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. The commercially available products contain a racemic mixture of the two optical isomers.
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. Warfarin sodium powder for injection should be protected from light and used immediately after reconstituting.
Pharmacology - 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 K11 can override this effect.
Uses/Indications - In veterinary medicine, warfarin is used primarily for the oral, long-term treatment (or prevention of recurrence) of thrombotic conditions, usually in cats, dogs or horses.
Pharmacokinetics - 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 protein binding; 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 are distributed 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 the urine 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 patients with 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 should not be used in patients with active bleeding from the GI, respiratory or GU tract. Contraindications also include aneurysm, acute nephritis, cerebrovascular hemorrhage, blood dyscrasias, uncontrolled or malignant hypertension, hepatic insufficiency, pericardial effusion and visceral carcinomas.
Warfarin is embryotoxic, can cause congenital malformations and is considered contraindicated during 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-threatening hemorrhage. In dogs and cats, single doses of 5 - 50 mg/kg have been associated with toxicity. It must be remembered that a lag time of 2-5 days may occur before signs and symptoms of toxicity occur 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 1 mg/kg for 7 days in cats.
If overdosage is detected early, prevent absorption from the gut using standard protocols. If symptoms 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 with warfarin. 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 monitoring is required. It is also recommended to refer to other references on drug interactions for more specific information.
Drug/Laboratory Interactions - Warfarin may cause falsely decreased theophylline values if using the Schack and Waxler ultraviolet method of assay.
As an anticoagulant:
a) 30 - 75 mg/450 kg body weight PO. (Robinson 1987)
b) Initially, 0.018 mg/kg PO once daily and increase dose by 20% every day until baseline PT is doubled. Final dose rates may be from 0.012 mg/kg to 0.57 mg/kg daily. (Vrins, Carlson, and Feldman 1983)
Monitoring Parameters - Note: The frequency of monitoring is controversial, and is dependent on several factors including dose, patient’s condition, concomitant problems, etc. See the Dosage section above for more information.
1) While Prothrombin Times (PT) are most commonly used to monitor warfarin, PIVKA (proteins induced by vitamin K antagonists) has been suggested as being more sensitive.
2) Platelet counts and hematocrit (PCV) should be done periodically
3) Occult blood in stool and urine; other observations for bleeding
4) Clinical efficacy
Client Information - Clients must be counseled on both the importance of administering the drug as directed and also to immediately report any signs or symptoms of hemorrhage.
Dosage Forms/Preparations/FDA Approval Status/Withholding Times -
Veterinary-Approved Products: None.
Warfarin Sodium Tablets (scored) 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7.5 mg, 10 mg; Coumadin ® (DuPont), (Rx)
Warfarin Sodium Powder for Injection lyophilized 2 mg in 5 mg vials; Coumadin® (DuPont) ; (Rx)
A method of suspending warfarin tablets in an oral suspension has been described (Enos 1989). To make 30 ml of a 0.25 mg/ml suspension: Crush three 2.5 mg tablets in a mortar and pestle. Add 10 ml glycerin to form a paste. Then 10 ml of water; and q.s. to 30 ml with dark corn syrup (Karo®). Warm gently. Shake well and use within 30 days.
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