LD₅₀ Values

Mouse: 3 mg/kg (Oral), 165 mg/kg (IV), 750 mg/kg (IP)^L6622

Rat: 1.6 mg/kg (Oral), 320 mg/kg (Inhaled), 1400 mg/kg (Skin)^L6622

Rabbit: 800 mg/kg (Oral)^L6622

Pig: 1 mg/kg (Oral)^L6622

Dog: 3 mg/kg (Oral)^L6622

Cat: 6 mg/kg (Oral)^L6622

Chicken: 942 mg/kg (Oral)^L6622

Guinea Pig: 180 mg/kg (Oral)^L6622

Overdose

Doses of 1-2 mg/kg/day over a period of 15 days have been fatal in humans.^L6625 Warfarin overdose is primarily associated with major bleeding particularly from the mucous membranes, gastrointestinal tract, and genitourinary system.label,L6625 Epistaxis, ecchymoses, as well as renal and hepatic bleeding are also associated. These symptoms become apparent within 2-4 days of overdose although increases in prothrombin time can be observed within 24 hours. Treatment for overdosed patients includes discontinuation of warfarin and administration of vitamin K. For more urgent reversal of anticoagulation prothrombin complex concentrate, blood plasma, or coagulation factor VIIa infusion can be used.label Patients can be safely re-anticoagulated after reversal of the overdose.

Carcinogenicity & Mutagenicity

The carcinogenicity and mutagenicity of warfarin have not been thoroughly investigated.label

Reproductive Toxicity

Warfarin is known to be a teratogen and its use during pregnancy is contraindicated in the absence of high thrombotic risk.label,L6625 Fetal warfarin syndrome, attributed to exposure during the 1st trimester, is characterized by nasal hypoplasia with or without stippled epiphyses, possible failure of nasal septum development, and low birth weight. Either dorsal midline dysplasia or ventral midline dysplasia can occur. Dorsal midline dysplasia includes agenisis of the corpus callosum, Dandy-Walker malformations, midline cerebellar hypoplasia. Ventral midline dysplasia is characterized by eye anomalies which can potentially include optic atrophy, blindness, and microphthalmia. Exposure during the 2nd and 3rd trimester is associated with hypoplasia of the extremities, developmental retardation, microcephaly, hydrocephaly, schizencephaly, seizures, scoliosis, deafness, congenital heart malformations, and fetal death. The critical exposure period is estimated to be week 6-9 based on case reports. Effects noted in the Canadian product monograph include developing a single kidney, asplenia, anencephaly, spina bifida, cranial nerve palsy, polydactyl malformations, corneal leukoma, diaphragm hernia, and cleft palate.^L6616

Lactation

Official product monographs mention a study in 15 women.label,L6616 Warfarin was not detected in the breast milk of any woman and 6 infants were documented as having normal prothrombin times. The remaining 9 infants were not tested. Another study in 13 women using doses of 2-12 mg also revealed no detectable warfarin in breast milk.^L6628 A woman who mistakenly took 25 mg of warfarin for 7 days while breastfeeding presented to an emergency room with an INR of 10 and prothrombin time of over 100 s. Her infant had a normal INR of 1.0 and prothrombin time of 10.3. The infant in this case has an increased prothrombin time of 33.8 s three weeks previous but this was judged not to be due to warfarin exposure.