cats, single doses of 5 - 50 mg/kg have been associated with toxicity. Itmust be remembered that a lag time of 2-5 days may occur before signs and symptoms of toxicityoccur and animals must be monitored and treated accordingly.
Cumulative toxic doses of warfarin have been reported as 1 - 5 mg/kg for 5-15 days in dogs and 1mg/kg for 7 days in cats.
If overdosage is detected early, prevent absorption from the gut using standard protocols. Ifsymptoms are noted, they should be treated with blood products and vitamin K1 (phytonadione).
Refer to the phytonadione monograph for more information.
Drug Interactions
A multitude of drugs have been documented or theorized to interact withwarfarin. The following drugs may increase the anticoagulant response of warfarin: allopurinol, amiodarone, anabolic steroids, chloral hydrate, chloramphenicol, cimetidine, clofibrate, co-trimoxazole (trimethoprim/sulfa), danazol, dextrothyroxine sodium, diazoxide, diflunisal, disulfiram, erythromycin, ethacrynic acid, fenoprofen, glucagon, ibuprofen, indomethicin, isoniazid, ketoprofen, meclofenamic acid (meclofenamate), metronidazole, miconazole, nalidixic acid, oral neomycin, pentoxyfilline, phenylbutazone, propoxyphene, propylthiouracil, quinidine, and salicylates.The following drugs may decrease the anticoagulant response of warfarin: barbiturates(phenobarbital, etc.), carbamazepine, corticosteroids, corticotropin, griseofulvin, mercaptopurine, estrogen-containing products, rifampin, spironolactone, sucralfate, and vitamin
K.Should concurrent use of any of the above drugs with warfarin be necessary, enhanced monitoringis required. It is also recommended to refer to other references on drug interactions for morespecific information.
Drug/Laboratory Interactions - Warfarin may cause falsely decreased theophylline values ifusing the Schack and Waxler ultraviolet method of assay.