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Warfarin (coumadin) - Complete Drug Information

Warfarin (Coumadin) inhibits the synthesis of Vitamin K dependent factors (Factor II, VII, IX, X, Protein C, and Protein S). It is thus used as an anticoagulant medicine for the treatment of the following disorder:

Myocardial infarction:
- It is used as an adjunct to reduce risk of systemic embolism (eg, recurrent MI, stroke) after myocardial infarction
Thromboembolic complications:
- It is used for prophylaxis and treatment of thromboembolic disorders (eg, venous, pulmonary) and embolic complications arising from atrial fibrillation or cardiac valve replacement
Off Label Usage of Warfarin in Adults:
It is used for recurrent stroke/Transient ischemic attacks (secondary prevention)

Warfarin Dose in Adults

Dosage in the treatment of Thromboembolic complications (prophylaxis/treatment) or myocardial infarction (risk reduction):

Initial dosing should be individualized.
Consider the patient (nutritional status, concomitant medications, hepatic function, cardiac function, age, risk of bleeding) in addition to the previous dose-response (if available) and the clinical situation.

Start 2 to 5 mg once daily for healthy individuals

It can also be given as 10 mg once daily for 2 days, then reduce the dose
lower initial doses (eg, 5 mg once daily) recommended for patients with confirmed HIT once platelet recovery has taken place.
In patients with acute venous thromboembolism, initiation might begin on the first or second day of parenteral anticoagulation.

The dose is adjusted according to INR results

The usual maintenance dose is from 2 to 10 mg daily (individual patients may require loading and maintenance doses outside these general guidelines).
When making dose adjustments during the maintenance phase (eg, after the first week of daily dosing), the dose given 2 to 3 days prior will have the most prominent effect on the current day INR.

Lower starting doses are required for patients with:

hepatic impairment,
high risk of bleeding,
poor nutrition,
heart failure,
elderly or patients who are debilitated, or
those with reduced function genomic variants of the catabolic enzymes CYP2C9 (*2 or *3 alleles) or VKORC1 (-1639 polymorphism)
Higher initial doses are reasonable in selected patients (ie, receiving enzyme-inducing agents and with low risk of bleeding).
Overlapping a parenteral anticoagulant and warfarin therapy for at least 5 days is necessary for the treatment of DVT/PE even if the INR is therapeutic earlier.
Although an elevation in INR (due to factor VII depletion) is seen early (within the first 24 to 48 hours) in warfarin therapy, it does not represent adequate anticoagulation.
Factors II and X must also be depleted which takes considerably longer.

Range of Expected Therapeutic Maintenance Dose Based on CYP2C9 and VKORC1 Genotypes

VKORC1	CYP2C9
GG	5 to 7 mg	5 to 7 mg	3 to 4 mg	3 to 4 mg	3 to 4 mg	0.5 to 2 mg
AG	5 to 7 mg	3 to 4 mg	3 to 4 mg	3 to 4 mg	0.5 to 2 mg	0.5 to 2 mg
AA	3 to 4 mg	3 to 4 mg	0.5 to 2 mg	0.5 to 2 mg	0.5 to 2 mg	0.5 to 2 mg
It must also be taken into account other patient-related factors when determining the initial dose (eg, age, body weight, concomitant medications, comorbidities).

Duration of therapy:

Warfarin Duration of Therapy according to Indication

Indication	Duration of therapy
Nonvalvular Atrial fibrillation or AF due to mitral stenosis or atrial flutter	Indefinite

Indefinite therapy is defined as after the first 3 months of treatment and with no scheduled stop date.
All patients receiving extended or indefinite therapy are reassessed at periodic intervals for continuing use of therapy.
In patients with AF or atrial flutter of ≥48 hours duration or when the duration is unknown, anticoagulation is advised for ≥3 weeks prior to and ≥4 weeks after cardioversion regardless of the CHA2DS2-VASc score and method used to restore sinus rhythm.

Indication	Duration of therapy
Bioprosthetic valves in the mitral position	3 months after valve insertion
Mechanical prosthetic cardiac valves	Indefinite
Anterior MI with LV thrombus or at high risk for LV thrombus	3 months after MI
Venous Thromboembolism
Provoked DVT or PE (without cancer)	3 months minimum or indefinite therapy is considered in patients who do not have a high risk of bleeding
Unprovoked DVT or PE	Indefinite therapy is recommended in patients who do not have a high risk of bleeding
In patients with Deep Vein Thrombosis of the leg or Pulmonary embolism and with cancer Note: LMWH is preferred over oral anticoagulation for the treatment of patients with cancer	Indefinite therapy is recommended, although high bleeding risk confers a lower grade of recommendation.

Warfarin Dose in Childrens

Dosage in the prophylaxis and treatment of Thromboembolic complications: Limited data available:

Individualize dose is used to achieve target INR based on the indication
INRs are primarily extrapolated from adult experience
There might be some exceptions, for most indications the therapeutic target INR is 2.5 (range: 2 to 3), and for low-dose prophylaxis, a target INR is 1.7 (range: 1.5 to 1.9)
Infants, Children, and Adolescents:
- Target INR between 2 and 3:
  - Day 1:
    - The initial loading dose is (if baseline INR is 1 to 1.3) 0.2 mg/kg/day once daily
    - the maximum dose is 10 mg/dose
    - use a reduced initial loading dose of 0.1 mg/kg if the patient has undergone a Fontan procedure or has liver dysfunction
  - Days 2 to 4:
  - Additional loading doses are dependent upon the patient's INR:
    - INR 1.1 to 1.3: Repeat the initial loading dose given
    - INR 1.4 to 1.9: Dose is 50% of the initial loading dose given
    - INR 2 to 3: Dose is 50% of the initial loading dose given
    - INR 3.1 to 3.5: Dose is 25% of the initial loading dose given
    - INR >3.5: Hold the drug until INR <3.5, then restart at half of the previous dose
  - Days ≥5:
  - Maintenance doses are dependent upon the patient's INR
    - INR 1.1 to 1.4: Increase dose by 20% of the previous dose given
    - INR 1.5 to 1.9: Increase dose by 10% of the previous dose given
    - INR 2 to 3: No change
    - INR 3.1 to 3.5: Decrease dose by 10% of the previous dose given
    - INR >3.5: Hold the drug until INR <3.5, then restart at 20% less than the previous dose given
- Usual maintenance dose:
  - Almost 0.1 mg/kg/day once daily
  - range is 0.05 to 0.34 mg/kg/day
  - Children receiving phenobarbital, carbamazepine, or enteral nutrition might require higher maintenance doses

Warfarin (coumadin) pregnancy Risk Category: D

Warfarin crosses the placenta
Concentrations in fetal plasma are equal to maternal values.
After first-trimester exposure, teratogenic effects were observed.
These included coumarin embryopathy and/or stippled Epiphyses. Also, limb hypoplasia could be present.
The following adverse CNS events have been observed in the fetus during any trimester.
They may include ventral midline dysplasia and dorsal middleline dysplasia.
It is possible for spontaneous abortion, fetal hemorhage and even fetal death to occur.
Contraindications are for women who are pregnant or have potential to become pregnant.
It is not recommended for women suffering from preeclampsia, eclampsia or threatened abortion.
Women who plan to become pregnant should have regular pregnancy tests.
Adjusted-dose heparin, low molecular weight heparin and LMWH should both be used as a substitute for warfarin as soon as possible.
Pregnant women with high-risk, mechanical heart valves should weigh the benefits and risks of warfarin therapy against the potential dangers of other treatments
Avoid warfarin use in the first trimester or close to delivery.
If the therapeutic INR is =5mg/day, warfarin can be used during the first trimester.
LMWH/adjusted-dose heparin may be used during pregnancy, or up to week 13 when warfarin therapy can be switched.
Close to delivery, LMWH and heparin should both be resumed.

Women with a high risk of thromboembolism (older mechanical prosthesis in the mitral position, history of thrombosis) can use warfarin throughout pregnancy.
Warfarin can then be replaced by LMWH or heparin at the end. Low-dose aspirin should also be used.
If a woman is considering pregnancy and has long-term anticoagulation needs with warfarin, LMWH replacement should be performed before conception.

If anti-Xa monitoring is not possible, do not use LMWH therapy on pregnant patients using a mechanical prosthetic.
Consider the following: fetal outcomes (i.e. pregnancy loss, malformations), maternal results (i.e. VTE, hemorhage), the burden of treatment, and maternal preference when choosing therapy.

Warfarin use during breastfeeding:

According to available data, breast milk is almost always free of warfarin.
Warfarin can be used to treat breastfeeding mothers
According to the American College of Chest Physicians, warfarin can be used by lactating mothers who want to breastfeed their babies.
Manufacturers also recommend monitoring breastfeeding infants for bleeding or bruising.

Warfarin Dose in Kidney Disease:

No dosage adjustment required.
However, patients having renal impairment have an increased risk for bleeding diathesis;
monitor INR closely.

Hemodialysis:

It is not dialyzable.

Warfarin (Coumadin) dose in Liver disease:

There are no dosage adjustments given in the manufacturer's labeling.
However, the response to oral anticoagulants might be markedly enhanced in obstructive jaundice, hepatitis, and cirrhosis.
INR should also be closely monitored.

Side effects of warfarin (coumadin):

Bleeding is the major adverse effect of warfarin.
Hemorrhage might occur at virtually any site.
The risk of bleeding is also dependent on multiple variables, including the intensity of anticoagulation and patient susceptibility.

Less Common Side Effects of Warfarin Include:

Hematologic & oncologic:
- Major hemorrhage

Rare side effects of warfarin:

Cardiovascular:
- Purple-toe syndrome
- Systemic cholesterol micro-embolism
- Vasculitis
Central nervous system:
- Chills
Dermatologic:
- Alopecia
- Bullous rash
- Dermatitis
- Pruritus
- Skin necrosis
- Urticaria
Gastrointestinal:
- Abdominal pain
- Bloating
- Diarrhea
- Dysgeusia
- Flatulence
- Nausea
- Vomiting
Hematologic & oncologic:
- Minor hemorrhage
Hepatic:
- Hepatitis
Hypersensitivity:
- Anaphylaxis
- Hypersensitivity reaction
Renal:
- Acute renal failure (in patients with altered glomerular integrity or with a history of kidney disease)
Respiratory:
- Tracheobronchial calcification

Contraindication to Warfarin Include:

Hypersensitivity to warfarin and any component of the formulation
Hemorrhagic tendencies include active GI ulceration, CNS hemorhage, dissecting aortic eneurysm, spinal puncture patients bleeding from their GI, respiratory or GU tract, and other diagnostic or therapeutic procedures that have the potential to cause significant bleeding.
Recent or imminent surgery on the eye or CNS
Major regional lumbar block or trauma surgery causing large, open areas
blood dyscrasias
Malignant hypertension
Pericarditis and pericardial effusion
bacterial endocarditis
Patients with high-risk conditions that are unsupervised and are at risk of noncompliance should be supervised
eclampsia/preeclampsia, threatened abortion, pregnancy (except in women having mechanical heart valves at high risk for thromboembolism)

Warnings and precautions

Acute kidney injury
- Patients with a history or altered glomerular integrity may experience acute kidney injury due to episodes of excess anticoagulation and/or hematuria.
Anaphylaxis/hypersensitivity:
- It can cause anaphylaxis and hypersensitivity reactions.
- Patients with anaphylactic conditions should be treated with caution.
Bleeding: [US Boxed Warning]
- It can cause severe or fatal bleeding.
- Regularly monitor INR levels in all patients being treated.
- Concomitant medications, diet modifications, and/or smoking can affect the INR levels achieved with warfarin therapy.
- Risk factors for bleeding include:
  - High-Intensity Anticoagulation (INR>4)
  - Age (>=65 Years)
  - Heart disease is a serious condition
  - anemia,
  - Variable INRs
  - History of GI bleeding
  - hypertension,
  - cerebrovascular disease
  - severe diabetes,
  - Malignancy
  - trauma,
  - Insufficiency of the kidneys
  - Polycythemia vera
  - Vasculitis
  - open wound,
  - History of PUD
  - indwelling catheters,
  - Postpartum and menstruating women
  - drug-drug interactions,
  - A long-term therapy or
  - Known genetic defect in CYP2C9 activity.
- It is important that the patient be instructed to report any bleeding, accidents, or falls, as well as any new, discontinued, herbal, or alternative products, changes in smoking habits, and any other medications.
- Anticoagulation might uncover unrecognized bleeding areas (eg, colon carcinoma).
Calciphylaxis
- Patients with or without end-stage kidney disease have been known to suffer from fatal and severe calciphylaxis (calcium Uremic Arteriolopathy).
- Stop therapy if calciphylaxis has been diagnosed.
- You might consider other anticoagulation therapies.
Skin necrosis/gangrene:
- Paradoxical local thrombosis can cause gangrene or necrosis of the skin or other tissue. It is rare, but it is possible. Usually, the symptoms appear within the first few days. Often, the site of origin is the penis, breast or limbs.
- Patients with protein C or S deficiencies are at greater risk.
- If anticoagulation is necessary, you might consider other therapies.
Atheroemboli/cholesterol microemboli:
- Warfarin therapy can help to release plaque emboli from atheromatous plaques
- The location of embolization will determine the symptoms, which are most often found in the kidneys, liver and pancreas.
- It can lead to death or necrosis in some cases.
- Due to cholesterol microembolization, "Purple Toe" syndrome has rarely been seen with anticoagulants of the coumarin type.
- This usually occurs after several weeks of therapy. It can appear as dark, purplish or mottled discoloration on the plantar and/or lateral surfaces.
- There are also other manifestations of cholesterol microembolization:
  - Rash
  - Pain in the back, stomach, or flanks
  - Hematuria
  - Renal insufficiency
  - hypertension
  - livedo reticularis
  - gangrene
  - Sudden and severe pain in the lower extremities of cerebral ischemia
  - Infarction of the spinal cord
  - Other symptoms that may indicate vascular compromise
Bariatric surgery
- Post-surgery, there is a high chance of hemorhage
- If possible, avoid warfarin immediately following gastric bypass and Sleeve gastrectomy
- The change in dose requirement can be multifactorial but is most likely due to attributable variation in the time to resuming full solid intake and the consequent alteration in the intake of vitamin K containing foods.
- Monitor INR closely during the first year post-op and for up to one year following surgery if you notice significant nutritional or supplementation change.
Insufficiency in the diet:
- Use cautiously in patients with prolonged dietary insufficiencies (vitamin K deficiency).
Heparin-induced hemocytopenia
- Patients with heparin-induced DVT and thrombocytopenia should be cautious
- Necrosis, limb ischemia, and gangrene were all seen after warfarin was discontinued.
- Warfarin monotherapy in the initial treatment for active HIT is contraindicated
- Warfarin inhibits the initial synthesis of protein A, which could accelerate the underlying active-thrombotic process.
Hepatic impairment
- A decreased liver function could lead to increased sensitivity to warfarin, regardless of the etiology.
Infection
- Patients with active TB, acute infection, or disruptions to normal GI flora should be cautious.
- Warfarin can be affected by fever and antibiotics.
Renal impairment
- Patients with impaired renal function should be cautious.
- Patients with kidney impairment are more at risk of bleeding diathesis
Thyroid disease:
- Patients with thyroid disease should be cautious.
- Increased Warfarin response may be a result

Warfarin: Drug Interaction

Risk Factor C (Monitor therapy)
Acetaminophen	May enhance the anticoagulant effect of Vitamin K Antagonists. This appears most likely with daily acetaminophen doses exceeding 1.3 or 2 g/day for multiple consecutive days.
Adalimumab	May decrease the serum concentration of Warfarin.
Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.)	May enhance the anticoagulant effect of Anticoagulants.
Alcohol (Ethyl)	May decrease the serum concentration of Vitamin K Antagonists. More specifically, this effect has been described in heavy drinking alcoholic patients (over 250 g alcohol daily for over 3 months). The role of alcohol itself is unclear.
Alpelisib	May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers).
Anticoagulants	May enhance the anticoagulant effect of Vitamin K Antagonists.
Antihepaciviral NS5B RNA Polymerase Inhibitors	May diminish the anticoagulant effect of Vitamin K Antagonists.
Apalutamide	May decrease the serum concentration of Warfarin.
Aprepitant	May decrease the serum concentration of Warfarin.
Atazanavir	May increase the serum concentration of Warfarin.
AzaTHIOprine	May diminish the anticoagulant effect of Vitamin K Antagonists.
Benzbromarone	May increase the serum concentration of Warfarin.
Bicalutamide	May increase the serum concentration of Vitamin K Antagonists. Specifically, free concentrations of the vitamin K antagonists may be increased.
Bifonazole	May enhance the anticoagulant effect of Warfarin.
Bile Acid Sequestrants	May decrease the absorption of Vitamin K Antagonists.
Bosentan	May increase the metabolism of Vitamin K Antagonists.
Bromperidol	May enhance the adverse/toxic effect of Anticoagulants.
Caplacizumab	May enhance the anticoagulant effect of Anticoagulants.
Cephalosporins	May enhance the anticoagulant effect of Vitamin K Antagonists.
Ceritinib	May increase the serum concentration of Warfarin.
Chenodiol	May enhance the anticoagulant effect of Vitamin K Antagonists.
Chloral Betaine	May increase the serum concentration of Vitamin K Antagonists.
Chloral Hydrate	May increase the serum concentration of Vitamin K Antagonists.
Chloramphenicol (Systemic)	May enhance the anticoagulant effect of Vitamin K Antagonists. Chloramphenicol (Systemic) may increase the serum concentration of Vitamin K Antagonists.
Chondroitin Sulfate	May enhance the anticoagulant effect of Warfarin.
Cloxacillin	May diminish the anticoagulant effect of Vitamin K Antagonists. Cloxacillin may enhance the anticoagulant effect of Vitamin K Antagonists.
Cobicistat	May increase the serum concentration of Warfarin.
Coenzyme Q-10	May diminish the anticoagulant effect of Vitamin K Antagonists. Coenzyme Q10 may enhance the anticoagulant effect of Vitamin K Antagonists.
Collagenase (Systemic)	Anticoagulants may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased.
Corticosteroids (Systemic)	May enhance the anticoagulant effect of Warfarin.
Cranberry	May enhance the anticoagulant effect of Vitamin K Antagonists.
CYP2C9 Inducers (Moderate)	May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers).
CYP2C9 Inhibitors (Moderate)	May decrease the metabolism of CYP2C9 Substrates (High risk with Inhibitors).
Daclatasvir	May enhance the anticoagulant effect of Warfarin.
Darunavir	May decrease the serum concentration of Warfarin. Darunavir may increase the serum concentration of Warfarin.
Dasatinib	May enhance the anticoagulant effect of Anticoagulants.
Deferasirox	Anticoagulants may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased.
Deoxycholic Acid	Anticoagulants may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased.
Desvenlafaxine	May enhance the adverse/toxic effect of Vitamin K Antagonists. Specifically, the risk for bleeding may be increased.
Dexmethylphenidate	May increase the serum concentration of Vitamin K Antagonists.
Dicloxacillin	May diminish the anticoagulant effect of Vitamin K Antagonists.
Disulfiram	May increase the serum concentration of Vitamin K Antagonists.
Dronabinol	May increase the serum concentration of Warfarin. Specifically, dronabinol may displace warfarin from its protein-binding sites, leading to an increased concentration of active, unbound drug.
Dronedarone	May increase the serum concentration of Vitamin K Antagonists.
Econazole	May increase the serum concentration of Vitamin K Antagonists.
Efavirenz	May decrease the serum concentration of Vitamin K Antagonists. Efavirenz may increase the serum concentration of Vitamin K Antagonists.
Erlotinib	May increase the serum concentration of Warfarin.
Erythromycin (Ophthalmic)	May increase the serum concentration of Vitamin K Antagonists.
Eslicarbazepine	May decrease the serum concentration of Warfarin. Specifically, S-warfarin serum concentrations may be decreased.
Esomeprazole	May increase the serum concentration of Vitamin K Antagonists.
Ethacrynic Acid	May increase the serum concentration of Vitamin K Antagonists.
Etoposide	May enhance the anticoagulant effect of Vitamin K Antagonists.
Etoposide Phosphate	May enhance the anticoagulant effect of Vitamin K Antagonists.
Exenatide	May enhance the anticoagulant effect of Vitamin K Antagonists.
Fat Emulsion (Fish Oil and Plant Based)	May diminish the anticoagulant effect of Vitamin K Antagonists.
Fat Emulsion (Fish Oil Based)	May enhance the anticoagulant effect of Anticoagulants.
Flucloxacillin	May diminish the anticoagulant effect of Vitamin K Antagonists. Flucloxacillin may decrease the serum concentration of Vitamin K Antagonists.
Fluorouracil (Topical)	May increase the serum concentration of Vitamin K Antagonists.
Fosamprenavir	May increase the serum concentration of Warfarin.
Fosaprepitant	May decrease the serum concentration of Warfarin. The active metabolite aprepitant is likely responsible for this effect.
Frankincense, Indian	May enhance the anticoagulant effect of Warfarin.
Gefitinib	May enhance the anticoagulant effect of Vitamin K Antagonists.
Gemcitabine	May enhance the anticoagulant effect of Warfarin.
Ginseng (American)	May decrease the serum concentration of Warfarin.
Glucagon	May enhance the anticoagulant effect of Vitamin K Antagonists.
Glucosamine	May enhance the anticoagulant effect of Warfarin.
Grazoprevir	May enhance the anticoagulant effect of Warfarin.
Green Tea	May enhance the adverse/toxic effect of Warfarin. Particularly, the risk of bleeding may be increased due to possible antiplatelet effects of green tea. Green Tea may diminish the anticoagulant effect of Warfarin.
Griseofulvin	May decrease the serum concentration of Vitamin K Antagonists.
HMG-CoA Reductase Inhibitors (Statins)	May enhance the anticoagulant effect of Vitamin K Antagonists. Exceptions: AtorvaSTATin.
Ibritumomab Tiuxetan	Anticoagulants may enhance the adverse/toxic effect of Ibritumomab Tiuxetan. Both agents may contribute to an increased risk of bleeding.
Ibrutinib	May enhance the adverse/toxic effect of Anticoagulants.
Ifosfamide	May enhance the anticoagulant effect of Vitamin K Antagonists.
Inotersen	May enhance the anticoagulant effect of Anticoagulants.
Itraconazole	May increase the serum concentration of Vitamin K Antagonists.
Ivermectin (Systemic	May enhance the anticoagulant effect of Vitamin K Antagonists.
Ketoconazole (Systemic)	May increase the serum concentration of Vitamin K Antagonists.
Lansoprazole	May increase the serum concentration of Vitamin K Antagonists.
Leflunomide	May enhance the anticoagulant effect of Vitamin K Antagonists. Leflunomide may diminish the anticoagulant effect of Vitamin K Antagonists.
Letermovir	May decrease the serum concentration of Warfarin.
LevOCARNitine	May enhance the anticoagulant effect of Vitamin K Antagonists.
Levomilnacipran	May enhance the adverse/toxic effect of Vitamin K Antagonists. Specifically, the risk for bleeding may be increased.
Limaprost	May enhance the adverse/toxic effect of Anticoagulants. The risk for bleeding may be increased.
Lomitapide	May increase the serum concentration of Warfarin.
Lopinavir	May decrease the serum concentration of Warfarin.
Lumacaftor	May decrease the serum concentration of CYP2C9 Substrates (High Risk with Inhibitors or Inducers). Lumacaftor may increase the serum concentration of CYP2C9 Substrates (High Risk with Inhibitors or Inducers).
Macrolide Antibiotics	May increase the serum concentration of Vitamin K Antagonists. Exceptions: Fidaxomicin; Roxithromycin; Spiramycin.
Maitake	May increase the serum concentration of Warfarin.
Menadiol Diphosphate	May diminish the anticoagulant effect of Vitamin K Antagonists.
Mercaptopurine	May diminish the anticoagulant effect of Vitamin K Antagonists.
Methylphenidate	May increase the serum concentration of Vitamin K Antagonists.
Metreleptin	May decrease the serum concentration of Warfarin. Metreleptin may increase the serum concentration of Warfarin.
Miconazole (Oral)	May increase the serum concentration of Warfarin.
Milnacipran	May enhance the adverse/toxic effect of Vitamin K Antagonists. Specifically, the risk for bleeding may be increased.
Mirtazapine	May enhance the anticoagulant effect of Warfarin.
Multivitamins/Fluoride (with ADE)	May enhance the anticoagulant effect of Vitamin K Antagonists.
Multivitamins/Minerals (with ADEK, Folate, Iron)	May enhance the anticoagulant effect of Vitamin K Antagonists. Multivitamins/Minerals (with ADEK, Folate, Iron) may diminish the anticoagulant effect of Vitamin K Antagonists.
Multivitamins/Minerals (with AE, No Iron)	May enhance the anticoagulant effect of Vitamin K Antagonists.
Nelfinavir	May decrease the serum concentration of Warfarin. Nelfinavir may increase the serum concentration of Warfarin.
Neomycin	May enhance the anticoagulant effect of Vitamin K Antagonists.
Nevirapine	May diminish the anticoagulant effect of Warfarin.
Nintedanib	Anticoagulants may enhance the adverse/toxic effect of Nintedanib. Specifically, the risk for bleeding may be increased.
Nonsteroidal Anti-Inflammatory Agents	May enhance the anticoagulant effect of Anticoagulants.
Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective)	May enhance the anticoagulant effect of Vitamin K Antagonists. Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective) may increase the serum concentration of Vitamin K Antagonists.
Obeticholic Acid	May diminish the anticoagulant effect of Warfarin.
Obinutuzumab	Anticoagulants may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased.
Ombitasvir, Paritaprevir, and Ritonavir	May diminish the anticoagulant effect of Warfarin.
Omega-3 Fatty Acids	May enhance the anticoagulant effect of Anticoagulants.
Omeprazole	May increase the serum concentration of Vitamin K Antagonists.
Oritavancin	May increase the serum concentration of Vitamin K Antagonists.
Oritavancin	May diminish the therapeutic effect of Anticoagulants. Specifically, oritavancin may artificially increase the results of laboratory tests commonly used to monitor anticoagulant effectiveness, which could lead to incorrect decisions to decrease anticoagulant doses.
Orlistat	May enhance the anticoagulant effect of Vitamin K Antagonists.
Penicillins	May enhance the anticoagulant effect of Vitamin K Antagonists. Exceptions: Dicloxacillin; Nafcillin.
Pentosan Polysulfate Sodium	May enhance the anticoagulant effect of Anticoagulants.
Pentoxifylline	May enhance the anticoagulant effect of Vitamin K Antagonists.
Posaconazole	May increase the serum concentration of Vitamin K Antagonists.
Proguanil	May enhance the anticoagulant effect of Warfarin.
Propacetamol	May enhance the anticoagulant effect of Vitamin K Antagonists. This appears most likely with higher doses (equivalent to acetaminophen doses exceeding 1.3 to 2 g/day) for multiple consecutive days.
Propafenone	May increase the serum concentration of Vitamin K Antagonists.
Prostacyclin Analogues	May enhance the adverse/toxic effect of Anticoagulants. Specifically, the antiplatelet effects of these agents may lead to an increased risk of bleeding with the combination.
QuiNIDine	May enhance the anticoagulant effect of Vitamin K Antagonists. Note that the INR/PT might be unchanged in the face of increased bleeding.
QuiNINE	May enhance the anticoagulant effect of Vitamin K Antagonists.
Quinolones	May enhance the anticoagulant effect of Vitamin K Antagonists.
RaNITIdine	May increase the serum concentration of Warfarin.
Regorafenib	Warfarin may enhance the adverse/toxic effect of Regorafenib. Specifically, the risk for bleeding may be increased.
Revaprazan	May diminish the anticoagulant effect of Warfarin.
Ribavirin (Systemic)	May diminish the anticoagulant effect of Vitamin K Antagonists.
Rifamycin Derivatives	May increase the metabolism of Vitamin K Antagonists.
Rifapentine	May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers).
Ritonavir	May decrease the serum concentration of Warfarin.
RomiDEPsin	May enhance the anticoagulant effect of Warfarin.
Roxithromycin	May enhance the anticholinergic effect of Warfarin.
Rucaparib	May increase the serum concentration of Warfarin.
Salicylates	May enhance the anticoagulant effect of Anticoagulants.
Salicylates (Topical)	May enhance the anticoagulant effect of Warfarin.
Saquinavir	May increase the serum concentration of Warfarin.
Selective Serotonin Reuptake Inhibitors	May enhance the anticoagulant effect of Vitamin K Antagonists.
Simeprevir	May enhance the anticoagulant effect of Warfarin.
Sugammadex	May enhance the anticoagulant effect of Anticoagulants.
Sulfonylureas	May enhance the anticoagulant effect of Vitamin K Antagonists. Vitamin K Antagonists may enhance the hypoglycemic effect of Sulfonylureas.
Sulodexide	May enhance the anticoagulant effect of Anticoagulants.
Telavancin	May diminish the therapeutic effect of Anticoagulants. Specifically, telavancin may artificially increase the results of laboratory tests commonly used to monitor anticoagulant effectiveness, which could lead to incorrect decisions to decrease anticoagulant doses.
Teriflunomide	May decrease the serum concentration of Warfarin.
Tetracyclines	May enhance the anticoagulant effect of Vitamin K Antagonists.
Thrombolytic Agents	May enhance the anticoagulant effect of Anticoagulants. Management: See full drug monograph for guidelines for the use of alteplase for acute ischemic stroke during treatment with oral anticoagulants.
Thyroid Products	May enhance the anticoagulant effect of Vitamin K Antagonists.
Tibolone	May enhance the anticoagulant effect of Anticoagulants.
Tigecycline	May increase the serum concentration of Warfarin.
Tipranavir	May enhance the anticoagulant effect of Anticoagulants.
Tobacco (Smoked)	May decrease the serum concentration of Warfarin.
Tolterodine	May enhance the anticoagulant effect of Warfarin.
Toremifene	May enhance the anticoagulant effect of Vitamin K Antagonists.
Torsemide	May increase the serum concentration of Warfarin.
TraMADol	May enhance the anticoagulant effect of Vitamin K Antagonists.
Tranilast (Systemic)	May enhance the adverse/toxic effect of Warfarin. Tranilast (Systemic) may diminish the therapeutic effect of Warfarin.
TraZODone	May diminish the anticoagulant effect of Warfarin.
Tricyclic Antidepressants	May enhance the anticoagulant effect of Vitamin K Antagonists.
Valproate Products	May decrease the protein binding of Warfarin.
Vemurafenib	May increase the serum concentration of Warfarin.
Venetoclax	May increase the serum concentration of Warfarin.
Venlafaxine	May enhance the adverse/toxic effect of Vitamin K Antagonists. Specifically, the risk for bleeding may be increased.
Vitamin E (Systemic)	May enhance the anticoagulant effect of Anticoagulants.
Voriconazole	May increase the serum concentration of Vitamin K Antagonists.
Vorinostat	May enhance the anticoagulant effect of Vitamin K Antagonists.
Zafirlukast	May increase the serum concentration of Vitamin K Antagonists.
Zileuton	May increase the serum concentration of Warfarin.
Risk Factor D (Consider therapy modification)
Allopurinol	May enhance the anticoagulant effect of Vitamin K Antagonists.
Amiodarone	May enhance the anticoagulant effect of Vitamin K Antagonists. Amiodarone may increase the serum concentration of Vitamin K Antagonists. Management: Monitor patients extra closely for evidence of increased anticoagulant effects if amiodarone is started. Consider empiric reduction of 30% to 50% in warfarin dose, though no specific guidelines on dose adjustment have been published.
Androgens	May enhance the anticoagulant effect of Vitamin K Antagonists.
Antithyroid Agents	May diminish the anticoagulant effect of Vitamin K Antagonists.
Barbiturates	May increase the metabolism of Vitamin K Antagonists. Management: Monitor INR more closely. An anticoagulant dose increase may be needed after a barbiturate is initiated or given at an increased dose. Anticoagulant dose decreases may be needed following barbiturate discontinuation or dose reduction.
Capecitabine	May increase the serum concentration of Vitamin K Antagonists.
CarBAMazepine	May decrease the serum concentration of Vitamin K Antagonists. Management: Monitor for decreased INR and effects of vitamin K antagonists if carbamazepine is initiated/dose increased, or increased INR and effects if carbamazepine is discontinued/dose decreased. Warfarin dose adjustments will likely be required.
Cimetidine	May enhance the anticoagulant effect of Vitamin K Antagonists.
Clopidogrel	May enhance the anticoagulant effect of Warfarin.
Dabrafenib	May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP2C9 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects).
Desirudin	Anticoagulants may enhance the anticoagulant effect of Desirudin.
Enzalutamide	May decrease the serum concentration of Warfarin. More specifically, enzalutamide may decrease concentrations of the S-warfarin enantiomer. Management: Avoid concurrent use of warfarin and enzalutamide whenever possible. If the combination must be used, conduct additional INR monitoring as serum concentrations may be decreased.
Estrogen Derivatives	May diminish the anticoagulant effect of Anticoagulants. More specifically, the potential prothrombotic effects of some estrogens and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of estrogens against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Exceptions: Tibolone.
Estrogen Derivatives (Contraceptive)	May diminish the anticoagulant effect of Vitamin K Antagonists. In contrast, enhanced anticoagulant effects have also been noted with some products.
Ethotoin	May enhance the anticoagulant effect of Vitamin K Antagonists. Vitamin K Antagonists may increase the serum concentration of Ethotoin. Management: Anticoagulant dose adjustment will likely be necessary when ethotoin is initiated or discontinued. Monitor patients extra closely (INR and signs/symptoms of bleeding) when using this combination.
Fenofibrate and Derivatives	May enhance the anticoagulant effect of Warfarin. Fenofibrate and Derivatives may increase the serum concentration of Warfarin.
Fenugreek	May enhance the anticoagulant effect of Vitamin K Antagonists. Management: Seek alternatives to fenugreek in patients receiving vitamin K antagonists. Monitor patients receiving these combinations closely for increases in INR and systemic effects of the vitamin K antagonist (particularly easy bruising and bleeding).
Fibric Acid Derivatives	May enhance the anticoagulant effect of Vitamin K Antagonists.
Floxuridine	May increase the serum concentration of Vitamin K Antagonists. Management: Monitor INR and signs/symptoms of bleeding closely when starting or stopping floxuridine in a patient receiving a vitamin K antagonist. Anticoagulant dose adjustment will likely be necessary.
Fluconazole	May increase the serum concentration of Vitamin K Antagonists.
Fluorouracil (Systemic)	May increase the serum concentration of Vitamin K Antagonists.
Fosphenytoin	May enhance the anticoagulant effect of Vitamin K Antagonists. Vitamin K Antagonists may increase the serum concentration of Fosphenytoin. Management: Anticoagulant dose adjustment will likely be necessary when phenytoin is initiated or discontinued. Monitor patients extra closely (INR and signs/symptoms of bleeding) when using this combination.
Fusidic Acid (Systemic)	May increase the serum concentration of Vitamin K Antagonists. Management: Vitamin K antagonist dose adjustments may be required when used with systemic fusidic acid. Patients using this combination should be monitored extra closely for evidence of bleeding and to determine appropriate dose.
Ginkgo Biloba	May enhance the adverse/toxic effect of Vitamin K Antagonists. Management: Consider avoiding the use of this combination of agents. Monitor for signs and symptoms of bleeding if vitamin K antagonists and Ginkgo biloba are used concomitantly.
Glutethimide	May increase the metabolism of Vitamin K Antagonists.
Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry)	May enhance the adverse/toxic effect of Anticoagulants. Bleeding may occur. Management: Avoid such combinations when possible. If used concomitantly, increase diligence in monitoring for adverse effects (eg, bleeding, bruising, altered mental status due to CNS bleeds).
Imatinib	May enhance the anticoagulant effect of Warfarin. Imatinib may decrease the metabolism of Warfarin.
Menatetrenone	May diminish the anticoagulant effect of Vitamin K Antagonists.
MetroNIDAZOLE (Systemic)	May increase the serum concentration of Vitamin K Antagonists. Management: Consider alternatives to concomitant therapy with these agents. If concomitant therapy cannot be avoided, consider reducing the dose of the vitamin K antagonist and monitor for increased INR/bleeding.
Miconazole (Topical)	May increase the serum concentration of Vitamin K Antagonists.
Nafcillin	May diminish the anticoagulant effect of Vitamin K Antagonists. Management: Consider choosing an alternative antibiotic. Monitor for decreased therapeutic effects and need for dose adjustments of oral anticoagulants if nafcillin is initiated/dose increased, or increased effects if nafcillin is discontinued/dose decreased.
Nonsteroidal Anti-Inflammatory Agents (Nonselective)	May enhance the anticoagulant effect of Vitamin K Antagonists.
Phenytoin	May enhance the anticoagulant effect of Vitamin K Antagonists. Vitamin K Antagonists may increase the serum concentration of Phenytoin. Management: Anticoagulant dose adjustment will likely be necessary when phenytoin is initiated or discontinued. Monitor patients extra closely (INR and signs/symptoms of bleeding) when using this combination.
Phytonadione	May diminish the anticoagulant effect of Vitamin K Antagonists.
Progestins	May diminish the therapeutic effect of Anticoagulants. More specifically, the potential prothrombotic effects of some progestins and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of progestins against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations.
Progestins (Contraceptive)	May diminish the anticoagulant effect of Vitamin K Antagonists. In contrast, enhanced anticoagulant effects have also been noted with some products. Management: When possible, concomitant hormonal contraceptives and coumarin derivatives should be avoided in order to eliminate the risk of thromboembolic disorders. Consider using an alternative, nonhormonal contraceptive.
Salicylates	May enhance the anticoagulant effect of Vitamin K Antagonists. Exceptions: Salsalate.
Sodium Zirconium Cyclosilicate	May increase the serum concentration of Warfarin. Management: Separate the administration of sodium zirconium cyclosilicate and warfarin by at least 2 hours. If simultaneous administration is required, monitor for signs and symptoms of warfarin toxicity (eg, elevated INR, bleeding).
SORAfenib	May enhance the anticoagulant effect of Warfarin. SORAfenib may increase the serum concentration of Warfarin. Management: Warfarin dose adjustment will likely be necessary. Increase frequency of INR monitoring during sorafenib therapy (particularly when starting or stopping therapy), and increase monitoring for signs and symptoms of bleeding.
St John's Wort	May increase the metabolism of Vitamin K Antagonists.
Sucralfate	May diminish the anticoagulant effect of Vitamin K Antagonists. Sucralfate may decrease the serum concentration of Vitamin K Antagonists. Specifically, sucralfate may decrease the absorption of Vitamin K Antagonists. Management: Administer vitamin K antagonists at least 2 hours before or at least 6 hours after sucralfate.
Sulfinpyrazone	May decrease the metabolism of Vitamin K Antagonists. Sulfinpyrazone may decrease the protein binding of Vitamin K Antagonists.
Sulfonamide Antibiotics	May enhance the anticoagulant effect of Vitamin K Antagonists.
Tegafur	May increase the serum concentration of Vitamin K Antagonists. Management: Monitor INR and signs/symptoms of bleeding closely when starting or stopping this combination. Anticoagulant dose adjustment will likely be necessary.
Risk Factor X (Avoid combination)
Hemin	May enhance the anticoagulant effect of Anticoagulants.
MiFEPRIStone	May enhance the adverse/toxic effect of Anticoagulants. Specifically, the risk of bleeding may be increased.
Omacetaxine	Anticoagulants may enhance the adverse/toxic effect of Omacetaxine. Specifically, the risk for bleeding-related events may be increased. Management: Avoid concurrent use of anticoagulants with omacetaxine in patients with a platelet count of less than 50,000/uL.
Oxatomide	May enhance the anticoagulant effect of Vitamin K Antagonists.
Streptokinase	May enhance the anticoagulant effect of Vitamin K Antagonists.
Tamoxifen	May increase the serum concentration of Vitamin K Antagonists.
Urokinase	May enhance the anticoagulant effect of Anticoagulants.
Vorapaxar	May enhance the adverse/toxic effect of Anticoagulants. More specifically, this combination is expected to increase the risk of bleeding.

Monitor:

Prothrombin time
hematocrit
INR (frequency varies depending on INR stability)
genotyping of CYP2C9 and VKORC1 prior to initiation of therapy

How to administer Warfarin (Coumadin)?

Give orally with or without food.

Mechanism of action of Warfarin (Coumadin):

Vitamin K is required for hepatic synthesis coagulation factors II (half life 42 to 72 hours), VII (4 to 6 hours), and X (5 half-life 27 to 48hrs), as well as protein C and S.
These clotting factors can be biologically activated through the addition of carboxyl group to key glutamic acid residues in the proteins' structure.
The "active" vitaminK is oxidatively converted to an "inactive", which is then reactivated using vitamin K epoxide reduces complex 1 (VKORC1).
Warfarin competely inhibits subunit 1 in the multi-unit VKOR complex, which depletes functional Vitamin K reserves and reduces the synthesis active clotting factors.

The onset of action:

Initial anticoagulant effect on INR may be seen as soon as 24 to 72 hours

Duration:

2 to 5 days

Absorption:

Rapid, complete

Distribution:

0.14 L/kg

Protein binding:

Metabolism:

Mainly Hepatic, primarily via CYP2C9; minor pathways include CYP2C8, 2C18, 2C19, 1A2, and 3A4

Half-life elimination:

20 - 60 hours; Mean: 40 hours; highly variable among individuals

Time to peak, plasma:

~4 hours

Excretion:

via Urine (92%, primarily as metabolites; minimal as unchanged drug

International Brands of Warfarin:

APO-Warfarin
Coumadin
MYLAN-Warfarin
NOVO-Warfarin
TARO-Warfarin
Aldocumar
Azwar
Befarin
Circuvit
Cofarin
Coumadan
Coumadin
Coumadine
Dagonal
Farin
Haemofarin
Lawarin
Lennon-Warfarin
Mafarin
Maforan
Marevan
Marfarin
Marivarin
Martefarin
Morfarin
Oldin
Orfarin
Panwarfin
Rilaquin
Simarc-2
UniWarfin
Varfarin
Varfine
Waran
Warf
Warfant
Warfar
Warfarina
Warfil 5
Warfin
Warik
Warin
Win
Xclot
Zofarin
Zydarin

Warfarin (coumadin) brands in Pakistan:

Warfarin (Na) [Tabs 1 Mg]
Coagurin	Atco Laboratories Limited
Fericard	Global Pharmaceuticals
Warfin	Shaigan Pharmaceuticals (Pvt) Ltd

Warfarin (Na) [Tabs 5 Mg]
Anticoag	Don Valley Pharmaceuticals (Pvt) Ltd.
Coagurin	Atco Laboratories Limited
Fericard	Global Pharmaceuticals
Freewarin	Rakaposhi Pharmaceutical (Pvt) Ltd.
Hemolyte	Valor Pharmaceuticals
Warcorin	Lahore Chemical & Pharmaceutical Works (Pvt) Ltd
Warfarin	Rehman Medicine Co.
Warfarin	Delta Pharma (Pvt) Ltd.
Warfarin	Global Brands Distributors
Warfin	Shaigan Pharmaceuticals (Pvt) Ltd
Werifirin	Werrick Pharmaceuticals

Warfarin (Na) [Tabs 10 Mg]
Hemolyte	Valor Pharmaceuticals

Warfarin (Na) [Tabs 2.5 Mg]
Anticoag	Don Valley Pharmaceuticals (Pvt) Ltd.
Coagurin	Atco Laboratories Limited
Hemolyte	Valor Pharmaceuticals
Warfin	Shaigan Pharmaceuticals (Pvt) Ltd