Warfarin

Warfarin is an anticoagulant agent belonging to Vitamin K Antagonist.

Warfarin is a vitamin K antagonist used to treat venous thromboembolism, pulmonary embolism, thromboembolism with atrial fibrillation, thromboembolism with cardiac valve replacement, and thromboembolic events post-myocardial infarction.

Warfarin is essentially completely absorbed from the GI tract after oral administration, with peak concentration generally attained within the first 4 hours. Warfarin distributes into a relatively small apparent volume of distribution of about 0.14 L/kg. A distribution phase lasting 6 to 12 hours is distinguishable after rapid intravenous or oral administration of an aqueous solution. Approximately 99% of the drug is bound to plasma proteins. Warfarin is metabolized in the liver. The Elimination half-life of Warfarin is approximately 20-60 hours. Warfarin is excreted in urine (92%, mainly as metabolites and small amounts as an unchanged drug).

Warfarin shows common side effects like Bloating, abdominal pain, change in the way things taste, loss of hair, feeling cold, or having chills.

Warfarin is available in the form of Oral tablets.

Warfarin is available in India, the US, the UK, Italy, Germany, Spain, France, Australia, and Russia.

Warfarin belonging to the Vitamin K Antagonist acts as an anticoagulant agent.

Warfarin inhibits the synthesis of vitamin K-dependent coagulation factors II, VII, IX, and X as well as the anticoagulant protein C and its cofactor protein S. These clotting factors are biologically activated by the addition of carboxyl groups to key glutamic acid residues within the proteins' structure. Warfarin competitively inhibits the C1 subunit of the multi-unit vitamin K epoxide reductase (VKORC1) enzyme complex, thus depleting functional vitamin K reserves and subsequently reducing the synthesis of active clotting factors.

The onset of action of Warfarin occurs within 36-48 hours.

The Duration of Action for Warfarin in the body is approximately 2-5 days.

The Tmax was found within 1.5-3 days following the administration of Warfarin.

Warfarin is available in the form of an Oral tablets.

Warfarin Oral tablet is taken by mouth usually once a day.

Warfarin is a vitamin K antagonist used to treat venous thromboembolism, pulmonary embolism, thromboembolism with atrial fibrillation, thromboembolism with cardiac valve replacement, and thromboembolic events post-myocardial infarction.

Warfarin is an anticoagulant agent belonging to Vitamin K Antagonist.

Warfarin interferes with the hepatic synthesis of Vitamin K-dependent coagulation factors (II, VII, IX, X).

Warfarin is approved for use in the following clinical indications

• Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, and pulmonary embolism.
• Warfarin is indicated for the prophylaxis and/or treatment of thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement.
• Warfarin is indicated to reduce the risk of death, recurrent myocardial infarction, and thromboembolic events such as stroke or systemic embolization after myocardial infarction.

• Adult Dose for Thromboembolic Stroke Prophylaxis

Initial dose: 2 to 5 mg orally once a day.

Maintenance dose: 2 to 10 mg orally once a day.

• Adult Dose for Pulmonary Embolism

Initial dose: 2 to 5 mg orally once a day.

Maintenance dose: 2 to 10 mg orally once a day.

• Adult Dose for Prevention of Thromboembolism in Atrial Fibrillation

Initial dose: 2 to 5 mg orally once a day

Maintenance dose: 2 to 10 mg orally once a day.

• Adult Dose for Prosthetic Heart Valves - Tissue Valves

Initial dose: 2 to 5 mg orally once a day.

Maintenance dose: 2 to 10 mg orally once a day.

• Adult Dose for Prosthetic Heart Valves - Mechanical Valves

Initial dose: 2 to 5 mg orally once a day.

Maintenance dose: 2 to 10 mg orally once a day.

• Adult Dose for Myocardial Infarction

Initial dose: 2 to 5 mg orally once a day.

Maintenance dose: 2 to 10 mg orally once a day.

• Adult Dose for Deep Vein Thrombosis – Prophylaxis

Initial dose: 2 to 5 mg orally once a day.

Maintenance dose: 2 to 10 mg orally once a day.

• Pediatric Dose for Thrombotic/Thromboembolic Disorder

Initial dose (if baseline INR is 1 to 1.3): 0.2 mg/kg orally; subsequent dose adjustments should be made to maintain an INR between 2 and 3.

Warfarin is available in various strengths as 1mg, 2mg, and 2.5mg.

Warfarin is available in the form of Oral Tablets.

Avoid the consumption of foods rich in vitamin K (e.g. green leafy vegetables, broccoli, brussels sprouts) it can reduce the anticoagulant effect. Grapefruit juice, cranberry juice, and pomegranate juice may interact with warfarin and lead to unwanted side effects. Avoid the use of these juice products while taking Warfarin.

• Warfarin is contraindicated in patients with
• Pregnancy
• Hemorrhagic tendencies or blood dyscrasias
• Recent or contemplated surgery of the central nervous system or eye, or traumatic surgery resulting in large open surfaces
• Bleeding tendencies associated with:
• Active ulceration or overt bleeding of the gastrointestinal, genitourinary, or respiratory tract
• Central nervous system hemorrhage
• Cerebral aneurysms, dissecting aorta
• Pericarditis and pericardial effusions
• Bacterial endocarditis
• Threatened abortion, eclampsia, and preeclampsia
• Unsupervised patients with conditions associated with potentially high levels of non-compliance
• Spinal puncture and other diagnostic or therapeutic procedures with the potential for uncontrollable bleeding
• Hypersensitivity to warfarin or to any other components of this product (e.g., anaphylaxis)
• Major regional or lumbar block anesthesia
• Malignant hypertension

• Hemorrhage

Warfarin can cause major or fatal bleeding. Bleeding is more likely to occur within the first month. Risk factors for bleeding include the high intensity of anticoagulation (INR >4.0), age greater than or equal to 65, history of highly variable INRs, history of gastrointestinal bleeding, hypertension, cerebrovascular disease, anemia, malignancy, trauma, renal impairment, certain genetic factors, certain concomitant drugs, and long duration of warfarin therapy. Perform regular monitoring of INR in all treated patients. Those at high risk of bleeding may benefit from more frequent INR monitoring, careful dose adjustment to desired INR, and the shortest duration of therapy appropriate for the clinical condition. However, maintenance of INR in the therapeutic range does not eliminate the risk of bleeding. Drugs, dietary changes, and other factors affect INR levels achieved with Warfarin therapy. Perform more frequent INR monitoring when starting or stopping other drugs, including botanicals, or when changing dosages of other drugs. Instruct patients about prevention measures to minimize the risk of bleeding and to report signs and symptoms of bleeding.

• Tissue Necrosis

Necrosis and/or gangrene of skin and other tissues is an uncommon but serious risk (<0.1%). Necrosis may be associated with local thrombosis and usually appears within a few days of the start of Warfarin therapy. In severe cases of necrosis, treatment through debridement or amputation of the affected tissue, limb, breast, or penis has been reported. Careful clinical evaluation is required to determine whether necrosis is caused by an underlying disease. Although various treatments have been attempted, no treatment for necrosis has been considered uniformly effective. Discontinue Warfarin therapy if necrosis occurs. Consider alternative drugs if continued anticoagulation therapy is necessary.

• Calciphylaxis

Fatal and serious calciphylaxis or calcium uremic arteriolopathy has been reported in patients with and without end-stage renal disease. When calciphylaxis is diagnosed in these patients, discontinue Warfarin, and treat calciphylaxis as appropriate. Consider alternative anticoagulation therapy.

• Acute Kidney Injury

In patients with altered glomerular integrity or with a history of kidney disease, acute kidney injury may occur with Warfarin, possibly in relation to episodes of excessive anticoagulation and hematuria. More frequent monitoring of anticoagulation is advised in patients with compromised renal function.

• Systemic Atheroemboli and Cholesterol Microemboli

Anticoagulation therapy with Warfarin may enhance the release of atheromatous plaque emboli. Systemic atheroemboli and cholesterol microemboli can present with a variety of signs and symptoms depending on the site of embolization. The most commonly involved visceral organs are the kidneys, followed by the pancreas, spleen, and liver. Some cases have progressed to necrosis or death. A distinct syndrome resulting from microemboli to the feet is known as “purple toes syndrome.” Discontinue Warfarin therapy if such phenomena are observed. Consider alternative drugs if continued anticoagulation therapy is necessary.

• Limb Ischemia, Necrosis, And Gangrene in Patients with HIT And HITS

Do not use Warfarin as initial therapy in patients with heparin-induced thrombocytopenia (HIT) and with heparin-induced thrombocytopenia with thrombosis syndrome (HITTS). Cases of limb ischemia, necrosis, and gangrene have occurred in patients with HIT and HITTS when heparin treatment was discontinued and warfarin therapy was started or continued. In some patients, sequelae have included amputation of the involved area and/or death. Treatment with Warfarin may be considered after the platelet count has normalized.

Alcohol consumption is not recommended in patients receiving Warfarin due to an increase in the risk of bleeding.

Based on published data from 15 nursing mothers, warfarin was not detected in human milk. Among the 15 full-term newborns, 6 nursing infants had documented prothrombin times within the expected range. Prothrombin times were not obtained for the other 9 nursing infants. Monitor breast-feeding infants for bruising or bleeding. Effects in premature infants have not been evaluated. Caution should be exercised when Warfarin is administered to a nursing woman.

Warfarin is contraindicated in women who are pregnant except in pregnant women with mechanical heart valves, who are at high risk of thromboembolism, and for whom the benefits of Warfarin may outweigh the risks. Warfarin can cause fetal harm when administered to a pregnant woman. Warfarin exposure during pregnancy causes a recognized pattern of major congenital malformations (warfarin embryopathy), fetal hemorrhage, and an increased risk of spontaneous abortion and fetal mortality. The reproductive and developmental effects of Warfarin have not been evaluated in animals. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Avoid the consumption of foods rich in vitamin K (e.g., green leafy vegetables, broccoli, brussels sprouts) it can reduce the anticoagulant effect. Grapefruit juice, cranberry juice, and pomegranate juice may interact with warfarin and lead to unwanted side effects. Avoid the use of these juice products while taking Warfarin.

• Common Adverse effects

Gangrene of skin and/or subcutaneous tissues, skin necrosis, Vasculitis, alopecia, bullous rash, dermatitis, pruritus, abdominal pain, bloating, diarrhea, dysgeusia, flatulence, nausea, vomiting, hepatitis, increased liver enzymes, anaphylaxis, chills, tracheobronchial calcification

• Rare Adverse effects

Atheromatous embolism, cholesterol embolus syndrome, livedo reticularis, purple toe syndrome, vascular calcification (calcium uremic arteriolopathy and calciphylaxis), skin rash, hematuria, hemorrhage, decreased bone mineral density, lower extremity pain, Acute kidney injury.

• CYP2C9 Inducers

May decrease the serum concentration of Vitamin K Antagonists. Management: Monitor for decreased effects of vitamin K antagonists (e.g., decreased INR, thrombosis) if combined with moderate CYP2C9 inducers. Vitamin K antagonist dose adjustments will likely be required.

• CYP2C9 Inhibitors

May increase the serum concentration of Vitamin K Antagonists.

• Desirudin

Anticoagulants may enhance the anticoagulant effect of Desirudin. Management: Discontinue treatment with other anticoagulants prior to desirudin initiation. If concomitant use cannot be avoided, monitor patients receiving these combinations closely for clinical and laboratory evidence of excessive anticoagulation.

• Fenofibrate and Derivatives

May enhance the anticoagulant effect of Warfarin. Fenofibrate and Derivatives may increase the serum concentration of Warfarin. Management: Monitor for signs and symptoms of bleeding and increase INR monitoring in patients taking warfarin who are initiated on fenofibrate derivatives. Warfarin dose reductions will likely be required.

• Ivosidenib

May decrease the serum concentration of CYP2C9 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Management: Consider alternatives to this combination when possible. If combined, monitor for decreased effectiveness of these CYP2C9 substrates if combined with Ivosidenib.

• Lornoxicam

May enhance the anticoagulant effect of Vitamin K Antagonists. Lornoxicam may increase the serum concentration of Vitamin K Antagonists. Management: Consider alternatives to this combination when possible. If the combination must be used, monitor coagulation status closely and advise patients to promptly report any evidence of bleeding or bruising.

• Fluconazole

May increase the serum concentration of Vitamin K Antagonists. Management: Consider alternatives when possible. If combined, consider reducing the vitamin K antagonist dose by 10% to 20% if combined with fluconazole. Monitor for increased anticoagulant effects (ie, increased INR, bleeding) to guide further dose adjustments.

• Antibiotics And Antifungals

There have been reports of changes in INR in patients taking warfarin and antibiotics or antifungals, but clinical pharmacokinetic studies have not shown consistent effects of these agents on plasma concentrations of warfarin. Closely monitor INR when starting or stopping any antibiotic or antifungal in patients taking warfarin.

• Fibric Acid Derivatives

May enhance the anticoagulant effect of Vitamin K Antagonists. Management: Consider reducing the oral anticoagulant dose by 25% to 33% when initiating a fibric acid derivative (e.g., fenofibric acid, fenofibrate, and gemfibrozil). Monitor for toxic or reduced anticoagulant effects if a fibric acid derivative is initiated/dose increased, or discontinued/dose decreased, respectively.

• Nonsteroidal Anti-Inflammatory Agents

May enhance the anticoagulant effect of Vitamin K Antagonists. Management: Consider alternatives to this combination when possible. If the combination must be used, monitor coagulation status closely and advise patients to promptly report any evidence of bleeding or bruising.

The common side effects of Warfarin include the following

• Common

Bloating, abdominal pain, change in the way things taste, loss of hair, feeling cold, or having chills.

• Rare

Hives, rash, Itching, difficulty breathing or swallowing, swelling of the face, throat, tongue, lips, or eyes, hoarseness, chest pain or pressure, swelling of the hands, feet, ankles, or lower legs, fever, infection, nausea, vomiting, diarrhea, extreme tiredness, lack of energy, loss of appetite, pain in the upper right part of the stomach, yellowing of the skin or eyes, flu-like symptoms.

• Pregnancy

Pregnancy Category D (women with mechanical heart valves) and Pregnancy Category X (other pregnant populations).

Warfarin is contraindicated in women who are pregnant except in pregnant women with mechanical heart valves, who are at high risk of thromboembolism, and for whom the benefits of Warfarin may outweigh the risks. Warfarin can cause fetal harm when administered to a pregnant woman. Warfarin exposure during pregnancy causes a recognized pattern of major congenital malformations (warfarin embryopathy), fetal hemorrhage, and an increased risk of spontaneous abortion and fetal mortality. The reproductive and developmental effects of Warfarin have not been evaluated in animals. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. In humans, warfarin crosses the placenta, and concentrations in fetal plasma approach the maternal values. Exposure to warfarin during the first trimester of pregnancy caused a pattern of congenital malformations in about 5% of exposed offspring. Warfarin embryopathy is characterized by nasal hypoplasia with or without stippled epiphyses (chondrodysplasia punctata) and growth retardation (including low birth weight). Central nervous system and eye abnormalities have also been reported, including dorsal midline dysplasia characterized by agenesis of the corpus callosum, Dandy-Walker malformation, midline cerebellar atrophy, and ventral midline dysplasia characterized by optic atrophy. Mental retardation, blindness, schizencephaly, microcephaly, hydrocephalus, and other adverse pregnancy outcomes have been reported following warfarin exposure during the second and third trimesters of pregnancy.

• Nursing Mothers

Based on published data from 15 nursing mothers, warfarin was not detected in human milk. Among the 15 full-term newborns, 6 nursing infants had documented prothrombin times within the expected range. Prothrombin times were not obtained for the other 9 nursing infants. Monitor breastfeeding infants for bruising or bleeding. Effects in premature infants have not been evaluated. Caution should be exercised when Warfarin is administered to a nursing woman.

• Pediatric Use

Adequate and well-controlled studies with Warfarin have not been conducted in any pediatric population, and the optimum dosing, safety, and efficacy in pediatric patients are unknown. Pediatric use of Warfarin is based on adult data and recommendations, and available limited pediatric data from observational studies and patient registries. Pediatric patients administered Warfarin should avoid any activity or sport that may result in traumatic injury.

The developing hemostatic system in infants and children results in a changing physiology of thrombosis and response to anticoagulants. Dosing of warfarin in the pediatric population varies by patient age, with infants generally having the highest, and adolescents having the lowest milligram per kilogram dose requirements to maintain target INR. Because of changing warfarin requirements due to age, concomitant medications, diet, and existing medical conditions, target INR ranges may be difficult to achieve and maintain in pediatric patients, and more frequent INR determinations are recommended. Bleeding rates varied by patient population and clinical care center in pediatric observational studies and patient registries. Infants and children receiving vitamin K-supplemented nutrition, including infant formulas, may be resistant to warfarin therapy, while human milk-fed infants may be sensitive to warfarin therapy.

• Geriatric Use

Patients 60 years or older appear to exhibit greater than expected INR response to the anticoagulant effects of warfarin. Warfarin is contraindicated in any unsupervised patient with senility. Observe caution with the administration of Warfarin to elderly patients in any situation or with any physical condition where added risk of hemorrhage is present. Consider lower initiation and maintenance doses of Warfarin in elderly patients.

• Symptoms: Abnormal bleeding manifested by haematuria, blood in the stools, melaena, petechiae, excessive menstrual bleeding, excessive bruising, or persistent oozing from superficial injuries.
• Management: Discontinue warfarin. Activated charcoal may be considered if a patient presents within 1 hour of ingestion of 0.25 mg/kg or more than the patient's therapeutic dose. If necessary, administer 10-20 mg of vitamin K1 (phytomenadione) orally (250 mcg/kg for the child).

Delay oral vitamin K1 at least 4 hours after administering activated charcoal. Repeat INR after 24 hours and consider further vitamin K1. In life-threatening cases, administer prothrombin complex concentrate (factors II, VII, IX, and X) 30-50 units/kg or fresh-frozen plasma 15 mL/kg if the concentrate is not available. For non-life-threatening cases, give phytomenadione via slow IV inj. If rapid re-anticoagulation is necessary (e.g., valve replacements), administer prothrombin complex concentrate (factors II, VII, IX, and X) 30-50 units/kg or fresh-frozen plasma 15 mL/kg if the concentrate is not available. Monitor INR for at least 48 hours post-overdose and determine when to restart normal therapy.

Pharmacodynamic

An anticoagulation effect generally occurs within 24 hours after warfarin administration. However, the peak anticoagulant effect may be delayed 72 to 96 hours. The duration of action of a single dose of racemic warfarin is 2 to 5 days. The effects of WARFARIN may become more pronounced as the effects of daily maintenance doses overlap. This is consistent with the half-lives of the affected vitamin K-dependent clotting factors and anticoagulation proteins: Factor II - 60 hours, VII - 4 to 6 hours, IX - 24 hours, X - 48 to 72 hours, and proteins C and S are approximately 8 hours and 30 hours, respectively.

Pharmacokinetics

• Absorption

Warfarin is essentially completely absorbed from the GI tract after oral administration, with peak concentration generally attained within the first 4 hours.

• Distribution

Warfarin distributes into a relatively small apparent volume of distribution of about 0.14 L/kg. A distribution phase lasting 6 to 12 hours is distinguishable after rapid intravenous or oral administration of an aqueous solution. Approximately 99% of the drug is bound to plasma proteins.

• Metabolism and Excretion

Warfarin is metabolized in the liver, mainly by CYP2C9 (CYP2C8, 2C18, 2C19, 1A2, and 3A4 as minor pathways). The Elimination half-life of Warfarin is approximately 20-60 hours. Warfarin is excreted in urine (92%, mainly as metabolites and small amounts as an unchanged drug).

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