Warfarin

Uses

Warfarin is used for the following conditions-

• Prophylaxis and/or treatment of thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement
• Indicated to reduce the risk of death, recurrent myocardial infarction, and thromboembolic events such as stroke or systemic embolization after myocardial infarction
• Prophylaxis and treatment of venous thrombosis and pulmonary embolism
• Transient ischaemic attacks.

Warfarin is also used to associated treatment for these conditions: Myocardial Infarction, Pulmonary Embolism, Stroke, Systemic Embolism, Thromboembolism, Thrombosis, Venous, Transient Ischemic Attack

How Warfarin works

Warfarin is a [vitamin K] antagonist which acts to inhibit the production of vitamin K by vitamin K epoxide reductase. The reduced form of vitamin K, vitamin KH₂ is a cofactor used in the γ-carboxylation of coagulation factors VII, IX, X, and thrombin. Carboxylation induces a conformational change allowing the factors to bind Ca^{2+ Factors IX, X, and finally thrombin degrade later with half lives of 24, 36, and 50 hours resulting in a dominant anticoagulation effect. In order to reverse this anticoagulation vitamin K must be supplied, either exogenously or by removal of the vitamin K epoxide reductase inhibition, and time allowed for new coagulation factors to be synthesized. It takes approximately 2 days for new coagulation factors to be synthesized in the liver. Vitamin K₂, functionally identical to vitamin K₁, is synthesized by gut bacteria leading to interactions with antibiotics as elimination of these bacteria can reduce vitamin K₂supply and result in a greater anticoagulation effect.}

Dosage

Warfarin dosage

Whenever possible, the baseline prothrombin time should be determined but the initial dose should not be delayed whilst awaiting the result.The usual adult induction dose of warfarin: 10 mg daily for 2 days. The subsequent maintenance dose depends upon the prothrombin time, reported as INR (international normalized ratio). The daily maintenance dose of warfarin is usually 3 to 9 mg (taken at the same time each day). The maintenance dose is omitted if the prothrombin time is excessively prolonged. Once the maintenance dose is established in the therapeutic range, it is rarely necessary to alter. In emergencies, anticoagulant therapy should be initiated with heparin and warfarin together. Where there is less urgency, as in patients disposed to or at special risk of thromboembolism, anticoagulant therapy may be initiated with warfarin alone. Control tests must be made at regular intervals and maintenance dosage further adjusted according to the results obtained.Use in children: Safety and efficacy in children <18 years old have not been established. However, there is evidence of use and the initial dose is usually 0.1 mg.kg-1.d-1 adjusted subsequently to aim for an INR range the same as in adults.

Side Effects

Hemorrhage is the principal adverse effect of oral anticoagulants. Other adverse reactions include nausea, vomiting, diarrhea, hypersensitivity, rash, alopecia, and unexplained drop in haematocrit, "purple toes", skin necrosis, jaundice, and hepatic dysfunction.

Toxicity

LD₅₀ Values

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

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

Rabbit: 800 mg/kg (Oral)

Pig: 1 mg/kg (Oral)

Dog: 3 mg/kg (Oral)

Cat: 6 mg/kg (Oral)

Chicken: 942 mg/kg (Oral)

Guinea Pig: 180 mg/kg (Oral)

Overdose

Doses of 1-2 mg/kg/day over a period of 15 days have been fatal in humans. Warfarin overdose is primarily associated with major bleeding particularly from the mucous membranes, gastrointestinal tract, and genitourinary system. 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. Patients can be safely re-anticoagulated after reversal of the overdose.

Carcinogenicity & Mutagenicity

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

Reproductive Toxicity

Warfarin is known to be a teratogen and its use during pregnancy is contraindicated in the absence of high thrombotic risk. 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.

Lactation

Official product monographs mention a study in 15 women. 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. 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.

Precaution

Periodic determination of prothrombin time (PT)/international normalized ratio (INR) or other suitable coagulation test is essential. Numerous factors, alone or in combination, including travel, changes in diet, environment, physical state and medication may influence response of the patient to anticoagulants. It is generally good practice to monitor the patient's response with additional PT/INR determination in the period immediately after discharge from the hospital, and whenever other medications are initiated, discontinued or taken irregularly. The following factors may exaggerate the effects of warfarin and necessitate a reduction in dosage; loss of weight, elderly subject, acute illness, deficient renal function, decreased dietary intake of vitamin K, administration of certain drugs (see drug interaction). Factors which may call for an increase in maintenance dosage include weight gain, diarrhea and vomiting, increased intake of vitamin K, fats and oils, and the administration of certain drugs (see drug interaction). Careful additional laboratory control is necessary if the patient is to be changed from one formulation to another. Reversal of warfarin anticoagulation by vitamin K takes several days. In emergency situations fresh frozen plasma should be given.

Interaction

Oral anticoagulants have a greater potential for clinically significant drug interactions. Warfarin all patients about potential hazards and instruct against taking any drug, including non-prescription products, without the advice of a physician.

Food Interaction

• Avoid drastic dietary changes.
• Avoid foods rich in vitamin K. Vitamin K in foods such as leafy vegetables can reduce warfarin efficacy.
• Avoid grapefruit products. They may interfere with warfarin metabolism and increase INR, increasing the risk of bleeding.
• Avoid herbs and supplements with anticoagulant/antiplatelet activity. Examples include garlic, ginger, bilberry, danshen, piracetam, and ginkgo biloba.
• Avoid St. John's Wort. This drug may reduce warfarin efficacy.

[Moderate] MONITOR: Vitamin K may antagonize the hypoprothrombinemic effect of oral anticoagulants.

Vitamin K is a cofactor in the synthesis of blood clotting factors that are inhibited by oral anticoagulants, thus intake of vitamin K through supplements or diet can reverse the action of oral anticoagulants.

Resistance to oral anticoagulants has been associated with consumption of foods or enteral feedings high in vitamin K content.

Likewise, a reduction of vitamin K intake following stabilization of anticoagulant therapy may result in elevation of the INR and bleeding complications.

Foods rich in vitamin K include beef liver, broccoli, Brussels sprouts, cabbage, collard greens, endive, kale, lettuce, mustard greens, parsley, soy beans, spinach, Swiss chard, turnip greens, watercress, and other green leafy vegetables.

Moderate to high levels of vitamin K are also found in other foods such as asparagus, avocados, dill pickles, green peas, green tea, canola oil, margarine, mayonnaise, olive oil, and soybean oil.

Snack foods containing the fat substitute, olestra, are fortified with 80 mcg of vitamin K per each one ounce serving so as to offset any depletion of vitamin K that may occur due to olestra interference with its absorption.

Whether these foods can alter the effect of oral anticoagulants has not been extensively studied.

One small study found that moderate consumption (1.5 servings
Consumption of large amounts of mango fruit has been associated with enhanced effects of warfarin.

The exact mechanism of interaction is unknown but may be related to the vitamin A content, which may inhibit metabolism of warfarin.

In one report, thirteen patients with an average INR increase of 38% reportedly had consumed one to six mangos daily 2 to 30 days prior to their appointment.

The average INR decreased by 17.7% after discontinuation of mango ingestion for 2 weeks.

Rechallenge in two patients appeared to confirm the interaction.

Limited data also suggest a potential interaction between warfarin and cranberry juice resulting in changes in the INR and

The mechanism is unknown but may involve alterations in warfarin metabolism induced by flavonoids contained in cranberry juice.

At least a dozen reports of suspected interaction have been filed with the Committee on Safety of Medicines in the U.K. since 1999, including one fatality.

In the fatal case, the patient's INR increased dramatically (greater than 50) six weeks after he started drinking cranberry juice, and he died from gastrointestinal and pericardial hemorrhage.

However, the patient was also taking cephalexin for a chest infection and had not eaten for two weeks prior to hospitalization, which may have been contributing factors.

Other cases involved less dramatic increases or instabilities in INR following cranberry juice consumption, and a decrease was reported in one, although details are generally lacking.

In a rare published report, a 71-year-old patient developed hemoptysis, hematochezia, and shortness of breath two weeks after he started drinking 24 ounces of cranberry juice a day.

Laboratory test results on admission revealed a decrease in hemoglobin, an INR greater than 18, and prothrombin time exceeding 120 seconds.

The patient recovered after warfarin doses were withheld for several days and he was given packed red blood cells, fresh-frozen plasma, and subcutaneous vitamin K.

It is not known if variations in the constituents of different brands of cranberry juice may affect the potential for drug interactions.

There have been several case reports in the medical literature of patients consuming grapefruit, grapefruit juice, or grapefruit seed extract who experienced increases in INR.

R(+) warfarin, the less active of the two enantiomers of warfarin, is partially metabolized by CYP450 3A4.

Depending on brand, concentration, dose and preparation, grapefruit juice may be considered a moderate to strong inhibitor of CYP450 3A4, thus coadministration with warfarin may decrease the clearance of R(+) warfarin.

However, the clinical significance of this effect has not been established.

A pharmacokinetic study found no effect on the PT or INR values of nine warfarin patients given 8 oz of grapefruit juice three times a day for one week.

A patient who was stabilized on warfarin developed a large hematoma in her calf in association with an elevated INR of 14 following consumption of approximately 3 liters of pomegranate juice in the week prior to admission.

In vitro data suggest that pomegranate juice can inhibit CYP450 2C9, the isoenzyme responsible for the metabolic clearance of the biologically more active S(-) enantiomer of warfarin.

In rats, pomegranate juice has also been shown to inhibit intestinal CYP450 3A4, the isoenzyme that contributes to the metabolism of R(+) warfarin.

Black currant juice and black currant seed oil may theoretically increase the risk of bleeding or bruising if used in combination with anticoagulants.

The proposed mechanism is the antiplatelet effects of the gamma-linolenic acid constituent in black currants.

Soy protein in the form of soy milk was thought to be responsible for a case of possible warfarin antagonism in an elderly male stabilized on warfarin.

The exact mechanism of interaction is unknown, as soy milk contains only trace amounts of vitamin K.

Subtherapeutic INR values were observed approximately 4 weeks after the patient began consuming soy milk daily for the treatment of hypertriglyceridemia.

No other changes in diet or medications were noted during this time.

The patient's INR returned to normal following discontinuation of the soy milk with no other intervention.

An interaction with chewing tobacco was suspected in a case of warfarin therapy failure in a young male who was treated with up to 25 to 30 mg

The inability to achieve adequate INR values led to eventual discontinuation of the chewing tobacco, which resulted in an INR increase from 1.1 to 2.3 in six days.

The authors attributed the interaction to the relatively high vitamin K content in smokeless tobacco.

MANAGEMENT: Intake of vitamin K through supplements or diet should not vary significantly during oral anticoagulant therapy.

The diet in general should remain consistent, as other foods containing little or no vitamin K such as mangos and soy milk have been reported to interact with warfarin.

Some experts recommend that continuous enteral nutrition should be interrupted for one hour before and one hour after administration of the anticoagulant dose and that enteral formulas containing soy protein should be avoided.

Patients should also consider avoiding or limiting the consumption of cranberry juice or other cranberry formulations (e.g., encapsulated dried cranberry powder), pomegranate juice, black currant juice, and black currant seed oil.

Warfarin Alcohol interaction

[Moderate]

Enhanced hypoprothrombinemic response to warfarin has been reported in patients with acute alcohol intoxication and/or liver disease.

The proposed mechanisms are inhibition of warfarin metabolism and decreased synthesis of clotting factors.

Binge drinking may exacerbate liver impairment and its metabolic ability in patients with liver dysfunction.

The risk of bleeding may be increased.

Conversely, reductions in INR/PT have also been reported in chronic alcoholics with liver disease.

The proposed mechanism is that continual drinking of large amounts of alcohol induces the hepatic metabolism of anticoagulants.

Effects are highly variable and significant INR/PT fluctuations are possible.

Patients taking oral anticoagulants should be counseled to avoid large amounts of ethanol, but moderate consumption (one to two drinks per day) are not likely to affect the response to the anticoagulant in patients with normal liver function.

Frequent INR/PT monitoring is recommended, especially if alcohol intake changes considerably.

It may be advisable to avoid oral anticoagulant therapy in patients with uncontrollable drinking problems.

Patients should be advised to promptly report any signs of bleeding to their doctor, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.

Warfarin Cholesterol interaction

[Moderate] Patients with edema, hereditary coumarin resistance, hyperlipidemia, hypothyroidism, or nephrotic syndrome may exhibit lower than expected hypoprothrombinemic response to oral anticoagulants.

Thus, more frequent laboratory (PT

Warfarin Hypertension interaction

[Major] In general, the use of oral anticoagulants is contraindicated in patients with malignant or severe, uncontrolled hypertension.

These patients may be at increased risk for cerebral hemorrhage.

Therapy with oral anticoagulants should be administered cautiously in patients with moderate hypertension.

Warfarin multivitamins interaction

[Moderate] Multivitamin preparations containing vitamin K may antagonize the hypoprothrombinemic effect of oral anticoagulants in some patients.

Vitamin K1 in its active, reduced form serves as a cofactor in the generation of functional clotting factors, during which it becomes oxidized.

It is reactivated in a process that is inhibited by oral anticoagulants, thus intake of additional vitamin K through supplements or diet can reverse the action of oral anticoagulants.

Although the amount of vitamin K in over-the-counter multivitamin preparations is generally well below the dose thought to affect anticoagulation, there have been isolated case reports of patients stabilized on warfarin whose INR decreased following initiation of a multivitamin supplement and returned to therapeutic levels upon cessation of the multivitamin.

Increases in warfarin dosage were required in some cases when the multivitamin was continued.

One patient whose warfarin dosage was increased developed a subcapsular hematoma in her right kidney two weeks after she discontinued the multivitamin without informing her physician.

Her INR was 13.2 and she was treated with vitamin K and fresh frozen plasma.

It is possible that patients with low vitamin K status may be particularly susceptible to the interaction.

Investigators have shown that vitamin K deficiency can cause an oversensitivity to even small increases in vitamin K intake.

In one study where warfarin-stabilized patients were given a multivitamin tablet containing 25 mcg of vitamin K1 daily for 4 weeks, subtherapeutic INRs occurred in 9 of 9 patients with low vitamin K1 levels (4.5 mcg

INR decreased by a median of 0.51 and warfarin dosage had to be increased by 5.3% in patients with low vitamin K1 levels, whereas INR and warfarin dosage did not change significantly in patients with normal vitamin K1 levels.

The prevalence of vitamin K deficiency may be small, but significant in the anticoagulated population.

In a survey of 179 consecutive ambulatory patients on stable warfarin therapy attending an anticoagulation clinic, 22 (12.3%) were found to have vitamin K1 deficiency (
The potential for multivitamin supplements containing even low levels of vitamin K to affect anticoagulation should be recognized.

In particular, elderly and

Warfarin Drug Interaction

Major: aspirin, clopidogrelModerate: rosuvastatin, duloxetine, omega-3 polyunsaturated fatty acids, esomeprazole, levothyroxine, acetaminophenMinor: atorvastatin, ascorbic acidUnknown: fluticasone / salmeterol, calcium / vitamin d, insulin glargine, furosemide, pregabalin, metoprolol, metoprolol, tiotropium, cyanocobalamin, cholecalciferol

Warfarin Disease Interaction

Major: bleeding, diabetes, hypertension, liver disease, protein C deficiencyModerate: decreased response, increased response, renal dysfunction

Volume of Distribution

Vd of 0.14 L/kg. Warfarin has a distrubution phase lasting 6-12 hours. It is known to cross the placenta and achieves fetal serum concentrations similar to maternal concentrations.

Elimination Route

Completely absorbed from the GI tract. The mean Tmax for warfarin sodium tablets is 4 hours.

Half Life

R-warfarin is cleared more slowly than S-warfarin, at about half the rate. T_1/2 for R-warfarin is 37-89 hours. T_1/2 for S-warfarin is 21-43 hours.

Clearance

Clearance of warfarin varies depending on CYP2C9 genotype. The *2 and *3 alleles appear in the Caucasian population at frequencies of 11% and 7% and are known to reduce clearance warfarin. Additional clearance reducing genotypes include the *5, *6, *9 and *11 alleles. Genotypes for which population clearance estimates have been found are listed below.

*1/*1 = 0.065 mL/min/kg

*1/*2, *1/*3 = 0.041 mL/min/kg

*2/*2, *2/*3, *3/*3 = 0.020 mg/min/kg

Elimination Route

The elimination of warfarin is almost entirely by metabolism with a small amount excreted unchanged. 80% of the total dose is excreted in the urine with the remaining 20% appearing in the feces.

Pregnancy & Breastfeeding use

Warfarin is contraindicated in the first trimester of pregnancy because of the risk of teratogenicity. It should not be used in women who are or may become pregnant because the drug passes through the placental barrier and may cause fatal hemorrhage to the fetus. Warfarin appears in the milk of nursing mothers in an inactive form. Infants nursed by mothers treated with Warfarin had no change in prothrombin times. Effects in premature infants have not been evaluated.

Contraindication

• Actual or potential haemorrhagic conditions, eg. Peptic ulcer, or to patients with uncontrolled hypertension
• Severe hepatic or renal disease
• Pregnancy
• Known hypersensitivity to warfarin
• Bacterial endocarditis

Its use within 24 hours following surgery or labour should be undertaken with caution, if at all.

Acute Overdose

If hemorrhage occurs or a potential bleeding state arises, excessive depression of the coagulation activity can be corrected by temporary withdrawal of warfarin accompanied, if necessary, by infusion of fresh-frozen plasma or whole blood. Vitamin K, 5 to 10 mg orally or intravenously, may be required to supplement specific treatment with factor concentrates.

Storage Condition

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