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WARFARIN AND RELATED AGENTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Warfarin is a coumarin anticoagulant, which interferes with the hepatic synthesis of Vitamin K-dependent coagulation factors II (prothrombin), VII, IX, and X.

Specific Substances

    1) Anthrombin
    2) Coumafene
    3) Warfarin
    4) Zoocoumarin
    5) 3-(ACETONYLBENZYL)-4-HYDROXYCOUMARIN
    6) 3-(alpha-ACETONYLBENZYL)-4-HYDROXYCOUMARIN
    7) 4-HYDROXY-3-(3-OXO-1-PHENYLBUTYL)-2H-1-BENZOPYRAN-2-ONE
    8) CAS 81-81-2
    9) Prothromadin (CAS 129-06-6)
    10) Prothromadin (CAS 81-81-2)
    1.2.1) MOLECULAR FORMULA
    1) C19-H16-O4

Available Forms Sources

    A) FORMS
    1) Coumarins (drugs):
    1) Dicoumarol (bishydroxycoumarin): 25, 50 and 100 mg tablets and 25 and 50 mg capsules
    2) Warfarin potassium: 5 mg tablets
    3) Warfarin sodium (ORAL): 1 (pink) , 2 (lavender), 2.5 (green), 3 (tan), 4 (blue), 5 (peach), 6 (teal), 7.5 (yellow) and 10 (white) mg single score tablets inscribed with COUMADIN on plain face (Prod Info COUMADIN(R) oral tablets, IV injection, 2007)
    4) Warfarin sodium (INTRAVENOUS): 5 mg vial. Reconstitute with 2.7 mL of sterile water for injection to yield 2 mg/mL. Intramuscular administration NOT recommended (Prod Info COUMADIN(R) oral tablets, IV injection, 2007).
    2) INDANDIONES (drugs):
    1) Anisindione: 50 mg tablets
    2) Phenindione: 50 mg tablets
    3) Phenprocoumon: 3 mg tablets
    3) COUMARINS (Rodenticides)
    1) Coumachlor (Tomorin)
    2) Coumafuryl (Tomarin, Fumarin)
    3) Warfarin, coumafene, zoocoumarin (Kypfarin, Ratox, RAX, Rodex, Tox-Hid, Warfarin Plus)

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Therapeutic anticoagulation medication used for the treatment of deep venous thrombosis, pulmonary embolism, and other hypercoagulable states, and to prevent thromboembolic complications in patients with atrial fibrillation, prosthetic heart valves, or recent myocardial infarction. It may also be used to prevent thromboembolic complications in patients with stroke, impaired left ventricular function, or cancer.
    B) EPIDEMIOLOGY: Exposures are common. Inadvertent exposures rarely produce clinical effects. A single deliberate overdose generally does not result in coagulopathy, but a large ingestion by a patient who is chronically using warfarin may produce significant coagulopathy. Adverse events during therapeutic dosing are common.
    C) PHARMACOLOGY: Inhibits hepatic synthesis of Vitamin K dependent factors: II, VII, IX, and X, and also inhibits the activity of vitamin K 2,3-epoxide reductase.
    D) TOXICOLOGY: Excessive inhibition of factors II, VII, IX, and X can cause significant prolongation of INR and excessive bleeding after minor trauma. The risk of hemorrhage depends on patient comorbidities and severity of anticoagulation.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: The primary adverse effect is bleeding, which can be more severe with comorbid conditions, such as advanced age and liver dysfunction. Warfarin can also cause skin necrosis. Warfarin is a human teratogen and increases the risk of fetal death.
    F) WITH POISONING/EXPOSURE
    1) OVERDOSE: GENERAL: Excessive chronic doses, drug interactions, and less commonly acute overdose can cause profound anticoagulation. Effects can include bleeding at virtually any site: epistaxis, bleeding from gums, ecchymosis, hematochezia, hematuria, menorrhagia, hemarthrosis, and bleeding from minor skin or soft tissue trauma.
    2) SEVERE TOXICITY: More life-threatening complications include intracranial hemorrhage, retroperitoneal hemorrhage, or massive gastrointestinal bleed.
    0.2.5) CARDIOVASCULAR
    A) WITH THERAPEUTIC USE
    1) Hypotension and cardiac tamponade have been reported following warfarin therapy.
    0.2.6) RESPIRATORY
    A) WITH THERAPEUTIC USE
    1) Upper airway bleeding may result in pain, dysphonia, dysphagia, dyspnea and inability to clear secretions.
    2) Alveolar hemorrhage is an uncommon occurrence. It has resulted in dyspnea, chest tightness, and anemia.
    3) A hemothorax was reported following warfarin therapy to treat ischemic cardiomyopathy.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Intracranial hemorrhage and hematomyelia may occur following warfarin therapy.
    B) WITH POISONING/EXPOSURE
    1) Intracranial hemorrhage and hematomyelia may occur following warfarin therapy.
    0.2.8) GASTROINTESTINAL
    A) WITH THERAPEUTIC USE
    1) Abdominal pain, vomiting, gastrointestinal bleeding, hemoptysis, hematochezia, and melena may occur.
    B) WITH POISONING/EXPOSURE
    1) Abdominal pain, vomiting, gastrointestinal bleeding, hemoptysis, hematochezia, and melena may occur.
    0.2.9) HEPATIC
    A) WITH THERAPEUTIC USE
    1) RELATED COMPOUND - Hepatitis and hepatic hematomas have been reported following oral coumarin anticoagulant use.
    0.2.10) GENITOURINARY
    A) WITH POISONING/EXPOSURE
    1) Hematuria may occur
    0.2.13) HEMATOLOGIC
    A) WITH POISONING/EXPOSURE
    1) Bleeding is the most common sign. It may manifest as epistaxis, hemoptysis, hematuria, hematospermia, subconjunctival hemorrhage, gingival bleeding, gastrointestinal bleeding, hematochezia, melena, vaginal bleeding, bruising, or abdominal and back pain.
    0.2.14) DERMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Skin necrosis, rash, alopecia, and "purple toe" syndrome may occur.
    2) Dermal necrosis has been reported with therapeutic warfarin administration for as little as 72 hours. The lesions may be ecchymotic, mottled, or erythematous.
    B) WITH POISONING/EXPOSURE
    1) Warfarin may be absorbed through the skin and cause systemic poisoning.
    0.2.15) MUSCULOSKELETAL
    A) WITH THERAPEUTIC USE
    1) Acute compartment syndrome and carpal tunnel syndrome have been reported following therapeutic use of warfarin.
    0.2.20) REPRODUCTIVE
    A) Warfarin is contraindicated in pregnant women. Warfarin passes through the placental barrier and there is the potential for fatal hemorrhage to the fetus in utero. The use of warfarin during pregnancy has been associated with teratogenic effects.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no data were available to assess the carcinogenic potential of this agent.
    0.2.22) OTHER
    A) WITH THERAPEUTIC USE
    1) Hereditary resistance to the anticoagulant effects of warfarin has been reported.

Laboratory Monitoring

    A) Asymptomatic children with an inadvertent ingestion do not require any testing.
    B) Monitor INR, vital signs, and complete a clinical exam for evidence bleeding. If the INR is normal, no additional testing is required with the initial evaluation, but serial INR testing over several days may be needed as the INR may not increase for several days.
    C) Monitor serial hemoglobin and/or hematocrit in patients with a prolonged INR or clinical evidence of bleeding.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Monitor INR and hemoglobin, evaluate for clinical evidence of bleeding. Warfarin should be withheld until INR approaches therapeutic range.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Supportive care, including intravenous crystalloids, oxygen, and mechanical ventilation may be required. With significant bleeding, hemorrhagic shock may result, and patients may require transfusions of packed red blood cells and fresh frozen plasma. Products such as cryoprecipitate, and other factor concentrates may be required for severe bleeding. Vitamin K1 (5 to 10 mg) every 6 hours should also be administered, higher doses for more significant ingestions. Surgical consultation may be required depending on the extent and location of hemorrhage.
    C) DECONTAMINATION
    1) PREHOSPITAL: Emesis should probably be avoided because of the risk of subsequent bleeding. Patients on chronic anticoagulation therapy should receive activated charcoal after an acute overdose unless contraindicated.
    2) HOSPITAL: Activated charcoal should be considered following a large, recent ingestion in a patient who does not have evidence of significant GI bleeding.
    D) ANTIDOTE
    1) PHYTONADIONE: Vitamin K1 (phytonadione): An oral formulation is preferred for patients who do not have severe hemorrhage. For acute ingestions, vitamin K1 is rarely indicated. Low dose vitamin K1 may be administered for patients with mildly elevated INRs who are clinically asymptomatic. For treatment of significantly elevated INR and/or bleeding, the following guidelines are recommended by the American College of Chest Physicians: INR LESS THAN 5.0, NO SIGNIFICANT BLEEDING: Lower warfarin dose or omit next dose of warfarin and monitor INR; INR BETWEEN 5.0 AND 9.0, NO SIGNIFICANT BLEEDING: Omit next 1 or 2 doses of warfarin OR omit next warfarin dose and administer oral Vitamin K1 (1 to 2.5 mg). If more rapid reversal is necessary, give oral Vitamin K1 (less than or equal to 5 mg) and repeat INR in 24 hours. Give additional vitamin K1 orally (1 to 2 mg) as needed. INR GREATER THAN 9.0, NO SIGNIFICANT BLEEDING: Hold warfarin therapy and give oral Vitamin K1 (2.5 to 5 mg). Repeat INR in 24 hours. Give additional Vitamin K1, if necessary. SERIOUS BLEEDING: Hold warfarin. Administer 10 mg Vitamin K1 by slow intravenous infusion along with fresh frozen plasma, prothrombin complex concentrates (PCC), or factor VII until bleeding is controlled. Follow INR. Vitamin K1 administration may need to be repeated every 12 hours.
    E) ENHANCED ELIMINATION
    1) There is no role for enhanced elimination.
    F) PITFALLS
    1) Failure to recognize signs and symptoms of hemorrhagic shock, delay in the diagnosis of a source of hemorrhagic shock and a delay in supportive care. Follow-up requires following reversal of anticoagulation, especially in patients on chronic anticoagulation. Full reversal may not be desirable if the patient's underlying medical condition requires anticoagulation. Failure to recognize drug interactions that cause excessive anticoagulation in patients on warfarin.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Children with inadvertent ingestions of 0.5 mg/kg or less of warfarin can be observed at home. While children with larger single ingestions may develop prolongation of INR/PT, clinically significant bleeding has not been reported in this setting; a PT or INR is probably NOT routinely necessary in these children unless bleeding develops. A medical evaluation may be necessary, if there is any suspicion of chronic ingestion, coingestants, or in a child with a history of bleeding diathesis.
    2) OBSERVATION CRITERIA: Any patient with deliberate ingestions, a significant ingestion, or patients with comorbidities, should be referred to a health care facility for observation. Patients who are asymptomatic and who have a normal INR at baseline can be followed as an outpatient or on a psychiatric ward with twice daily INR. All symptomatic patients should be sent to a health care facility for observation.
    3) ADMISSION CRITERIA: Patients with bleeding should be admitted. Patients with significantly elevated INR, and significant comorbidities, may also require admission until the INR is improving. Patients with hypotension, or significant hemorrhage, should be admitted to an intensive care unit.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity. A hematology consult should also be considered. If significant hemorrhage develops, surgical consultation may be warranted.
    H) PHARMACOKINETICS
    1) Warfarin is completely absorbed by GI tract, and peak concentrations occur in the first 3 hours. Metabolized by multiple CYP enzymes, including CYP1A2, 3A4, and 2C9. Protein binding is 99%; a volume of distribution of approximately 0.14 L/kg. The terminal half-life of warfarin after a single dose is approximately 1 week; however the effective half-life ranges from 20 to 60 hours (mean: approximately 40 hours). In therapeutic use, an anticoagulant effect usually occurs within 24 hours after drug administration. The duration of action of a single dose of racemic warfarin is 2 to 5 days.
    I) DRUG INTERACTIONS
    1) Many xenobiotics can interact with warfarin anticoagulation, both by potentiation and antagonism, either by affecting warfarin protein biding, or affecting metabolism by cytochrome P450 (CYP2C9 (primary isoenzyme), CYP2C19, CYP2C8, CYP2C18, CYP1A2, and CYP3A4).
    J) DIFFERENTIAL DIAGNOSIS
    1) Superwarfarin overdose, other oral anticoagulant overdose, heparin or low molecular heparin overdose (this will cause bleeding with generally normal INR), DIC, hepatic failure, factor deficiency, Vitamin K deficiency, or von Willebrand disease.
    0.4.3) INHALATION EXPOSURE
    A) Absorbed by inhalation. Respirators must be used when spraying this agent.
    B) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) Significant dermal absorption may occur.
    2) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

    A) TOXICITY: A toxic dose is highly variable. ADULT: Small ingestions (10 to 20 mg) in adults will not cause serious intoxication. However, chronic or repeated supratherapeutic ingestions of small amounts, or drug interactions in patients on a stable warfarin dose, can cause significant anticoagulation. PEDIATRIC: Greater than 0.5 mg/kg may prolong PT/INR; usually without bleeding. A relationship between mg/kg ingested and amount of hypocoagulability has not yet been established.
    B) THERAPEUTIC DOSE: ADULT: INITIAL DOSE: 2 to 5 mg/day orally with dosage adjustments based on INR response. MAINTENANCE DOSE: Range 2 to 10 mg/day orally. PEDIATRIC: INFANTS and CHILDREN: Loading: 0.2 mg/kg/dose, daily for 2 days, followed by daily doses determined by the INR; Maximum: Up to 10 mg/dose.
    C) Death from severe hemorrhagic complications has been reported in persons who ate food made with warfarin sodium baited cornmeal. Ingestion of a total of 1 g of warfarin over a 13-day period resulted in death.
    D) BAITS: Large amounts of warfarin containing grain bait do not usually produce significant toxicity because of the small concentration of the warfarin and poor absorption in large amounts of grain.

Clinical Effects

Summary Of Exposure

    A) USES: Therapeutic anticoagulation medication used for the treatment of deep venous thrombosis, pulmonary embolism, and other hypercoagulable states, and to prevent thromboembolic complications in patients with atrial fibrillation, prosthetic heart valves, or recent myocardial infarction. It may also be used to prevent thromboembolic complications in patients with stroke, impaired left ventricular function, or cancer.
    B) EPIDEMIOLOGY: Exposures are common. Inadvertent exposures rarely produce clinical effects. A single deliberate overdose generally does not result in coagulopathy, but a large ingestion by a patient who is chronically using warfarin may produce significant coagulopathy. Adverse events during therapeutic dosing are common.
    C) PHARMACOLOGY: Inhibits hepatic synthesis of Vitamin K dependent factors: II, VII, IX, and X, and also inhibits the activity of vitamin K 2,3-epoxide reductase.
    D) TOXICOLOGY: Excessive inhibition of factors II, VII, IX, and X can cause significant prolongation of INR and excessive bleeding after minor trauma. The risk of hemorrhage depends on patient comorbidities and severity of anticoagulation.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: The primary adverse effect is bleeding, which can be more severe with comorbid conditions, such as advanced age and liver dysfunction. Warfarin can also cause skin necrosis. Warfarin is a human teratogen and increases the risk of fetal death.
    F) WITH POISONING/EXPOSURE
    1) OVERDOSE: GENERAL: Excessive chronic doses, drug interactions, and less commonly acute overdose can cause profound anticoagulation. Effects can include bleeding at virtually any site: epistaxis, bleeding from gums, ecchymosis, hematochezia, hematuria, menorrhagia, hemarthrosis, and bleeding from minor skin or soft tissue trauma.
    2) SEVERE TOXICITY: More life-threatening complications include intracranial hemorrhage, retroperitoneal hemorrhage, or massive gastrointestinal bleed.

Vital Signs

    3.3.4) BLOOD PRESSURE
    A) WITH THERAPEUTIC USE
    1) Hypotension may occur as a result of hemorrhage due to warfarin therapy, particularly in patients who are over anticoagulated (Papagiannis et al, 1995).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) CONGENITAL EYE ABNORMALITIES
    a) The offspring of women taking therapeutic warfarin during pregnancy have had a variety of ophthalmic disorders including optic atrophy, large eyes, microphthalmos, and opacified lenses (Grant, 1993).
    B) WITH POISONING/EXPOSURE
    1) RETINAL HEMORRHAGE
    a) Retinal hemorrhage may occur in warfarin poisoning (Grant, 1993).
    2) HYPHEMAS
    a) Hyphemas may be seen in warfarin poisoning (Grant, 1993).
    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) EPISTAXIS
    a) Epistaxis has been reported as a result of anticoagulation therapy with warfarin (Kumer & Nwangwu, 1981; Denholm et al, 1993).
    3.4.6) THROAT
    A) WITH THERAPEUTIC USE
    1) ARYTENOID HEMATOMA
    a) Arytenoid hematoma has been reported in a patient with over anticoagulation secondary to warfarin therapy and a 10-day history of cough secondary to acute bronchitis (Jandreau & Mayer, 1998).
    b) LINGUAL HEMORRHAGE
    1) CASE REPORT: A 72-year-old woman presented with progressive tongue swelling, pitting edema of the lower extremities and swelling of the distal forearms bilaterally. Her medications included: benazepril, famotidine, felodipine, warfarin, thyroxine, and digoxin. Laboratory analysis showed an INR of 39.5. One month prior to presentation, the patient's INR was within the therapeutic range of 2.0 to 3.0. Several hours after admission the patient exhibited ecchymoses and she was intubated for airway protection. Following administration of fresh frozen plasma and vitamin K, the patient recovered and was subsequently extubated uneventfully. It is believed that diffuse lingual hemorrhage was the cause of the patient's tongue swelling, although the exact cause of the excessive anticoagulation was unclear (Shojania, 2000).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Hypotension and cardiac tamponade have been reported following warfarin therapy.
    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypotension may occur as a result of hemorrhage, most commonly in patients who are over anticoagulated (Papagiannis et al, 1995).
    B) PERICARDIAL EFFUSION
    1) WITH THERAPEUTIC USE
    a) CARDIAC TAMPONADE: A 67-year-old man, ingesting warfarin therapeutically for 2 years, presented with a 3-week history of weight gain, abdominal distension, exertional dyspnea and a PT of 30 seconds. Echocardiographies revealed pericardial effusion and cardiac tamponade. The patient's symptoms resolved following discontinuation of the warfarin and administration of vitamin K (Lee & Marwick, 1993).

Respiratory

    3.6.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Upper airway bleeding may result in pain, dysphonia, dysphagia, dyspnea and inability to clear secretions.
    2) Alveolar hemorrhage is an uncommon occurrence. It has resulted in dyspnea, chest tightness, and anemia.
    3) A hemothorax was reported following warfarin therapy to treat ischemic cardiomyopathy.
    3.6.2) CLINICAL EFFECTS
    A) PULMONARY HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) UPPER AIRWAY HEMORRHAGE: Spontaneous upper airway hemorrhage can result in fatal asphyxia; 7 of 12 reported cases required airway control. Presenting symptoms include pain (all cases), dysphonia, dysphagia, dyspnea and inability to clear secretions (Boster & Bergin, 1983).
    b) ALVEOLAR HEMORRHAGE: Diffuse alveolar hemorrhage developed in a 33-year-old man, resulting in dyspnea, chest tightness, and anemia. The patient's medications, prior to the presenting symptoms, included warfarin and meperidine, his INR was 61.4 and his warfarin plasma level was 7.4 mcg/mL (Papagiannis et al, 1995).
    B) HEMOTHORAX
    1) WITH THERAPEUTIC USE
    a) A 53-year-old man developed shortness of breath, cough, and exertional dyspnea following chronic use of warfarin (PT greater than 40 seconds). A chest radiograph revealed a large pleural effusion within the left chest, and a hemothorax was demonstrated on thoracotomy (Kollef & Gronski, 1994).

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Intracranial hemorrhage and hematomyelia may occur following warfarin therapy.
    B) WITH POISONING/EXPOSURE
    1) Intracranial hemorrhage and hematomyelia may occur following warfarin therapy.
    3.7.2) CLINICAL EFFECTS
    A) INTRACRANIAL HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) Hylek and Singer (1994) conducted a case-control study to determine the risk of intracranial hemorrhage in warfarin users, especially among the elderly. Results of this study showed that an increase in prothrombin time ratio (PTR) above 2.0 increased the risk for an intracranial hemorrhage. Age was also a risk factor. The risk for a subdural hemorrhage doubled with each 10-year increase in age. These two risk factors indicate the necessity of careful control of anticoagulation with warfarin, especially among elderly patients (Hylek & Singer, 1994).
    b) Acute intracranial hemorrhage was reported in two patients with atrial fibrillation who were on warfarin therapy (Freeman et al, 2004).
    1) The first patient was a 77-year-old man who presented to the ED with a severe headache and a GCS of 14. The patient was disoriented and had developed a left homonymous hemianopia and left hemiparesis. A CT scan revealed acute intracranial hemorrhage. Following intravenous administration of recombinant factor VIIa, fresh frozen plasma, subcutaneous vitamin K, and an emergent craniotomy, the patient was eventually discharged with persistent left homonymous hemianopia and left hemiparesis.
    2) The second patient was an 81-year-old woman who presented to the ED with weakness in her right arm, leg, and face. A neurologic exam showed global aphasia, right hemiparesis, and right homonymous hemianopia. The patient's initial GCS was 14. A CT scan revealed an acute left thalamic intracranial hemorrhage. Following intravenous administration of recombinant factor VIIa, fresh frozen plasma, and subcutaneous administration of vitamin K, the patient was eventually discharged with persistent right hemiparesis and aphasia.
    c) According to a study that used multiple logistic regression analyses to predict functional outcome and in-hospital mortality of patients admitted for oral anticoagulant-induced intracerebral hemorrhage, the diameter of the hematoma on CT scan was more predictive of clinical outcome than the INR measurement (Berwaerts et al, 2000).
    2) WITH POISONING/EXPOSURE
    a) A 39-year-old woman presented to the ED with symptoms of headache, dyspnea, nausea, vomiting, and double vision. Prior to the presentation of these symptoms, the patient had been administering weekly applications of a warfarin-type rat poison, with her bare hands, to areas of her house. She would not routinely wash her hands afterwards. The patient's PT and PTT were prolonged (31.1 and 59.9 seconds respectively) and a CT scan of the head revealed an intracerebellar hematoma (Abell et al, 1994).
    B) HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) HEMATOMYELIA: Hematomyelia, an uncommon occurrence, has been reported following warfarin therapy. Symptoms include paresis, back or neck pain, and urinary incontinence. A CT scan or magnetic resonance imaging (MRI) usually confirms the diagnosis (Murphy & Nye, 1991; Constantini et al, 1992; Liebeschuetz et al, 1994; Pullarkat et al, 2000).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Abdominal pain, vomiting, gastrointestinal bleeding, hemoptysis, hematochezia, and melena may occur.
    B) WITH POISONING/EXPOSURE
    1) Abdominal pain, vomiting, gastrointestinal bleeding, hemoptysis, hematochezia, and melena may occur.
    3.8.2) CLINICAL EFFECTS
    A) GASTROINTESTINAL HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) Abdominal pain, vomiting, gastrointestinal bleeding, hemoptysis, hematochezia, and melena may occur following warfarin administration (Avent et al, 1992; Kollef & Gronski, 1994).
    1) One study on the management and prognosis of life-threatening bleeding during warfarin therapy, demonstrated that the gastrointestinal tract was the site of bleeding in two-thirds of the patients (White et al, 1996).
    2) WITH POISONING/EXPOSURE
    a) Abdominal pain, vomiting, gastrointestinal bleeding, hemoptysis, hematochezia, and melena may occur following warfarin exposure (Kumer & Nwangwu, 1981; EPA, 1985).
    B) GASTROINTESTINAL TRACT FINDING
    1) WITH THERAPEUTIC USE
    a) Nausea, vomiting, diarrhea, taste perversion, abdominal pain, flatulence and bloating can develop with therapeutic use of warfarin (Prod Info COUMADIN(R) oral tablets, intravenous injection powder lyophilized for solution, 2011).
    C) ULCER OF ESOPHAGUS
    1) WITH THERAPEUTIC USE
    a) A 58-year-old woman presented with severe interscapular pain and vomiting 4 weeks after beginning warfarin therapy. An upper intestinal endoscopy revealed a midesophageal ulcer with an overlying blood clot. The lower third of the esophagus, stomach, and duodenum appeared to be normal (Loft et al, 1989).

Hepatic

    3.9.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) RELATED COMPOUND - Hepatitis and hepatic hematomas have been reported following oral coumarin anticoagulant use.
    3.9.2) CLINICAL EFFECTS
    A) TOXIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) RELATED COMPOUND: A 56-year-old woman developed jaundice and markedly elevated liver enzymes eight months after beginning oral anticoagulant therapy with phenprocoumon. A liver biopsy revealed acute hepatitis. Anticoagulation was changed to intravenous heparin, resolving the hepatitis. Exposure, one month later, to phenprocoumon caused fatigue, jaundice, and elevated liver enzyme levels in the patient. A liver biopsy showed signs of mild cholestasis. The phenprocoumon was again discontinued and IV heparin was begun, with subsequent normalization of liver enzyme levels to return to normal. The patient was started on oral warfarin therapy, causing the liver enzyme levels to once again rise. The warfarin was discontinued and subcutaneous low molecular weight heparin was started, with subsequent normalization of liver enzyme levels (Hohler et al, 1994).
    B) HEMORRHAGE OF LIVER
    1) WITH THERAPEUTIC USE
    a) Erichson et al (1993) reported the case of a 55-year-old woman who developed severe epigastric pain following the combination use of warfarin and trimethoprim-sulfamethoxazole. Ultrasonography and CT scans revealed several large liver hematomas.

Genitourinary

    3.10.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Hematuria may occur
    3.10.2) CLINICAL EFFECTS
    A) HEMORRHAGE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 38-year-old man, with a history of aortic valve replacement, presented with acute left flank pain and hematuria after ingesting an unknown amount of warfarin as a suicide attempt. Laboratory analysis showed a PT of 48 seconds. Excretory urography and a CT scan of the kidney indicated a uroepithelial hemorrhage. The patient recovered after discontinuation of the warfarin (Vitellas et al, 2000).

Hematologic

    3.13.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Bleeding is the most common sign. It may manifest as epistaxis, hemoptysis, hematuria, hematospermia, subconjunctival hemorrhage, gingival bleeding, gastrointestinal bleeding, hematochezia, melena, vaginal bleeding, bruising, or abdominal and back pain.
    3.13.2) CLINICAL EFFECTS
    A) HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) SUMMARY: Warfarin can lead to severe or fatal bleeding. Bleeding is most likely to occur within the first month of starting therapy (Prod Info COUMADIN(R) oral tablets, intravenous injection powder lyophilized for solution, 2011).
    b) RISK FACTORS: High intensity of anticoagulation (INR greater that 4.0), older than 65 years of age, history of highly variable INRs, history of GI bleeding, hypertension, cerebrovascular disease, anemia, malignancy, trauma renal impairment, certain genetic factors, certain concomitant drugs and long duration of warfarin therapy (Prod Info COUMADIN(R) oral tablets, intravenous injection powder lyophilized for solution, 2011).
    c) Other bleeding complications reported include epistaxis, hemoptysis, hematuria, gingival bleeding, hematochezia, guaiac positive stool, bruising, vaginal bleeding, subconjunctival hemorrhage, and hematospermia (Gurwitz et al, 1988).
    2) WITH POISONING/EXPOSURE
    a) Signs/symptoms: Bleeding is the most common sign, and may manifest as epistaxis, gingival bleeding, hemoptysis, hematuria, gastrointestinal bleeding, hematochezia, melena, bruising, hematomas around joints and on buttocks, or abdominal and back pain (Kumer & Nwangwu, 1981; Sittig, 1985; Vanscoy & McAuley, 1991; Norcross et al, 1993).
    1) In rare instances, warfarin has produced retinal hemorrhages and hyphema (Grant, 1993). Later, paralysis due to cerebral hemorrhage, and finally hemorrhagic shock and death may occur (EPA, 1985).
    b) Onset: Increased prothrombin time from a toxic dose usually appears within 24 hours of ingestion and peaks between 36 to 72 hours (Kumer & Nwangwu, 1981).
    c) Fatalities: Most fatal bleeding was cerebral in origin (Levine et al, 1989).
    d) Risk factors: Persons with a history of blood disorders with bleeding tendencies would be expected to be at increased risk from exposure (EPA, 1985). Hereditary resistance of people to warfarin, as well as suspected hereditary susceptibility, has been reported (HSDB , 1991).
    3.13.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HYPOVITAMINOSIS
    a) ANIMAL STUDIES: Animal data have shown that warfarin can cross the skin and induce acute Vitamin K deficiency in baboons in less than three days (Dreyfus et al, 1983).

Dermatologic

    3.14.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Skin necrosis, rash, alopecia, and "purple toe" syndrome may occur.
    2) Dermal necrosis has been reported with therapeutic warfarin administration for as little as 72 hours. The lesions may be ecchymotic, mottled, or erythematous.
    B) WITH POISONING/EXPOSURE
    1) Warfarin may be absorbed through the skin and cause systemic poisoning.
    3.14.2) CLINICAL EFFECTS
    A) SKIN NECROSIS
    1) WITH THERAPEUTIC USE
    a) SUMMARY: Tissue necrosis and/or gangrene of the skin has occurred infrequently, but may be a serious risk (Prod Info COUMADIN(R) oral tablets, intravenous injection powder lyophilized for solution, 2011).
    b) A 45-year-old woman developed bilateral breast necrosis following warfarin therapy. Amputation of both breasts was necessary (Valle & Hebert, 1992).
    c) RELATED COMPOUND: Skin necrosis may result from therapeutic levels of both bishydroxycoumarin (dicoumarol) and warfarin sodium (Lacy & Goodin, 1975; Humphries et al, 1991; Colman et al, 1993; Eby, 1993; LaPrade et al, 1993; Locht & Lindstrom, 1993; DeFranzo et al, 1995; Gelwix & Beeson, 1998).
    d) RELATED COMPOUND: Dermal necrosis has been reported with therapeutic warfarin sodium administration for as little as 72 hours (Martin et al, 1970).
    e) Necrotic areas may be ecchymotic, mottled, or erythematous (Martin et al, 1970).
    f) Skin necrosis and venous limb gangrene have been reported in several patients with heparin-induced thrombocytopenia who received warfarin as alternative anticoagulant therapy, either as sole therapy or in combination with a direct thrombin inhibitor (Srinivasan et al, 2004).
    B) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Rash, dermatitis (including bullous eruptions), and pruritus can occur with therapeutic use of warfarin (Prod Info COUMADIN(R) oral tablets, intravenous injection powder lyophilized for solution, 2011).
    b) Although rare, maculopapular rash secondary to coumarin derivatives is reported (Kruis-de Vries et al, 1989; Antony et al, 1993).
    C) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) Alopecia may develop with therapy (Prod Info COUMADIN(R) oral tablets, intravenous injection powder lyophilized for solution, 2011; Umlas & Harken, 1988). The response is directly related to the highest dose given and not to the duration of treatment. Hair is shed diffusely 2 or 3 months after an adequate dose of the drug (Rook, 1965).
    D) DISCOLORATION OF SKIN
    1) WITH THERAPEUTIC USE
    a) "PURPLE TOE" SYNDROME: The "purple toe" syndrome, characterized as a dark cutaneous lesion with blue discoloration of the feet and lower leg, has been reported as an unusual adverse effect following therapeutic use of warfarin (Soisson et al, 1994).
    E) SKIN ABSORPTION
    1) WITH POISONING/EXPOSURE
    a) Warfarin may be absorbed through the skin (Fristedt & Sterner, 1965).
    b) Hemorrhagic disease has been reported following the application and transcutaneous uptake of warfarin-contaminated talc (Martin-Bouyer et al, 1983; Dreyfus et al, 1983).
    3.14.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) PERCUTANEOUS ABSORPTION
    a) Animal data have shown that warfarin can be absorbed through the skin and induce acute Vitamin K deficiency in baboons in less than three days (Dreyfus et al, 1983).

Musculoskeletal

    3.15.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Acute compartment syndrome and carpal tunnel syndrome have been reported following therapeutic use of warfarin.
    3.15.2) CLINICAL EFFECTS
    A) COMPARTMENT SYNDROME
    1) WITH THERAPEUTIC USE
    a) Hay et al (1992) reported four cases of disproportionate intracompartmental bleeding, developing into a compartment syndrome, in patients chronically ingesting warfarin and suffering from minor muscle trauma. All patients made complete recoveries.
    B) TENDINITIS
    1) WITH THERAPEUTIC USE
    a) CARPAL TUNNEL SYNDROME: A 26-year-old woman developed severe pain and swelling in her left hand three months after initiating warfarin therapy (PT 26 seconds). The symptoms became apparent following mild trauma to her left hand. Surgery revealed a hematoma in the carpal canal. Complete resolution of symptoms occurred following carpal tunnel release surgery (Bonatz & Seabol, 1993).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) ADRENAL CORTICAL HYPOFUNCTION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 55-year-old woman taking warfarin for a deep venous thrombosis developed acute adrenal insufficiency complicated by refractory hypotension secondary to bilateral adrenal hemorrhage (LeMense & Strange, 1994).

Reproductive

    3.20.1) SUMMARY
    A) Warfarin is contraindicated in pregnant women. Warfarin passes through the placental barrier and there is the potential for fatal hemorrhage to the fetus in utero. The use of warfarin during pregnancy has been associated with teratogenic effects.
    3.20.2) TERATOGENICITY
    A) SKELETAL MALFORMATION
    1) Characteristic skeletal anomalies (warfarin embryopathy) have been commonly associated with warfarin use during the first trimester and central nervous system defects when given later in pregnancy (Kaplan, 1985; Schardein, 1985).
    B) CONGENITAL ANOMALY
    1) FIRST TRIMESTER: The use of coumarin derivatives during the first trimester of pregnancy has resulted in characteristic anomalies (fetal warfarin syndrome), including nasal hypoplasia with or without choanal atresia, secondary respiratory deficiency, dextrocardia, abdominal situs inversus, calcified stippled epiphyses, reduced birth weight, rhizomelia (short proximal limbs), scoliosis, short phalanges, and growth or mental retardation (Prod Info COUMADIN(R) oral tablets, IV injection, 2007; Hall et al, 1980; Mason et al, 1992; Wong et al, 1993; Barker et al, 1994; Wellesley et al, 1998).
    2) SECOND AND THIRD TRIMESTER: Second- and third-trimester exposure have been associated with central nervous system (CNS) defects, although not characteristically grouped (Hall et al, 1980; Iturbe-Alessio et al, 1986; Pauli, 1988; Pati & Helmbrecht, 1994). CNS defects include mental retardation, optic atrophy, spasticity, and seizures. Fetal death, neonatal hemorrhage, and increased risk of maternal hemorrhage are also potential complications of second- or third-trimester anticoagulant therapy (Prod Info COUMADIN(R) oral tablets, IV injection, 2007; Abadi et al, 2002; Wong et al, 1993).
    3) Asplenia and delayed psychomotor development have also been reported (Cox, 1977; Holzgreve, 1976). Craniofacial (including nose and tongue), musculoskeletal, skin, gastrointestinal, and cardiovascular developmental abnormalities have been observed in humans (Lewis, 1996).
    4) CONGENITAL OPHTHALMIC ABNORMALITIES: The offspring of women taking therapeutic warfarin during pregnancy have had a variety of ophthalmic disorders including optic atrophy, large eyes, microphthalmos, and opacified lenses (Grant, 1993).
    5) EXCESSIVE DOSES: Some of these complications have been associated with excessive doses and failure to stop warfarin for a sufficient time prior to delivery (Witter et al, 1981; Lamontagne et al, 1984; Hall et al, 1980; Kort & Cassel, 1981).
    6) DOSE-DEPENDENCE: In a retrospective review of 43 women with mechanical heart valves and 58 pregnancies over a 10-year period, investigators observed a dose-dependent effect of warfarin on fetal complications. The patients received warfarin throughout pregnancy to maintain the international normalized ratio (INR) between 2.5 and 3.5, and underwent planned caesarian section at 38 weeks, 2 days after temporary warfarin discontinuation. The 58 pregnancies resulted in 31 healthy infants and 27 fetal complications. Among 33 pregnancies in women on a warfarin dose of 5 mg/day or less, there were 28 healthy infants (27 full-term and 1 premature) and 5 fetal complications (4 miscarriages and 1 growth retardation). Among 25 pregnancies in women on a warfarin dose above 5 mg/day, there were 3 full-term healthy infants and 22 fetal complications (18 miscarriages, 2 warfarin embryopathies of cartilage maldevelopment, 1 stillbirth, and 1 ventricular septal defect). The difference in fetal complications between the two warfarin dose groups was statistically significant (p=0.0001). Maternal complications included two cases of valve thrombosis, with no bleeding events (Vitale et al, 1999).
    7) Long term anticoagulant therapy is often indicated in patients with heart valves or thromboembolic disease, and the teratogenic potential of these therapeutic agents may contraindicate pregnancy. However, high-risk pregnancies may be inherent in this patient population, regardless of drug treatment (Hall et al, 1980a; Nageotte et al, 1981; Born et al, 1992).
    8) ANIMAL STUDIES
    a) In rodent studies, postimplantation mortality, fetotoxicity, musculoskeletal and craniofacial developmental abnormalities, biochemical and metabolic changes, fetal death, extra-embryonic structures, fertility changes and still births have been observed ((RTECS, 1998)).
    C) LACK OF EFFECT
    1) In one case, serial fetal blood samples showed adequate clotting status between 33 and 38 weeks of gestation when a pregnant woman was treated with warfarin 1 mg/day for antithrombin III deficiency that could not be managed with heparin (Porreco et al, 1993). It cannot, however, be concluded from this single case that this dose of warfarin is safe for the unborn, because the child would require long-term follow-up evaluation to exclude latent developmental effects.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY DISORDER
    1) Because warfarin passes through the placental barrier, fatal hemorrhage to the fetus in utero may occur (Prod Info COUMADIN(R) oral tablets, intravenous injection, 2015; Prod Info COUMADIN(R) oral tablets, IV injection, 2007).
    2) An increased risk of spontaneous abortion with no congenital abnormalities has been associated with warfarin therapy received during weeks 13 through 37 of pregnancy (Lee, 1986).
    3) In one study, nearly 29% of pregnancies in 115 women receiving coumarin derivatives resulted in malformations, including structural defects (13.9%), in utero fetal death (13%), and neonatal hemorrhage (1.8%) (Guillot, 1979). In another study of 418 pregnancies exposed to warfarin, 2 out of 3 had normal outcomes, 1 of 6 had malformations, and 1 of 6 resulted in abortion or stillbirth (Hall et al, 1980).
    4) In a study of 40 patients with heart disease who received warfarin therapy during pregnancy, fetal mortality was 12.5%, but no cases of congenital epiphyseal stippling were detected. Maternal postpartum bleeding, however, was frequent (Kort & Cassel, 1981).
    5) In a study of 52 patients with mechanical valve prostheses who had a total of 71 pregnancies (52 first pregnancies and 19 subsequent pregnancies) and who were on long-term warfarin therapy for the duration of their pregnancies, spontaneous abortions occurred in 23 of the pregnancies, stillbirths occurred in 5 of the pregnancies, and embryopathies occurred in 2 of the pregnancies. Poor pregnancy outcome appeared to be directly related to the warfarin dose. A warfarin daily dose of greater than 5 mg was associated with a poor pregnancy outcome in 27 of 30 pregnancies as compared with a warfarin daily dose of 5 mg or less that was associated with a poor pregnancy outcome in 3 of 30 pregnancies (Cotrufo et al, 2002).
    B) HEMORRHAGE
    1) FETAL INTRAVENTRICULAR HEMORRHAGE was detected in the third trimester of pregnancy following maternal ingestion of warfarin. The infants died at 29 and 33 weeks gestation (Ville et al, 1993).
    C) RISK SUMMARY
    1) Warfarin is contraindicated in pregnant women (Prod Info COUMADIN(R) oral tablets, intravenous injection, 2015), except for women with mechanical heart valves who are pregnant and at high risk for thromboembolism (Prod Info COUMADIN(R) oral tablets, intravenous injection, 2015).
    D) PREGNANCY CATEGORY
    1) Anisindione is classified as FDA pregnancy category X (Prod Info MIRADON(R) oral tablets, 2001). Coumarin derivatives, dicumarol, nicoumalone, phenindione, and phenprocoum are all classified as FDA pregnancy category D (Briggs et al, 1998).
    E) PLACENTAL BARRIER
    1) Warfarin freely crosses the placenta and results in hemorrhagic complications in the fetus. Warfarin (administered as sodium warfarin) was found to bind less tightly to fetal albumin in comparison to albumin in both pregnant and nonpregnant women. Levels of free warfarin were higher in the fetus (Bajoria et al, 1996). This implies that the fetus would be exposed to higher effective concentrations of warfarin than the mother.
    F) ABORTION
    1) A high incidence of spontaneous abortion (9 of 18 pregnancies) in the absence of congenital malformations occurred when warfarin was given between the 13th and 37th weeks of pregnancy (Lee, 1986a).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) LACK OF EFFECT
    a) Based on limited data, warfarin is not present in the breast milk of nursing mothers treated with warfarin. There are no reports of the effect of concomitant breast feeding and warfarin use on a premature nursing infant (Prod Info COUMADIN(R) oral tablets, intravenous injection, 2015; Prod Info COUMADIN(R) oral tablets, IV injection, 2007). Breast milk assays from a total of 28 mothers receiving 2 to 12 mg/day of warfarin exhibited nearly undetectable levels, and none of the infants had detectable plasma warfarin levels (Orme et al, 1977; DeSwiet & Lewis, 1977; McKenna et al, 1983).
    2) BREAST MILK
    a) Prolonged prothrombin times have been reported in some breastfed infants of mothers treated with warfarin; however, the prothrombin time in the mother is more prolonged (Prod Info COUMADIN(R) oral tablets, IV injection, 2007). Warfarin is considered compatible with breast feeding by The American Academy of Pediatrics and the World Health Organization (WHO) (Anon, 2002; Anon, 2001).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) No information about possible male reproductive effects was found in available references at the time of this review.

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no data were available to assess the carcinogenic potential of this agent.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the carcinogenic potential of this agent.

Genotoxicity

    A) Warfarin sodium induced mutations and DNA inhibition in mouse leukocytes.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Asymptomatic children with an inadvertent ingestion do not require any testing.
    B) Monitor INR, vital signs, and complete a clinical exam for evidence bleeding. If the INR is normal, no additional testing is required with the initial evaluation, but serial INR testing over several days may be needed as the INR may not increase for several days.
    C) Monitor serial hemoglobin and/or hematocrit in patients with a prolonged INR or clinical evidence of bleeding.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Warfarin plasma levels are generally not available.
    B) COAGULATION STUDIES
    1) PATIENTS NOT PRESENTLY ON ANTICOAGULANTS: The international normalized ratio (INR) or prothrombin time in patients consuming large quantities, or suspected of chronic ingestion, is helpful in diagnosis.
    a) Should be drawn between 12 and 24 hours postingestion.
    b) Any increase in INR or prolongation of prothrombin time when compared to normal controls, indicates toxicity. The risk of bleeding is minimal with a PT of 1.3 to 1.5 times control. At PT of 2 times control or greater there is an exponentially increased risk of bleeding.
    2) PATIENTS PRESENTLY ON ANTICOAGULANTS: Obtain INR or prothrombin time immediately. The INR (or PT) should be checked 6 hours after administration of FFP to determine the need for further therapy.
    3) Persons exposed to warfarin for more than a few days at a time should be monitored for increases in prothrombin time. Many clinical laboratories report unreliable results for prothrombin time. The most reliable indicator of prothrombin time is the International Normalized Ratio (INR). Only 50% of laboratories surveyed in Utah use this format, however, and of those that did, many reported incorrect values (Garr & Rodgers, 1994).
    4) Prothrombin time does not necessarily predict risk of bleeding for patients on warfarin, because the former is the end result of a complex mechanism involving several enzymatic reactions and 3 vitamin K dependent clotting factors (Thompson, 1996).
    C) HEMATOLOGIC
    1) Follow hematocrit closely, at least every 4 hours until stable.
    4.1.3) URINE
    A) URINALYSIS
    1) Check for blood in urine in symptomatic patients or in those with increased INR or prolonged PT.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Check stool and vomitus for occult blood in symptomatic patients or in those with increased INR or prolonged PT.

Radiographic Studies

    A) RADIOGRAPHIC-OTHER
    1) A lateral soft-tissue x-ray of the neck may show displacement or partial occlusion of the airway in cases of spontaneous hemorrhage into the neck (Lepore, 1976).
    2) Various imaging studies may be helpful in diagnosing spontaneous hemorrhage into various tissues or body compartments.

Methods

    A) Reverse-phase HPLC has been used to detect warfarin in plasma at concentrations as low as 6 ng/mL. Using this method, the terminal phase half-life of warfarin was approximately 1 week in healthy male volunteers (King et al, 1995).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with bleeding should be admitted. Patients with significantly elevated INR, and significant comorbidities, may also require admission until the INR is improving. Patients with hypotension, or significant hemorrhage, should be admitted to an intensive care unit.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Children with inadvertent ingestions of 0.5 mg/kg or less of warfarin can be observed at home. While children with larger single ingestions may develop prolongation of INR/PT, clinically significant bleeding has not been reported in this setting; a PT or INR is probably NOT routinely necessary in these children unless bleeding develops. A medical evaluation may be necessary, if there is any suspicion of chronic ingestion, coingestants, or in a child with a history of bleeding diathesis.
    1) Based on several studies, children with inadvertent ingestions of 0.5 mg/kg or less of warfarin can be observed at home. While children with larger single ingestions may develop prolongation of INR/PT (Carpentieri et al, 1976; Montanio et al, 1993).
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity. A hematology consult should also be considered. If significant hemorrhage develops, surgical consultation may be warranted.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Any patient with deliberate ingestions, a significant ingestion, or patients with comorbidities, should be referred to a health care facility for observation. Patients who are asymptomatic and who have a normal INR at baseline can be followed as an outpatient or on a psychiatric ward with twice daily INR. All symptomatic patients should be sent to a health care facility for observation.

Monitoring

    A) Asymptomatic children with an inadvertent ingestion do not require any testing.
    B) Monitor INR, vital signs, and complete a clinical exam for evidence bleeding. If the INR is normal, no additional testing is required with the initial evaluation, but serial INR testing over several days may be needed as the INR may not increase for several days.
    C) Monitor serial hemoglobin and/or hematocrit in patients with a prolonged INR or clinical evidence of bleeding.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Patients on chronic anticoagulation therapy should receive activated charcoal after an acute overdose unless contraindicated. Avoid emesis because of the risk of subsequent bleeding.
    a) An average child eating a few mouthfuls of 0.025% to 0.05% rat bait at a single sitting is generally not at risk. Prophylactic treatment is not necessary. Recent ingestion of large amounts may require gastrointestinal decontamination with activated charcoal.
    2) EMESIS/NOT RECOMMENDED
    a) In the setting of a warfarin overdose, emesis should probably be avoided because of the risk of subsequent bleeding.
    3) ACTIVATED CHARCOAL
    a) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    1) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    a) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    b) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    b) CHARCOAL DOSE
    1) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    a) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    2) ADVERSE EFFECTS/CONTRAINDICATIONS
    a) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    b) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    B) GASTRIC LAVAGE
    1) AVOID EMESIS OR LAVAGE in patients presently on anticoagulants because of the potential for trauma and bleeding. Administer activated charcoal as indicated above if recent ingestion suspected (as opposed to drug interaction or chronic supratherapeutic dosing).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Asymptomatic children with an inadvertent ingestion do not require any testing.
    2) Monitor INR, vital signs, and perform a clinical exam for evidence of bleeding. If the INR is normal, no additional testing is required at the time of initial evaluation, but serial INR testing over several days may be needed as the INR may not increase for several days.
    3) Monitor serial hemoglobin and/or hematocrit in patients with prolonged INR or clinical evidence of bleeding.
    B) SUPPORT
    1) PATIENTS NOT PRESENTLY ON ANTICOAGULANTS
    a) SMALL INGESTIONS: The average child eating a few mouthfuls of 0.025% to 0.050% rat bait at a single sitting is generally not at risk and prophylactic treatment is not necessary.
    b) AIM OF THERAPY: To restore the prothrombin level to normal.
    c) VITAMIN K
    1) INDICATIONS: Prophylactic treatment for a suspected large ingestion of warfarin is not recommended. PT or INR should be checked 24 hours after ingestion. If results are normal, PT and INR should be repeated at 48 hours after ingestion. If PT or INR is elevated, then Vitamin K1 (phytonadione, Aquamephyton(R)) may be given.
    2) DOSE: 1 to 5 mg orally (Child); 10 mg/orally (Adult). Parenteral dosing may be used in patients with active bleeding. SubQ or IM administration is generally associated with a lower risk of anaphylactoid reactions than IV administration.
    3) MAXIMUM DOSES: Doses of 25 to 50 mg in adults and up to 0.6 mg/kg in children under 12 years may be used. Repeat dose daily as necessary.
    a) IV USE: IV infusion of Aquamephyton(R) diluted in saline or glucose solution at an injection rate not exceeding 5% of the total dose per minute is recommended only in patients with significant bleeding or sever coagulopathy.
    4) ADVERSE EFFECTS: There is a slight risk of an anaphylactoid reaction with IV administration. The risk appears to be smaller after subQ or IM administration. Coagulopathy secondary to liver disease usually does not respond to vitamin K1 administration.
    d) TRANSFUSION
    1) Administer fresh frozen plasma and/or prothrombin complex concentrate and packed red blood cells as needed for significant active bleeding.
    2) The usual dose of fresh frozen plasma given to correct coagulation factor deficiency is 15 milliliters per kilogram, but the recommended dose required to reverse over anticoagulation due to warfarin has not been established (Baglin, 1998).
    2) PATIENTS PRESENTLY ON ANTICOAGULANTS
    a) MONITORING PARAMETERS
    1) Measure prothrombin level or INR immediately.
    2) Follow hematocrit closely, at least a reading every four hours until it is stable.
    3) All stools and vomitus should be hematested for occult blood.
    b) VITAMIN K
    1) The 2008 warfarin reversal guidelines from the American College of Chest Physicians (ACCP) consensus conference on antithrombotic therapy are as follows (Ansell et al, 2008):
    a) INR MORE THAN THERAPEUTIC RANGE, BUT LESS THAN 5: In the absence of clinically significant bleeding, lower dose or omit dose; monitor more frequently and resume at a lower dose when INR therapeutic; if only minimally above the therapeutic range, no dose reduction may be necessary.
    b) INR GREATER THAN OR EQUAL TO 5, BUT LESS THAN 9: In the absence of clinically significant bleeding, omit next 1 or 2 doses, monitor more frequently, and resume at an appropriately adjusted dose when INR is within therapeutic range. Alternatively, omit dose and give vitamin K (1 to 2.5 mg orally), particularly if the patient is at risk of bleeding.
    1) If more rapid reversal is required because the patient requires urgent surgery, vitamin K (less than or equal to 5 mg orally) can be given with the expectation that a reduction of the INR will occur in 24 hours. If the INR is still high, additional vitamin K (1 to 2 mg orally) can be given.
    c) INR GREATER THAN OR EQUAL TO 9: In the absence of clinically significant bleeding, hold warfarin therapy and give higher dose of vitamin K (2.5 to 5 mg orally) with the expectation that the INR will be reduced substantially in 24 to 48 hours. Monitor more frequently and use additional vitamin K, if necessary. Therapy can be resumed at the appropriate warfarin dose when INR is therapeutic.
    d) SERIOUS BLEEDING AT ANY ELEVATION OF INR: Hold warfarin therapy and give vitamin K (10 mg by slow IV infusion), supplemented with fresh frozen plasma (FFP), prothrombin complex concentrate (PCC), or recombinant factor VIIa (rVIIa), depending on the urgency of the situation; vitamin K can be repeated every 12 hours.
    e) LIFE-THREATENING BLEEDING: Hold warfarin therapy and give FFP, PCC or rVIIa supplemented with vitamin K (10 mg by slow IV infusion). Repeat, if necessary, depending on INR.
    f) ADMINISTRATION OF VITAMIN K: In patients with mild to moderated elevated INRs without major bleeding, give vitamin K orally rather than subQ.
    2) IV USE: If IV Aquamephyton(R) is used, it should be diluted in saline or glucose solution and administered at an injection rate not exceeding 5% of the total dose per minute.
    a) ADVERSE EFFECTS: There is a slight risk of an anaphylactoid reaction with IV administration. This risk appears to be smaller after subQ or IM administration. Coagulopathy secondary to liver disease usually does not respond to vitamin K administration (Shields et al, 2001).
    3) CASE REPORT/OVERDOSE: A 59-year-old woman intentionally ingested 540 mg of warfarin, clonazepam (4 mg) and 3 mouthfuls of bleach 6 hours prior to presentation. She vomited once after ingesting the bleach. Her physical exam was within normal limits with no evidence of bleeding. She was noted to have superficial self-inflicted cuts on her extremities. Upon admission, laboratory values included an INR of 5.1; PT, 18 and PTT, 57.2 seconds. Coagulation factors were VII, 7%; IX, 24%; and X, 8% (normal ranges, 75% to 150%). The patient received vitamin K (10 mg IV) and recombinant factors Vlla, and 3-factor concentrates shortly after admission. Six hours after vitamin K administration, INR was 0.5. The patient was then maintained on vitamin K 5 mg orally every 6 hours. After her transfer to psychiatry, vitamin K (5 mg) was reduced to 3 times a day. Thirteen days after admission, INR was 1.0 and vital signs were stable. She was discharged on aspirin only (Matthews et al, 2014).
    4) CASE REPORT: A 75-year-old man was diagnosed with atrial fibrillation and was arbitrarily prescribed 10 mg of warfarin daily as prophylactic therapy. Two months after initiating warfarin therapy, the patient presented with an elevated INR following a clinic visit. The patient's INR at the time was estimated to be 288; however, this was a gross calculation that had no meaning, but was indicative of excessive anticoagulation. His initial PT was 106 seconds. The patient was not actively bleeding and his CBC appeared to be normal. His INR gradually decreased to 1.8 ten hours after IV administration of 10 mg of vitamin K (Kitchens, 2001). It was later determined that the appropriate warfarin dose for this patient should be 2 to 2.5 mg/day.
    5) CLINICAL TRIALS
    a) In a clinical study to determine the effectiveness of subQ phytonadione (Vitamin K) in reversing warfarin-induced elevation of the INR, 47% of patients, with initial INRs in the range of 8 to 14 (n=17), experienced an INR reduction to 4.5 or less within 24 hours after receiving a 1 mg-dose of phytonadione subQ, and 93% (n=15) experienced an INR reduction to 4.5 or less within 48 hours after receiving a single 1 mg-dose phytonadione subQ. Three of 4 patients with initial INRs in the range of 14 to 20 experienced an INR reduction to 4.5 or less within 48 hours after receiving a 2 mg-dose of phytonadione subQ (Byrd et al, 1999).
    b) Randomized, placebo-controlled trials were conducted, involving administration of oral vitamin K for the treatment of warfarin-associated coagulopathies (INRs ranging from 4.5 to 10.0). Patients that were given vitamin K orally (1 to 2.5 mg) exhibited a more rapid decrease in their INR than those patients given a placebo, indicating that administration of oral vitamin K in combination with omitting warfarin therapy may bring the INR within the therapeutic range more quickly than only withholding warfarin therapy (Crowther et al, 2000; Patel et al, 2000).
    c) A prospective study was conducted to determine the efficacy of oral vitamin K in patients with excessive anticoagulation. The study included a total of 30 patients, 20 who were asymptomatic and 10 who exhibited signs of bleeding and/or excessive bruising. The INRs of all 30 patients were greater than 8. One day after oral administration of 1 mg of vitamin K resulted in significant declines in the INR. Five patients had an INR of greater than 7, 13 patients had INRs between 4.5 and 6.9, 10 patients had INRs between 2 and 4.5, and 2 patients had INRs below 2. There were no adverse effects with this regimen, indicating that a 1 mg oral dose of vitamin K is effective in reducing the INR level, within 24 hours, of over-anticoagulated patients but without excessive under-anticoagulation (Pendry et al, 2001).
    d) A retrospective analysis was conducted comparing various routes and doses of phytonadione (vitamin K1) in treating warfarin-induced excessive anticoagulation. The study involved 33 patients and included administration of phytonadione in the following routes and doses: low-dose (less than or equal to 0.5 mg) IV (LDIV), high-dose (1 to 10 mg) IV (HDIV), 1 to 10 mg subQ, and 2.5 to 5 mg orally. Initially the mean INRs of the various groups were as follows: 11.9 (ranging from 6.8 to 17.0) in the LDIV group, 13.9 (ranging from 6.6 to 21.5) in the HDIV group, 14.9 (ranging from 5.7 to 37.8) in the SC group, and 9.4 (ranging from 7.8 to 13.1) in the PO group. Of the 4 groups, HDIV was the most effective in lowering the INR of all 9 patients to less than 5.0, however overcorrection occurred more frequently in this group (4 patients in the HDIV group as compared with 1 patient in the LDIV group and no patients in the SC or PO groups). In the LDIV group, the INRs of 5 of 8 patients were corrected to less than 5.0. INRs were corrected to less than 5.0 in 7 of 10 patients in the SC group, and in 5 of 6 patients in the PO group. Based on the results of this study, it appears that low-dose IV and oral administration may be acceptable alternative methods to the standard methods of high-dose and subQ administration (Whitling et al, 1998).
    e) A meta-analysis (10 randomized controlled trials and 11 prospective, nonrandomized trials) was performed to evaluate the efficacy of various routes and doses of vitamin K (phytonadione) in treating patients with excessive anticoagulation. These studies used vitamin K (oral, 1 to 2.5 mg; IV, 0.5 to 3 mg; SubQ, varied) to treat patients without major bleeding with an INR greater than 4.0 due to oral anticoagulant use. Most patients who received oral (82%; 95% CI, 70%-93%) and IV (77%; 95% CI, 60%-95%) vitamin K achieved an INR of 1.8 to 4.0 at 24 hours after vitamin K use (the primary outcome). In contrast, SubQ (31%; 95% CI, 7%-55%) was inferior to oral and IV but was similar to placebo (20%; 95% CI, 0%-47%). Oral and IV vitamin K appear to be equivalent and more effective for excessive anticoagulation than withholding warfarin sodium or administering vitamin K subQ (Dezee et al, 2006).
    6) HEPARIN
    a) Substitution of heparin as an anticoagulant may be necessary until prothrombin time or INR is therapeutic.
    7) TRANSFUSION
    a) Administer fresh frozen plasma and/or prothrombin complex concentrate and packed red blood cells as needed for active bleeding. The PT or INR should be checked 6 hours after administration of FFP to determine the need for further therapy.
    b) The usual dose of fresh frozen plasma given to correct coagulation factor deficiency is 15 mL/kg, but the recommended dose required to reverse over anticoagulation due to warfarin has not been established (Baglin, 1998).
    c) Prothrombin complex concentrate, 500 International Units (12.5 International Units/kg and 17.2 International Units/kg) and 10 mg of vitamin K were administered to 2 elderly patients, who became over-anticoagulated (INRs of 6.69 and greater than 10.0, respectively) while on warfarin therapy. Within 10 minutes of administration, INRs decreased to 1.85 and 1.12, respectively, and the plasma levels of protein C and coagulant factors IIa, VIIa, IXa, and Xa were increased (Yasaka et al, 2003).
    d) RECOMBINANT FACTOR VIIA: A retrospective analysis was conducted involving 7 patients with warfarin-related acute intracranial hemorrhage and who were given recombinant factor VIIa (rFVIIa) as an IV bolus. Administration of rFVIIa decreased the mean INR from 2.7 (range: 1.6 to 5.6) to 1.08. The mean time from onset of symptoms to treatment was 6.2 hours. The mean initial IV dose of rFVIIa was 62.1 mcg/kg (range: 15 to 90 mcg/kg) and the mean total dose was 4.25 mg (range: 0.68 to 7.48 mg). Six of the 7 patients also received vitamin K and fresh frozen plasma. Two of the 7 patients died during hospitalization with both deaths attributed to neurologic injury (Freeman et al, 2004).
    8) VITAMIN C
    a) Administration of ascorbic acid has been recommended by some to limit capillary injury caused by anticoagulants (Kumer & Nwangwu, 1981).

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

    A) SUMMARY
    1) There is no role for enhanced elimination.
    B) CHOLESTYRAMINE
    1) The warfarin elimination half-life was decreased from 53 hours to 33 hours (38%) following administration of oral cholestyramine 4 g four times a day, in a 25-year-old man who overdosed on warfarin (Renowden et al, 1985).
    2) A decrease in elimination half-life of around 30% has been demonstrated in volunteers given 4 g 3 times a day following a single IV dose of warfarin (Jahnchen et al, 1978).

Range Of Toxicity

Summary

    A) TOXICITY: A toxic dose is highly variable. ADULT: Small ingestions (10 to 20 mg) in adults will not cause serious intoxication. However, chronic or repeated supratherapeutic ingestions of small amounts, or drug interactions in patients on a stable warfarin dose, can cause significant anticoagulation. PEDIATRIC: Greater than 0.5 mg/kg may prolong PT/INR; usually without bleeding. A relationship between mg/kg ingested and amount of hypocoagulability has not yet been established.
    B) THERAPEUTIC DOSE: ADULT: INITIAL DOSE: 2 to 5 mg/day orally with dosage adjustments based on INR response. MAINTENANCE DOSE: Range 2 to 10 mg/day orally. PEDIATRIC: INFANTS and CHILDREN: Loading: 0.2 mg/kg/dose, daily for 2 days, followed by daily doses determined by the INR; Maximum: Up to 10 mg/dose.
    C) Death from severe hemorrhagic complications has been reported in persons who ate food made with warfarin sodium baited cornmeal. Ingestion of a total of 1 g of warfarin over a 13-day period resulted in death.
    D) BAITS: Large amounts of warfarin containing grain bait do not usually produce significant toxicity because of the small concentration of the warfarin and poor absorption in large amounts of grain.

Therapeutic Dose

    7.2.1) ADULT
    A) ORAL
    1) INITIAL DOSE: The initial oral dose is 2 to 5 mg/day with dosage adjustments based on individual results of PT/INR determinations (Prod Info COUMADIN(R) oral tablets, IV injection, 2007).
    a) MAINTENANCE DOSE: Usual oral maintenance range is 2 to 10 mg/day. The individual dose and interval is dependent on the patient's prothrombin response. Acquired or inherited warfarin resistance is rare, but should be considered if large daily doses of warfarin are needed beyond the normal therapeutic range (Prod Info COUMADIN(R) oral tablets, IV injection, 2007).
    B) PARENTERAL
    1) The intravenous dose is the same as that used orally (initial dose 2 to 5 mg/daily; maintenance 2 to 10 mg/daily). Administer as a slow bolus injection over 1 to 2 minutes after reconstituting with 2.7 mL of sterile water for injection via a peripheral vein. Intramuscular injection not recommended (Prod Info COUMADIN(R) oral tablets, IV injection, 2007).
    7.2.2) PEDIATRIC
    A) SUMMARY
    1) In infants and children, the developing hemostatic system can alter the response to anticoagulants. Warfarin dosing varies by age in the pediatric population, infants generally have the highest, and adolescents the lowest milligram per dose requirements to maintain target INRs (Prod Info COUMADIN(R) oral tablets, intravenous injection powder lyophilized for solution, 2011).
    B) THROMBOSIS
    1) PROPHYLAXIS OR TREATMENT
    a) LOADING DOSE: 0.2 mg/kg ORAL on Day 1 if baseline INR is between 1 and 1.3 (Monagle et al, 2011; Streif et al, 1999; Andrew et al, 1994).
    b) Maximum Dose: 10 mg (Ageno et al, 2012). A reduced loading dose of 0.1 mg/kg has been used for children with liver impairment or children who have undergone a Fontan procedure (Monagle et al, 2011; Streif et al, 1999; Andrew et al, 1994).
    c) MAINTENANCE THERAPY: Monitor INR frequently; INR ranges may be difficult to achieve and maintain in pediatric patients.

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) SUMMARY
    a) An estimated dose of 0.075 to 0.48 milligram/kilogram, in an adult may produce a peak total warfarin concentration of 0.5 to 3 micrograms/milliliter. This is associated with a prothrombin ratio value of 1.5 to 2.5 (Porter et al, 1986).
    b) Therapeutic free warfarin concentrations in limited numbers of patients are suggested to range from 5 to 23 ng/mL (Yacobi & Levy, 1977) (Routledge et al, 1979).
    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) SUMMARY
    a) Warfarin plasma concentrations above 1 microgram/milliliter were required for prothrombin complex activity (PCA) synthesis rate to be depressed below 80%. Complete inhibition of PCA is associated with concentrations above 11.3 micrograms/milliliter (Nagashima et al, 1969).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (ORAL)MOUSE:
    1) 60 mg/kg (RTECS, 1990)
    2) 331 mg/kg (Sax & Lewis, 1989)
    B) LD50- (ORAL)RAT:
    1) 1600 mcg/kg (RTECS, 1990)
    2) 3 mg/kg (Sax & Lewis, 1989)
    3) Female, 5.63 mg/kg
    C) LD50- (SKIN)RAT:
    1) 1400 mg/kg (RTECS, 1990)
    D) LD50- (ORAL)MOUSE:
    1) 374 mg/kg
    E) LD50- (ORAL)RAT:
    1) 8700 mcg/kg

Minimum Lethal Exposure

    A) SUMMARY
    1) Persons with a history of blood disorders with bleeding tendencies would be expected to be at increased risk from exposure (EPA, 1985).
    2) The minimum lethal exposure would depend in part on whether or not an individual is on anticoagulant therapy; individuals on therapy would be expected to react to lower exposures than non-treated persons.
    3) Hereditary resistance of people to warfarin, as well as, suspected hereditary susceptibility, has been reported (HSDB , 1991).
    4) Death from severe hemorrhagic complications has been reported in persons who ate food made with warfarin sodium baited cornmeal. Ingestion of a total of 1 g of warfarin over a 13-day period resulted in death.
    5) ANIMAL DATA: Animal toxicity studies show that warfarin is most toxic when ingested daily over a period of 5 to 7 days. Rats and mice are very susceptible and died after ingesting 1 mg/kg/day for 6 days (or 50 to 150 mg/kg in a single dose). Fowl are most resistant, horses are resistant, and pigs are more susceptible than rats and mice. Ingestion of 0.05 to 0.4 mg/kg/day for 7 days can kill pigs (HSDB , 1991).
    B) ACUTE
    1) The lowest oral lethal dose reported in humans ranges from 6 mg/kg (RTECS , 1991) to 15 mg/kg (Sax & Lewis, 1989).
    2) LDLo (ORAL) HUMAN: 6667 mcg/kg (RTECS , 1990).
    3) LDLo (ORAL) HUMAN: 15 mg/kg (Sax & Lewis, 1989).
    C) CASE REPORTS
    1) Ingestion of a total of 1 g of warfarin over a 13-day period resulted in death; the patient died on day 15 (Baselt & Cravey, 1989).
    2) Death can occur from significant transcutaneous uptake of warfarin. In August, 1981, pediatric hospitals in Ho Chi Minh City (formerly Saigon), Vietnam, reported 741 cases of a hemorrhagic syndrome in infants. The cause of this phenomenon was identified as talcum powder contaminated with warfarin in concentrations between 1.7% and 6.5%. Of the 741 pediatric cases, 177 patients died (Martin-Bouyer et al, 1984).

Maximum Tolerated Exposure

    A) SUMMARY
    1) Usual oral maintenance range is 2 to 10 mg/day. A maintenance dose of 2 to 10 mg once daily is typical (Prod Info COUMADIN(R) oral tablets, intravenous injection powder lyophilized for solution, 2011).
    a) Evidence of overdose is not based on a specific dose, but rather the appearance of bleeding (eg, occult blood, hematuria, excessive menstrual bleeding, melena, petechia, excessive bruising or persistent oozing from superficial injuries, and unexplained decrease in hemoglobin) as a sign of excessive anticoagulation (Prod Info COUMADIN(R) oral tablets, intravenous injection powder lyophilized for solution, 2011).
    B) SPECIFIC SUBSTANCE
    1) WARFARIN/DRUG PRODUCTS
    a) ADULT
    1) SUMMARY: The lowest toxic dose in humans ranges from 10 mg/kg to 15 mg/kg (RTECS , 1991; Sax & Lewis, 1989).
    a) TDLo (ORAL) MAN: 10200 mcg/kg (Blood) (RTECS , 1990)
    b) TDLo (ORAL) WOMAN: 15 mg/kg/21wk-I (Gastrointestinal and Blood) (RTECS , 1990)
    c) An estimated dose of 0.075 to 0.48 mg/kg in an adult may produce a peak total warfarin concentration of 0.5 to 3 mcg/mL. This is associated with a prothrombin ratio value of 1.5 to 2.5. (See calculation explanation in section 6.7.B.)
    d) Dosing adults with 5 to 20 mg/day produces the desired degree of hypocoagulability. While toxicity occasionally occurs at this level, monitoring of prothrombin time allows for reductions of dosage before major toxicity. Ingestion in excess of this level may cause complications.
    2) CASE SERIES: In one study, the mean minimum warfarin concentration necessary for any inhibition of active clotting factor synthesis was 0.39 mcg/mL in 26 inpatients and 0.36 mcg/mL in 30 outpatients (Murray et al, 1985). This corresponds to an estimated dose of 0.054 to 0.0624 mg/kg.
    3) CASE REPORT/OVERDOSE: A 59-year-old woman intentionally ingested 540 mg of warfarin, clonazepam (4 mg) and 3 mouthfuls of bleach 6 hours prior to presentation. She vomited once after ingesting the bleach. Her physical exam was within normal limits with no evidence of bleeding. She was noted to have superficial self-inflicted cuts on her extremities. Upon admission, laboratory values included an INR of 5.1; PT, 18 and PTT, 57.2 seconds. Coagulation factors were VII, 7%; IX, 24%; and X, 8% (normal ranges, 75% to 150%). The patient received vitamin K (10 mg IV) and recombinant factors Vlla, and 3-factor concentrates shortly after admission. Six hours after vitamin K administration, INR was 0.5. The patient was then maintained on vitamin K 5 mg orally every 6 hours. After her transfer to psychiatry, vitamin K (5 mg) was reduced to 3 times a day. Thirteen days after admission, INR was 1.0 and vital signs were stable. She was discharged on aspirin only (Matthews et al, 2014).
    4) CASE REPORTS/OVERDOSE: Overdose ingestions of warfarin (120 to 150 mg) in 3 patients resulted in increased INRs, ranging from approximately 2.5 to approximately 10. There was no clinical evidence of bleeding in any of the patients (Isbister et al, 2003).
    b) PEDIATRIC
    1) SUMMARY: Extrapolation from the amount needed in adults to acutely and reliably prolong the PT (40 mg) predicts a dose of about 0.5 mg/kg in children that would be considered potentially toxic. This dose resulted in PTs between 18 and 30 seconds in children receiving a single loading dose after heart valve surgery (Carpentieri et al, 1976).
    2) CASE REPORT: A 20-month-old child ingested approximately 50 mg (4 mg/kg) of warfarin sodium and subsequently developed prolonged PT. The child, however, remained asymptomatic with no signs of bleeding or bruising (Montanio et al, 1993).
    3) CASE REPORTS: A dose of 0.2 mg/kg/day for 2 days resulted in a wide range of PTs independent of age, weight, or body surface area in 15 children. The mean PT was 19.5 +/- 4.6 seconds (Doyle et al, 1988).
    4) CASE REPORT: A 15-year-old adolescent's INR peaked at 5.0, without any other signs or symptoms, 3 days after intentionally ingesting 50 5-mg and 100 1-mg warfarin tablets. The patient's INR normalized after receiving fresh frozen plasma and vitamin K (Ramanan et al, 2002).
    5) CASE SERIES: REGULATING INR IN PEDIATRIC PATIENTS: In a study to analyze warfarin therapy in children requiring anticoagulation, therapeutic dosing of warfarin was found to be highly variable. Younger children required higher doses of warfarin than older children to achieve a therapeutic concentration. To achieve a therapeutic INR range, daily warfarin doses of 0.16 mg/kg were required in young children compared to 0.04 to 0.08 mg/kg in adults (Streif et al, 1999a).
    2) WARFARIN/RODENTICIDES
    a) ACUTE: 100 g (3-1/3 ounces) of 0.025% rat bait contains 25 mg of warfarin, and is poorly absorbed in these large quantities of grain.
    b) CHRONIC: Ingestion of a few ounces of rat poison over 3 to 5 days will produce marked hypoprothrombinemia and bleeding.
    1) Fourteen reported cases of unintentional poisoning in Korea involved eating cornmeal containing 0.25% warfarin included in rat bait. The corn meal was eaten over a period of 15 days. All 14 became severely ill with hemorrhage; 2 patients died. The estimated dosage was 1 to 2 mg/kg/day (HSDB , 1991; Baselt & Cravey, 1989; Morgan, 1989).
    3) ACENOCOUMAROL
    a) 3-(alpha-acetonyl-4-nitrobenzyl)-4-hydroxycoumarin is more potent than warfarin. Ingestion of 60 mg by a 27-year-old woman resulted in a severe hemorrhagic diathesis 5 days later (Prod Info Sintrom(R), acenocoumarol, 1968).
    C) ANIMAL DATA
    1) WARFARIN
    a) Warfarin was administered to adult female albino rats as a technical grade (99.8%) carried in peanut oil. The dose levels were 1, 2, 4, 8 and 12 mg/kg body weight. None of adult female albino rats died from a single dose of warfarin as high as 12 mg/kg. Repeated doses between 4 and 6 days killed 25.0, 37.5, 75.0 and 100% of the rats (Bai et al, 1992).
    D) ROUTE OF EXPOSURE
    1) WARFARIN/DERMAL EXPOSURE
    a) Talcum powder contaminated with 1.7% to 6.5% warfarin resulted in 177 infant deaths in Vietnam in 1981. Experimentally, a baboon exposed daily to talc containing 3% warfarin applied on the buttocks under a diaper, died of hemorrhagic diathesis 5 days later (Martin-Bouyer et al, 1983).
    b) One case of a hemorrhagic diathesis resulted from mixing successive batches of poisoned bait. Inhalation, or more probably, cutaneous absorption was the mechanism of exposure (Green, 1955).
    c) A farmer whose hands were intermittently wetted with an 0.5% solution of warfarin over a period of 24 days developed gross hematuria 2 days after the last contact with the solution; the following day, spontaneous hematomas appeared on the arms and legs. Within 4 days, other effects included epistaxis, punctate hemorrhages of the palate and mouth, and bleeding from the lower lip. Four days later, after treatment for 2 days with phytonadione, hematologic indices had returned to the normal range (Proctor et al, 1988).

Pharmacology Toxicology

Toxicologic Mechanism

    A) Warfarin acts by blocking liver prothrombin production and by causing vascular injury at the capillary level (Kumer & Nwangu, 1981).
    B) It is rapidly absorbed following ingestion and produces its toxic effects by either large acute, or smaller chronic, ingestions.

Physicochemical

Physical Characteristics

    A) Warfarin is a colorless, odorless, tasteless crystalline solid (Sax & Lewis, 1989; HSDB , 1991).
    1) WARFARIN SODIUM and WARFARIN POTASSIUM, two formulations of warfarin available as therapeutic anticoagulant drugs, are white, odorless, crystalline powders, having a slightly bitter taste (HSDB , 1991).
    2) WARFARIN SODIUM is discolored by exposure to light (Martindale, 1992).

Ph

    A) 7.2-8.3 (HSDB , 1991)

Molecular Weight

    A) 308.35 (RTECS , 1991; Sax & Lewis, 1989)
    B) 308.32 (EPA, 1985; ACGIH, 1986)

Animal Toxicology

Clinical Effects

    11.1.13) OTHER
    A) OTHER
    1) Signs are related to the hemorrhagic process and may include weakness, progressive posterior paralysis, anorexia, pale mucous membranes, vomiting, oral and fecal bleeding, and seizures (Aronson, 1984).

Treatment

    11.2.2) LIFE SUPPORT
    A) GENERAL
    1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.
    11.2.5) TREATMENT
    A) GENERAL TREATMENT
    1) As with human exposures, vitamin K1 (phytonadione) is a specific antidote. Menadione may be ineffective and should not be used (Fitzgerald & Bronstein, 1987). Fresh frozen plasma should be given as required.
    2) VITAMIN K1 DOSE - 5 mg/kg in 3 divided daily doses.

Range Of Toxicity

    11.3.2) MINIMAL TOXIC DOSE
    A) GENERAL
    1) The estimated toxic dose in acute ingestion is 20 to 50 mg/kg and in chronic ingestion 1 to 5 mg/kg for 5 to 15 days (Aronson, 1984).

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