Jantoven (warfarin sodium)

Warfarin dosage is expressed in terms of warfarin sodium.

Nonproprietary (generic) preparations of warfarin sodium are available, and the manufacturers warn that patients should be carefully instructed about the preparation they are receiving so that overdosage from inadvertent simultaneous use of equivalent preparations is avoided.

Warfarin sodium dosage requirements vary greatly among individual patients, and dosage must be carefully individualized based on the patient's INR in order to obtain optimum therapeutic effects while minimizing the risk of hemorrhage. Factors influencing initial dose selection include clinical factors (e.g., age, sex, comorbidities, concomitant medications) and genetic factors (e.g., CYP2C9 and VKORC1 genotypes).

Duration and intensity of anticoagulation (i.e., INR) is based on the indication for use. Pharmacogenomic factors (e.g., genetic variations in enzymes that metabolize warfarin or modulate its effect on clotting factor synthesis) also may be considered in determining the warfarin dosage.

Administer warfarin sodium orally as a single daily dose without regard to food. Adhere strictly to the prescribed dosage and schedule of warfarin. Take warfarin tablets at the same time each day.

If a dose of warfarin is missed at the intended time of day, take the dose as soon as possible on the same day. A double dose of warfarin should not be taken the next day to make up for the missed dose.

Warfarin is discolored by light; warfarin preparations should be stored at controlled room temperature (20-25degreesC) in tight, light-resistant containers.

Concurrent administration of numerous drugs or dietary or herbal supplements has been reported to affect patient response to warfarin.

Drugs may increase patient sensitivity to warfarin by decreasing intestinal synthesis or absorption of vitamin K or affecting distribution of the vitamin; decreasing the rate of anticoagulant metabolism by competing for sites of metabolism or inhibiting the function or synthesis of metabolic enzymes; increasing affinity of the anticoagulant for receptor sites; decreasing synthesis and/or increasing catabolism of functional blood coagulation factors II, VII, IX, and X; interfering with other components of normal hemostasis such as platelet function or fibrinolysis; and by producing ulcerogenic effects.

Certain drugs may decrease patient response to warfarin by decreasing absorption of the anticoagulant; increasing the rate of metabolism of the anticoagulant by enzyme induction; or by increasing synthesis of functional blood coagulation factors II, VII, IX, and X.

Some dietary or herbal supplements contain naturally occurring coumarins or salicylates that may have anticoagulant, antiplatelet, or fibrinolytic effects; these supplements would be expected to increase the anticoagulant effects of concomitantly administered warfarin.

Certain dietary or herbal supplements also may decrease response to warfarin, possibly as a result of induction of hepatic microsomal enzymes (e.g., St. John's wort) or because of procoagulant effects (e.g., coenzyme Q10).

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Anticoagulant;Antiplatelet;Thrombolytic/Alipogene Tiparvovec

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Alipogene tiparvovec is given as a one-time series of intramuscular (IM)injections. Depending upon patient weight 27 to 60 injections are given, each at a different site.

CLINICAL EFFECTS: Concurrent use of anticoagulant, antiplatelet, or thrombolytic agents increase bleeding risk at IM injection sites.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Antiplatelet or other anticoagulant agents must not be taken for at least one week prior to alipogene tiparvovec therapy. Assure that abnormal bleeding parameters have been corrected prior to administration. Antiplatelet or anticoagulant therapy may be resumed one day after alipogene tiparvovec administration. If concurrent therapy is deemed medically necessary, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Alipogene tiparvovec is given as a one-time series of intramuscular (IM)injections for the treatment of familial lipoprotein lipase deficiency. Depending upon patient weight 27 to 60 injections are given, each at a different site. Concurrent use of anticoagulant, antiplatelet, or thrombolytic agents increase bleeding risk at IM injection sites.

Anticoagulants/Hemin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Mild, transient anticoagulant effects has been reported with the use of hemin.(1)

CLINICAL EFFECTS: Concurrent use of hemin with anticoagulants may increase the risk of bleeding.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The manufacturer of hemin states concurrent use with anticoagulant therapy should be avoided.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Mild, transient anticoagulant effects have been reported during clinical studies with hemin.(1)

Anticoagulants/Iv And Im Diclofenac

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The exact mechanism is unknown. Diclofenac impairs platelet function and may prolong bleeding time.(1-2) Diclofenac also has the potential to produce gastrointestinal ulceration and bleeding.(1-2)

CLINICAL EFFECTS: Concurrent use of diclofenac and anticoagulants may increase the risk of bleeding complications.(1-2)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The Middle East manufacturer of injectable diclofenac states the use of intravenous diclofenac in patients on anticoagulants, including low-dose heparin, is contraindicated.(1) The UK manufacturer of injectable diclofenac states the use of intramuscular and intravenous diclofenac in patients on anticoagulants, including low-dose heparin, is contraindicated.(2) The Israeli and Swedish manufacturers of injectable diclofenac advise caution and close monitoring during concurrent use of anticoagulants.(3-4) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Although clinical investigations do not appear to indicate that diclofenac affects the action of anticoagulants, there are reports of an increased risk of hemorrhage in patients receiving diclofenac and anticoagulants concomitantly.(2) The Middle East and UK manufacturers of diclofenac state the use of intravenous and intramuscular diclofenac in patients on anticoagulants, including low-dose heparin, is contraindicated.(1-2)

Anticoagulants; Antiplatelets/Mifepristone

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Anticoagulants may result in excessive bleeding following the abortion.

CLINICAL EFFECTS: The concurrent use of mifepristone with anticoagulants may result in excessive bleeding following the abortion.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The manufacturer of mifepristone states that mifepristone is contraindicated in patients receiving concurrent anticoagulant therapy.(1) If concurrent therapy is deemed medically necessary, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: The manufacturer of mifepristone states that mifepristone is contraindicated in patients receiving concurrent anticoagulant therapy.(1)

Anticoagulants; Thrombolytics/Apixaban

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Additive effects on hemostasis.

CLINICAL EFFECTS: Concurrent use of apixaban with anticoagulants or thrombolytics may increase the risk of bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The long-term use of concurrent therapy with direct oral anticoagulants (DOACs) and other anticoagulants is generally considered contraindicated. However, overlap may be necessary when switching therapy from one agent to another in order to prevent thrombotic events. Manufacturer recommendations concerning overlap (if any) and timing of discontinuation versus initiation vary depending upon which agent is being discontinued and initiated. Refer to current prescribing information for both agents for additional details. Specific recommendations for converting between anticoagulants: - When converting between apixaban and anticoagulants other than warfarin, discontinue the current anticoagulant and begin the new one when next dose is due. - When converting from warfarin to apixaban, discontinue warfarin and begin apixaban when the international normalized ratio (INR) is below 2.0. - Apixaban affects INR. Therefore concurrent administration with warfarin when converting from apixaban to warfarin is not useful in determining target warfarin dose. If continuous anticoagulation is warranted, discontinue apixaban and begin both warfarin and a parenteral anticoagulant when next dose of apixaban is due. Once INR is within range, discontinue the parenteral anticoagulant. The use of concurrent therapy with Direct Oral Anticoagulants (DOACs) and thrombolytics is generally considered contraindicated. The manufacturer of alteplase states that the use of alteplase for an indication of acute ischemic stroke is contraindicated in patients receiving anticoagulants. Concurrent use of alteplase and anticoagulants is dependent on the therapeutic indication. In Acute Ischemic Stroke: - Clinical practice guidelines for acute ischemic stroke state the use of thrombolytic therapy for an indication of acute ischemic stroke is contraindicated in patients who have received thrombin inhibitors or factor Xa inhibitors in the previous 48 hours (in normal renal function) and have abnormal laboratory tests such as activated partial thromboplastin time (aPTT), INR, platelet count, ecarin clotting time (ECT), thrombin time, or direct factor Xa assays at presentation. In Acute Myocardial Infarction: - Patients who are receiving thrombolytics for an indication of acute myocardial infarction should be carefully monitored for signs of bleeding, especially at arterial puncture sites, if apixaban is used concurrently. - The use of thrombolytics in patients with acute myocardial infarction should follow standard management of myocardial infarction, including minimizing arterial and venous puncture; avoid noncompressible arterial puncture; and minimize internal jugular and subclavian venous punctures to decrease bleeding from the noncompressible sites. For all indications: - In the event of serious bleeding, anticoagulants should be discontinued immediately. - If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. - When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. - Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: Limited overlap of DOACs with other anticoagulants may be required when initiating or discontinuing DOACs in order to prevent thrombotic events. However, long-term concomitant treatment is not recommended because of increased risk of bleeding. Patients who are receiving thrombolytics should be carefully monitored for signs of bleeding if anticoagulants are being used concurrently or have recently been used.

Anticoagulants; Thrombolytics/Betrixaban

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Additive effects on hemostasis.

CLINICAL EFFECTS: Concurrent use of betrixaban with anticoagulants or thrombolytics may increase the risk of bleeding.

PREDISPOSING FACTORS: Patients with severe renal impairment (CrCl< 30 ml/min) or taking a concomitant P-gp inhibitor.

PATIENT MANAGEMENT: The long-term use of concurrent therapy with direct oral anticoagulants (DOACs) and other anticoagulants is generally considered contraindicated. However, overlap may be necessary when switching therapy from one agent to another in order to prevent thrombotic events. Manufacturer recommendations concerning overlap (if any) and timing of discontinuation versus initiation vary depending upon which agent is being discontinued and initiated. Refer to current prescribing information for both agents for additional details. The use of concurrent therapy with Direct Oral Anticoagulants (DOACs) and thrombolytics is generally considered contraindicated. The manufacturer of alteplase states that the use of alteplase for an indication of acute ischemic stroke is contraindicated in patients receiving anticoagulants. Concurrent use of alteplase and anticoagulants is dependent on the therapeutic indication. In Acute Ischemic Stroke: - Clinical practice guidelines for acute ischemic stroke state the use of thrombolytic therapy for an indication of acute ischemic stroke is contraindicated in patients who have received thrombin inhibitors or factor Xa inhibitors in the previous 48 hours (in normal renal function) and have abnormal laboratory tests such as activated partial thromboplastin time (aPTT), INR, platelet count, ecarin clotting time (ECT), thrombin time, or direct factor Xa assays at presentation. In Acute Myocardial Infarction: - Patients who are receiving thrombolytics for an indication of acute myocardial infarction should be carefully monitored for signs of bleeding, especially at arterial puncture sites, if betrixaban is used concurrently. - The use of thrombolytics in patients with acute myocardial infarction should follow standard management of myocardial infarction, including minimizing arterial and venous puncture; avoid noncompressible arterial puncture; and minimize internal jugular and subclavian venous punctures to decrease bleeding from the noncompressible sites. For all indications: - In the event of serious bleeding, anticoagulants should be discontinued immediately. - If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. - When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. - Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: Patients who are receiving thrombolytics should be carefully monitored for signs of bleeding if anticoagulants are being used concurrently or have recently been used.

Anticoagulants; Thrombolytics/Dabigatran

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Dabigatran is a direct thrombin inhibitor. When taken with agents that affect clotting factors, increased bleeding episodes can occur.

CLINICAL EFFECTS: Concurrent use of dabigatran with anticoagulants or thrombolytics may result in additive or synergistic effects resulting in unwanted bleeding episodes.

PREDISPOSING FACTORS: Factors associated with an increase risk for bleeding include renal impairment, concomitant use of P-glycoprotein inhibitors, patient age >74 years, coexisting conditions (e.g. recent trauma) or use of drugs (e.g. NSAIDs) associated with bleeding risk, and patient weight <50 kg.(1-3) The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The long-term use of concurrent therapy with direct oral anticoagulants (DOACs) and other anticoagulants is generally considered contraindicated. However, overlap may be necessary when switching therapy from one agent to another in order to prevent thrombotic events. Manufacturer recommendations concerning overlap (if any) and timing of discontinuation versus initiation vary depending upon which agent is being discontinued and initiated. Refer to current prescribing information for both agents for additional details. Specific recommendations for converting between anticoagulants: - When converting from parenteral anticoagulants to dabigatran, administer dabigatran 0-2 hours before the next dose of the parenteral drug is due. - When converting from dabigatran to a parenteral anticoagulant in adults, begin parenteral anticoagulant: --12 hours after last dose of dabigatran in patients with CrCl greater than or equal to 30 ml/min, --24 hours after last dose of dabigatran in patients with CrCl less than 30 ml/min. - When converting from dabigatran to a parenteral anticoagulant in pedatrics, begin the parenteral anticoagulant 12 hours after the last dose of dabigatran. - When converting from warfarin to dabigatran, discontinue warfarin and begin dabigatran when the patient's INR is below 2.0. - When converting from dabigatran to warfarin in adults, start warfarin: --3 days before discontinuing dabigatran in patients with CrCl greater than 50 ml/min, --2 days before discontinuing dabigatran in patients with CrCl of 30 ml/min to 50 ml/min, --1 day before discontinuing dabigatran in patients with CrCl of 15 ml/min to 30 ml/min. --There is no recommendation available for converting dabigatran to warfarin in patients with CrCl less than 15 ml/min. - When converting from dabigatran to warfarin in pediatrics, start warfarin: --3 days before discontinuing dabigatran in patient with eGFR >= 50 ml/min/1.73 m2. --There is no data on using dabigatran in pediatric patients with eGFR < 50 ml/min/1.73 m2. - Dabigatran affects INR. Therefore the INR will better reflect warfarin's effect only after stopping dabigatran for at least 2 days. The use of concurrent therapy with Direct Oral Anticoagulants (DOACs) and thrombolytics is generally considered contraindicated. The manufacturer of alteplase states that the use of alteplase for an indication of acute ischemic stroke is contraindicated in patients receiving anticoagulants. Concurrent use of alteplase and anticoagulants is dependent on the therapeutic indication. In Acute Ischemic Stroke: - Clinical practice guidelines for acute ischemic stroke state the use of thrombolytic therapy for an indication of acute ischemic stroke is contraindicated in patients who have received thrombin inhibitors or factor Xa inhibitors in the previous 48 hours (in normal renal function) and have abnormal laboratory tests such as activated partial thromboplastin time (aPTT), INR, platelet count, ecarin clotting time (ECT), thrombin time, or direct factor Xa assays at presentation. In Acute Myocardial Infarction: - Patients who are receiving thrombolytics for an indication of acute myocardial infarction should be carefully monitored for signs of bleeding, especially at arterial puncture sites, if dabigatran is used concurrently. - The use of thrombolytics in patients with acute myocardial infarction should follow standard management of myocardial infarction, including minimizing arterial and venous puncture; avoid noncompressible arterial puncture; and minimize internal jugular and subclavian venous punctures to decrease bleeding from the noncompressible sites. For all indications: - In the event of serious bleeding, anticoagulants should be discontinued immediately. - If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. - When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. - Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: Patients who are receiving thrombolytics should be carefully monitored for signs of bleeding if anticoagulants are being used concurrently or have recently been used.

Anticoagulants; Thrombolytics/Edoxaban

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Additive effects on hemostasis.

CLINICAL EFFECTS: Concurrent use of edoxaban with anticoagulants or thrombolytics may increase the risk of bleeding.

PREDISPOSING FACTORS: Bleeding risk may be increased in patients with renal impairment and in patients > 75 years of age. Use of multiple agents which affect hemostasis increases the risk for bleeding.

PATIENT MANAGEMENT: The long-term use of concurrent therapy with direct oral anticoagulants (DOACs) and other anticoagulants is generally considered contraindicated. However, overlap may be necessary when switching therapy from one agent to another in order to prevent thrombotic events. Manufacturer recommendations concerning overlap (if any) and timing of discontinuation versus initiation vary depending upon which agent is being discontinued and initiated. Refer to current prescribing information for both agents for additional details. Specific recommendations for converting between anticoagulants: - When converting from other (non-vitamin K antagonist) oral anticoagulants to edoxaban, discontinue current oral anticoagulant and start edoxaban at the time of the next scheduled dose of the old oral anticoagulant. - When converting from a low molecular weight heparin (LMWH) to edoxaban, start edoxaban at the time of the next scheduled administration of LMWH. - When converting from unfractionated heparin to edoxaban, discontinue the infusion and start edoxaban 4 hours later. - When converting from edoxaban to another DOAC, discontinue edoxaban and begin the new oral anticoagulant at the time of the next scheduled dose of edoxaban. - When converting from edoxaban to parenteral anticoagulation, start the parenteral anticoagulant at the time of the next dose of edoxaban. - When converting from warfarin to edoxaban, discontinue warfarin and start edoxaban when the INR is < or = to 2.5. - When converting from edoxaban to warfarin, for patients taking 60 mg of edoxaban, reduce the dose to 30 mg and begin warfarin concomitantly. For patients receiving 30 mg of edoxaban, reduce the dose to 15 mg and begin warfarin concomitantly. INR must be measured at least weekly and just prior to the daily dose of edoxaban to minimize the effects of edoxaban on INR measurement. Once a stable INR = or > 2.0 is achieved, edoxaban should be discontinued and the warfarin continued. - A second edoxaban to warfarin conversion option: Discontinue edoxaban and administer a parenteral anticoagulant and warfarin at the time of the next scheduled edoxaban dose. Once a stable INR = or > 2.0 is achieved, the parenteral anticoagulant should be discontinued and the warfarin continued. The use of concurrent therapy with Direct Oral Anticoagulants (DOACs) and thrombolytics is generally considered contraindicated. The manufacturer of alteplase states that the use of alteplase for an indication of acute ischemic stroke is contraindicated in patients receiving anticoagulants. Concurrent use of alteplase and anticoagulants is dependent on the therapeutic indication. In Acute Ischemic Stroke: - Clinical practice guidelines for acute ischemic stroke state the use of thrombolytic therapy for an indication of acute ischemic stroke is contraindicated in patients who have received thrombin inhibitors or factor Xa inhibitors in the previous 48 hours (in normal renal function) and have abnormal laboratory tests such as activated partial thromboplastin time (aPTT), INR, platelet count, ecarin clotting time (ECT), thrombin time, or direct factor Xa assays at presentation. In Acute Myocardial Infarction: - Patients who are receiving thrombolytics for an indication of acute myocardial infarction should be carefully monitored for signs of bleeding, especially at arterial puncture sites, if edoxaban is used concurrently. - The use of thrombolytics in patients with acute myocardial infarction should follow standard management of myocardial infarction, including minimizing arterial and venous puncture; avoid noncompressible arterial puncture; and minimize internal jugular and subclavian venous punctures to decrease bleeding from the noncompressible sites. For all indications: - In the event of serious bleeding, anticoagulants should be discontinued immediately. - If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. - When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. - Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: Limited overlap of DOACs with other anticoagulants may be required when initiating or discontinuing DOACs in order to prevent thrombotic events. However, long-term concomitant treatment is not recommended because of increased risk of bleeding. Patients who are receiving thrombolytics should be carefully monitored for signs of bleeding if anticoagulants are being used concurrently or have recently been used.

Anticoagulants; Thrombolytics/Rivaroxaban

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Additive effects on hemostasis.

CLINICAL EFFECTS: Concurrent use of rivaroxaban with anticoagulants or thrombolytics may increase the risk of bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The long-term use of concurrent therapy with direct oral anticoagulants (DOACs) and other anticoagulants is generally considered contraindicated. However, overlap may be necessary when switching therapy from one agent to another in order to prevent thrombotic events. Manufacturer recommendations concerning overlap (if any) and timing of discontinuation versus initiation vary depending upon which agent is being discontinued and initiated. Refer to current prescribing information for both agents for additional details. Specific recommendations for converting between anticoagulants: - When converting from rivaroxaban to anticoagulants other than warfarin and switching to an anticoagulant with rapid onset, discontinue rivaroxaban and begin new anticoagulant when next dose of rivaroxaban is due. - When converting from anticoagulants other than warfarin to rivaroxaban, discontinue current anticoagulant and begin rivaroxaban between 0-2 hours before next evening dose of the drug is due. For patients receiving continuous infusion of unfractionated heparin, simultaneously stop the infusion and administer rivaroxaban. - When converting from warfarin to rivaroxaban, discontinue warfarin and begin rivaroxaban once international normalized ratio (INR) is below 3.0 in adults and below 2.5 in pediatric patients. - When converting from rivaroxaban to warfarin in adults, rivaroxaban affects INR. Therefore concurrent administration with warfarin is not useful in determining target warfarin dose. If continuous anticoagulation is warranted, discontinue rivaroxaban and begin both warfarin and a parenteral anticoagulant when the next dose of rivaroxaban is due. Once INR is within range, discontinue the parenteral anticoagulant. - When converting from rivaroxaban to warfarin in pediatrics, continue rivaroxaban for at least 2 days after the first dose of warfarin. After two days, INR should be measured just prior to the next scheduled dose of rivaroxaban. Once a stable INR = or > 2.0 is achieved, rivaroxaban should be discontinued and warfarin continued. The use of concurrent therapy with Direct Oral Anticoagulants (DOACs) and thrombolytics is generally considered contraindicated. The manufacturer of alteplase states that the use of alteplase for an indication of acute ischemic stroke is contraindicated in patients receiving anticoagulants. Concurrent use of alteplase and anticoagulants is dependent on the therapeutic indication. In Acute Ischemic Stroke: - Clinical practice guidelines for acute ischemic stroke state the use of thrombolytic therapy for an indication of acute ischemic stroke is contraindicated in patients who have received thrombin inhibitors or factor Xa inhibitors in the previous 48 hours (in normal renal function) and have abnormal laboratory tests such as activated partial thromboplastin time (aPTT), INR, platelet count, ecarin clotting time (ECT), thrombin time, or direct factor Xa assays at presentation. In Acute Myocardial Infarction: - Patients who are receiving thrombolytics for an indication of acute myocardial infarction should be carefully monitored for signs of bleeding, especially at arterial puncture sites, if rivaroxaban is used concurrently. - The use of thrombolytics in patients with acute myocardial infarction should follow standard management of myocardial infarction, including minimizing arterial and venous puncture; avoid noncompressible arterial puncture; and minimize internal jugular and subclavian venous punctures to decrease bleeding from the noncompressible sites. For all indications: - In the event of serious bleeding, anticoagulants should be discontinued immediately. - If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. - When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. - Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: Patients who are receiving thrombolytics should be carefully monitored for signs of bleeding if anticoagulants are being used concurrently or have recently been used.

Gpis;Heparin;Thrombolytics;Warfarin/Bivalirudin; Desirudin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Concurrent use may result in additive effects on hemostasis.(1,2)

CLINICAL EFFECTS: Concurrent use of bivalirudin with GPIs, heparin, or warfarin may increase the risk of bleeding.(1,2)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Concurrent use of bivalirudin and GPIs, heparin, or warfarin should be avoided.(1) Discontinue agents that may increase the risk of hemorrhage prior to initiation of desirudin.(2) The Australian manufacturer of bivalirudin states patients can be started on bivalirudin 30 minutes after discontinuation of unfractionated heparin or 8 hours after discontinuation of low molecular weight heparin.(3) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: In clinical trials, concurrent use of bivalirudin with GPIs, heparin, or warfarin was associated with increased risks of major bleeding events compared to patients not receiving concurrent therapy.(1) Concurrent administration of warfarin did not affect the pharmacokinetics of desirudin; however, greater inhibition of hemostasis was observed as seen by aPPT, PT and INR measurements.(2)

Oral Anticoagulants; Warfarin/Tenecteplase

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Tenecteplase catalyzes the cleavage of endogenous plasminogen to generate plasmin which degrades the fibrin matrix of a thrombus.(1-3)

CLINICAL EFFECTS: The concurrent use of tenecteplase and warfarin or oral anticoagulants may increase the risk of bleeding.(1-4)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The Australian(1), Canadian(2) and UK(3) manufacturers of tenecteplase state that use in patients on current oral anticoagulants (INR > 1.3) is contraindicated. The US manufacturer of tenecteplase states that the risks of concurrent therapy with oral anticoagulants must be weighed against the anticipated benefits.(4) Concurrent use of tenecteplase and anticoagulants is dependent on the therapeutic indication. In Acute Ischemic Stroke: - Clinical practice guidelines for acute ischemic stroke state the use of thrombolytic therapy for an indication of acute ischemic stroke is contraindicated in patients who have received warfarin and have an elevated activated partial thromboplastin time (aPTT) > 40 seconds, prothrombin time (PT) > 15 seconds, INR > 1.7, or platelets <100,000/mm3 at presentation. In Acute Myocardial Infarction: - Patients who are receiving tenecteplase for an indication of acute myocardial infarction should be carefully monitored for signs of bleeding, especially at arterial puncture sites, if heparin is used concurrently. - The use of tenecteplase in patients with acute myocardial infarction should follow standard management of myocardial infarction, including minimizing arterial and venous puncture; avoid noncompressible arterial puncture; and minimize internal jugular and subclavian venous punctures to decrease bleeding from the noncompressible sites. For all indications: - In the event of serious bleeding, anticoagulants should be discontinued immediately. - If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. - When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. - Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: Patients receiving warfarin were excluded from participation in thrombolytic clinical trials due to bleeding risk.(1-4)

Selected Anticoagulants (Vit K Antagonists)/Imatinib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Imatinib may inhibit the metabolism of warfarin by CYP2C9.(1)

CLINICAL EFFECTS: The concurrent use of imatinib and warfarin may result in an increased risk for bleeding.

PREDISPOSING FACTORS: Risk for bleeding episodes may be greater in patients with disease-associated bleeding risk (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism, and drugs which have an inherent risk for bleeding (e.g. NSAIDs). Pharmacogenomic risk variables: Patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective and safe anticoagulation than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: The manufacturer of imatinib states under the "Drug Interaction" section of the imatinib prescribing information that patients receiving imatinib who require anticoagulation should receive low-molecular weight or standard heparin instead of warfarin.(1) If imatinib and warfarin are used together, INR values should be closely monitored when imatinib is initiated and discontinued. Patients should be observed for signs of excessive anticoagulation during concurrent therapy. If concurrent therapy is deemed medically necessary, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Because imatinib has been shown to inhibit CYP2C9 in vitro, the manufacturer states under the "Drug Interaction" section of the imatinib prescribing information that patients receiving imatinib who require anticoagulation should receive low-molecular weight or standard heparin instead of warfarin.(1)

Selected Anticoagulants; Thrombolytics/Defibrotide

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Concurrent use may result in additive effects on hemostasis.(1)

CLINICAL EFFECTS: Concurrent use of defibrotide with anticoagulants or thrombolytics may increase the risk of bleeding.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The US manufacturer of defibrotide states that concomitant use with systemic anticoagulant or antithrombotic therapy is contraindicated.(1) In patients who have received prior anticoagulant or thrombolytic therapy, consider delaying the start of defibrotide until the effects of the anticoagulant have abated.(1) If concurrent therapy is deemed medically necessary, closely monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding; gingival bleeding; nosebleeds; unusual bruising; orange/red urine or dark/black stools; new onset of headache, confusion, slurred speech, or vision; acute abdominal pain; or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: In pivotal clinical trials, 176 patients received defibrotide; the use of anticoagulants or thrombolytics was not allowed. Bleeding events not attributed to underlying disease were as follows: epistaxis (14%), pulmonary alveolar hemorrhage (9%), gastrointestinal hemorrhage (9%), pulmonary hemorrhage (9%), intracranial hemorrhage (3%), cerebral hemorrhage (2%).

Warfarin/Adagrasib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Adagrasib is a moderate CYP2C9 inhibitor(1) which may decrease the metabolism of the S-enantiomer of warfarin.(1,2)

CLINICAL EFFECTS: Concurrent use of adagrasib may result in elevated levels of warfarin and increased INR.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Pharmacogenomic information: patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective and safe anticoagulation than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: The US manufacturer of adagrasib states that concurrent administration with sensitive CYP2C9 substrates should be avoided.(1) Monitor INRs more frequently until stable in patients who start adagrasib therapy.(1,2) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. Discontinue anticoagulation in patients with active pathologic bleeding.

DISCUSSION: In clinical studies, coadministration of adagrasib 600 mg twice daily increased the area-under-the-curve (AUC) and maximum concentration (Cmax) of S-warfarin by 2.9-fold and 1.1-fold, respectively.(1)

Warfarin/Defactinib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The exact mechanism is unknown. Defactinib may inhibit the metabolism of warfarin by CYP2C9 or CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of defactinib may result in increased INR and risk of bleeding.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The manufacturer of defactinib states that concurrent administration with warfarin should be avoided. If concurrent use cannot be avoided, monitor INR frequently during treatment with defactinib.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. Discontinue anticoagulation in patients with active pathologic bleeding.

DISCUSSION: In clinical trials, cases of bleeding and increased INR occurred in patients taking defactinib concomitantly with warfarin.(1)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Agents That Affect Iodide/Radioactive Iodide

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Many compounds can affect iodide protein binding and alter iodide pharmacokinetics and pharmacodynamics.(1)

CLINICAL EFFECTS: Compounds that affect iodide pharmacokinetics and pharmacodynamics may impact the effectiveness of radioactive iodide.(1)

PREDISPOSING FACTORS: Compounds that affect iodide pharmacokinetics and pharmacodynamics are expected to have the most impact during therapy using radioactive iodide. Diagnostic procedures would be expected to be impacted less.

PATIENT MANAGEMENT: Discuss the use of agents that affect iodide pharmacokinetics and pharmacodynamics with the patient's oncologist.(1) Because indocyanine green contains sodium iodide, the iodine-binding capacity of thyroid tissue may be reduced for at least one week following administration. Do not perform radioactive iodine uptake studies for at least one week following administration of indocyanine green.(2) The manufacturer of iopamidol states administration may interfere with thyroid uptake of radioactive iodine and decrease therapeutic and diagnostic efficacy. Avoid thyroid therapy or testing for up to 6 weeks post administration of iopamidol.(3)

DISCUSSION: Many agents interact with radioactive iodine. The average duration of effect is: anticoagulants - 1 week antihistamines - 1 week anti-thyroid drugs, e.g: carbimazole, methimazole, propylthiouracil - 3-5 days corticosteroids - 1 week iodide-containing medications, e.g: amiodarone - 1-6 months expectorants - 2 weeks Lugol solution - 3 weeks saturated solution of potassium iodine - 3 weeks vitamins - 10-14 days iodide-containing X-ray contrast agents - up to 1 year lithium - 4 weeks phenylbutazone - 1-2 weeks sulfonamides - 1 week thyroid hormones (natural or synthetic), e.g.: thyroxine - 4 weeks tri-iodothyronine - 2 weeks tolbutamide - 1 week topical iodide - 1-9 months (1)

Agents That Affect Iodide/Sodium Iodide I 131

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Many compounds can affect iodide protein binding and alter iodide pharmacokinetics and pharmacodynamics.(1,2)

CLINICAL EFFECTS: Compounds that affect iodide pharmacokinetics and pharmacodynamics may impact the effectiveness of radioactive iodide.(1,2)

PREDISPOSING FACTORS: Compounds that affect iodide pharmacokinetics and pharmacodynamics are expected to have the most impact during therapy using radioactive iodide. Diagnostic procedures would be expected to be impacted less.

PATIENT MANAGEMENT: Discuss the use of agents that affect iodide pharmacokinetics and pharmacodynamics with the patient's oncologist.(1,2) Because indocyanine green contains sodium iodide, the iodine-binding capacity of thyroid tissue may be reduced for at least one week following administration. Do not perform radioactive iodine uptake studies for at least one week following administration of indocyanine green.(3) The manufacturer of iopamidol states administration may interfere with thyroid uptake of radioactive iodine and decrease therapeutic and diagnostic efficacy. Avoid thyroid therapy or testing for up to 6 weeks post administration of iopamidol.(4)

DISCUSSION: Many agents interact with radioactive iodine. The average duration of effect is: anticoagulants - 1 week antihistamines - 1 week anti-thyroid drugs, e.g: carbimazole, methimazole, propylthiouracil - 3-5 days corticosteroids - 1 week iodide-containing medications, e.g: amiodarone - 1-6 months expectorants - 2 weeks Lugol solution - 3 weeks saturated solution of potassium iodine - 3 weeks vitamins - 10-14 days iodide-containing X-ray contrast agents - up to 1 year lithium - 4 weeks phenylbutazone - 1-2 weeks sulfonamides - 1 week thyroid hormones (natural or synthetic), e.g.: thyroxine - 4 weeks tri-iodothyronine - 2 weeks tolbutamide - 1 week topical iodide - 1-9 months (1,2)

Anticoagulants/Dextrothyroxine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Unknown. However, dextrothyroxine may influence concentrations of vitamin K-dependent clotting factors.

CLINICAL EFFECTS: Concurrent therapy may result in increase anticoagulant effects and increase the risk for bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Monitor prothrombin activity and adjust the anticoagulant dosage accordingly during initiation of warfarin therapy in patients receiving dextrothyroxine therapy. The dosage of warfarin may be less than expected in patients currently receiving dextrothyroxine. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Any change in thyroid status in patients stabilized on warfarin may necessitate a change in warfarin dosage requirements. Initiation of dextrothyroxine therapy in patients stabilized on warfarin may result in increases in the effects of warfarin. A decrease in the dose of warfarin usually becomes necessary within one to four weeks after starting therapy with dextrothyroxine.

Anticoagulants/Donanemab

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Microhemorrhage has been reported with the use of donanemab. Radiographic changes on brain MRI have been noted as amyloid related imaging abnormalities-hemosiderin deposition (ARIA-H) which included microhemorrhage. In addition, intracerebral hemorrhages (ICH) greater than 1 cm in diameter have occurred in patients treated with donanemab.(1)

CLINICAL EFFECTS: Concurrent use of donanemab with anticoagulants agents may increase the risk of hemorrhage.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Donanemab should be used with extreme caution in patients treated with anticoagulants. Evaluate the risks and benefits of concurrent use of donanemab with anticoagulants.(1) The manufacturer of donanemab recommends testing for AP0E4 status prior to initiation of treatment.(1) Use of anticoagulant agents in patients who are homozygous for the APOE4 gene, may have an increased risk of ARIA with donanemab therapy.(1-3) If concurrent therapy is warranted, patients receiving concurrent therapy with donanemab and anticoagulants should be closely monitored for signs and symptoms of bleeding and changes in platelet count or International Normalized Ratio (INR).(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of microhemorrhage, including headache, nausea/vomiting, confusion, dizziness, visual disturbance, gait difficulties, and loss of coordination. General signs of blood loss include decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as confusion, headache, dizziness, nausea, visual changes, unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: In a double-blind, placebo-controlled clinical study of 1736 participants randomized to receive donanemab (n = 860) or placebo (n = 876), donanemab was observed to increase amyloid related imaging abnormalities-hemosiderin deposition (ARIA-H), including microhemorrhage and intracerebral hemorrhage (ICH). Radiographic changes were classified as mild (<=4 new incidences), moderate (5 to 9 new incidences), or severe (10 or more new incidences). The maximum severity of ARIA-H microhemorrhage was observed as mild in 17% (143/853), moderate in 4% (34/853), and severe in 5% (40/853) of patients taking donanemab.(1) Baseline use of antithrombotic medication (aspirin, other antiplatelets, or anticoagulants) was allowed. The majority of exposures to antithrombotic medications were to aspirin. The incidence of ARIA-H was 30% (106/349) in patients taking donanemab with a concomitant antithrombotic medication within 30 days compared to 29% (148/504) who did not receive an antithrombotic within 30 days of an ARIA-H event.(1) The incidence of ICH greater than 1 cm in diameter was 0.6% (2/349 patients) in patients taking donanemab with a concomitant antithrombotic medication compared to 0.4% (2/504) in those who did not receive an antithrombotic. One fatal ICH occurred in a patient taking donanemab in the setting of focal neurologic symptoms of ARIA and the use of a thrombolytic agent.(1) The manufacturer of donanemab states the number of events and the limited exposure to non-aspirin antithrombotic medications limit definitive conclusions about the risk of ARIA or ICH in patients taking antithrombotic medications concurrently with donanemab. If concurrent therapy is warranted, patients should be closely monitored for signs and symptoms of bleeding and changes in platelet count or INR.(1)

Anticoagulants/Ketorolac

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown. Ketorolac impairs platelet function and may prolong bleeding time.(1) Ketorolac also has the potential to produce gastrointestinal ulceration and bleeding.(1-3)

CLINICAL EFFECTS: Concurrent use of ketorolac and anticoagulants may increase the risk of bleeding complications.(1-3)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The Australian(1) and UK(2) manufacturers of ketorolac state that the use of ketorolac in patients on anticoagulants, including low-dose heparin,(2) is contraindicated. The US manufacturer of ketorolac states that concurrent therapy with anticoagulants should be undertaken with extreme caution after carefully weighing the benefits of concurrent therapy against the risks and that patients receiving concurrent therapy should be closely monitored.(3) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Ketorolac has been shown to inhibit platelet aggregation and may prolong bleeding times. Ketorolac-induced inhibition of platelet function disappears within 24 to 48 hours after ketorolac discontinuation. Ketorolac does not affect platelet count, prothrombin time (PT), or partial thromboplastin time (PTT).(1) Ketorolac has been shown in vitro to only slightly reduce warfarin protein binding (from 99.5% to 99.3%.(3) In a study in 12 subjects, ketorolac had no effects on the pharmacokinetics or pharmacodynamics of a single dose of warfarin (25 mg). In another study in 11 subjects, ketorolac increased the mean template bleeding time for 2 doses of heparin from 6.0 to 6.4 minutes.(3)

Anticoagulants/Lecanemab

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Microhemorrhage has been reported with the use of lecanemab. Radiographic changes on brain MRI have been noted as amyloid related imaging abnormalities-hemosiderin deposition (ARIA-H) which included microhemorrhage. In addition, intracerebral hemorrhages (ICH) greater than 1 cm in diameter have occurred in patients treated with lecanemab.(1)

CLINICAL EFFECTS: Concurrent use of lecanemab with anticoagulants agents may increase the risk of hemorrhage.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The US manufacturer of lecanemab advises extreme caution in patients treated with anticoagulants. Evaluate the risks and benefits of concurrent use of lecanemab with anticoagulants.(1) Appropriate use recommendations for lecanemab state patients on anticoagulants should not receive lecanemab.(2) The UK manufacturer of lecanemab contraindicates initiation of lecanemab in patients receiving ongoing anticoagulant therapy. If anticoagulation is necessary, then lecanemab should be paused. Lecanemab can be reinstated if anticoagulation is no longer medically indicated.(3) If concurrent therapy is warranted, patients should be closely monitored for signs and symptoms of microhemorrhage, including headache, nausea/vomiting, confusion, dizziness, visual disturbance, gait difficulties, and loss of coordination, as well as other bleeding and changes in platelet count or International Normalized Ratio (INR).(1) When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as confusion, headache, dizziness, nausea, visual changes, unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: In clinical studies, lecanemab was observed to increase ARIA-H, including microhemorrhage and intracerebral hemorrhage. Radiographic changes were classified as mild (<=4 new incidences), moderate (5 to 9 new incidences), or severe (10 or more new incidences. Patients were excluded from clinical trials if taking concurrent anticoagulants or anti-platelets.(1) In Studies 1 and 2, the maximum severity of ARIA-H microhemorrhage was mild in 9% (79/898), moderate in 2% (19/898), and severe in 3% (28/898) of patients. Intracerebral hemorrhage greater than 1 cm in diameter was reported in 0.7% (6/898) of patients in Study 2 after treatment with lecanemab compared to 0.1% (1/897) on placebo. Fatal events of intracerebral hemorrhage in patients taking lecanemab have been observed.(1) In Study 2, baseline use of antithrombotic medications (aspirin, other antiplatelets, or anticoagulants) were allowed if patient was on a stable dose. Aspirin was the most common antithrombotic agent. The incidence of ICH was 0.9% (3/328 patients) in patients taking lecanemab with a concomitant antithrombotic medication at the time of the event compared to 0.6% (3/545 patients) in those who did not receive an antithrombotic. Patients taking lecanemab with an anticoagulant alone or combined with an antiplatelet medication or aspirin had an incidence of intracerebral hemorrhage of 2.5% (2/79 patients) compared to none in patients who received placebo.

Anticoagulants; Antiplatelets/Inotersen

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Inotersen causes reductions in platelet count that may result in sudden and unpredictable thrombocytopenia.(1)

CLINICAL EFFECTS: Concurrent use of inotersen with anticoagulants and/or antiplatelet agents may result in additive or synergistic effects, including fatal and non-fatal intracranial hemorrhage.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may also be greater in patients greater than 60 years or have a prior history of major bleeding events. Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Inotersen should be administered with caution in patients receiving anticoagulants and/or antiplatelet agents.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Monitor platelet count frequently. If platelet count is less than 50, stop inotersen treatment and consider discontinuation of any anticoagulant and/or antiplatelet agents. Monitor for signs and symptoms of thrombocytopenia; such as, unusual or prolonged bleeding (petechiae, easy bruising, hematoma, subconjunctival bleeding, gingival bleeding, epistaxis, hemoptysis, irregular or heavier than normal menstrual bleeding, hematemesis, hematuria, hematochezia, melena), neck stiffness, or atypical severe headache.

DISCUSSION: In a clinical study, platelet counts below 100 occurred in 25% of inotersen-treated patients, compared with 2% of patients on placebo. Platelet counts below 75 occurred in 14% of inotersen-treated patients, compared to no patients on placebo. In study 1 and its extension study, 39% of inotersen-treated patients with a baseline platelet count below 200 had a nadir platelet count below 75, compared to 6% of patients with baseline platelet counts 200 or higher. Three inotersen-treated patients (3%) had sudden severe thrombocytopenia (platelet count below 25). One patient experienced a fatal intracranial hemorrhage.(1) Inotersen is only available through a Tegsedi REMS program because of the risk of severe thrombocytopenia and the risk of glomerulonephritis.(1)

Anticoagulants; Antiplatelets/Tipranavir

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Tipranavir has been shown to inhibit platelet aggregation in vitro in human platelets(1-3) and in rodents.(1,2) The mechanism behind this platelet aggregation is unknown.(1,2)

CLINICAL EFFECTS: Concurrent use of tipranavir with anticoagulants and/or antiplatelet agents may result in additive or synergistic effects, including fatal and non-fatal intracranial hemorrhage.(1-3)

PREDISPOSING FACTORS: The risk of intracranial hemorrhage may be increased by CNS lesions, head trauma, neurosurgery, coagulopathy, hypertension, or alcohol abuse.(1-3) The risk for bleeding episodes may also be greater in patients with other disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Tipranavir should be administered with caution in patients receiving anticoagulants and/or antiplatelet agents. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Patients should be warned that tipranavir has been associated with fatal and non-fatal intracranial hemorrhage and instructed to report any unusual or unexplained bleeding to their physician.(1-3) Signs or symptoms of bleeding may include unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: As of June 7, 2006,(3) the manufacturer of tipranavir has has identified 14 cases of intracranial hemorrhage, including 8 fatalities, in 13 out of 6,840 HIV+ subjects in clinical trials.(1,3) No pattern of abnormal coagulation parameters has been noted in patients receiving tipranavir in general or preceding the development of intracranial hemorrhage.(1-3) In vitro tests showed that tipranavir inhibits human platelet aggregation at concentrations consistent with normal exposure during therapy. In rodents, tipranavir resulted in increased prothrombin and activated partial thromboplastin times. At higher doses and in extreme cases, these changes resulted in bleeding in multiple organs and death. This effect was not seen in studies in dogs.(1,2)

Anticoagulants; Antiplatelets; Thrombolytics/Caplacizumab

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Bleeding has been reported with the use of caplacizumab.(1)

CLINICAL EFFECTS: Concurrent use of caplacizumab with anticoagulants, antiplatelets, or thrombolytics may increase the risk of hemorrhage.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. hemophilia, coagulation factor deficiencies). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Avoid the use of caplacizumab with anticoagulants, antiplatelets, and thrombolytics. Interrupt caplacizumab therapy if clinically significant bleeding occurs. Patients may require von Willebrand factor concentrate to rapidly correct hemostasis. If caplacizumab is restarted, closely monitor for signs of bleeding.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Bleeding has been reported with caplacizumab. In clinical studies, severe bleeding adverse reactions of epistaxis, gingival bleeding, upper gastrointestinal hemorrhage, and metrorrhagia were each reported in 1% of patients. Overall, bleeding events occurred in approximately 58% of patients on caplacizumab versus 43% of patients on placebo.(1) In post-marketing reports, cases of life-threatening and fatal bleeding were reported with caplacizumab.(1)

Anticoagulants; Fibrinolytics/Aducanumab

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Microhemorrhage has been reported with the use of aducanumab. Radiographic changes on brain MRI have been noted as amyloid related imaging abnormalities-hemosiderin deposition (ARIA-H) which included microhemorrhage.(1)

CLINICAL EFFECTS: Concurrent use of aducanumab with either anticoagulants or fibrinolytics may increase the risk of hemorrhage.(1-3)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Evaluate concurrent use of aducanumab with anticoagulants or fibrinolytics.(1-3) Patients receiving concurrent therapy with aducanumab and anticoagulants or fibrinolytics should be closely monitored for signs and symptoms of bleeding and changes in platelet count or International Normalized Ratio (INR).(1) Enhanced observation is recommended for the first 8 doses of aducanumab, particularly with dose titration. MRI should be considered if a patient develops clinical symptoms of microhemorrhage.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of microhemorrhage, including headache, nausea/vomiting, confusion, dizziness, visual disturbance, gait difficulties, and loss of coordination. General signs of blood loss include decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as confusion, headache, dizziness, nausea, visual changes, unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: In two phase 3 studies, aducanumab was observed to increase ARIA-H, including microhemorrhage. Radiographic changes were classified as mild (<=4 new incidences), moderate (5 to 9 new incidences), or severe (10 or more new incidences. Patients were excluded from clinical trials if taking concurrent anticoagulants or anti-platelets.(1) In Studies 1 and 2, ARIA was observed in 41% of patients treated with aducanumab with a planned dose of 10 mg/kg, compared to 10% of patients on placebo.(1)

Anticoagulants; Thrombolytics/Urokinase

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The concurrent use of urokinase with anticoagulants or thrombolytics may increase the risk of bleeding.(1,2)

CLINICAL EFFECTS: The concurrent use of urokinase with anticoagulants or thrombolytics may result in bleeding episodes.(1,2)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The UK and US manufacturers of urokinase state that the concurrent use with thrombolytic agents or anticoagulants may increase the risk of serious bleeding.(1,2) If anticoagulation therapy is recommended after infusion of urokinase, monitor aPTT and do not begin anticoagulation until the aPTT is less than twice the normal control value. If heparin is started after urokinase infusion, do not administer a loading dose of heparin. When concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: The UK and US manufacturers of urokinase states that use with agents that alter anticoagulation or platelet function may increase the risk of serious bleeding. The manufacturer of urokinase states administration of urokinase prior to, during, or after thrombolytic therapy may increase the risk of serious bleeding. Use of urokinase with other agents that alter coagulation or are thrombolytic, careful monitoring of bleeding is recommended.(1,2)

Coumarin Anticoagulants/Amiodarone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Amiodarone inhibits the CYP2C9 mediated metabolism of the S-enantiomer, and the CYP3A4 mediated metabolism of the R-enantiomer of warfarin in vivo.(1-5) Amiodarone may also inhibit the metabolism of acenocoumarol(6) and other coumarin anticoagulants.

CLINICAL EFFECTS: The concurrent administration of amiodarone and a coumarin anticoagulant may result in an increase in the clinical effects of the anticoagulant and an increased risk of bleeding.(1-23) It may take several weeks of concurrent therapy before the full effects of this interaction are noted. The effect of amiodarone on anticoagulant levels may continue for several months after amiodarone is discontinued.

PREDISPOSING FACTORS: Amiodarone-induced thyrotoxicosis may increase the metabolic clearance of some vitamin K-dependent clotting factors, decreasing anticoagulant requirements.(8) In patients with the CYP2C9 intermediate and extensive metabolizer genotypes, long-acting amiodarone inhibition of CYP2C9 may increase the risk of phenoconversion to the poor metabolizer phenotype.(24) Patients with CYP2C9 intermediate metabolizer genotype are expected to be the most susceptible to this interaction and conversion to the poor metabolizer phenotype. Patients with a pre-existing CYP2C9 poor metabolizer genotype would be less susceptible to this interaction. However, these patients with reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) have an inherently higher risk for bleeding at usual anticoagulant doses and thus generally require lower doses to achieve effective and safe anticoagulation. In addition, CYP2C9 poor metabolizers require more a prolonged time (>2 to 4 weeks) to achieve maximum INR effect for a given dosage regimen than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: The US manufacturer of amiodarone states that amiodarone will almost always potentiate the anticoagulant response in patients receiving coumarin anticoagulants. They recommend decreasing the anticoagulant dosage by 1/3 to 1/2 when amiodarone therapy is initiated. Although amiodarone has a long half-life, significant increases in the INR/prothrombin time may start in 3 to 4 days. Monitor INR closely and adjust anticoagulant dose until stabile.(23) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Several studies and case reports have documented the potential interaction between warfarin and amiodarone. In several studies, the dosage of warfarin had to be decreased between 32.9% and 70% to maintain satisfactory prothrombin activity.(1-5,7-12) Several case reports and retrospective chart reviews have also documented the potential interaction between amiodarone and acenocoumarol. The dosage reduction of acenocoumarol required to maintain satisfactory prothrombin activity ranged from 20% to 60%.(13-19) A case report describes a 66-year-old male with a history of recurrent atrial fibrillation. While taking both amiodarone and a low-dose warfarin therapy, prothrombin times were prolonged, INR values were increased and bleeding occurred. Both drugs were withheld, and the effect of the interaction continued for an extended period of time.(20) One study evaluated the role desethylamiodarone, the active metabolite of amiodarone, played on concurrent warfarin therapy. After analyzing 25 patients with structural heart disease and arrhythmias, it was found that the concentration of desethylamiodarone played a larger role in augmenting the INR, than the concentration of amiodarone alone. Additional examination revealed that amiodarone primarily inhibits CYP1A2 and CYP3A4, whereas desethylamiodarone primarily inhibits CYP2C9, the isozyme responsible for the metabolism of S-warfarin.(21) An observational, cohort study reviewed the interaction of amiodarone with warfarin for a period of at least one year, while evaluating the adjustments needed to achieve an INR ratio between 2 and 3. After analyzing 43 patients, baseline warfarin therapy required a mean 44% reduction in dose after seven weeks of coadministration with amiodarone. Five subjects experienced minor bleeding. For patients receiving amiodarone maintenance, warfarin dose reductions were as follows: 400 mg/d, reduce warfarin dose 40%; 300 mg/d, reduce warfarin dose 35%; 200/d, reduce warfarin dose 30%; and 100 mg/d, reduce warfarin dose by 25%. All warfarin dose reductions are approximations and must be based on aggressive INR monitoring.(22)

Coumarin Anticoagulants/Penicillinase Resistant Penicillins

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown; however, increased hepatic metabolism of warfarin by the penicillins has been postulated.

CLINICAL EFFECTS: Penicillinase resistant penicillins may decrease the effects of anticoagulants, increasing the risk of clots.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor anticoagulant function during combined administration of these classes of drugs and for several weeks after stopping the penicillin. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: A study compared INR measurements of 236 patients taking warfarin or phenprocoumon to before and after dicloxacillin exposure. Prior to dicloxacillin exposure the mean INR level was 2.59 compared to 1.97 after 2-4 weeks of dicloxacillin therapy (a mean decrease of 0.62). 61% of patients (n = 144) had subtherapeutic INR levels (less than 2.0) after 2-4 weeks of concomitant dicloxacillin and warfarin therapy. Of 64 patients taking phenprocoumon, the mean INR level was 2.61 before dicloxacillin therapy compared to 2.30 after 2-4 weeks of dicloxacillin therapy (a mean decrease of 0.31). 41% of patients (n = 26) had subtherapeutic INR levels after 2-4 weeks of concomitant phenprocoumon and dicloxacillin therapy.(1) In a study of seven patients receiving long-term warfarin therapy, administration of dicloxacillin sodium (500mg four times daily for seven days) resulted in a significant reduction in the PT. All patients had a decrease in PT from baseline values. The mean decrease was 1.9+/-1.8 seconds, but one patient had a decrease of 5.6 seconds (24.3%).(2) A large systematic review was performed on 72 warfarin drug-drug interactions studies that reported on bleeding, thromboembolic events, or death. Most studies were retrospective cohorts. A meta-analysis of 11 of those studies found a higher rate of clinically significant bleeding in patients on warfarin and antimicrobials (OR=1.63; 95% CI 1.45-1.83). Increased bleeding risk was also seen in subgroup analyses with penicillins (OR=1.59; 95% CI 1.14-2.20).(21) In a retrospective review, five patients with durable, continuous flow left ventricular assist devices who were maintained on warfarin required an mean increase in weekly warfarin dosage of 51.8% to maintain a therapeutic INR during dicloxacillin therapy. Dicloxacillin was discontinued in three patients and these patients required a decrease in weekly warfarin dosage by 30.6% to maintain a therapeutic INR.(3) In a retrospective, observational, cohort study four patients had their warfarin dose increased 57-130% with concomitant flucloxacillin administration.(4) Several case reports have documented a decrease in the anticoagulant effects of warfarin during concurrent administration of penicillinase-resistant penicillins, including four reports with cloxacillin,(5-6) three with dicloxacillin,(7-9) three with flucloxacillin,(10-12) and eight with nafcillin.(13-19) The effects of the interaction have been reported to be delayed up to nine days after taking both drugs concurrently and the effects of the interaction may persist for up to one month after stopping the antibiotic. In the case of dicloxacillin, some patients required twice their normal dosage of warfarin to maintain therapeutic INRs. One patient taking flucloxacillin developed a cardioembolic ischemic stroke. In the case of nafcillin, one patient required 4.5 times the normal dosage of warfarin. Conversely, there is one report of increased warfarin effects following the addition of cloxacillin to therapy.(20) In a cohort study of 1023 patients, short- and long-term dicloxacillin treatments decreased INR levels by a mean of -0.65 and -0.76, respectively. The effect of dicloxacillin on INR levels was largest after 2 weeks and more than 90% of patients had a subtherapeutic INR level (INR below 2) after long-term dicloxacillin treatment. The initiation of dicloxacillin decreased the mean INR from 2.5 to 1.84 within 1-3 weeks of exposure. Flucloxacillin decreased INR levels by -0.37. Subtherapeutic INR levels were noted in 42% of patients on flucloxacillin.(22)

Coumarin Anticoagulants/Romidepsin; Vorinostat

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Romidepsin(1) and vorinostat(2) may increase the effects of coumarin anticoagulants when co-administered.

CLINICAL EFFECTS: Concurrent use of romidepsin(1) or vorinostat(2) with a coumarin anticoagulants may increase the risk of bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The manufacturers of romidepsin(1) and vorinostat(2) recommend close monitoring of patients taking these agents with coumarin anticoagulants using an appropriate measure, such as the International Normalized Ratio (INR). If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Prolongation of prothrombin time (PT) and INR have been observed in patients taking coumarin anticoagulants with romidepsin(1) and vorinostat.(2)

Coumarin Anticoagulants/Select Azole Antifungal Agents

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The more potent warfarin S-enantiomer is metabolized by CYP2C9 while the weaker R-enantiomer is metabolized by CYP1A2 and CYP3A4. Miconazole is a moderate-strong inhibitor of CYP2C9; fluconazole is a moderate inhibitor of CYP2C9 and CYP3A4; voriconazole and ketoconazole are both weak inhibitors of CYP2C9 and strong inhibitors of CYP3A4.

CLINICAL EFFECTS: Concurrent use of select azole antifungals and coumarin anticoagulants may increase the risk for bleeding.

PREDISPOSING FACTORS: The antifungal dose and inhibitory potency, particularly for CYP2C9, are drug factors which affect the magnitude of this interaction. The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Additional drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Azole antifungal inhibition of CYP2C9, may increase the risk of conversion to the CYP2C9 poor metabolizer phenotype. Patients with CYP2C9 intermediate metabolizer genotype are expected to be the most susceptible to this phenoconversion. Patients with a pre-existing CYP2C9 poor metabolizer genotype would be less susceptible to this interaction. However, patients with reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) have an inherently higher risk for bleeding at usual anticoagulant doses and thus generally require lower doses to achieve effective and safe anticoagulation. In addition, CYP2C9 poor metabolizers require more a prolonged time (>2 to 4 weeks) to achieve maximum INR effect for a given dosage regimen than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: In patients receiving warfarin when fluconazole, voriconazole, miconazole or ketoconazole is started, anticipate the need for a dose reduction. Check the baseline INR then closely monitor and adjust the dose of warfarin until the INR has stabilized on the combination. After the azole therapy is discontinued, close monitoring is again needed as the INR may fall after removal of the inhibitor. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Selected azole antifungal agents can cause an increase in the anticoagulant effects of warfarin. The drug-related risk is dependent on the specific azole, dose and route. A large systematic review was performed on 72 warfarin drug-drug interactions studies that reported on bleeding, thromboembolic events, or death. Most studies were retrospective cohorts. A meta-analysis of 11 of those studies found a higher rate of clinically significant bleeding in patients on warfarin and antimicrobials (OR=1.63; 95% CI 1.45-1.83). Increased bleeding risk was also seen in subgroup analyses with azole antifungals (OR=1.86; 95% CI 1.40-2.47). A retrospective review compared the changes in warfarin effects with coadministration of fluconazole, itraconazole, or voriconazole in 18, 6, and 5 patients, respectively. Mean INR increased from 1.4 to 2.94 in patients taking fluconazole (p<0.001) and increased >20% in 15 out of 18 patients. Mean INR increased from 1.95 to 2.89 in patients taking voriconazole (p<0.05) and increased >20% in 4 out of 5 patients. Mean INR increased slightly from 1.86 to 1.92 in patients taking itraconazole (p=0.37) and did not increase >20% in any patient. In healthy subjects, the administration of voriconazole (300 mg every 12 hours for 12 days) prior to warfarin (30 mg single dose) doubled the prothrombin time when compared to warfarin plus placebo. A large epidemiologic study evaluated the risk for hospitalization due to gastrointestinal (GI) bleeding in warfarin patients treated with or without various anti-infective agents, including fluconazole. Warfarin patients treated with fluconazole had an approximately 2-fold increase in risk for hospitalization due to a GI bleed compared with warfarin patients without infection or warfarin patients receiving alternative anti-infective treatment (e.g. cephalexin, amoxicillin). This risk was highest in patients who received fluconazole 6 to 15 days prior to admission, leading authors to suggest this risk was due to a pharmacokinetic interaction between warfarin and fluconazole, and not due to infection or infection sequelae (e.g. change in diet or gut bacteria). A drug-drug interaction study was performed to evaluate the effect of a single 150 mg dose of fluconazole on prothrombin times in 6 women who had received warfarin therapy for at least 6 months and had stable, therapeutic INRs. Three of 6 women had an INR > 4 or had a bleeding episode: one woman had an INR of 4.6 on day 2, one woman had an INR of 5.2 on day 5, and one woman developed a subconjunctival hemorrhage in the absence of trauma or physical straining on day 6 (INR = 3.4). Miconazole is the most potent known CYP2C9 inhibitor in vivo. In an interaction study in 6 healthy volunteers, oral miconazole 125 mg daily for 18 days increased warfarin exposure (AUC, area-under-curve) 4.7-fold. Black stools have been reported with warfarin and administration of miconazole oral gel. Documentation for oral ketoconazole is less conclusive. However, as ketoconazole is considered a moderate CYP2C9 inhibitor an interaction with warfarin would be expected.

Coumarin Anticoagulants/Tamoxifen; Toremifene

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Tamoxifen and toremifene may inhibit the CYP2C9 mediated metabolism of warfarin.

CLINICAL EFFECTS: The concurrent use of tamoxifen or toremifene and warfarin may result in an increased risk for bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Pharmacogenomic information: patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve to achieve effective and safe anticoagulation than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: Closely monitor INR when tamoxifen or toremifene are added to or discontinued from concurrent anticoagulant therapy.(1,2) In high risk women taking tamoxifen for a reduction in breast cancer risk and in women with ductal carcinoma in situ (DCIS), concurrent therapy with coumarin anticoagulants is contraindicated.(1)

DISCUSSION: There is one case report of an increase in prothrombin time when tamoxifen was added to warfarin therapy. This case led to a retrospective chart review of five patients. Two patients also had increases in prothrombin time. The other three patients required a smaller than normal dose of warfarin to maintain appropriate prothrombin times.(3) In another case report, a patient developed hematuria and hematemesis three weeks after the addition of tamoxifen to warfarin therapy.(4) In a retrospective review of 22 patients who received concurrent therapy with warfarin and tamoxifen, no problems were noted. Two patients had increased prothrombin times with no signs of bleeding. One patient experienced a subconjunctival hemorrhage, despite no problems with control of prothrombin times. Another patient experienced difficulty in control of prothrombin times and a thigh hematoma. Another patient developed an intraocular hemorrhage and hemorrhagic rashes after the addition of tamoxifen to warfarin therapy.(5) One set of authors postulated that the antitumor activity of tamoxifen may be reduced if warfarin competitively inhibits the formation of the active metabolite of tamoxifen; however, this has not been demonstrated.(3) In a case report, a 50-year-old woman with a history of breast cancer started warfarin after mitral valve replacement. She had been on toremifene but it was held during hospitalization for the MVR due to unavailable supply. Warfarin was dosed up to 21 mg/week in the absence of toremifene. After hospital discharge, patient resumed toremifene and warfarin dose had to be reduced by 37.5% to avoid supratherapeutic INR.(6)

Selected Anticoagulants (Vit K Antag)/Sulfonamide Antibact

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The mechanism may involve several processes. Some sulfonamides, e.g. cotrimoxazole, sulfamethizole, sulfaphenazole, inhibit the CYP2C9 mediated metabolism of warfarin. Sulfonamides have also been shown to displace plasma protein bound warfarin. The use of sulfonamides may decrease vitamin-K producing bacteria in the gastrointestinal tract. Disease related factors such as fever, decreased oral intake and acute illness may also play a role in bleeding risk.

CLINICAL EFFECTS: Concurrent use of anticoagulants and sulfonamides may increase the risk for bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective and safe anticoagulation than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Perform agent-specific laboratory test (e.g. INR) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Numerous studies and case reports have documented an interaction between warfarin and sulfamethoxazole/trimethoprim. The effects are generally seen within two to six days and may or may not be accompanied by increased warfarin concentrations. Case reports also document an interaction between warfarin and sulfisoxazole and sulfamethizole resulting in increased bleeding, warfarin half-life and decreased warfarin clearance rates. Because of the proposed mechanism, it is prudent to expect similar results during the concurrent administration of warfarin and other sulfonamides. A large systematic review was performed on 72 warfarin drug-drug interactions studies that reported on bleeding, thromboembolic events, or death. Most studies were retrospective cohorts. A meta-analysis of 11 of those studies found a higher rate of clinically significant bleeding in patients on warfarin and antimicrobials (OR=1.63; 95% CI 1.45-1.83). Increased bleeding risk was also seen in subgroup analyses with sulfonamides (OR=2.41; 95% CI 1.42-4.10).

Selected Anticoagulants (Vit K Antagonists)/Barbiturates

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: It is speculated that induction of hepatic microsomal enzymes results in increased metabolism of anticoagulants,(1) resulting in decreased anticoagulant response.(2,3) Phenobarbital and secobarbital are inducers of CYP2C9 and may result in decreased levels of anticoagulants.(4) Barbiturates may also increase the synthesis of clotting factors by the liver.(5) The absorption of dicumarol, but not warfarin, from the gastrointestinal may be decreased by barbiturates.(6)

CLINICAL EFFECTS: Concurrent use may result in decreased anticoagulant effects. Increased anticoagulant effects may occur if the barbiturate is withdrawn. The effect may be dose-related and may continue beyond the discontinuation of the barbiturate.

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: If possible, avoid the concurrent use of these agents. If a barbiturate is initiated or discontinued in a patient maintained on anticoagulant therapy, monitor prothrombin times and adjust the dose of the anticoagulant as needed. For hypnotic indications, benzodiazepines and diphenhydramine may be alternatives to barbiturates in patients stabilized on anticoagulant therapy.

DISCUSSION: Amobarbital,(7) aprobarbital,(8) barbital,(9) butabarbital,(10) pentobarbital,(5) phenobarbital,(1) and secobarbital(7) have been shown to interact with coumarin anticoagulants. Dicumarol,(6) warfarin(1), and phenprocoumon(4) have been reported to interact with the barbiturates. It would be prudent to assume that all barbiturates and the indanedione derivatives would interact in a similar fashion. Primidone is metabolized to phenobarbital. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated, altered, or discontinued.

Selected Anticoagulants (Vit K Antagonists)/Chloramphenicol

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The mechanism has not been clearly established, but may involve deficiency of Vitamin K. Normally, the chief source of Vitamin K is the diet (2). If this source is absent, synthesis of vitamin K by gut bacteria becomes important, and antibiotics, by decreasing the intestinal flora, can produce Vitamin K deficiency (3). This situation increases the effect of a given dose of anticoagulant.

CLINICAL EFFECTS: Increased hypoprothrombinemic effect of the anticoagulant with possible bleeding.

PREDISPOSING FACTORS: Low or absent dietary Vitamin K intake is a crucial predisposing factor, unless supplemental Vitamin K is administered. The combination of chloramphenicol with poor nutrition, infection and diarrhea caused marked Vitamin K deficiency and bleeding in two infants even in the absence of any anticoagulant (5). The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. If chloramphenicol is given simultaneously, and nutritional status is acutely or chronically poor, very close monitoring is required. When applicable, perform agent-specific laboratory test (e.g. INR) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Chloramphenicol has been reported to produce a two- to four fold increase in the half-life of dicumarol. Although this interaction is potentially very dangerous, there are few if any convincing clinical reports of its actual occurrence. Well controlled studies are needed.

Selected Anticoagulants (Vit K Antagonists)/Cimetidine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Cimetidine is a weak inhibitor of CYP1A2, CYP2C9, and CYP3A4. The more potent S-warfarin isomer is metabolized by CYP2C9 where as the weaker warfarin R-enantiomer is metabolized by CYP1A2 and CYP3A4. The cimetidine inhibitory effect appears to be greater on the less active R-warfarin isomer.

CLINICAL EFFECTS: The pharmacologic effects of warfarin may be increased resulting in a higher risk for bleeding.

PREDISPOSING FACTORS: Interaction magnitude is expected to be greater with use of prescription doses of cimetidine, e.g. 800 mg to 1,600 mg daily. The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Pharmacogenomic information: warfarin patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective and safe anticoagulation than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: Given the availability of alternatives, coadministration of cimetidine and warfarin should be avoided, particularly if high doses of cimetidine are prescribed. Consider use of H-2 antagonists famotidine or nizatidine which are unlikely to interact with warfarin. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: The majority of drug interaction reports involving H-2 antagonists and warfarin have occurred with cimetidine. Reports of a possibly significant interaction between ranitidine and warfarin have been equivocal. Famotidine and nizatidine do not appear to affect prothrombin time. A study of 6 healthy subjects receiving cimetidine and warfarin concomitant therapy had no significant effect on the S-warfarin however increased R-warfarin trough concentrations 28% (p<0.05) and decreased R-warfarin clearance by 23% (p<0.05).

Selected Anticoagulants (Vit K Antagonists)/Fibrates

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown. Fibric acid derivatives may displace anticoagulants from their plasma protein binding sites or may affect anticoagulant receptor sites. It has also been suggested that the effect may be related to the hypolipidemic action of the fibric acid derivatives.

CLINICAL EFFECTS: Concurrent use of selected anticoagulants and fibric acid derivatives may increase the risk for bleeding.

PREDISPOSING FACTORS: Severe hyperlipidemia, larger doses of the fibric acid derivative, and older age may predispose patients to this interaction. The risk for bleeding episodes may also be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Patients receiving concurrent therapy with selected anticoagulants and a fibric acid derivative should be closely monitored for excessive anticoagulant effects. The dose of the anticoagulant may need to be adjusted if the fibric acid derivative is added to or discontinued from stabilized anticoagulant therapy. The time of highest risk for an anticoagulant drug interaction is when the precipitant drug is initiated or discontinued. When concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: There have been case reports of bezafibrate,(1) clofibrate, (2-5) fenofibrate,(6-8) and gemfibrozil(9-11) interacting with warfarin. The interactions between clofibrate(12-14) and and warfarin and gemfibrozil(15) and warfarin have also been documented in clinical trials. There are also case reports of bezafibrate(16) and clofibrate(17) interacting with dicumarol. A study showed that bezafibrate increased the effects of phenprocoumon.(18)

Selected Anticoagulants (Vit K Antagonists)/Natisedine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: It is speculated that induction of hepatic microsomal enzymes results in increased metabolism of anticoagulants,(1) resulting in decreased anticoagulant response.(2,3) Barbiturates or barbiturate containing products may also increase the synthesis of clotting factors by the liver.(4) The absorption of dicumarol, but not warfarin, from the gastrointestinal may be decreased by barbiturates.(5)

CLINICAL EFFECTS: Concurrent use may result in decreased anticoagulant effects. Increased anticoagulant effects may occur if the barbiturate or barbiturate containing product is withdrawn. The effect may be dose-related and may continue beyond the discontinuation of the barbiturate.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If possible, avoid the concurrent use of these agents. If a barbiturate or barbiturate containing product is initiated or discontinued in a patient maintained on anticoagulant therapy, monitor prothrombin times and adjust the dose of the anticoagulant as needed. For hypnotic indications, benzodiazepines and diphenhydramine may be alternatives to barbiturates in patients stabilized on anticoagulant therapy.

DISCUSSION: Phenobarbital,(1) and secobarbital(6) have been shown to interact with coumarin anticoagulants. Dicumarol,(5) warfarin(1), and phenprocoumon(4) have been reported to interact with the barbiturates. It would be prudent to assume that all barbiturates and the indanedione derivatives would interact in a similar fashion. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated, altered, or discontinued.

Selected Anticoagulants (Vit K Antagonists)/Nsaids

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown. Some NSAIDs may displace anticoagulants from plasma protein binding sites. NSAIDs also have the potential to produce gastrointestinal ulceration and bleeding. Some NSAIDs may impair platelet function and prolong bleeding times.

CLINICAL EFFECTS: Concurrent use of anticoagulants and NSAIDs may increase the risk for bleeding.

PREDISPOSING FACTORS: Bleeding risk may be increased in patients with renal impairment and in patients older than 75 years. The risk for bleeding episodes may be greater in patients with multiple disease-associated factors (e.g. thrombocytopenia, advanced liver disease). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g., other anticoagulants, antiplatelets, corticosteroids, selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). Risk of GI bleed may be increased in patients who are of older age, in poor health status, or who use alcohol or smoke. Risk may also be increased with longer duration of NSAID use and prior history of peptic ulcer disease and/or GI bleeding.

PATIENT MANAGEMENT: If concurrent therapy with anticoagulants and NSAIDs is warranted, patients should be closely monitored for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: The effects of NSAIDs on the hypoprothrombinemic response to anticoagulants appears to vary between patients as well as with different NSAIDs. Documentation is frequently contradictory - while studies have shown several NSAIDs to have no effect on the pharmacokinetics of warfarin, case reports have documented increased effects with and without bleeding when these same NSAIDs were administered concurrently with warfarin. While celecoxib has been shown not to affect platelet aggregation or bleeding times and had no effects on the anticoagulant effect of warfarin in healthy subjects, increased prothrombin times and bleeding episodes, some of which were fatal, have been reported, predominantly in the elderly, in patients receiving concurrent therapy with celecoxib and warfarin. Rofecoxib has been shown to increase prothrombin times in subjects who received concurrent warfarin therapy. A post hoc analysis of nonselective NSAIDs in the RE-LY study (compared dabigatran 150 and 110 mg twice daily with warfarin in atrial fibrillation) assessed clinical outcomes by comparing nonselective NSAID use (at least once during trial) with no NSAID use in 2279 patients. The use of NSAIDs was associated an increased risk of major bleeding (hazard ratio (HR) 1.68), gastrointestinal major bleeding (HR 1.81), stroke or systemic embolism (HR 1.50), and hospitalization (HR 1.64).(22) A self-controlled case study of 1,622 oral anticoagulant-precipitant drug pairs were reviewed and found 14% of drug pairs were associated with a statistically significant elevated risk of thromboembolism. Concurrent use of warfarin and sulindac resulted in a ratio of rate ratios (RR) (95% CI) of 3.7 (1.79-7.62); warfarin and etodolac ratio of RR 2.61 (1.6-4.25); warfarin and ibuprofen ratio of RR 1.94 (1.5-2.5); warfarin and naproxen ratio of RR 1.72 (1.35-2.19); warfarin and indomethacin ratio of RR 1.62 (1.03-2.55); warfarin and diclofenac ratio of RR 1.43 (1.07-1.92; warfarin and celecoxib ratio of RR 1.24 (1.02-1.53); and warfarin and meloxicam ratio of RR 1.23 (1.02-1.47).(23) In a nationwide cohort study, patients were evaluated for thromboembolic cardiovascular and clinically relevant bleeding events with concurrent antithrombotic and ongoing NSAID treatment. A total of 108,232 patients were followed for a mean of 2.3 +/- 1.8 years after diagnosis of myocardial infarction. Concomitant NSAID treatment significantly increased the risk for cardiovascular events (hazard ratio (HR) 6.96; 95% CI 6.24 - 6.77; p<0.001) and bleeding events (HR 4.08; 95% CI 3.51 - 4.73; p<0.001) compared to no NSAID treatment. NSAIDs were further evaluated and revealed the use of celecoxib (HR: 4.65; 95% CI: 3.17 to 6.82; p < 0.001, and 3.44; 95% CI: 2.20 to 5.39; p < 0.001, respectively) and meloxicam (HR: 3.03; 95% CI: 1.68 to 5.47; p < 0.001, and 2.80; 95% CI: 1.40 to 5.60; p < 0.001, respectively) had the lowest risk for cardiovascular and bleeding events, receptively. A large systematic review was performed on 72 warfarin drug-drug interactions studies that reported on bleeding, thromboembolic events, or death. Most studies were retrospective cohorts. A meta-analysis of 8 of those studies found a higher rate of clinically significant bleeding in patients on warfarin and NSAIDs (OR=1.83; 95% CI 1.29-2.59). Increased bleeding risk was seen in subgroup analyses with non-selective NSAIDs (OR=1.86; 95% CI 1.10-3.17) and COX-2 inhibitors (OR=1.81; 95% CI 1.3-2.52).(24) If concurrent therapy with anticoagulants and NSAIDs is warranted, it would be prudent to monitor patients closely for increased anticoagulant effects.

Selected Anticoagulants (Vit K Antagonists)/Quinine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Quinine may have the potential to depress hepatic enzyme synthesis of vitamin K-dependent clotting factors.(1)

CLINICAL EFFECTS: Concurrent use of selected anticoagulants (vitamin K antagonists) and quinine may increase the risk for bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: This interaction has not been reported with quinine, only with quinidine; however, if an interaction occurs, the consequences could be severe.

Selected Anticoagulants (Vit K Antagonists)/Quinolones

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown. Some quinolones may affect the metabolism of anticoagulants or the infection process may be responsible for the changes seen.

CLINICAL EFFECTS: Concurrent use of quinolones may be associated with an increase in hypoprothrombinemic effects of anticoagulants, which may result in an increased risk of bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. A study suggested not preemptively reducing the dose of warfarin upon initiation of levofloxacin, but instead just a short-term INR follow-up appears reasonable.(33) When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: A large systematic review was performed on 72 warfarin drug-drug interactions studies that reported on bleeding, thromboembolic events, or death. Most studies were retrospective cohorts. A meta-analysis of 11 of those studies found a higher rate of clinically significant bleeding in patients on warfarin and antimicrobials (OR=1.63; 95% CI 1.45-1.83). Increased bleeding risk was also seen in subgroup analyses with fluoroquinolones (OR=1.68; 95% CI 1.34-2.11).(42) In a study in 16 patients stabilized on warfarin therapy, the addition of ciprofloxacin (500 mg twice daily for 10 days) had no significant effects on INR values and no patients experienced a bleeding event.(1) In a study in 36 patients stabilized on warfarin therapy, the addition of ciprofloxacin (750 mg twice daily for 12 days) had no effects on the amount of S-warfarin. Levels of R-warfarin increased 1.15-fold, concentrations of clotting factors decreased, and the mean PT ratio increased slightly. However, no patient required warfarin dosage adjustment and no bleeding episodes were reported.(2) In contrast to these studies, there have been several case reports of bleeding episodes following the addition of ciprofloxacin to warfarin therapy,(3-9) including 66 reports to the FDA from 1987 to 1997.(4) Of these 66 reports, 15 resulted in hospitalization, 25 in bleeding, and 1 in death.(4) As of January 14, 2004, Health Canada had received 10 case reports of interactions between warfarin and ciprofloxacin. Four of these patients died.(10) Another study showed that ciprofloxacin prolonged release (PR) concomitantly administered with warfarin does not alter the pharmacokinetics and pharmacodynamics of warfarin.(31) In a study in 6 healthy males, concurrent enoxacin did not affect the hypothrombinemic effects of warfarin, but did decrease the clearance of R-warfarin.(11) In a case report, enoxacin did interact with warfarin.(12) Gatifloxacin has been reported to interact with warfarin in a case report.(13) As of January 14, 2004, Health Canada had received 13 reports of interactions between warfarin and gatifloxacin. Two of these patients died.(10) In a study in 16 healthy subjects, the addition of grepafloxacin (600 mg daily for 14 days) had no effects on the pharmacodynamics of warfarin or the pharmacokinetics of grepafloxacin.(14) In a study in 6 patients stabilized on warfarin therapy, the addition of levofloxacin had no effect on INR values.(15) In a study in 16 healthy subjects, levofloxacin (500 mg twice daily for 6 days) had no effects on the pharmacokinetics or pharmacodynamics of a single dose of warfarin (30 mg).(16) In contrast, there are several case reports documenting an interaction between levofloxacin and warfarin.(17-19) As of January 14, 2004, Health Canada had received 16 reports of interactions between warfarin and levofloxacin. One of these patients died.(10) In a retrospective study, the addition of levofloxacin to warfarin therapy showed an increase in INR.(35) However, in another retrospective study, the addition of levofloxacin to long-term warfarin therapy showed no interaction.(34) An article on the pharmacokinetics of levofloxacin states that with warfarin there were no pharmacokinetic alterations detected for either the R- or S-enantiomers and there were no significant differences in prothrombin times.(32) There are several reports of an interaction between moxifloxacin and warfarin.(20-21) As of January 14, 2004, Health Canada had received 12 reports of interactions between warfarin and moxifloxacin.(10) According to the Institute of Clinical Pharmacology, moxifloxacin shows no pharmacokinetic interaction with warfarin.(38,39) According to moxifloxacin official package insert, warfarin did not significantly affect the pharmacokinetics of moxifloxacin because the in vitro studies suggest that moxifloxacin is unlikely to significantly alter the metabolic clearance of drugs metabolized by the cytochrome P450 system.(41) One case report, of an elderly female concomitantly administered moxifloxacin and warfarin, observed an INR increase from 2.3 to 5.1 and development of hemoperitoneum and left abdominal wall hematoma.(40) Another case report of an elderly female concomitantly administered warfarin and moxifloxacin observed a prolonged INR level despite withholding warfarin for 6 days; however, the INR did decrease after 2 days upon discontinuing moxifloxacin.(36,37) Two case reports show an interaction between moxifloxacin and warfarin due to evidence of elevated PT and INR following coadministration.(36) There are case reports documenting interactions between nalidixic acid and warfarin(22-24) and nicoumalone.(25) In a study in 10 healthy subjects, norfloxacin (400 mg twice daily for 6 days) had no effects on the pharmacokinetics or pharmacodynamics of a single dose of warfarin (30 mg).(26) In a case report, norfloxacin did interact with warfarin.(27) As of January 14, 2004, Health Canada had received 6 reports of interactions between warfarin and norfloxacin.(10) There are reports of an interaction between ofloxacin and warfarin.(28-29) In a study in 10 healthy subjects, temafloxacin (600 mg twice daily for 4 days) had no effects on prothrombin times.(30)

Selected Anticoagulants (Vit K Antagonists)/Sulfinpyrazone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Multiple processes may be involved: 1) Sulfinpyrazone inhibits CYP2C9 hepatic metabolism of acenocoumarol and S-warfarin, the most active warfarin enantiomer. 2) Sulfinpyrazone inhibits platelet activation.

CLINICAL EFFECTS: Concurrent use of sulfinpyrazone with acenocoumarol or warfarin may increase anticoagulant exposure (AUC, area-under-curve) and the risk of bleeding.

PREDISPOSING FACTORS: Patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) result in an inherently higher warfarin or acenocoumarol half-life and risk for anticoagulant-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective and safe anticoagulation than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: If both drugs are administered, monitor prothrombin activity and adjust the acenocoumarol or warfarin dosage accordingly. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a warfarin drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: In an interaction study performed in healthy males, sulfinpyrazone 200 mg twice daily for 4 days, followed by a single dose of warfarin 1.5 mg/kg, resulted in a 1.9-fold increase in S-warfarin exposure (AUC).

Selected Anticoagulants (Vitamin K Antagonists)/Allopurinol

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Possible inhibition of anticoagulant metabolism by allopurinol.

CLINICAL EFFECTS: Concurrent use of anticoagulants and allopurinol may increase the risk for bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Documentation is lacking; however, if an interaction occurs, the consequences could be severe.

Selected Anticoagulants (Vitamin K Antagonists)/Aprepitant

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Aprepitant may induce the metabolism of S-warfarin by CYP2C9.(1-3)

CLINICAL EFFECTS: Use of aprepitant in patients maintained on warfarin may result in decreased levels and effectiveness of warfarin 7-10 days after initiation of aprepitant.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturers of aprepitant recommend careful monitoring of INR values in the 2 week period, particularly at 7-10 days, following initiation of the 3 day course of aprepitant therapy with each chemotherapy cycle.(1-3)

DISCUSSION: In a study in healthy subjects maintained on warfarin, a single 125 mg dose of aprepitant was administered on Day 1, followed by single 80 mg doses on Days 2 and 3. There was no effect on the area-under-curve (AUC) of R-warfarin or S-warfarin on Day 3. However, there was a 34% decrease in S-warfarin AUC and a 14% decrease in INR 5 days after the completion of aprepitant therapy (Day 8).(1-3)

Selected Anticoagulants (Vitamin K Antagonists)/Hydantoins

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown. Possible mechanisms include alteration of hepatic metabolism of both agents and alteration in levels of vitamin-K dependent clotting factors by hydantoins.

CLINICAL EFFECTS: Multiple effects may be seen including an increase or decrease in INR. Anticoagulant effects have been found to increase initially when hydantoins are initiated and then to decrease thereafter in some patients. In patients receiving acenocoumarol or dicoumarol, elevation of hydantoin plasma levels has been described. Phenytoin has a narrow therapeutic range. Early symptoms of hydantoin toxicity may include nystagmus, ataxia, dysarthria, tremor, hyperreflexia, lethargy, slurred speech, blurred vision, nausea, and vomiting. Severe toxicity may produce organ dysfunction (e.g. coma, irreversible cerebellar dysfunction and atrophy, hypotension, bradycardia, seizures, and cardiac arrest) and may be fatal.(10) Concurrent use of hydantoins and anticoagulants may increase the risk for bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective and safe anticoagulation than patients without these CYP2C9 variants. Risk factors for hydantoin toxicity include renal impairment, hepatic impairment, or hypoalbuminemia.

PATIENT MANAGEMENT: The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Use caution when initiating, altering the dose or discontinuing either drug. Monitor INR and adjust the anticoagulant dose accordingly. Extended monitoring may be needed as an initial increase in the INR may be followed by a fall in the INR due to phenytoin induction of warfarin metabolism. Monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. Patients receiving acenocoumarol or dicoumarol and a hydantoin should also have hydantoin levels monitored and adjusted when anticoagulant therapy is initiated. Monitor the patient for signs of hydantoin toxicity (e.g. nystagmus, ataxia, dysarthria, tremor, hyperreflexia, lethargy, slurred speech, blurred vision, nausea, and vomiting).

DISCUSSION: In one case report, a patient had been stabilized on warfarin 2.5 mg 5 days of the week and 5 mg 2 days of the week with a maximum prothrombin time of 21 seconds. When phenytoin (300 mg daily) was initiated, the patient's warfarin dose was decreased to 2.5 mg daily, but the patient's prothrombin time increased to 32 seconds over the course of one month (5). In another case report, a patient had been stabilized on warfarin (5 mg daily) for 43 days at which time the patient experienced a seizure during hospitalization. Phenytoin (250 mg every 8 hours for four doses followed by 200 mg daily) was initiated along with a dose reduction in warfarin. The anticoagulant effect increased over the following six days and then decreased to an anticoagulant response lower than the response prior to initiation of phenytoin (3). In another report, a patient developed a retroperitoneal hemorrhage 7 days after the addition of phenytoin (300 mg daily) to his warfarin regimen. His INR at the time was 10.41. He died 3 days later of cardiac arrest.(4) Another article describes 2 case reports of elevated PTTs following the addition of phenytoin (300 mg daily) to previously stable warfarin regimens.(5) In contrast to these reports, a patient experienced elevated INR levels following the discontinuation of phenytoin.(6) In a population pharmacokinetic study of patients receiving warfarin, phenytoin use was associated with a 30% increase in warfarin clearance.(7) In a small study of six subjects, diphenylhydantoin (300 mg daily) was administered until a stable concentration was achieved. Then, dicoumarol was administered for one week to give a prothrombin value of about 30% and the effects on serum diphenylhydantoin concentrations were evaluated. An increase ranging from 38-250% was found in all six subjects.(8). In a case report, a patient previously stabilized on acenocoumarol developed elevated INR levels following the addition of phenytoin (100 mg 3 times daily) to her regimen. She also had unexpectedly high phenytoin levels and experienced phenytoin toxicity. She was found to have a mutation in CYP2C9, resulting in slowed metabolism of both agents.(9)

Selected Anticoagulants (Vitamin K Antagonists)/Oxandrolone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Oxandrolone is a CYP2C9 inhibitor and can inhibit metabolism of warfarin and other anticoagulants by this(1) and perhaps other metabolic pathways.

CLINICAL EFFECTS: The concurrent use of an anticoagulant and oxandrolone may increase the risk for bleeding episodes.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective and safe anticoagulation than patients without these CYP2C9 variants.(2)

PATIENT MANAGEMENT: Close monitoring and anticoagulant dose adjustment should be performed until patients have been stabilized on the combination. Patients on a stabile anticoagulant dose when oxandrolone therapy is started are at risk for supratherapeutic anticoagulation and bleeding episodes. In an interaction study, warfarin dose reductions of approximately 80% were required to maintain therapeutic INRs.(3) If warfarin is started in a patient already receiving oxandrolone, start with a low anticoagulant dosage. In a warfarin-oxandrolone interaction study performed in healthy adults, doses of 0.75 - 1.5 mg daily maintained subjects at targeted INR values of 1.5.(3) If oxandrolone is subsequently discontinued, additional monitoring is needed to assure adequate anticoagulation. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: In a study in 15 healthy subjects, oxandrolone increased the half-life of S-warfarin from 26 to 48 hours and increased the area-under-curve (AUC) of S-warfarin by 1.7-fold. Although not metabolized by CYP2C9, similar effects on R-warfarin were noted. Subjects required an 80-85% reduction in warfarin dosage, from a mean dose of 6.13 mg daily to 1.13 mg daily, to maintain a target INR of 1.5. Microscopic hematuria was observed in 9 subjects and gingival bleeding was observed in another.(3) The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated, altered, or discontinued.

Selected Anticoagulants (Vitamin K Antagonists)/Rifamycins

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Rifamycins may induce the hepatic metabolism of the anticoagulants.

CLINICAL EFFECTS: Concurrent or recent use of a rifamycin may result in decreased levels of and clinical effects from anticoagulants. If the rifamycin is withdrawn, levels and effects of the anticoagulant may increase, increasing the risk of hemorrhage. This effect may be dose-related and continue beyond discontinuation of the rifamycin.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If concurrent use of rifamycins and warfarin is warranted, use caution during concurrent use and monitor patients closely. The dose of the anticoagulant will need to be adjusted when the rifamycin is initiated or discontinued. If concurrent use of rifampin and warfarin is warranted, monitor INR closely to maintain target INR. The dose of warfarin may need to be increased 3-5 times higher than a stable baseline dose. Goal INR may be delayed and labile for months after starting rifampin. After discontinuation of rifampin, INR requires close monitoring to de-escalate warfarin dose as induction effects fade. Evaluate patients closely for benefits of bridging with LMWH with risks of additional bleeding.(2) The time of highest risk for an anticoagulant drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose, or discontinuing either drug.

DISCUSSION: In a study in 4 healthy subjects, concurrent rifampin (300 mg twice daily) decreased warfarin (0.75 mg/kg) area-under-curve (AUC) by 70%.(1) In a study in 10 healthy males, concurrent rifampin (600 mg daily) decreased oral warfarin (1.5 mg/kg) AUC by 57%. Prothrombin time decreased by 52%. Intravenous warfarin AUC decreased by 58%. Prothrombin time decreased by 56%.(3) In a study in 8 healthy subjects, concurrent rifampin (600 mg daily) decreased warfarin (dosed to therapeutic effect) plasma levels by 85%. On warfarin alone, subjects averaged 25% of normal prothrombin activity. On concurrent rifampin, subjects averaged 85% of normal prothrombin activity.(4) There are several case reports of decreased warfarin(5-8) and phenprocoumon(9) effects during concurrent rifampin therapy. A self-controlled case study of 1,622 oral anticoagulant-precipitant drug pairs were reviewed and found 14% of drug pairs were associated with a statistically significant elevated risk of thromboembolism. Concurrent use of warfarin and rifampin resulted in a ratio of rate ratios (RR) (95% CI) of 2.25 (1.1-4.61).(10)

Selected Anticoagulants (Vitamin K Antagonists)/Ssris; Snris

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: SSRI or SNRI inhibition of platelet serotonin uptake may result in impaired platelet aggregation.(1-11) This effect may be additive or synergistic when combined with other agents which impair hemostasis. Fluvoxamine is an inhibitor of CYP2C9 mediated metabolism of warfarin.(9)

CLINICAL EFFECTS: Concurrent use of selected anticoagulants and SSRIs or SNRIs may increase the risk for bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Renal impairment has been associated with an elevated risk of GI bleed in patients on SSRIs.(11) Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: For the combination of fluvoxamine and warfarin: when possible change to a SSRI which does not inhibit warfarin metabolism (e.g. citalopram or paroxetine). For patients who require this combination, monitor for an increase in INR when fluvoxamine is started or the dose is increased. The warfarin dose may need to be reduced. For all anticoagulant/SSRI or SNRI combinations, if concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: The manufacturer's product information for fluvoxamine reports a study in which the plasma warfarin concentrations increased 98% and prothrombin times were prolonged in patients who received concurrent fluvoxamine and warfarin.(9) In a single study in 24 healthy patients, concurrent administration of paroxetine and warfarin resulted in clinically significant bleeding in five patients. No changes in paroxetine or warfarin disposition were seen.(13) In a review describing the bleeding risk with SRIs, warfarin was associated with an increased rate of hemorrhage among SRI users (adjusted relative risk = 1.41).(14) In a cohort study of patients taking warfarin in combination with an SSRI versus warfarin treatment alone, an analysis including first bleedings revealed a hazard ratio of 3.49 for bleeding during treatment with a combination of SSRI and warfarin compared with warfarin only.(15) A retrospective study of warfarin-treated patients prescribed or not prescribed an antidepressant showed that use of an SSRI with warfarin was significantly associated with increased risk of any bleed (overall risk (OR)=2.6), major bleeding (OR=4.4), and hospitalization secondary to bleeding (OR=7.0) as compared to those not taking an SSRI.(16) A population based study of patient outcomes in 176 primary intracerebral hemorrhage patients showed that 19 patients taking SSRI/SNRIs together with warfarin had an increased 30-day case fatality rate of 78.9% compared to warfarin alone (50.7%).(17) In a study of the Anticoagulation and Risk factors in Atrial fibrillation (ATRIA) cohort, hemorrhage rates were higher during periods of SSRI exposure compared with periods on no antidepressants (2.32 per 100 person-years vs 1.35 per 100 person-years). After adjusting for bleeding risk and time in INR range > 3, SSRI exposure was associated with an increased rate of hemorrhage compared with no antidepressants (adjusted relative risk = 1.41).(18) Increased bleeding risk has been found when patients receive 3 agents which can affect bleeding risk: an anticoagulant, SSRI and NSAID.(19) In a retrospective review of 5 years of data from the Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper gastro-intestinal bleeding in antidepressant users were compared to those in non-antidepressant users. The risk of a bleed in a patient using an NSAID only based on an observed-expected ratio was 4.5 and in a patient using low-dose aspirin only was 2.5. Concurrent use of a SSRI with NSAIDs or low-dose aspirin increased the risk of bleeding to 12.2 and 5.2, respectively.(19) In another study, there were 16 cases of upper gastrointestinal bleeding in patients receiving concurrent therapy with SSRIs and NSAIDs. Adjusted relative risk of bleeding with NSAIDs, SSRIs, or both were 3.7, 2.6, or 15.6, respectively.(20) A large systematic review was performed on 72 warfarin drug-drug interactions studies that reported on bleeding, thromboembolic events, or death. Most studies were retrospective cohorts. A meta-analysis of 10 of those studies found a higher rate of clinically significant bleeding in patients on warfarin and antidepressants (OR=1.54; 95% CI 1.4-1.7). Increased bleeding risk was also seen in subgroup analyses with SSRIs (OR=1.62; 95% CI 1.42-1.85) but not SNRIs. There was an increased case fatality rate for intracerebral hemorrhage with SSRIs and SNRIs (OR=3.64; 95% CI 1.15-11.53).(21) There are two published case reports involving increased effects of warfarin following addition of fluoxetine. Another case report is inconclusive. In a study in seven healthy volunteers, neither single dose or eight days of consecutive therapy resulted in alteration of warfarin clearance.(22, 23) In a parallel group study involving 12 healthy volunteers, the prothrombin time and area-under-curve (AUC) were increased and the normalization of prothrombin time was decreased with concurrent warfarin and sertraline. There was also a clinically insignificant increase in warfarin protein binding.(24) There is one case report of increased INR during concurrent warfarin and duloxetine.(25)

Selected Anticoagulants (Vitamin K Antagonists)/Vitamin K

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Anticoagulants interfere with the activation of vitamin K-dependent clotting factors. Vitamin K administration may reverse this effect.

CLINICAL EFFECTS: The pharmacological effect of anticoagulants may be reversed resulting in thrombus formation.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving anticoagulants should avoid eating unusual increases in foods high in vitamin K content. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Numerous reports have demonstrated that vitamin K interferes with the hypoprothrombinemic effects of anticoagulants. However, reports of clinically important consequences are uncommon. A clearer understanding of the mechanism by which these drugs act has made it possible to use vitamin K to control bleeding side effects of warfarin therapy. One should be aware of the vitamin K content of enteral feeding products being administered to patients on anticoagulant therapy. Prothrombin time should be monitored when these products are given.

Sensitive Cyp3a4; Cyp2c9; Cyp2c19 Substrates/Enzalutamide

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Enzalutamide may induce the metabolism of agents metabolized by CYP3A4, CYP2C9, and CYP2C19.(1)

CLINICAL EFFECTS: Concurrent use of enzalutamide with agents metabolized by CYP3A4, CYP2C9, and CYP2C19 may result in decreased levels and effectiveness of these agents.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concurrent use of agents metabolized by CYP3A4, CYP2C9, or CYP2C19 that have a narrow therapeutic index with enzalutamide. If concurrent use is required, consider increased monitoring of the affected agent.(1) Dosage adjustments may be required.

DISCUSSION: In a clinical trial in healthy subjects, enzalutamide was shown to reduce the area-under-curve (AUC) of midazolam (a sensitive CYP3A4 substrate), warfarin (a sensitive CYP2C9 substrate), and omeprazole (a sensitive CYP2C19 substrate.(1) A case report in a 77-year-old Caucasian male was initiated on 160 mg of enzalutamide after being stable on warfarin with an INR of 3.5. The INR dropped to 1.4 after approximately 20 days on enzalutamide therapy. Due to the drop in INR, the warfarin dose was increased by 50% which lead to a therapeutic INR. When enzalutamide was discontinued, the warfarin dose was decreased by 33% to remain at a therapeutic level. Upon reinitiation, the warfarin dose was increased once by 50% to achieve a therapeutic INR.(2) Sensitive CYP3A4 substrates with narrow therapeutic indexes include: astemizole, cisapride, clarithromycin, cyclosporine, dihydroergotamine, ergonovine, ergotamine, pimozide, sirolimus, tacrolimus, temsirolimus, and terfenadine.(1,3,4) Sensitive CYP2C9 substrates with narrow therapeutic indexes include: warfarin.(1,3) Sensitive CYP2C19 substrates with narrow therapeutic indexes include: S-mephenytoin.(1,3)

Slt Anticoag (Vit K Antag)/Metronid; Secnidazole; Tinidazole

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Possible inhibition of anticoagulant metabolism by metronidazole, secnidazole, or tinidazole. Metronidazole is a weak CYP2C9 inhibitor and may inhibit the metabolism of the more potent warfarin isomer, S-warfarin.(1)

CLINICAL EFFECTS: Concurrent use of anticoagulants with metronidazole, secnidazole, or tinidazole may increase the risk for bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be most susceptible to this interaction. Patients with a pre-existing CYP2C9 poor metabolizer genotype would be less susceptible to this interaction. However, patients with reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) have an inherently higher risk for bleeding at usual anticoagulant doses and thus generally require lower doses to achieve effective and safe anticoagulation. In addition, CYP2C9 poor metabolizers may require more time (>2 to 4 weeks) to achieve maximum INR effect for a given dosage regimen than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: INR values should be closely monitored during and for several days after the conclusion of concurrent metronidazole, secnidazole, or tinidazole. Anticoagulant dosage may need to be adjusted up to 10 days after concurrent therapy ends. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: In two studies, metronidazole significantly enhanced the hypoprothrombinemic effect of warfarin.(2,3) The onset of the interaction occurred within four(2) to ten days(3) and appeared as excessive bruising of the legs. In eight normal subjects, metronidazole significantly increased the half-life of racemic warfarin and the S-enantiomer of warfarin. The R-enantiomer of warfarin, which is metabolized primarily by the reduction of side chains, was unaffected by metronidazole.(4) In an animal study, metronidazole preferentially inhibited the S-enantiomer of warfarin.(5) This interaction should also be considered during concurrent administration and for eight days after concurrent anticoagulants and tinidazole.(6)

Slt Anticoag (Vit K)/Vitamin E (Alpha Tocopherol) >=800 Unit

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Vitamin E may decrease vitamin K-dependent clotting factors, resulting in additive effects with vitamin K antagonists.(1)

CLINICAL EFFECTS: Dose of vitamin E of 800 units/day or more may increase the pharmacologic effects of vitamin K antagonists.(1-7)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving vitamin E supplements of 800 units/day or more may require lower dosages of vitamin K antagonists. In patients maintained on warfarin who initiate vitamin E supplements in dosages of 800 units/day or more, measured INR one to two weeks after initiation of vitamin E and also every two to four weeks during the first two months.(2)

DISCUSSION: Vitamin E doses up to 400 units/day is believed not to affect the prothrombin time in patients concomitantly receiving warfarin.(2) Vitamin E doses of 800 International Units/day and more have been reported to increase the hypoprothrombinemic effect of warfarin. However, in a double blind clinical trial, with only 13 subjects completing the study, patients who had received chronic warfarin therapy with the addition of vitamin E dose as high as 1,200 IU/day for 1 month saw negligible change in the INR or prothrombin time.(3) Selumetinib capsules contain a significant amount of vitamin E. Each 10 mg capsule contains 32 mg (48 units) and each 25 mg capsule contains (54 units) of vitamin E. The daily dose of selumetinib may contain up to 256 mg (384 units) of vitamin E. Vitamin E supplementation is not recommended if it will result in a daily vitamin E intake exceeding recommended or safe amounts.(4) Agenerase brand of amprenavir capsules and oral solution contain a significant amount of vitamin E. Each 150 mg capsule contains 109 International Units vitamin E, with a total of 1,744 International Units of vitamin E in the recommended daily adult dose. Each mL of oral solution contains 46 International Units of vitamin E.(5) One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Slt Anticoags (Vit K Antag)/Oxyphenbutazone; Phenylbutazone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent oxyphenbutazone or phenylbutazone may displace the anticoagulant from its plasma protein binding site and inhibit anticoagulant metabolism.

CLINICAL EFFECTS: Concurrent oxyphenbutazone or phenylbutazone may result in increased bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Pharmacogenomic information: patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective and safe anticoagulation than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: Avoid concomitant administration of these drugs. The Australian manufacturer of fluindione states concurrent use with phenylbutazone is contraindicated.(2) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: In a study of four subjects, increased prothrombin times and decreased total plasma warfarin levels were found after receiving ten days of phenylbutazone, then a single dose of warfarin (1.5 mg/kg), followed by ten more days of phenylbutazone. The study was repeated in another six subjects who were assessed with fluorometric assay. An 86% increase in prothrombin time and a 30% decrease in total plasma warfarin based on a logarithmic scale were found.(3)

Slt Anticoagulants (Vit K Antag)/Aspirin(>100Mg);Salicylates

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Multiple processes are involved: 1) Salicylate doses greater than 3 gm daily decrease plasma prothrombin levels. 2) Salicylates may also displace anticoagulants from plasma protein binding sites. 3) Aspirin is an irreversible platelet inhibitor. Salicylates impair platelet function, resulting in prolonged bleeding time. 4) Salicylates may cause gastrointestinal(GI) bleeding due to irritation.

CLINICAL EFFECTS: The concurrent use of anticoagulants and salicylates leads to blockade of two distinct coagulation pathways and may increase the risk for bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Avoid concomitant administration of these drugs. When aspirin is required for cardioprotection, a low dose (less than 100 mg daily) is recommended to decrease the risk for aspirin-induced GI bleeding. The Australian manufacturer of fluindione states use is contraindicated with anti-inflammatory doses of acetylsalicylic acid (>= 1 g/dose and/or >= 3 g/day) and analgesic or antipyretic doses (>= 500 mg per dose and/or < 3 g per day) with a history of duodenal ulcer. Use is not recommend for analgesic or antipyretic doses (>= 500 mg per dose and/or <3 g per day) in the absence of a history of duodenal ulcer. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: This interaction has been reported between aspirin and warfarin and between aspirin and dicumarol. Diflunisal, sodium salicylate, and topical methyl salicylate have been shown to interact with anticoagulants as well. Based on the proposed mechanisms, other salicylates would be expected to interact with anticoagulants as well. A self-controlled case study of 1,622 oral anticoagulant-precipitant drug pairs were reviewed and found 14% of drug pairs were associated with a statistically significant elevated risk of thromboembolism. Concurrent use of warfarin and diflunisal resulted in a ratio of rate ratios (RR) (95% CI) of 3.85 (1.34-11.03); warfarin and aspirin ratio of RR 2.13 (1.72-2.64); warfarin and dipyridamole ratio of RR 2.07 (1.65-2.6); and warfarin and clopidogrel ratio of RR 1.69 (1.56-1.84). A large systematic review was performed on 72 warfarin drug-drug interactions studies that reported on bleeding, thromboembolic events, or death. Most studies were retrospective cohorts. A meta-analysis of 38 of those studies found a higher rate of clinically significant bleeding in patients on warfarin and antiplatelets (OR=1.74; 95% CI 1.56-1.94). Increased bleeding risk was also seen in subgroup analyses with aspirin (OR=1.50; 95% CI 1.29-1.74), clopidogrel (OR=3.55; 95% CI 2.78-4.54), and aspirin plus clopidogrel or ticlopidine (OR=2.07, 95% CI 1.33-3.21).(17)

Slt Anticoagulants (Vit K Antag)/Chloral Hydrate; Triclofos

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Chloral hydrate may cause protein binding displacement of anticoagulants.

CLINICAL EFFECTS: Concurrent use of anticoagulants and chloral hydrate or triclofos may increase the risk for bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: This interaction is well documented.

Slt Anticoagulants (Vit K Antag)/Fluorouracil & Prodrugs

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Capecitabine inhibits the CYP2C9 mediated metabolism of warfarin.(1) The interaction mechanism with fluorouracil is not clear.

CLINICAL EFFECTS: Concurrent use of fluorouracil (5-FU) or its prodrug, capecitabine, and a Vitamin K antagonist anticoagulant may result in elevated levels of the anticoagulant(2-10) and increase the risk for bleeding.

PREDISPOSING FACTORS: Patients who are older than 60 years of age may be predisposed to this interaction.(2) The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Pharmacogenomic information: patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective and safe anticoagulation than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with capecitabine or fluorouracil and a Vitamin K antagonist anticoagulant (e.g. warfarin) should have their INR closely monitored and adjusted for an extended period of time as the maximal increase in INR may not occur for 30 - 40 days or more.(10) If patient has been stabilized on the combination of a Vitamin K antagonist and fluorouracil or capecitabine, and the fluoropyrimidine is subsequently discontinued, the dosage of anticoagulant may need to be gradually increased to maintain a therapeutic INR. When concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: In four patients with cancer, concurrent use of capecitabine (1250 mg/m2 twice daily) with a single dose of warfarin (20 mg) increased the area-under-curve (AUC) of the more active S-isomer of warfarin by 57%. The clearance S-warfarin was decreased by 37%. The baseline corrected AUC of the International Normalized Ration (INR) and the maximum observed mean INR value increase by 2.8-fold and 91%, respectively. A retrospective cohort study evaluated changes in INR for 24 patients treated with either 5-fluorouracil or capecitabine and warfarin over a 90 day period. The median change in INR was 2.8. Altered coagulation parameters and/or bleeding, including death have been reported in patients taking capecitabine with warfarin or phenprocoumon. There have been postmarketing reports of clinically significant increases in prothrombin time and INR in patients who were previously stabilized on anticoagulants when capecitabine was introduced. These events occurred within several days or months of beginning concurrent therapy or within a month of discontinuing concurrent therapy.(1) There are several case reports of elevated warfarin response, including hemorrhage, during the concurrent administration of warfarin and fluorouracil.(2-8)

Slt Anticoagulants (Vit K Antag)/Slt Macrolide Antibiotics

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Macrolide antibiotics may inhibit the metabolism of anticoagulants.

CLINICAL EFFECTS: Concurrent use of a macrolide antibiotic may result in increased effects of the anticoagulant with possible elevated INR and/or bleeding.

PREDISPOSING FACTORS: Poor nutrition, fever, larger macrolide doses, and older age. The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Closely monitor INR values in patients maintained on anticoagulants in whom macrolide antibiotics are initiated or discontinued. The dose of the anticoagulant may need to be adjusted. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose, or discontinuing either drug.

DISCUSSION: In a retrospective review comparing patients who received concurrent warfarin and azithromycin to matched controls who received only warfarin, azithromycin had no significant effects on INR values.(1) Another retrospective review compared patients who received concurrent warfarin and azithromycin to matched controls who received concurrent warfarin and felodipine. Azithromycin had no significant effects on INR values.(2) In contrast, there are several case reports of increased warfarin effects 4 to 8 days after the addition of azithromycin.(3-7) There is a case report of a patient with an INR of 8.2 after adding azithromycin to concurrent warfarin therapy. During this time, she also decreased her smoking from (1 pack/day to 2 packs/3 days).(5) There are several case reports of increased INRs after the addition of clarithromycin to warfarin therapy.(8-11) In a study in 8 patients, the addition of erythromycin base (333 mg 3 times daily for 7 days) to warfarin therapy resulted in a 9.9% increase in prothrombin time ratio from baseline (from 1.61 to 1.77). However, values were still within therapeutic range and no patient experienced adverse effects.(12) In another study in 12 healthy subjects, erythromycin (250 mg 4 times daily for 8 days) increased the clearance of a single dose of warfarin (1 mg/kg) by 14%.(13) There are several published case reports of interactions between erythromycin and warfarin(14-19) and acenocoumarol.(20) In a study in 21 healthy subjects, roxithromycin (150 mg twice daily) had no effect on warfarin pharmacokinetics or pharmacodynamics.(21) However, there has been one case report of a parietal abdominal hematoma following concurrent roxithromycin and acenocoumarol.(22) There have been several case reports of increased warfarin effects following the addition of telithromycin to therapy.(23,24)

Slt Anticoagulants (Vit K Antagonists)/Slt Anabolic Steroids

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown. It has been hypothesized that the C-17 alkylated androgens may increase turnover of clotting factors and decrease their synthesis. Increased affinity for the anticoagulant receptor site has also been hypothesized. The C-17 alkylated androgens have not been shown to alter the metabolism of anticoagulants.

CLINICAL EFFECTS: The concurrent use of anticoagulants and anabolic steroids may result in an increased risk for bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Patients should be closely monitored for increased anticoagulant activity. The dose of the anticoagulant may need to be adjusted. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. When concurrent therapy is warranted, also monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: Danazol, methandrostenolone, methyltestosterone, oxymetholone, and stanozolol have been shown to increase the hypoprothrombinemic actions of warfarin. Methyltestosterone has also been shown to increase the effects of dicumarol. Oxymetholone and ethylestrenol have been shown to increase the effects of phenindione. Limited data suggest that the non-C-17-alkylated androgens do not affect anticoagulants.

Slt Anticoagulants (Vit K Antagonists)/Slt Cephalosporins

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown, but may involve a combination of the cephalosporin's N-methylthiotetrazole (NMTT) side chain antagonizing vitamin K, cephalosporin induced platelet inhibition, and alteration of gut flora.

CLINICAL EFFECTS: Concurrent use of some cephalosporins may increase the hypoprothrombinemic effect of the anticoagulant with possible bleeding.

PREDISPOSING FACTORS: High doses, hepatic and/or renal impairment, and poor nutrition may increase the risk of bleeding. The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Monitor prothrombin activity (INR) and adjust the anticoagulant dosage accordingly. Consider using an alternative antibiotic. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Cephalosporins with a NMTT side chain have been reported to significantly prolong bleeding time and cause hypoprothrombinemia; therefore, the risk of serious bleeding may be increased in patients taking concurrent anticoagulants. A large systematic review was performed on 72 warfarin drug-drug interactions studies that reported on bleeding, thromboembolic events, or death. Most studies were retrospective cohorts. A meta-analysis of 11 of those studies found a higher rate of clinically significant bleeding in patients on warfarin and antimicrobials (OR=1.63; 95% CI 1.45-1.83). Increased bleeding risk was also seen in subgroup analyses with cephalosporins (OR=1.50; 95% CI 1.21-1.86).

Slt Anticoagulants (Vit K Antagonists)/Topical Salicylates

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Multiple processes are involved: 1) Salicylate doses greater than 3 gm daily decrease plasma prothrombin levels. 2) Salicylates may also displace anticoagulants from plasma protein binding sites. 3) Aspirin is an irreversible platelet inhibitor. Salicylates impair platelet function, resulting in prolonged bleeding time. 4) Salicylates may cause gastrointestinal(GI) bleeding due to irritation.

CLINICAL EFFECTS: The concurrent use of anticoagulants and salicylates leads to blockade of two distinct coagulation pathways and may increase the risk for bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Avoid concomitant administration of these drugs. When aspirin is required for cardioprotection, a low dose (< 100 mg daily) is recommended to decrease the risk for aspirin-induced GI bleeding. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: Topical use of methyl salicylate has been reported to increase the effects of warfarin.(1-7) In a case series on 11 patients who used significant amounts of methyl salicylate (2-4 g of ointment for previous 2 weeks), all had significant increases in INR and positive blood levels of salicylates. Two patients experienced diffuse bruising and one experienced gastrointestinal bleeding.(1) A self-controlled case study of 1,622 oral anticoagulant-precipitant drug pairs were reviewed and found 14% of drug pairs were associated with a statistically significant elevated risk of thromboembolism. Concurrent use of warfarin and diflunisal resulted in a ratio of rate ratios (RR) (95% CI) of 3.85 (1.34-11.03); and warfarin and aspirin ratio of RR 2.13 (1.72-2.64).

Slt Anticoagulants (Vitamin K Antag); Heparins/Abciximab

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of abciximab and anticoagulants may result in additive effects on clotting mechanisms.(1)

CLINICAL EFFECTS: Use of abciximab within 7 days of oral anticoagulants or concurrently with other anticoagulants may increase the risk of bleeding.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The US manufacturer of abciximab states that the use of abciximab in patients who have received oral anticoagulants in the previous 7 days is contraindicated unless prothrombin time is less than or equal to 1.2 times control values. Concurrent use with other anticoagulants should be approached with caution.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: Abciximab has the potential to increase the risk of bleeding, especially with concurrent anticoagulation, including from heparin, other anticoagulants, or thrombolytics.(1) A large systematic review was performed on 72 warfarin drug-drug interactions studies that reported on bleeding, thromboembolic events, or death. Most studies were retrospective cohorts. A meta-analysis of 38 of those studies found a higher rate of clinically significant bleeding in patients on warfarin and antiplatelets (OR=1.74; 95% CI 1.56-1.94).(2)

Slt Anticoagulants (Vitamin K Antag); Heparins/Alteplase

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The concurrent use of alteplase and anticoagulants may increase the risk of bleeding.(1)

CLINICAL EFFECTS: The concurrent use of alteplase and anticoagulants may result in bleeding episodes.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The manufacturer of alteplase states that the use of alteplase for an indication of acute ischemic stroke is contraindicated in patients receiving anticoagulants.(1) Concurrent use of alteplase and anticoagulants is dependent on the therapeutic indication. In Acute Ischemic Stroke: - Clinical practice guidelines for acute ischemic stroke state the use of thrombolytic therapy for an indication of acute ischemic stroke is contraindicated in patients who have received warfarin and have an elevated activated partial thromboplastin time (aPTT) > 40 seconds, prothrombin time (PT) > 15 seconds, INR > 1.7, or platelets <100,000/mm3 at presentation. In Acute Myocardial Infarction: - Patients who are receiving alteplase for an indication of acute myocardial infarction should be carefully monitored for signs of bleeding, especially at arterial puncture sites, if heparin is used concurrently. - The use of alteplase in patients with acute myocardial infarction should follow standard management of myocardial infarction, including minimizing arterial and venous puncture; avoid noncompressible arterial puncture; and minimize internal jugular and subclavian venous punctures to decrease bleeding from the noncompressible sites. For all indications: - In the event of serious bleeding, anticoagulants should be discontinued immediately. - If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. - When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. - Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: The manufacturer of alteplase states that the use of alteplase for an indication of acute ischemic stroke is contraindicated in patients receiving anticoagulants.(1) Patients who are receiving alteplase for an indication of acute myocardial infarction or pulmonary embolism should be carefully monitored for signs of bleeding if anticoagulants are being used concurrently or have recently been used. In a retrospective review of 107 acute ischemic stroke patients receiving tPA with or without warfarin the incidence of symptomatic intracerebral hemorrhage(sICH) was found to be much greater in patients receiving warfarin, 30.8% in patients receiving warfarin compared to 3.2% in patients not undergoing warfarin therapy.(2)

Warfarin/Apalutamide

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Apalutamide may induce the metabolism of S-warfarin by CYP2C9.(1)

CLINICAL EFFECTS: Concurrent use of apalutamide may result in decreased levels and effectiveness of warfarin, which may increase the risk of clotting.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor INR response closely in patients maintained on warfarin when initiating, titrating, and discontinuing apalutamide. Patients maintained on apalutamide may require higher dosages of warfarin.

DISCUSSION: Concurrent apalutamide and warfarin decreased the area-under-curve (AUC) of S-warfarin by 46%.(1)

Warfarin/Mifepristone (Chronic Therapy)

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Mifepristone is a moderate inhibitor of CYP2C9 and may inhibit the CYP2C9-mediated metabolism of the S-enantiomer of warfarin.(2-4) Mifepristone is an antagonist at the progesterone receptor which can result in endometrium thickening, cystic dilatation of endometrial glands, or excessive vaginal bleeding. Concurrent use with warfarin may further increase risk.

CLINICAL EFFECTS: Concurrent use of warfarin with mifepristone may result in elevated levels and effects of warfarin, which may increase the risk of bleeding. The concurrent use of mifepristone with anticoagulants such as warfarin may result in endometrium thickening, cystic dilatation of endometrial glands, or excessive vaginal bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The manufacturer of mifepristone states that mifepristone should be used with caution in patients receiving concurrent anticoagulant therapy.(1) Monitor INR response closely in patients maintained on warfarin when initiating, titrating, and discontinuing mifepristone. If concurrent therapy is deemed medically necessary, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. Women experiencing vaginal bleeding during concurrent use should be referred to a gynecologist for further evaluation.

DISCUSSION: The manufacturer of mifepristone states that mifepristone should be used with caution in patients receiving concurrent anticoagulant or antiplatelet therapy.(1) No formal interaction studies have been done with warfarin and mifepristone. In clinical studies, coadministration of adagrasib 600 mg (moderate 2C9 inhibitor) twice daily increased the area-under-the-curve (AUC) and maximum concentration (Cmax) of S-warfarin by 2.9-fold and 1.1-fold, respectively.(5)

Warfarin/Mitotane

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Mitotane may induce the metabolism of warfarin by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent or recent use of mitotane may result in decreased levels and effectiveness of warfarin, which may increase the risk of clotting.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of mitotane states that concomitant use of warfarin should be avoided. If concomitant use cannot be avoided, monitor INR response more closely when initiating, titrating, and discontinuing mitotane and for several months after mitotane is discontinued. Patients maintained on mitotane or who discontinued mitotane in the previous six months may require higher dosages of warfarin.(1)

DISCUSSION: Mitotane use has been shown to result in elevate warfarin requirements.(1,2)

Warfarin/Rucaparib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Rucaparib is a weak CYP2C9 inhibitor which may decrease the metabolism of the S-enantiomer of warfarin.(1-3)

CLINICAL EFFECTS: Concurrent use of rucaparib may result in elevated levels of warfarin and increased INR.(1,2)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Pharmacogenomic information: patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective and safe anticoagulation than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: The US manufacturer of rucaparib states that concurrent administration with sensitive CYP2C9 substrates should be avoided.(1) If concurrent use cannot be avoided, monitor INRs more frequently until stable in patients who start rucaparib therapy.(1,2) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. Discontinue anticoagulation in patients with active pathologic bleeding.

DISCUSSION: In clinical studies, coadministration of rucaparib increased the area-under-the-curve (AUC) and maximum concentration (Cmax) of S-warfarin by 1.5-fold and <1.1-fold, respectively.(1)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Anticoagulant;Antiplatelet;Thrombolytic/Icosapent Ethyl

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: In vitro data suggests that fish oils can competitively inhibit cyclooxygenase which decreases synthesis of thromboxane A1 leading to a decrease in platelet aggregation.(1)

CLINICAL EFFECTS: Concurrent use of anticoagulant, antiplatelet, or thrombolytic agents increase bleeding risks.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: If concurrent therapy is deemed medically necessary, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Specific studies with icosapent ethyl and affects on bleeding risk have not been conducted. Concurrent use of anticoagulant, antiplatelet, or thrombolytic agents may increase bleeding risks by impairing platelet function and prolonging bleeding time.(1) Several case reports have shown increased bleeding time and an increased risk of adverse effects from concurrent therapy.(2,3,4) A randomized placebo controlled study of 40 people taking omega-3 fatty acids and oral anticoagulants showed a significant prolongation in bleeding time.(5)

Anticoagulants/Corticosteroids

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Corticosteroids may increase the coagulability of blood, thus decreasing the effect of the anticoagulant.(1,2) Corticosteroids may also lower vascular integrity, which could increase the risk of hemorrhage.(3,4)

CLINICAL EFFECTS: Concurrent use of corticosteroids may result in either increased (increased risk of bleeding) or decreased effects (increased risk of treatment failure) of anticoagulants.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The patient's clotting times should be monitored closely, along with any clinical signs of hemorrhage or clot formation. The dosage of the anticoagulant may need to be adjusted accordingly. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Corticotropin and other corticosteroids have been shown to both increase (3,5-11) and decrease (1,12,13) the effects of acenocoumarol, dicumarol, fluindione, and warfarin. Hemorrhagic episodes have been associated with concurrent use of these medications.(3,5) One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Anticoagulants/Lifileucel

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Internal organ hemorrhage, including intraabdominal and intracranial hemorrhage, has been reported in the presence of persistent or repeated thrombocytopenia following treatment with lifileucel.(1)

CLINICAL EFFECTS: Concurrent use or recent therapy with lifileucel and an anticoagulant may increase the risk of life-threatening hemorrhage, including intraabdominal and intracranial hemorrhage.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia).

PATIENT MANAGEMENT: The US manufacturer states patients with persistent or repeated thrombocytopenia after receiving lifileucel should not use anticoagulants. If anticoagulation therapy is warranted, close monitoring of patients must take place.(1) The US manufacturer recommends withholding or discontinuing lifileucel if internal organ hemorrhage is indicated, or patient is ineligible for IL-2 (aldesleukin) infusion.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: In the open-label single-arm study of 156 adult patients, two cases of internal organ hemorrhage (abdominal hemorrhage and intracranial hemorrhage) leading to death were reported.(1) The incidence of grade 3 or 4 laboratory abnormalities occurring in melanoma patients following treatment with lifileucel included thrombocytopenia (78.2%), neutropenia (69.2%) and anemia (58.3%). Prolonged thrombocytopenia occurred in 30.1% of patients.(1)

Anticoagulants; Antiplatelets/Fruquintinib; Surufatinib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Bleeding has been reported with the use of fruquintinib and surufatinib.(1,2)

CLINICAL EFFECTS: Concurrent use of fruquintinib or surufatinib with either anticoagulants or antiplatelets may increase the risk of hemorrhage.(1,2)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Patients receiving concurrent therapy with fruquintinib and anticoagulants and/or antiplatelets should be closely monitored for changes in platelet count or in International Normalized Ratio (INR). If a serious bleeding event occurs, the manufacturer recommends permanent discontinuation of fruquintinib.(1) Patients receiving concurrent therapy with surufatinib and anticoagulants and/or antiplatelets should be closely monitored for changes in platelet count or in INR.If a serious bleeding event occurs, the manufacturer recommends permanent discontinuation of surufatinib.(2) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Bleeding has been reported with fruquintinib in three randomized, double-blinded, placebo-controlled clinical trials. The incidence of grade 1 and grade 2 bleeding events was 28.2%, including gastrointestinal bleeding (10.9%), hematuria (10.6%), and epistaxis (7.5%). The incidence of grade 3 or higher bleeding events was 2.1% and included gastrointestinal bleeding (1.6%) and hemoptysis (0.5%).(1) Bleeding has been reported with surufatinib in clinical trials. Grade 1 and 2 bleeding events included gastrointestinal bleeding, blood in the urine, and gum bleeding. The incidence of grade 3 or greater bleeding events was 4.5%, including gastrointestinal hemorrhage (1.9%), and cerebral hemorrhage (1.1%). Fatalities due to bleeding were reported in 0.3% of patients. The incidence of permanent discontinuation due to bleeding was 2.6% and the incidence of suspension of surufatinib due to bleeding was 3.8%.(2)

Anticoagulants; Antiplatelets/Obinutuzumab

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Severe and life-threatening thrombocytopenia has been reported during obinutuzumab therapy.(1) Anticoagulants and antiplatelets may have an additive risk of bleeding.

CLINICAL EFFECTS: Concurrent use of obinutuzumab with anticoagulants or antiplatelet agents may result in additive or synergistic effects, including fatal and non-fatal hemorrhage.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Monitor all patients frequently for thrombocytopenia and signs of bleeding. Consider withholding concomitant anticoagulants and antiplatelets, especially during the first cycle of obinutuzumab.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: Obinutuzumab with chemotherapy has been reported to cause severe and life-threatening thrombocytopenia. Fatal hemorrhagic events have occurred in patients with NHL and CLL during obinutuzumab therapy, including during Cycle 1.(1)

Anticoagulants; Antiplatelets/Plasminogen

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Bleeding has been reported with the use of plasminogen.(1)

CLINICAL EFFECTS: Concurrent use of plasminogen with either anticoagulants or antiplatelets may increase the risk of active bleeding during plasminogen therapy, including bleeding from mucosal disease-related lesions that may manifest as gastrointestinal (GI) bleeding, hemoptysis, epistaxis, vaginal bleeding, or hematuria.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Patients receiving concurrent therapy with plasminogen and anticoagulants and/or antiplatelets should be closely monitored during plasminogen therapy for active bleeding from mucosal disease-related lesions, including GI bleeding, hemoptysis, epistaxis, vaginal bleeding, or hematuria.(1) Prior to initiation of treatment with plasminogen, confirm healing of lesions or wounds suspected as a source of a recent bleeding event. Monitor patients during and for 4 hours after infusion when administering plasminogen with concurrent anticoagulants, antiplatelet drugs, or other agents which may interfere with normal coagulation.(1) If patient experiences uncontrolled bleeding (defined as any gastrointestinal bleeding or bleeding from any other site that persists longer than 30 minutes), seek emergency care and discontinue plasminogen immediately.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Plasminogen has not been studied in patients at an increased risk of bleeding. Bleeding has been reported with plasminogen in a two single-arm, open-label clinical trials as well as in compassionate use programs. The incidence of hemorrhage in patients with Plasminogen Deficiency Type 1 was 16% (3/19 patients).(1) One of the bleeding events occurred two days after receiving the second dose of plasminogen in a patient with a recent history of GI bleeding due to gastric ulcers. The patient received plasminogen through a compassionate use program and the dose was 6.6 mg/kg body weight every 2 days. Endoscopy showed multiple ulcers with one actively bleeding ulcer near the pylorus.(1)

Anticoagulants; Antiplatelets/Tisotumab

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Bleeding, including hemorrhage, has been reported with the use of tisotumab.(1)

CLINICAL EFFECTS: Concurrent use of tisotumab with either anticoagulants, antiplatelets, or NSAIDs may increase the risk of hemorrhage.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Patients receiving concurrent therapy with tisotumab and anticoagulants, antiplatelets, and/or NSAIDs should be closely monitored for signs and symptoms of bleeding and changes in platelet count or International Normalized Ratio (INR). For patients experiencing pulmonary or central nervous system (CNS) hemorrhage, permanently discontinue tisotumab. For grade 2 or greater hemorrhage in any other location, withhold until bleeding has resolved, blood hemoglobin is stable, there is no bleeding diathesis that could increase the risk of continuing therapy, and there is no anatomical or pathologic condition that can increase the risk of hemorrhage. After resolution, either resume treatment or permanently discontinue tisotumab.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Hemorrhage occurred in 62% of patients with cervical cancer treated with tisotumab across clinical trials. The most common all grade hemorrhage adverse reactions were epistaxis (44%), hematuria (10%), and vaginal hemorrhage (10%). Grade 3 hemorrhage occurred in 5% of patients.(1)

Anticoagulants; Antiplatelets; Thrombolytics/Drotrecogin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Drotrecogin, anticoagulants, antiplatelets, and thrombolytics all affect hemostasis.(1)

CLINICAL EFFECTS: Concurrent use of drotrecogin with anticoagulants, antiplatelets, or thrombolytics, including heparin and aspirin, may increase the risk of bleeding.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Drotrecogin should be used with caution with other agents that affect hemostasis, including concurrent heparin for thrombotic or embolic events; recent administration (within 3 days) of thrombolytics; recent administration of oral anticoagulants (within 7 days) or glycoprotein IIb/IIIa inhibitors; or recent administration (within 7 days) of aspirin (greater than 650 mg daily) or other platelet inhibitors.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: Because of the increased risk of bleeding, drotrecogin should be used with caution with other agents that affect hemostasis, including concurrent heparin for thrombotic or embolic events; recent administration (within 3 days) of thrombolytics; recent administration of oral anticoagulants (within 7 days) or glycoprotein IIb/IIIa inhibitors; or recent administration (within 7 days) of aspirin (greater than 650 mg daily) or other platelet inhibitors.(1)

Anticoagulants; Thrombolytics/Remibrutinib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Remibrutinib may cause bleeding. Anticoagulants and thrombolytics also affect hemostasis.(1)

CLINICAL EFFECTS: Concurrent use of remibrutinib with anticoagulants or thrombolytics may increase the risk of bleeding.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Consider the risks and benefits of concomitant administration of antithrombotic agents with remibrutinib. Interrupt treatment with remibrutinib if bleeding is observed and resume if the benefit is expected to outweigh the risk. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. Interrupt treatment with remibrutinib for 3 to 7 days pre- and post-surgery or invasive procedures.(1)

DISCUSSION: No data are available on concomitant use of remibrutinib with anticoagulants. The concomitant use of remibrutinib and anticoagulants was not allowed in clinical studies. Use of the antiplatelet agents, acetyl salicylic acid at doses up to 100 mg daily or clopidogrel up to 75 mg daily, was allowed in the remibrutinib clinical studies.(1)

Coumarin Anticoagulants/Dabrafenib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Dabrafenib, a CYP3A4 inducer, may increase hepatic metabolism of coumarin anticoagulants.(1)

CLINICAL EFFECTS: The hypoprothrombinemic effect of coumarin anticoagulants may be decreased.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of dabrafenib recommends monitoring of anticoagulation parameters more frequently when starting or stopping dabrafenib in a patient receiving warfarin. Adjust the dose of warfarin accordingly.(1) The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Coadministration of 150 mg dabrafenib twice daily for 15 days followed by a single dose of 15 mg warfarin decreased the area-under-curve (AUC) of S-warfarin by 37% and the AUC of R-warfarin by 33%.(1)

Coumarin Anticoagulants/Dronedarone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Dronedarone may inhibit the metabolism of warfarin.(1)

CLINICAL EFFECTS: The concurrent administration of dronedarone and an anticoagulant may result in an increase in the clinical effects of the anticoagulant and an increased risk of bleeding. When an interaction occurs, most patients experience increased effects within 1 week of dronedarone initiation.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Pharmacogenomic information: patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective and safe anticoagulation than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: In patients already receiving warfarin, the manufacturer of dronedarone recommends monitoring of INR after initiation of dronedarone. When an interaction occurs, most warfarin patients will experience an increased INR within 1 week of dronedarone initiation.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: In healthy subjects, dronedarone (600 mg twice daily) increased exposure to S-warfarin by 1.2-fold. There were no significant changes in exposure to R-warfarin or INR values. There have been postmarketing reports of increased INR values, with and without bleeding, in patients maintained on warfarin in whom dronedarone was initiated.(1)

Coumarin Anticoagulants/Econazole

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Econazole has been shown to be a potent inhibitor of CYP3A4.(1) If absorbed systemically, topical econazole may inhibit the metabolism of coumarin anticoagulants.(2-3)

CLINICAL EFFECTS: The concurrent use of topical econazole and coumarin anticoagulants may increase international normalized ratio (INR) and result in an increased risk for bleeding.(2-4)

PREDISPOSING FACTORS: This interaction may occur if topical econazole is absorbed systemically. Factors contributing to increased systemic absorption include exposure to large body surface areas, occlusion of the area, and application onto areas of thin, macerated or broken skin.(2-4) The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Pharmacogenomic information: patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve to achieve effective and safe anticoagulation than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: Patients with risk factors for increased systemic absorption of topical econazole and receiving concurrent therapy with a coumarin anticoagulant (e.g. warfarin) should have their INR closely monitored.(1) When concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: Topical econazole is typically minimally absorbed (less than 2%).(3,4) However absorption may be increased if it is applied to large areas of the body or to thin, macerated, or broken skin, or if the area is occluded.(2-4) A 79-year-old man on chronic warfarin therapy with stable INRs for 3 years developed severe bruising on his hip from a minor injury and bleeding for over 24 hours from a small, superficial cut on his hand. His INR was found to be 12. He had started econazole cream one week before for Candidal infection of his scrotum and thighs. He had no other medication or diet changes and no acute illnesses. He recovered after discontinuation of econazole and treatment with vitamin K.(3) An 84-year-old woman stable on acenocoumarol 4 mg daily for ten years developed a bilateral cervical hematoma causing upper airway obstruction, dyspnea and difficulty speaking. Her INR exceeded laboratory limits. She had started using econazole lotion 1% for extensive dermatitis over her axillary, inguinal, and breast areas 17 days prior. She had no other changes to her medications, diet, or other chronic conditions, and no acute illnesses. The patient was treated with prothrombin complex concentrate and vitamin K and recovered.(3)

Coumarin Anticoagulants/Glucagon, Dasiglucagon

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Not defined.

CLINICAL EFFECTS: Excess hypoprothrombinemia and possible bleeding complications.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: If the duration of glucagon/dasiglucagon therapy is one day, a clinically important interaction is unlikely. Avoid using multiple doses of glucagon/dasiglucagon in anticoagulated patients. If this combination is necessary, decrease the warfarin dose prior to glucagon/dasiglucagon dosing. Monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform INR to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: If the duration of glucagon/dasiglucagon therapy is one day, a clinically important interaction is unlikely. However, the potentiation effects of glucagon/dasiglucagon on the anticoagulant effect of warfarin seems to occur rapidly and can reverse within one day of stopping glucagon.

Coumarin Anticoagulants/Glucosamine And-Or Chondroitin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown, but may be the result of additive or synergistic effects on coagulation. Glucosamine is a component of heparin(1) and chondroitin is a component of danaparoid.(2) Glucosamine has been shown not to inhibit CYP2C9,(3) thus inhibition of warfarin metabolism is thought to be unlikely.

CLINICAL EFFECTS: Concurrent use of glucosamine-chondroitin may result in increased effects on coagulation, including elevated International Normalized Ratio (INR) and bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Use caution with adding or discontinuing glucosamine-chondroitin to warfarin therapy. Monitor patients receiving concurrent therapy closely for elevated INR and signs of bleeding. Patients who discontinue glucosamine-chondroitin may need their warfarin dosage adjusted to maintain therapeutic INRs. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: There have been numerous reports of increased INR following the addition of glucosamine, glucosamine-chondroitin, or chondroitin alone to warfarin therapy, including 20 from the United States Food Drug Administration (US FDA), 22 from the World Health Organization (WHO), 3 from the Australian Therapeutic Goods Association (TGA), and 2 published reports. INR values typically increased between two and 20 days after the addition of glucosamine and/or chondroitin to warfarin therapy. In most cases, patients were asymptomatic; however, there were at least two reports of bleeding.(4-8) There has also been one report involving glucosamine and acenocoumarol.(9)

Coumarin Anticoagulants/Itraconazole; Posaconazole

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The more potent warfarin S-enantiomer is metabolized by CYP2C9 while the weaker R-enantiomer is metabolized by CYP1A2 and CYP3A4.(1) Itraconazole and posaconazole are strong inhibitors of CYP3A4.(2)

CLINICAL EFFECTS: Concurrent use of select azole antifungals and coumarin anticoagulants may increase the risk for bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Additional drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: In patients receiving warfarin when itraconazole or posaconazole is started, closely monitor INR and reduce the dose of warfarin as needed.(1,2) After the azole therapy is discontinued, close monitoring is again needed as the INR may fall after removal of the inhibitor. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: In a case report, a 61 year old woman stable on warfarin for 12 months had recently started itraconazole 200 mg twice daily. She was hospitalized for intractable bleeding and found to have an INR of 8. Warfarin and itraconazole were stopped and patient was treated with fresh frozen plasma, with a drop in INR to 2.4 after 2 days.(3) A prospective cohort study followed 1,172 patients on acenocoumarol who started antimicrobials for risk of overanticoagulation (INR >6). Patients who started itraconazole had an increased risk of overanticoagulation compared to patients on amoxicillin-clavulanate (HR 4.11; 95% CI 1.79-9.45; p = 0.001).(4) A retrospective review compared the changes in warfarin effects with coadministration of fluconazole, itraconazole, or voriconazole in 18, 6, and 5 patients, respectively. Mean INR increased slightly from 1.86 to 1.92 in patients taking itraconazole (p=0.37) and did not increase >20% in any patient.(5) A large systematic review was performed on 72 warfarin drug-drug interactions studies that reported on bleeding, thromboembolic events, or death. Most studies were retrospective cohorts. A meta-analysis of 11 of those studies found a higher rate of clinically significant bleeding in patients on warfarin and antimicrobials (OR=1.63; 95% CI 1.45-1.83). Increased bleeding risk was also seen in subgroup analyses with azole antifungals (OR=1.86; 95% CI 1.40-2.47).(6)

Coumarin Anticoagulants/Lepirudin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Lepirudin is a highly specific direct inhibitor of thrombin.(1) Coumarin anticoagulants are vitamin K antagonists that affect clotting function.

CLINICAL EFFECTS: Concurrent use of lepirudin and coumarin anticoagulants may increase the risk of bleeding.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The manufacturer recommends close monitoring of patients taking lepirudin and coumarin anticoagulants.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. In patients scheduled for a switch to oral anticoagulation, the dosage of lepirudin should be decreased until the aPTT ratio reaches just above 1.5 before initiating oral anticoagulation. Coumarin derivatives should be initiated after platelet counts are normalizing and without a loading dose. Parenteral anticoagulant should be continued for 4-5 days to avoid prothrombic effects.(1) The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Concurrent use of lepirudin and coumarin anticoagulants may increase the risk of bleeding. The manufacturer recommends close monitoring of patients taking lepirudin and coumarin anticoagulants. In patients scheduled for a switch to oral anticoagulation, the dosage of lepirudin should be decreased until the aPTT ratio reaches just above 1.5 before initiating oral anticoagulation. Coumarin derivatives should be initiated after platelet counts are normalizing and without a loading dose. Parenteral anticoagulant should be continued for 4-5 days to avoid prothrombic effects.(1)

Coumarin Anticoagulants/Medroxyprogesterone; Megestrol

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The mechanism of this interaction is unknown but may involve inhibition of anticoagulant metabolism by medroxyprogesterone and megestrol.(1,2)

CLINICAL EFFECTS: The concurrent use of medroxyprogesterone or megestrol and coumarin anticoagulants may increase international normalized ratio (INR) and result in an increased risk for bleeding.(1,2)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Pharmacogenomic information: patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve to achieve effective and safe anticoagulation than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with medroxyprogesterone or megestrol and a coumarin anticoagulant (e.g. warfarin) should have their INR closely monitored.(1) When concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: A study of four patients on high-dose progestins (two patients on medroxyprogesterone 500 mg twice daily and two patients on megestrol 160 mg once daily) and warfarin found that the progestins decreased the clearance of warfarin by 34.8% (from 2.3 to 1.5 mL/h*kg BW) and increased the half-life of warfarin by 71.4% (from 43.4 to 74.4 hours).(2)

Coumarin Anticoagulants/Tetracyclines

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown. Tetracyclines may interfere with vitamin-K producing gut flora.

CLINICAL EFFECTS: The addition of a tetracycline to a patient maintained on a coumarin anticoagulant may result in increased anticoagulant effects, including bleeding.

PREDISPOSING FACTORS: he risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Patients maintained on coumarin anticoagulants should be closely monitored when tetracyclines are initiated and discontinued. The dosage of the anticoagulant may need to be adjusted. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: In a retrospective review of patients receiving either acenocoumarol or phenprocoumon, use of doxycycline and tetracycline was associated with relative risk of major bleeding of 3 and 9, respectively.(1) There are several case reports of bleeding following the addition of doxycycline(2-4) and tetracycline(5,6) to warfarin therapy.

Selected Anticoagulants (Vit K Antag)/Selected Penicillins

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Unknown.

CLINICAL EFFECTS: Large doses of parenterally administered penicillins and oral amoxicillin appear to increase the risk of bleeding during concurrent administration of anticoagulants.

PREDISPOSING FACTORS: Renal failure may predispose patients to penicillin-induced coagulation abnormalities. A study suggests that various inflammatory syndromes or the nature of the infection can affect INR levels. The risk for bleeding episodes may be greater in patients with additional disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Monitor patient INR for an increase in the hypoprothrombinemic response to anticoagulants during concomitant administration of penicillins. Adjust the dose of warfarin accordingly. When concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: High dose parenteral administration of penicillins and oral amoxicillin have been reported to cause an increase in the hypoprothrombinemic effects of warfarin producing bleeding. Significant clinical effects have been reported with combined administration of warfarin and either carbenicillin or penicillin G. There have been several case reports and retrospective reviews documenting increased acenocoumarol and warfarin effects, including bleeding, following the addition of amoxicillin, with and without clavulanic acid, to therapy. In a randomized controlled trial, adult ambulatory patients that had no recent and ongoing infectious or inflammatory conditions received warfarin to a target INR between 2 and 3 with amoxicillin-clavulanic acid (1 gram twice daily for seven days) or placebo. The results showed the mean maximum INR increase from baseline to day 10 did not differ between amoxicillin/clavulanic acid (0.22 +/- 0.3) and the placebo period (0.24 +/- 0.6, p = 0.94). No patient experienced an INR of greater than 3.5. No bleeding events were reported during the entire study. A prospective cross-sectional observational study in 120 patients evaluated warfarin drug interactions, particularly with high-dose amoxicillin/clavulanate. The study found that patients on amoxicillin/clavulanate had a relative risk of having an INR >=4 of 4.8 compared to patients not on amoxicillin/clavulanate (95% CI 2.1-11.3, p < 0.001). This risk was primarily driven by patients on high-dose amoxicillin/clavulanate, who were 5.8 times more likely to have INR >=4 (95% CI 3.5-9.6, p<0.001). Significantly more patients on high-dose than normal dose amoxicillin/clavulanate had an INR value >= 4 (87.5% v. 28.9%, respectively). Nine out of ten patients who experienced bleeding during hospitalization were prescribed amoxicillin/clavulanate. A large systematic review was performed on 72 warfarin drug-drug interactions studies that reported on bleeding, thromboembolic events, or death. Most studies were retrospective cohorts. A meta-analysis of 11 of those studies found a higher rate of clinically significant bleeding in patients on warfarin and antimicrobials (OR=1.63; 95% CI 1.45-1.83). Increased bleeding risk was also seen in subgroup analyses with penicillins (OR=1.59; 95% CI 1.14-2.20) and amoxicillin (OR=1.78; 95% CI 1.14-2.79). A case-control nested cohort study of Medicare beneficiaries with warfarin prescriptions was evaluated for antibiotic use and warfarin toxicity in older adults. An increased risk of bleeding was associated with penicillins with an adjusted odds ratio of 1.92. Parenteral penicillins linked to this monograph include: almecillin, amdinocillin, amoxicillin, ampicillin, azlocillin, bacampicillin, carbenicillin, cyclacillin, hetacillin, mezlocillin, penicillin, penicillin G, penicillin V, phenethicillin, piperacillin, and ticarcillin. Oral penicillins linked to this monograph include: amoxicillin and penicillin.

Selected Anticoagulants (Vit K Antagonists)/Carbamazepine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Carbamazepine may induce the metabolism of warfarin by CYP2C9 and CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of carbamazepine may result in decreased levels and effectiveness of warfarin, which may increase the risk of clotting.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor INR response closely in patients maintained on warfarin when initiating, titrating, and discontinuing carbamazepine. Patients maintained on carbamazepine may require higher dosages of warfarin.(1) The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: A retrospective cohort study in 57 patients had an increase in warfarin dose with concurrent carbamazepine use. After initiation of carbamazepine, the mean weekly warfarin dose and ratio of dose/INR increased by 7.6 mg (24%) and 5.7 mg/INR (43%), respectively. Patients experienced no bleeding or thromboembolic events during the study period.(2) This interaction has also been documented in case reports.(3-7)

Selected Anticoagulants (Vit K Antagonists)/Disulfiram

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Disulfiram may inhibit the CYP2C9 mediated metabolism of warfarin or other selected vitamin K antagonists.

CLINICAL EFFECTS: The anticoagulant effect of warfarin may be increased resulting in bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Pharmacogenomic information: patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective and safe anticoagulation than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: Closely monitor patient INR until stabilized and adjust the anticoagulant dose accordingly. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. When concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: Disulfiram is classified as a weak inhibitor of CYP2C9 by the FDA. However, given the low therapeutic index of warfarin, even weak CYP2C9 inhibitors may have clinically significant effects. Clinical investigation has substantiated that combined administration of warfarin and disulfiram increases serum warfarin concentrations and produces an increase in the anticoagulant effect of warfarin. Case reports have documented the occurrence of bleeding.

Selected Anticoagulants (Vit K Antagonists)/Ethchlorvynol

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Not defined. It has been proposed that hepatic enzyme induction enhances metabolism of anticoagulants.

CLINICAL EFFECTS: Ethchlorvynol decreases prothrombin time with diminished anticoagulant response.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid use of ethchlorvynol. If both drugs are used, adjust the anticoagulant dose as needed based on prothrombin activity and patient response. Consider substituting a benzodiazepine in place of ethchlorvynol. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: The benzodiazepines chlordiazepoxide, diazepam and nitrazepam have not been found to interact with warfarin. This is probably the case with other benzodiazepines so these drugs should be considered as a substitute for ethchlorvynol.

Selected Anticoagulants (Vit K Antagonists)/Propafenone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Propafenone may inhibit the metabolism of warfarin via CYP1A2.(1,3)

CLINICAL EFFECTS: The concurrent administration of warfarin and propafenone may result in increased anticoagulant effects and risk of bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Pharmacogenomic information: patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective and safe anticoagulation than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: The dosage of warfarin may need to be adjusted when propafenone is initiated or discontinued. The patient INR should be monitored for changes in the effects of warfarin. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: In a study(2) in eight subjects, the concurrent administration of propafenone with warfarin resulted in a 38% increase in the mean steady-state plasma warfarin concentration when compared to the administration of warfarin alone. There were also significant changes in the mean prothrombin time during concurrent administration. While three subjects had little change, two subjects experienced a doubling in prothrombin time and three experienced a 50% increase in prothrombin time.

Selected Anticoagulants (Vit K Antagonists)/Propranolol

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism of this interaction is unknown. Propranolol may inhibit the hepatic metabolism of warfarin.

CLINICAL EFFECTS: Increased serum concentrations of warfarin may result in an increased risk for bleeding.

PREDISPOSING FACTORS: Risk for bleeding episodes may be greater in patients with disease-associated bleeding risk (e.g. thrombocytopenia). Drug risk factors include concurrent use of multiple drugs which inhibit warfarin metabolism, or have an inherent risk for bleeding (e.g. NSAIDs). Patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective and safe anticoagulation than patients without these CYP2C9 variants

PATIENT MANAGEMENT: Monitor the INR when propranolol is added to or discontinued from warfarin therapy, particularly when higher doses of propranolol (> 80 mg/dose) are prescribed. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: In two studies in healthy subjects, concurrent administration of warfarin and propranolol 80 mg every 12 hours resulted in increases of warfarin area-under-curve (AUC) by 14.7-16.3% and 23% increase in warfarin maximum concentration (Cmax). There were no significant changes in prothrombin times. In a case report, a patient's prothrombin time increased after the addition of propranolol to his warfarin therapy. The prothrombin time decreased to pre-propranolol treatment values when propranolol was discontinued. Studies have shown that warfarin AUC was unaffected by atenolol, metoprolol, or esmolol. Warfarin Cmax was unaffected by metoprolol and esmolol, but increased 12.5% with concurrent administration of atenolol. Prothrombin time, plasma clotting factor VII activity, and the mean warfarin elimination half-life were unchanged by either metoprolol or atenolol. In a study, administration of acebutolol did not result in a significant change in prothrombin time.

Selected Anticoagulants (Vit K Antagonists)/Quinidine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The mechanism is unknown but may be due to synergistic effects on vitamin K clotting factors in the liver.

CLINICAL EFFECTS: May observe reduced prothrombin activity or increased bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Excessive hypoprothrombinemia and hemorrhage has been reported in patients receiving warfarin 6 to 10 days after starting quinidine. Monitor INR and adjust anticoagulant dose to assure efficacy and safety of anticoagulation. Monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: Excessive hypoprothrombinemia and hemorrhage has been reported in patients receiving warfarin 6 to 10 days after starting quinidine. Anticipate a similar time period to be needed for the effects of quinidine to dissipate after stopping quinidine therapy.

Selected Anticoagulants (Vit K Antagonists)/Tibolone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Tibolone may lower fibrinogen levels and increase antithrombin III, plasminogen, and fibrinolytic activity(1) and it may decrease factor VIIa, a vitamin K dependent coagulation factor.(2)

CLINICAL EFFECTS: Concurrent use of tibolone and vitamin K antagonists may increase the risk for bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Patients maintained on anticoagulants should be closely monitored if tibolone is initiated, adjusted, or discontinued.(1) The dosage of the anticoagulant may need to be adjusted. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: A retrospective review identified five women in whom INR values were elevated following the addition of tibolone to their warfarin (four women) or phenindione (one woman) therapy. Elevated INR values were seen one to two weeks following the addition of tibolone. In another patient, INR values decreased following the discontinuation of tibolone from concurrent warfarin therapy, necessitating a warfarin dosage increase from 6 mg/day to 7.5 mg/day.(2)

Selected Anticoagulants (Vit K Antagonists)/Zafirlukast

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Zafirlukast may inhibit the CYP2C9 mediated metabolism of warfarin.(1,2)

CLINICAL EFFECTS: Concurrent use of select anticoagulants and zafirlukast may increase the risk for bleeding.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve to effective and safe anticoagulation than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with warfarin and zafirlukast should have their prothrombin or INR values monitored closely and their warfarin dosage adjusted accordingly.(1) The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: In a study reported in the manufacturer's prescribing information, the administration of a single dose of warfarin (25 mg) during concurrent administration of steady-state zafirlukast resulted in significant increases in the area-under-curve (AUC) and half-life (63% and 36%, respectively) of warfarin. Prothrombin times increased 35% during concurrent administration.(1) In contrast, concurrent administration of the recommended dose of montelukast with warfarin did not result in clinically significant effects on warfarin. (4)

Selected Anticoagulants (Vitamin K Antagonists)/Azathioprine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown. Azathioprine has been shown to decrease warfarin and acenocoumarol concentrations.(1)

CLINICAL EFFECTS: Concurrent use of azathioprine may result in decreased effectiveness of warfarin or acenocoumarol.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients maintained on warfarin or acenocoumarol should be closely monitored if azathioprine is initiated or discontinued. The dosage of warfarin or acenocoumarol may need to be adjusted.

DISCUSSION: In a case report, a 50 year-old female had been maintained on warfarin at a dosage of 40 mg weekly for 2 years with INR values around 3. During azathioprine therapy, her warfarin dosage requirements increased to 100-150 mg weekly with resultant INR values of 1.5-1.95. Following the discontinuation of azathioprine, her INR value increased to 8.3 and the dose of warfarin was decreased to 40 mg weekly.(1) In a case report, a 32 year-old female had received a six week course of warfarin at a dosage of 35 mg weekly. Ten days after warfarin completion, azathioprine was initiated and 9 days later the patient developed a deep vein thrombosis. While on azathioprine, the patient required a dose of warfarin of 120 mg weekly to maintain an INR of 2.0-3.0.(2) In a case report, a 41 year-old female had been maintained on warfarin at a dosage of 5 mg daily with therapeutic INR values. Following the addition of azathioprine to her regimen, she required a daily dose of warfarin of 12 mg to achieve a therapeutic INR.(3) In a case report, a patient maintained on azathioprine required a daily dose of warfarin of 17 mg daily to maintain a therapeutic prothrombin time. Following the discontinuation of azathioprine, the patient developed intermittent epistaxis over a 6 week period. The patient was admitted with hematemesis and a prothrombin time of 32 seconds. Warfarin was held and later restarted at a daily dose of 5 mg.(4) In a case report, a 30 year-old female maintained on azathioprine and prednisolone required a daily warfarin dose of 20 mg. Warfarin dosage required decreasing to 11 mg daily during azathioprine tapering from 150 mg to 50 mg daily. When azathioprine was reintroduced, the patient's INR fell to 1.3 and warfarin had to be increased to 17 mg daily to maintain and INR of 2.4.(5) In a case report, a 67 year-old female was treated with warfarin (24 mg weekly) for over three years. After the initiation of azathioprine (150 mg daily), warfarin dosage was increased to a mean dose of 60 to 75 mg weekly over the next 18 months. Her dose of azathioprine was then increased to 200 mg daily and her warfarin dosage was increased to a mean dose of 130 mg weekly to compensate for subtherapeutic INR levels. Her INR value before azathioprine discontinuation was 1.8. Four weeks following azathioprine discontinuation her INR was 14.0.(6) In a case report, a 3 year-old female was treated with acenocoumarol 2 mg and 3 mg alternating days (17.5 mg/week) for 17 days (INR 2.6). Three days after initiation of azathioprine, the INR was 1.48 and heparin was started because of thromboembolic risk. The dose of acenocoumarol was increased to 5 mg per day (35 mg/week)(INR 2.56).(7) In a case report, a 53 year-old female was treated with acenocoumarol 21 mg/week (mean INR 3.3) for 3.5 years. After initiation of azathioprine 100 mg daily, methotrexate, and all-trans retinoic acid, the dose of acenocoumarol had to be increased to 70 mg/week (INR 1.9). Five months later the INR was 3.4. A week after discontinuing azathioprine, the INR increased to 12. The acenocoumarol dose was reduced to original 3 mg/day dose without complications.(8)

Selected Anticoagulants (Vitamin K Antagonists)/Clomipramine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Clomipramine inhibition of platelet serotonin may result in impaired platelet aggregation.(1) This effect may be additive or synergistic when combined with other agents which impair hemostasis.

CLINICAL EFFECTS: Concurrent use of selected anticoagulants and clomipramine may increase the risk for bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: If concurrent therapy is warranted, monitor patients for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose, or discontinuing either drug.

DISCUSSION: Clomipramine is a potent inhibitor of platelet serotonin. In a study of clomipramine and fluoxetine effects on platelet and plasma 5-HT levels, clomipramine significantly reduced platelet 5-HT content to 8% and 19% and plasma 5-HT levels to 40% and 23% of their pretreatment values after 12 weeks, respectively.(1) In a review describing the bleeding risk with SRIs, warfarin was associated with an increased rate of hemorrhage among SRI users (adjusted relative risk = 1.41).(2) In a cohort study of patients taking warfarin in combination with an SSRI versus warfarin treatment alone, an analysis including first bleedings revealed a hazard ratio of 3.49 for bleeding during treatment with a combination of SSRI and warfarin compared with warfarin only.(3) A retrospective study of warfarin-treated patients prescribed or not prescribed an antidepressant showed that use of an SSRI with warfarin was significantly associated with increased risk of any bleed (overall risk (OR)=2.6), major bleeding (OR=4.4), and hospitalization secondary to bleeding (OR=7.0) as compared to those not taking an SSRI.(4) A population based study of patient outcomes in 176 primary intracerebral hemorrhage patients showed that 19 patients taking SSRI/SNRIs together with warfarin had an increased 30-day case fatality rate of 78.9% compared to warfarin alone (50.7%).(5) In a study of the Anticoagulation and Risk factors in Atrial fibrillation (ATRIA) cohort, hemorrhage rates were higher during periods of SSRI exposure compared with periods on no antidepressants (2.32 per 100 person-years vs 1.35 per 100 person-years). After adjusting for bleeding risk and time in INR range > 3, SSRI exposure was associated with an increased rate of hemorrhage compared with no antidepressants (adjusted relative risk = 1.41).(6) Increased bleeding risk has been found when patients receive 3 agents which can affect bleeding risk: an anticoagulant, SSRI and NSAID.(7) In a retrospective review of 5 years of data from the Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper gastro-intestinal bleeding in antidepressant users were compared to those in non-antidepressant users. The risk of a bleed in a patient using an NSAID only based on an observed-expected ratio was 4.5 and in a patient using low-dose aspirin only was 2.5. Concurrent use of a SSRI with NSAIDs or low-dose aspirin increased the risk of bleeding to 12.2 and 5.2, respectively.(7) In another study, there were 16 cases of upper gastrointestinal bleeding in patients receiving concurrent therapy with SSRIs and NSAIDs. Adjusted relative risk of bleeding with NSAIDs, SSRIs, or both were 3.7, 2.6, or 15.6, respectively.(8)

Selected Anticoagulants (Vitamin K Antagonists)/Danshen

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown. Danshen may decrease the elimination of warfarin.(1) In vitro tests have shown that danshen inhibits platelet aggregation.(2)

CLINICAL EFFECTS: The concurrent administration of warfarin and danshen may result in increased hypoprothrombic effects of warfarin, including bleeding.(3-5)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: If possible, the concurrent administration of warfarin and danshen should be avoided. If concurrent therapy is warranted, monitor patients for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. The dosage of warfarin may need to be adjusted. Danshen and/or warfarin may need to be discontinued. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: There are several case reports of increased warfarin effects following the addition of danshen to warfarin therapy. All of these patients required the administration of blood products to reverse clotting abnormalities. In the first report, the patient developed a massive right pleural effusion, from which 4.5 liters of non-clotted blood was drained, two weeks following the addition of danshen to warfarin therapy. The patient's INR was 8.4. Both warfarin and danshen were discontinued and the patient's INR dropped to 2.0 following the administration of fresh frozen plasma and packed red blood cells.(3) In the second report, the patient developed a decreased hemoglobin of 5.3 G/dl and an INR of greater than 5.62 following the intermittent administration of danshen with warfarin. Both agents were discontinued and fresh frozen plasma was administered. The patient's clotting abnormalities resolved after five days.(4) In the third report, a patient presented with melena following the addition of danshen and the concurrent administration of a 15% methyl salicylate medicated oil. His INR was over 5.5 and his hemoglobin level was 7.6 G/dl. The patient received 12 units of fresh frozen plasma and seven units of packed red blood cells. The patient was diagnosed with adenocarcinoma.(5) A study in rats revealed that danshen increased the absorption rate constant, area-under-curve (AUC), maximum concentration (Cmax), and elimination half-life of warfarin and decreased the clearance and apparent volume of distribution of warfarin. Prothrombin times were prolonged.(1)

Selected Anticoagulants (Vitamin K Antagonists)/Glutethimide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: It is speculated that induction of hepatic microsomal enzymes results in increased metabolism of anticoagulants.

CLINICAL EFFECTS: May observe decreased anticoagulant effects. Increased risk of hemorrhage when glutethimide is withdrawn. Effect may be dose-related and continue beyond discontinuation of glutethimide.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concomitant use of these drugs. If both drugs are administered, adjust the anticoagulant dose as needed based on prothrombin activity. Caution when glutethimide is started or stopped. Benzodiazepines and diphenhydramine do not react significantly with anticoagulants and should be considered as alternative hypnotics. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: This interaction is well documented.

Selected Anticoagulants (Vitamin K Antagonists)/Griseofulvin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Griseofulvin may induce the metabolism of Vitamin K antagonists, such as warfarin.

CLINICAL EFFECTS: Concurrent or recent use of griseofulvin may result in decreased anticoagulant response, which can increase the risk of thrombosis.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Use caution when griseofulvin is started or stopped in patients on anticoagulant therapy. Monitor INR closely and adjust the anticoagulant dose as necessary. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Several case reports have shown that the administration of griseofulvin (500mg/day to 1000mg/day) to patients maintained on warfarin resulted in a decreased prothrombin time, requiring an increase in the dose of warfarin.(1,2) This interaction usually occurs after several weeks of concurrent therapy. In one patient, an overall increase of 41% in warfarin dosage (from 8.5mg/day to 12mg/day) was needed to maintain the therapeutic effect of warfarin after 12 weeks of co-administration. Nine weeks after the griseofulvin dosage was reduced (from 500mg/day to 250mg/day), the prothrombin time increased to 2.3 times control. A reduction in the dose of warfarin to 10mg/day maintained the prothrombin time between 1.6 and 1.8 times control for the next seven weeks.(1) In a small study in which patients served as their own controls, 4 of 10 subjects experienced a decrease in prothrombin times following two weeks of griseofulvin therapy.(3)

Selected Anticoagulants (Vitamin K Antagonists)/Linezolid

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown. Linezolid may interfere with vitamin K-producing gut flora.

CLINICAL EFFECTS: Concurrent use of linezolid may increase may result in increased anticoagulant effects with possible bleeding.

PREDISPOSING FACTORS: High anticoagulant doses, hepatic or renal impairment, and poor nutrition may increase the risk of bleeding. The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g., thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g., NSAIDs).

PATIENT MANAGEMENT: Consider using an alternative antibiotic. If concurrent therapy is warranted, monitor prothrombin activity and adjust the anticoagulant dosage accordingly. Monitor patients for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g., INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: A retrospective study examined 16 patients with left ventricular assist system for severe heart failure taking warfarin (goal INR 3-4) and started on linezolid. INR increased non-significantly (from 3.74 to 4.06) but warfarin dose decreased (3.23 mg/day to 2.69 mg/day (p=0.001)) and INR/warfarin dose ratio increased significantly. Patients with fever (temperature > 38 degrees C), potentially interacting medications, on liquid diet or TPN or with decreased food intake were excluded.(1) A retrospective study of 6 patients on warfarin and linezolid after cardiovascular surgery found that INR increased from 1.62 to 3 on day 4-5 of concomitant therapy then decreased by day 10 after dose reduction or withdrawal of warfarin. Patients on potentially interacting medications were excluded.(2) In a case series, 4 patients who were 2-5 days post aortic or mitral valve replacement and started on acenocoumarol and linezolid all experienced increased INR ranging from >5 to >10.(3) A case report describes a patient stable on acenocoumarol for a prosthetic aortic valve who developed INR of 5.6 three days after starting linezolid.(4) Another case report describes a patient who experienced INR of 5.2 three days after concomitant therapy with acenocoumarol and linezolid.(5)

Selected Anticoagulants (Vitamin K Antagonists)/Sitaxsentan

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Sitaxsentan may inhibit the metabolism of some anticoagulants by CYP2C9.(1,2)

CLINICAL EFFECTS: Concurrent use of sitaxsentan may result in elevated levels of and clinical effects from the anticoagulant, including increased risk for bleeding.(1,2)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Pharmacogenomic information: patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve to achieve effective and safe anticoagulation than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: The Canadian manufacturer of sitaxsentan states that in clinical trials, the dose of warfarin was decreased by 80% when initiating sitaxsentan and then increased by no greater than 0.5 mg/day while titrating to the desired INR.(1) The UK manufacturer of sitaxsentan recommends that if vitamin-K antagonists are initiated in patients maintained on sitaxsentan, they should be initiated at the lowest possible dose and carefully titrated. If sitaxsentan is initiated in patients maintained on vitamin-K antagonists, the dosage of the anticoagulant should be reduced.(2) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Concurrent sitaxsentan (100 mg daily) increased the area-under-curve (AUC) of S-warfarin following a single dose (25 mg) by 96%. The clearance of S-warfarin decreased by 63%. Increased effects on PT and INR were observed. In clinical trials, the dose of warfarin was decreased by 80% when initiating sitaxsentan and then increased by no greater than 0.5 mg/day while titrating to the desired INR. The mean dose of warfarin after 18 weeks of concurrent therapy in the STRIDE 2 trial was 2.2 mg/day in patients receiving sitaxsentan compared with 3.6 mg/day for patients receiving placebo. The need to change the warfarin dosage as a result of changes in INR was similar in both groups.(1) Concurrent sitaxsentan increased S-warfarin exposure by 2.4-fold.(2)

Selected Anticoagulants/Acetaminophen

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Acetaminophen may reduce levels of functional Factor VI, thereby increasing the International Normalized Ratio (INR).(1) In one trial factors II and VII levels were also reduced, thereby increasing the INR. (2)

CLINICAL EFFECTS: Concurrent use of routine acetaminophen, especially at dosages greater than 2 grams/day, and coumarin anticoagulants may result in elevated anticoagulant effects.

PREDISPOSING FACTORS: Routine use of acetaminophen at dosages greater than 2 grams/day may increase the risk of the interaction.

PATIENT MANAGEMENT: Patients receiving routine acetaminophen at dosages greater than 2 grams/day with coumarin anticoagulants should be closely monitored for changes in anticoagulant effects. The dosage of the anticoagulant may need to be adjusted. Patients receiving coumarin anticoagulants should be counseled on the use of acetaminophen.

DISCUSSION: A large systematic review was performed on 72 warfarin drug-drug interactions studies that reported on bleeding, thromboembolic events, or death. Most studies were retrospective cohorts. A meta-analysis of 4 of those studies found a higher rate of clinically significant bleeding in patients on warfarin and non-NSAID analgesics (OR=2.12; 95% CI 1.65-2.73). Increased bleeding risk was also seen in subgroup analyses with acetaminophen (OR=2.32; 95% CI 1.22-4.44).(3) In a study in 11 patients maintained on warfarin, use of acetaminophen (4 grams daily for 14 days) increased INR values by an average of 1.04.(4) In a study in 36 patients maintained on warfarin, the addition of acetaminophen (2 grams/day or 4 grams/day) increased INR values.(5) In a study in 20 patients maintained on warfarin, the addition of acetaminophen (4 grams/day for 14 days) increased average INR values by 1.20 (from 2.6 to 3.45).(6) In a study, 12 patients maintained on various anticoagulants (anisindione, dicoumarol, phenprocoumon, and warfarin) who received 4 weeks of acetaminophen (2.6 grams/day) were compared to 50 subjects maintained on various anticoagulants who did not receive acetaminophen. By the third week of concurrent acetaminophen, prothrombin times increased from 23 seconds to 28.4 seconds. The average warfarin-equivalent dose decreased by 5.8 mg to 4.4 mg. In another phase, 50 subjects maintained on various anticoagulants received acetaminophen (2.6 grams/day for 14 days). The mean prothrombin increase was 3.6 seconds.(7) There have been case reports of increased INRs following concurrent acetaminophen in patients maintained on warfarin(8-11) and acenocoumarol.(12) In contrast to the above reports, other studies have found no effects on acenocoumarol,(14) phenprocoumon,(13-15) or warfarin(16,17) by acetaminophen. In a study in 45 patients maintained on warfarin, the addition of acetaminophen (2 or 3 grams/day for 10 days) increased average INR by 0.7 and 0.67 with 2 grams/day and 3 grams/day, respectively. This increase was apparent by day 3, and a decrease in factor II and VII was observed.(2) A self-controlled case study of 1,622 oral anticoagulant-precipitant drug pairs were reviewed and found 14% of drug pairs were associated with a statistically significant elevated risk of thromboembolism. Concurrent use of warfarin and acetaminophen resulted in a ratio of rate ratios (95% CI) of 1.28 (1.18-1.38).(18) One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Selected Anticoagulants/Antithyroid Drugs

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Antithyroid drugs may decrease breakdown of vitamin-K dependent clotting factors, thus increasing the amount of clotting factors available for use.

CLINICAL EFFECTS: Decreased clearance of vitamin K dependent clotting factors by antithyroid drugs may result in decreased therapeutic effects of anticoagulants. However, if thioamide-induced hypothrombinemia occurs, the activity of the anticoagulant may be increased.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If antithyroid treatment is started or discontinued in patients stabilized on anticoagulant therapy, INRs should be closely monitored and the anticoagulant dose should be adjusted as needed. Some patients may require alternative hyperthyroid medication in order to achieve therapeutic anticoagulation. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Caution should be used when this drug combination if given. In the clinically hyperthyroid patient, the breakdown of the vitamin k-dependent clotting factors is increased resulting in quicker and greater response to the anticoagulant. When antithyroid drugs are administered to correct this, the response to the anticoagulant may decrease. An increase in the anticoagulant dosage may be required. There are several reports of decreased anticoagulant effects in patients receiving antithyroid agents. There has been one case reported where the patient experienced an increased response to warfarin when propylthiouracil was added to the patient's drug regimen.

Selected Anticoagulants/Thyroid

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Unknown. However, thyroid hormones may influence concentrations of vitamin K-dependent clotting factors.

CLINICAL EFFECTS: Concurrent use of vitamin K antagonists and thyroid hormones may increase the risk for bleeding. Hypothyroidism may increase the oral anticoagulant requirements. Administration of thyroid hormones or hyperthyroidism may decrease oral anticoagulant requirements.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Monitor prothrombin activity and adjust the anticoagulant dosage accordingly during initiation of warfarin therapy in patients receiving thyroid replacement therapy, during the initiation or titration of thyroid replacement therapy in patients receiving warfarin, or if any changes in thyroid function occur. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Any change in thyroid status in patients stabilized on warfarin may necessitate a change in warfarin dosage requirements. Initiation of thyroid replacement therapy in patients stabilized on warfarin may result in increases in the effects of warfarin. A decrease in the dose of warfarin usually becomes necessary within one to four weeks after starting therapy with thyroid compounds. Warfarin therapy should be initiated in low doses in patients who are hyperthyroid. In a 16 year population based nested matched case control study, 10,532 hospitalizations for hemorrhage were evaluated and matched to 40,595 controls. The primary analysis showed no increase in risk of hemorrhage in older patients on warfarin initiated on levothyroxine in previous 30 days (OR 1.11, 95% CI 0.67-1.86). When patients were matched up to 90 days prior to the hemorrhage event, there was no significant association with levothyroxine 31-60 days prior to index date (OR 0.75 95% CI 0.26-2.25) or 61-90 days prior to index date (OR 0.67 95% CI 0.15-3.01). A retrospective, self-controlled study of 102 patients on chronic warfarin therapy were included if the patient had INR results 90 days before and after starting levothyroxine. The mean warfarin dose/INR ratio in the pre-period and post-period had no significant change (p=0.825). In patients who achieved euthyroid during post-period, warfarin dose/INR ratio was numerically lower in the post-period but not statistically significant (13.42 versus 12.7, respectively; p=0.338). In patients initiated on levothyroxine doses greater than 50 mcg, pre-period and post-period warfarin dose/INR ratio also had no significant difference (p>0.2).

Selected Anticoagulants; Antiplatelets/Ibrutinib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Ibrutinib administration lowers platelet count in the majority of patients.(1,2) In addition, ibrutinib has been shown to inhibit collagen-mediated platelet aggregation.(3-4) Bleeding has been reported with the use of ibrutinib,(1-4) anticoagulants, or antiplatelets alone.

CLINICAL EFFECTS: Concurrent use of ibrutinib with either anticoagulants or antiplatelets may increase the risk of hemorrhage.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The Canadian product monograph for ibrutinib recommends concurrent use with anticoagulants or antiplatelets should be approached with caution. If therapeutic anticoagulation is required, consider temporarily withholding ibrutinib therapy until stable anticoagulation in achieved.(2) The US prescribing information for ibrutinib states patients receiving concurrent therapy with ibrutinib and anticoagulants and/or antiplatelets should be closely monitored for changes in platelet count or in International Normalized Ratio (INR). Carefully weigh the risks vs. benefits of concurrent therapy in patients with significant thrombocytopenia. If a bleeding event occurs, follow manufacturer instructions for ibrutinib dose adjustment.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Bleeding has been reported with ibrutinib alone.(1-3) Across 27 clinical trials, grade 3 or higher bleeding events, e.g. subdural hematoma, gastrointestinal bleeding or hematuria, have occurred in up to 4% of patients, with 0.4% fatality. Grade 3 or 4 thrombocytopenia occurred in 5-19% of patients. Bleeding events of any grade occurred in 39% of patients treated with ibrutinib.(1) Concurrent use of anticoagulants or antiplatelets has been reported to increase the risk for major bleeding. In clinical trials, major bleeding occurred in 3.1% of patients taking ibrutinib without concurrent anticoagulants or antiplatelets, 4.4% of patients on concurrent antiplatelets with or without anticoagulants, and 6.1% of patients on concurrent anticoagulants with or without antiplatelets.(1) In an open-label, phase 2 trial of patients with relapsed/refractory mantle cell lymphoma on ibrutinib, 61 patients (55%) on concurrent anticoagulants or antiplatelets had a higher rate of bleeding (69% any grade, 8% grade 3-4) than patients not on anticoagulants or antiplatelets (28% any grade, 4% grade 3-4).(5) A retrospective trial found a hazard ratio of 20 (95% CI, 2.1-200) for patients on ibrutinib with concurrent anticoagulants and antiplatelets. There was a trend towards an increased bleeding risk in patients on either anticoagulants or antiplatelets, but this was not statistically significant on multivariate analysis.(6) A case report of 2 patients with chronic lymphocytic leukemia (CLL) on ibrutinib and dabigatran demonstrated no stroke nor bleeding events during the mean 11.5 month follow-up.(7) A case report of 4 patients with lymphoproliferative disease on concurrent dabigatran and ibrutinib demonstrated no stroke nor major bleeding events. 1 patient experienced grade 2 conjunctival hemorrhage whilst on both ibrutinib and dabigatran. The anticoagulant was withheld and successfully re-initiated at a lower dose with no further bleeding events.(8)

Selected Anticoagulants; Thrombolytics/Platelet Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Platelet aggregation inhibitors work by irreversibly modifying the platelet ADP receptor and inhibiting the activation of GP IIb/IIIa complex.(1) Concurrent use with anticoagulants may result in additive effects on the clotting cascade.

CLINICAL EFFECTS: The concurrent use of platelet aggregation inhibitors and anticoagulants may result in an increased risk of bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Use caution when administering platelet aggregation inhibitors concurrently with anticoagulants.(1) Careful monitoring of appropriate laboratory values for the patient's anticoagulant (e.g. PTT for heparin, anti Xa levels for low-molecular weight heparins, INR for warfarin) as well as signs and symptoms of bleeding is warranted. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Although a study in patients on long-term warfarin therapy found that the stable anticoagulation status was unaffected by concurrent clopidogrel use,(2) careful monitoring would be prudent. A self-controlled case study of 1,622 oral anticoagulant-precipitant drug pairs were reviewed and found 14% of drug pairs were associated with a statistically significant elevated risk of thromboembolism. Concurrent use of warfarin and dipyridamole resulted in a ratio of rate ratios (95% CI) of 2.07 (1.65-2.6); and warfarin and clopidogrel ratio of rate ratios 1.69 (1.56-1.84). A large systematic review was performed on 72 warfarin drug-drug interactions studies that reported on bleeding, thromboembolic events, or death. Most studies were retrospective cohorts. A meta-analysis of 38 of those studies found a higher rate of clinically significant bleeding in patients on warfarin and antiplatelets (OR=1.74; 95% CI 1.56-1.94). Increased bleeding risk was also seen in subgroup analyses with aspirin (OR=1.50; 95% CI 1.29-1.74), clopidogrel (OR=3.55; 95% CI 2.78-4.54), and aspirin plus clopidogrel or ticlopidine (OR=2.07, 95% CI 1.33-3.21).(4)

Selected Cyp2c9 Substrates/Lorlatinib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Lorlatinib is a moderate inducer of CYP2C9 and may increase the metabolism of drugs metabolized by the CYP2C9 enzyme.(1)

CLINICAL EFFECTS: Concurrent use of lorlatinib may lead to decreased serum levels and effectiveness of drugs metabolized by the CYP2C9 pathway.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients maintained on a CYP2C9 substrate who start therapy with lorlatinib may require closer monitoring and dose adjustment of the CYP2C9 substrate.

DISCUSSION: In a study, lorlatinib 100 mg daily for 15 days decreased the area-under-curve (AUC) and maximum concentration (Cmax) of single-dose tolbutamide 100 mg (a sensitive CYP2C9 substrate) by 43% and 15%, respectively.(1) CYP2C9 substrates with a narrow therapeutic index linked to this monograph include: dasabuvir, paclitaxel, and warfarin.(2,3)

Selected Cyp2c9 Substrates/Nitisinone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Nitisinone is a moderate inhibitor of CYP2C9.(1,2)

CLINICAL EFFECTS: Decreased clearance may increase systemic concentrations of drugs primarily metabolized by CYP2C9, leading to toxicity.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Decrease the dosage of the CYP2C9 substrate drug by one-half. Additional dose adjustments may be necessary. Closely monitor patients stable on CYP2C9 substrates for altered therapeutic effect or toxicity when nitisinone therapy is started or adjusted.(1)

DISCUSSION: In a study, 16 healthy subjects who were pre-treated with nitisinone (80 mg daily) for 14 days and received a single dose of tolbutamide (500 mg) had an increase in tolbutamide area-under-curve (AUC) and maximum concentration (Cmax) of 131 % and 16 %, respectively, compared to tolbutamide administered alone.(1,2) Medications linked to this interaction include fluvastatin, fosphenytoin, glimepiride, glipizide, phenytoin, tolbutamide, and warfarin. These drugs have a narrow therapeutic range or are designated as CYP2C9 Sensitive Substrates(3,4) (i.e. moderate 2C9 inhibitors are expected to increase exposure (AUC) to these agents by 2-fold to 5-fold).

Slt Anticoag (Vit K Antag)/Erlotinib; Gefitinib; Sorafenib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Bleeding has been reported with the use of erlotinib,(1) gefitinib,(2) and sorafenib(3) alone. Concurrent use of vitamin K antagonists may result in additive effects.

CLINICAL EFFECTS: Concurrent use of erlotinib,(1) gefitinib,(2) or sorafenib(3) and vitamin K antagonists may increase the risk of bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Patients receiving concurrent therapy with erlotinib, gefitinib, or sorafenib and vitamin K antagonists should be closely monitored for changes in International Normalized Ratio (INR) and signs of bleeding. Permanent discontinuation of erlotinib, gefitinib, and sorafenib should be considered in patients who experience a bleeding event that requires medical intervention. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Increased INR and bleeding events, including gastrointestinal and non-gastrointestinal (including fatalities) have been reported with concurrent erlotinib and warfarin.(1,4) Elevated INR and bleeding events have also been reported with gefitinib(2,5,6) and sorafenib(3,7,8) Bleeding has been reported with erlotinib,(1) gefitinib,(2) and sorafenib(3) alone.(3)

Slt Anticoagulants (Vit K Antag)/Cholestyramine; Colesevelam

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Cholestyramine and colesevelam may bind to anticoagulants, which may lead to reduced GI absorption and impaired enterohepatic circulation. Decreased absorption of vitamin K may also occur.

CLINICAL EFFECTS: Concurrent use of cholestyramine or colesevelam may result in decreased effectiveness of anticoagulants.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Changes in therapy may not be required. However, INR levels should be monitored and anticoagulant dose adjusted as necessary during initiation and discontinuation of cholestyramine or colesevelam therapy. Staggering doses of these two drugs may reduce problems, but may be unreliable because of the possibility of altering vitamin K absorption. Colestipol may be an alternative to cholestyramine or colesevelam in patients maintained on warfarin therapy who require treatment with a bile acid sequestrant.

DISCUSSION: In healthy volunteers, oral administration of cholestyramine decreased the anticoagulant effect of intravenously administered warfarin by 25% suggesting that cholestyramine interferes with the enterohepatic recirculation of warfarin. Cholestyramine has been used to treat anticoagulant overdoses. In healthy volunteers absorption of warfarin was 95% complete when administered with colestipol compared to 68% absorption when warfarin was given with cholestyramine. Although an in vivo study found no effect from colesevelam on warfarin levels, INR values were not assessed and there are post-marketing reports of decreased INR levels during concurrent therapy. If patient is receiving treatment with cholestyramine and an anticoagulant and the cholestyramine is stopped, serum anticoagulant concentrations may increase, increasing the hypoprothrombinemic effect of the anticoagulant.

Slt Anticoagulants (Vit K Antag)/Slt Direct-Acting Antiviral

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown. Warfarin sensitivity may be decreased during concurrent therapy with direct-acting antivirals. Improved hepatic function as a result of successful treatment of Hepatitis C may also play a role.

CLINICAL EFFECTS: Use of direct-acting antivirals in the treatment of Hepatitis C may result in decreased warfarin effects, which may increase the risk of thrombosis.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor INR response closely in patients maintained on warfarin during treatment with direct-acting antivirals. Consider more frequent monitoring of INR during concurrent therapy and after the completion of therapy with direct-acting antivirals until a stable warfarin dose is established.

DISCUSSION: In a clinical study of 43 patients treated with elbasvir-grazoprevir, the warfarin sensitivity index (WSI) (steady state INR/mean daily warfarin dose) decreased from 0.53 +/- 0.25 to 0.4 +/- 0.22 at treatment completion with elbasvir-grazoprevir which represents a 25.2% decrease. Twelve weeks after treatment completion the WSI returned to 0.51 +/- 0.28. Mean weekly warfarin dose requirement increased over the course of therapy, from 40.3 +/- 22.0 mg to 44.6 +/- 23.4 mg, and returned to near original warfarin dose requirement after therapy at 46 mg. Time in therapeutic range for INR dropped from 74.1% to 39.8% during treatment and returned to 64.9% after treatment.(1) In a retrospective review of patients treated with either ombitasvir-paritaprevir-ritonavir-dasabuvir or sofosbuvir, the warfarin sensitivity index (steady state INR/mean daily warfarin dose) decreased 23% during therapy. The percentage of subtherapeutic INRs increased from 28% prior to treatment to 58% during treatment.(2) Pharmacokinetic studies found no significant effects on warfarin from either ombitasvir-paritaprevir-ritonavir(3) or ombitasvir-paritaprevir-ritonavir-dasabuvir.(4) There have been case reports of decreased warfarin effects and increased warfarin dosage requirements during the treatment of Hepatitis C with: ombitasvir-paritaprevir-ritonavir-dasabuvir,(5) sofosbuvir,(6) sofosbuvir-ledipasvir,(7) and sofosbuvir-velpatasvir.(8) There is a case report of decreased INR following the addition of ombitasvir-paritaprevir-ritonavir-dasabuvir to acenocoumarol.(9)

Slt Anticoagulants (Vit K Antag)/Slt Hmg-Coa Reductase Inhib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism of this interaction is unknown. The HMG-CoA reductase inhibitor may inhibit the hepatic hydroxylation of warfarin. The HMG-CoA reductase inhibitors, which are highly plasma protein bound, may displace warfarin from its binding site.

CLINICAL EFFECTS: Increased hypoprothrombinemic effects of warfarin may result in a risk for bleeding.

PREDISPOSING FACTORS: Risk for bleeding episodes may be greater in patients with disease-associated bleeding risk (e.g. thrombocytopenia). Drug risk factors include concurrent use of multiple drugs which inhibit warfarin metabolism, or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Patients should be monitored for changes in prothrombin time when a HMG Co-A reductase inhibitor is added to or discontinued from warfarin therapy, or if the dosage of the HMG Co-A reductase inhibitor is adjusted. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Case reports in the medical literature and to the manufacturer have documented an interaction between lovastatin and warfarin. A case report has documented an interaction between pravastatin and fluindione (an orally administered indanedione anticoagulant), suggesting that pravastatin could also interact similarly with warfarin. Information concerning a potential interaction with simvastatin is conflicting. A case report has documented an interaction between simvastatin and acenocoumarol while another case report showed no interaction with warfarin. One group of authors reported three case reports of increased international normalized ratios (INRs) following the addition of fluvastatin to warfarin therapy. The addition of rosuvastatin to patients stabilized on warfarin resulted in clinically significant changes in INR. A cohort study identified concurrent use of warfarin with atorvastatin, rosuvastatin, and simvastatin. Concurrent use of warfarin and simvastatin increased INR from 2.4 to 2.71, with INRs peaking at 4 weeks after statin initiation (mean change 0.32 (95% CI 0.25-0.38) and median change 0.2 (IQR -0.3-0.8)). Concurrent use of warfarin with atorvastatin and rosuvastatin increased INR from 2.42 to 2.69 with a mean change of 0.27 (95% CI 0.12-0.42) and from 2.31 to 2.61 with a mean change of 0.3 (95% CI -0.09-0.69), respectively. One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Slt Anticoagulants (Vit K Antagonist)/Aspirin (< Or = 100Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Multiple processes are involved: 1)Aspirin is an irreversible platelet inhibitor. It impairs platelet function, resulting in prolonged bleeding time. 2) Aspirin may cause gastrointestinal (GI) bleeding due to irritation.

CLINICAL EFFECTS: The concurrent use of anticoagulants and aspirin leads to blockade of two distinct coagulation pathways and may increase the risk for bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Weigh the patient specific benefits versus risk for concomitant use. If concurrent therapy of low dose aspirin and an anticoagulant is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. The Australian manufacturer of fluindione states use is not recommended with antiplatelet doses (from 50 mg to 375 mg per day) with a history of duodenal ulcer. When applicable, perform agent-specific laboratory test (e.g. INR) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; severe headache, acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: This interaction has been reported between aspirin and warfarin and between aspirin and dicumarol. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated, altered, or discontinued. A self-controlled case study of 1,622 oral anticoagulant-precipitant drug pairs were reviewed and found 14% of drug pairs were associated with a statistically significant elevated risk of thromboembolism. Concurrent use of warfarin and aspirin resulted in a ratio of rate ratios (95% CI) of 2.13 (1.72-2.64). A large systematic review was performed on 72 warfarin drug-drug interactions studies that reported on bleeding, thromboembolic events, or death. Most studies were retrospective cohorts. A meta-analysis of 38 of those studies found a higher rate of clinically significant bleeding in patients on warfarin and antiplatelets (OR=1.74; 95% CI 1.56-1.94). Increased bleeding risk was also seen in subgroup analyses with aspirin (OR=1.50; 95% CI 1.29-1.74), clopidogrel (OR=3.55; 95% CI 2.78-4.54), and aspirin plus clopidogrel or ticlopidine (OR=2.07, 95% CI 1.33-3.21).(16)

Slt Anticoagulants (Vit K Antagonists)/Aminoglutethimide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Aminoglutethimide may increase the metabolism of warfarin by CYP1A2.

CLINICAL EFFECTS: The hypoprothrombinemic response to warfarin may be decreased.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor anticoagulant function when starting, stopping or altering the dose of aminoglutethimide. Adjust the dose of warfarin accordingly. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Case reports and limited studies indicate that aminoglutethimide increases the clearance of warfarin. In order to maintain adequate anticoagulation during the concurrent administration of aminoglutethimide, larger doses of warfarin may be needed than when the anticoagulant is administered alone.

Slt Anticoagulants (Vit K Antagonists)/Slt Cephalosporins

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown, but may involve a combination of cephalosporin induced platelet inhibition and alteration of gut flora.

CLINICAL EFFECTS: Concurrent use of some cephalosporins may increase the hypoprothrombinemic effect of the anticoagulant with possible bleeding.

PREDISPOSING FACTORS: High doses, hepatic and/or renal impairment, and poor nutrition may increase the risk of bleeding. The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Monitor prothrombin activity and adjust the anticoagulant dosage accordingly. Consider using an alternative antibiotic. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Although the majority of cephalosporins that have been documented to interact with anticoagulants have a NMTT side chain, there are reports of interactions with cefazolin, cefoxitin, ceftaroline, and ceftriaxone as well. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. A large systematic review was performed on 72 warfarin drug-drug interactions studies that reported on bleeding, thromboembolic events, or death. Most studies were retrospective cohorts. A meta-analysis of 11 of those studies found a higher rate of clinically significant bleeding in patients on warfarin and antimicrobials (OR=1.63; 95% CI 1.45-1.83). Increased bleeding risk was also seen in subgroup analyses with cephalosporins (OR=1.50; 95% CI 1.21-1.86).

Slt Anticoagulants (Vit K Antagonists)/Tramadol

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown.

CLINICAL EFFECTS: Concurrent use of propoxyphene or tramadol may result in increased effects of some anticoagulants, including bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Patients maintained on warfarin who begin therapy with propoxyphene or tramadol containing medication should be monitored closely for signs of increased warfarin effects. The dosage of warfarin may need to be adjusted or a different opioid may need to be used. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: There have been four case reports of increased INR values following the addition of tramadol to warfarin-containing regimens.(1-4) In one case, a patient was hospitalized due to hematochezia with an increased INR of 5.4 after concomitant use of tramadol with warfarin. The patient was switched to gabapentin to prevent future bleeding.(1) Another case report identified this interaction in a patient on a stable warfarin regimen whose INR increased to 10.6 after the addition of tramadol for 2 weeks to treat musculoskeletal pain. After discontinuation of tramadol, it took approximately 4 months for INR to normalize after adjustments were made to their warfarin regimen.(2) A different case report examines concomitant tramadol and warfarin use which required a 30% reduction in warfarin dose allowing the patient to remain on both therapies while maintaining INR goal.(3) A large systematic review was performed on 72 warfarin drug-drug interactions studies that reported on bleeding, thromboembolic events, or death. Most studies were retrospective cohorts. A meta-analysis of 4 of those studies found a higher rate of clinically significant bleeding in patients on warfarin and non-NSAID analgesics (OR=2.12; 95% CI 1.65-2.73). Increased bleeding risk was also seen in subgroup analyses with opioid analgesics (OR=2.81; 95% CI 1.89-4.17).(5) A retrospective review associated tramadol use with episodes of major bleeding in patients receiving phenprocoumon or acenocoumarol.(6) In contrast, a study in 19 patients receiving phenprocoumon found no effect on INR values following the addition of tramadol.(7) There have been three case reports of patients developing hematuria following the addition of a combination product containing propoxyphene and acetaminophen.(8-10)

Slt Anticoagulants (Vitamin K Antag); Heparins/Reteplase

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Reteplase catalyzes the cleavage of endogenous plasminogen to generate plasmin which degrades the fibrin matrix of a thrombus.(1)

CLINICAL EFFECTS: The concurrent use of reteplase and anticoagulants may increase the risk of bleeding.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Carefully weigh the benefit of reteplase versus the risks in patients receiving anticoagulants. Use caution with administering these agents together. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: The most common adverse reaction with reteplase is bleeding. Information regarding use concurrent use of reteplase and anticoagulants is lacking. The manufacturer of reteplase states that studies of concurrent reteplase and anticoagulants have not been conducted.(1)

Slt Anticoagulants (Vitamin K Antagonists); Citrate/Heparins

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Heparin inhibits thrombosis by inactivating activated Factor X and inhibiting the conversion of prothrombin to thrombin.(1)

CLINICAL EFFECTS: Concurrent use of anticoagulants with heparin can enhance the effects of heparin and may increase the risk of bleeding.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The manufacturer recommends baseline and periodic platelet counts and hematocrits for the entire duration of heparin administration.(1) Monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or blood pressure and promptly evaluate patients with any symptoms. Discontinue heparin in patients with active pathological bleeding unless the benefits outweigh the potential risk.(1) Partial thromboplastin time (aPTT) or whole-blood clotting time (WBC) may be monitored to assess coagulation status.(1) Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: A study of the use of heparin and warfarin in DVT patients concluded that it is safe to use heparin in combination with warfarin(2) with proper monitoring.

Warfarin Derivs/Lopinavir; Nelfinavir; Nevirapine; Ritonavir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Lopinavir, nelfinavir, nevirapine, and ritonavir may induce the metabolism of acenocoumarol and warfarin. The more potent S-enantiomer of warfarin is metabolized by CYP2C9 while the weaker R-enantiomer of warfarin is metabolized by CYP3A4 and CYP1A2. Although protease inhibitors can induce or inhibit multiple CYP450 pathways depending upon the drug and time course of therapy, all antiviral agents linked to this monograph are inducers of CYP2C9.

CLINICAL EFFECTS: Concurrent use warfarin derivatives and lopinavir, nelfinavir, nevirapine, and/or ritonavir may result in decreased levels and effectiveness of the anticoagulant, which may increase the risk of clotting.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor INR response closely in patients maintained on acenocoumarol or warfarin when initiating or titrating lopinavir, nelfinavir, nevirapine, or ritonavir. Patients maintained on these agents may require higher dosages of the anticoagulant beginning approximately 1-2 weeks after starting the antiviral. If the antiviral is discontinued, enzyme induction will gradually decrease and the anticoagulant concentration is expected to increase over time. Monitor the INR as the anticoagulant dose may need to be lowered. Also monitor INR closely when initiating warfarin in patients on current therapy or titrating doses of lopinavir, nelfinavir, nevirapine, and ritonavir.

DISCUSSION: In a study in 12 subjects, ritonavir (400mg every 12 hours for 12 days) increased the area-under-curve (AUC) of S-warfarin by 9% and decreased the AUC of R-warfarin by 33%, from a single dose of warfarin (5 mg). The maximum concentration (Cmax) of S-warfarin was decreased 9% and unchanged for R-warfarin. In a case-control study, use of ritonavir (200 mg daily) was associated with an increased warfarin maintenance dose of 3.9 mg. There have been case reports of increased acenocoumarol and warfarin requirements in patients taking lopinavir-ritonavir, nelfinavir, nevirapine, and/or ritonavir. In a retrospective study in 29 patients, INR levels were evaluated with concurrent use of nirmatrelvir-ritonavir and warfarin. In patients treated with nirmatrelvir-ritonavir, the first posttreatment INR was lower than baseline (median INR decrease of 0.40). Following completion of the 5-day course of nirmatrelvir-ritonavir, the measured INR was lower than the pretreatment nirmatrelvir-ritonavir INR (median INR decrease of 0.50). No thrombotic events occurred during the study period after nirmatrelvir-ritonavir use.

Warfarin/Asciminib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Asciminib in a moderate CYP2C9 inhibitor(1) which may decrease the metabolism of the S-enantiomer of warfarin. Also, asciminib and warfarin therapy may both increase the risk of bleeding.(1,2)

CLINICAL EFFECTS: Concurrent use of asciminib may result in elevated levels of warfarin and increased INR.(1) Concurrent use of warfarin and asciminib may increase the risk for bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Pharmacogenomic information: patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective and safe anticoagulation than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: Monitor INRs more frequently until stable in patients who start asciminib therapy, or have the asciminib dose adjusted.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. Discontinue anticoagulation in patients with active pathologic bleeding.

DISCUSSION: In clinical studies, coadministration of asciminib 40 mg twice daily, 80 mg once daily, and 200 mg twice daily, the area-under-the-curve (AUC) of S-warfarin increased by 41%, 52%, and 314%, respectively. Additionally, the maximum concentration (Cmax) of S-warfarin increased by 8%, 4%, and 7%, respectively.(1)

Warfarin/Cannabinoids

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Cannabidiol (CBD) and tetrahydrocannabinol (THC) have been shown to inhibit CYP2C9-mediated metabolism of S-warfarin in vitro.(1) Nabilone(2) and THC(1) may also displace warfarin from protein binding sites. Nabilone is an orally active synthetic cannabinoid.(2) Dronabinol is a synthetic form of THC.(3)

CLINICAL EFFECTS: Concurrent use of CBD and/or THC, dronabinol, or nabilone may result in elevated levels of warfarin and INR(1-5) and increase the risk of bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Pharmacogenomic information: patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective and safe anticoagulation than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: Monitor INRs frequently until stable in patients who start CBD and/or THC, dronabinol, or nabilone or have the dose adjusted.(1) A Health Canada Product InfoWatch regarding the use of cannabis and warfarin advises healthcare professionals to ask patients about their use of cannabis, particularly if patients are being treated with warfarin, due to the potential for increased INR values.(6) Monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. Discontinue anticoagulation in patients with active pathologic bleeding.

DISCUSSION: In a case report, a patient who had received warfarin therapy for 11 years was hospitalized twice with bleeding episodes (gastrointestinal and nosebleeds) and elevated INRs (10.41 and 11.55) during a period of increased marijuana use. After the patient ceased marijuana use, his INRs stabilized.(4) As of September 30, 2020, Health Canada received 2 adverse reaction reports of increased INR suspected of being associated with the use of warfarin and orally ingested or sublingually administered CBD oil or CBD-dominant cannabis oil products. The first case involved a 76-year-old woman who experienced an increase in INR (4.8) less than one week after starting CBD oil. The second case was reported in an 83-year-old man who experienced an increase in INR (6.2) approximately 3 months after starting a CBD-dominant cannabis oil (1 mg/mL THC and 20 mg/mL CBD). There were no other changes to his medications. In both cases, the cannabis product was discontinued, warfarin dose was adjusted and the INR went back within therapeutic range.(6) A systematic review of one in vitro study and two case reports reviewed the interaction between warfarin and cannabis. The review noted the interaction potential of cannabis as a CYP2C9 inhibitor at clinically relevant concentrations that may inhibit warfarin metabolism.(7) In a case report, a 44-year-old male patient took warfarin 7.5 mg daily with therapeutic INRs ranging from 2 to 2.6 for at least six months. After starting CBD oil 265 mg twice daily, the patient's INR increased to 6.86. The warfarin dose was decreased by 30% and the patient's INR returned to the therapeutic range of 2-3.(8) In a case report, a 46-year-old male patient was maintained on a weekly warfarin dose of 80 mg for 5 months (INR range: 1.7 to 3.3). He started cannabidiol 5 mg/kg divided twice daily with a final daily dose titration of 20 mg/kg. Over the course of multiple weeks during the cannabidiol dose titration, an increase in INR was observed (INR increased from 3.1 before the start of cannabidiol therapy and increased to 3.4 on week two and 3.5 on week three). The warfarin weekly dose was adjusted resulting in a 20% decrease and no reported adverse bleeding events.(9) In a case report of a 35-year-old male patient on long term warfarin 10 mg daily with an INR goal of 2.5, an increase in INR to 7.2 occurred following one month of edible cannabis ingestion and cannabis smoking. The INR dropped below 4 upon discontinuation of cannabis with dose adjustments to warfarin.(10) In a case report of a 67-year-old-male patient on long term warfarin 6 mg and 7.5 mg on alternating days, an increase in INR to 5.2 occurred with using two different medical cannabis supplements. Warfarin was held for 2 days and the INR dropped to 2.8. The warfarin weekly dose was decreased by 28-29% and the patient reported no bleeding adverse events.(11) In a case report of a 85-year-old patient, use of oralmucosal medical cannabis had minimal changes in INR over a 1 year period.(12) Delta-9-tetrahydrocannabinol was found to inhibit the CYP2C9 metabolism of S-warfarin in vitro. Studies performed on polycyclic aromatic hydrocarbons found no effect of these compounds on CYP2C9, indicating that combustion may not be required for CYP2C9 inhibition.(1)

Warfarin/Ceritinib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Ceritinib is a weak CYP2C9 inhibitor and a strong CYP3A inhibitor(1) which may decrease the metabolism of both the S-enantiomer and R-enantiomer of warfarin, respectively.(2-4)

CLINICAL EFFECTS: Concurrent use of ceritinib may result in elevated levels of warfarin and INR.(1) Concurrent use of warfarin and ceritinib may increase the risk for bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Pharmacogenomic information: patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective and safe anticoagulation than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: Monitor INRs frequently until stable in patients who start ceritinib therapy, or have the ceritinib dose adjusted.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. Discontinue anticoagulation in patients with active pathologic bleeding.

DISCUSSION: In a study, ceritinib (750 mg daily for 3 weeks) increased the area-under-the-curve (AUC) of a single dose of warfarin by 54 %, compared to warfarin alone. No change in the maximum concentration (Cmax) of warfarin was observed.(1)

Warfarin/Deutivacaftor

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Deutivacaftor is a CYP2C9 inhibitor(1) which may decrease the metabolism of the S-enantiomer of warfarin.(2)

CLINICAL EFFECTS: Concurrent use of deutivacaftor may result in elevated levels of warfarin and increased INR.(1,2)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Pharmacogenomic information: patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective and safe anticoagulation than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: Monitor INRs more frequently until stable in patients who start deutivacaftor therapy, or have the warfarin dose adjusted as indicated.(1) If concurrent therapy is warranted, monitor patients for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Deutivacaftor is a CYP2C9 inhibitor.(1)

Warfarin/Etoposide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Etoposide is a CYP2C9 inhibitor which may decrease the metabolism of the S-enantiomer of warfarin.(1-3)

CLINICAL EFFECTS: Concurrent use of etoposide may result in elevated levels of warfarin and increased INR.(1,2)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Pharmacogenomic information: patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective and safe anticoagulation than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: Monitor INR closely in patients maintained on warfarin when initiating, titrating, and discontinuing etoposide. Patients maintained on etoposide may require lower dosages of warfarin.(1,2) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. Discontinue anticoagulation in patients with active pathologic bleeding.

DISCUSSION: In case reports, patients maintained on warfarin had increased INR levels with concurrent etoposide chemotherapy regimens.(5-7)

Warfarin/Leflunomide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown.

CLINICAL EFFECTS: Concurrent use of leflunomide may result in elevated levels and effects of warfarin, which may increase the risk of bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Monitor INR response closely in patients maintained on warfarin when initiating, titrating, and discontinuing leflunomide. Patients maintained on leflunomide may require lower initial dosages of warfarin. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: In a case report, a 61 year-old female who had stable INRs for 4 months on warfarin dosage of 36 mg/week had an elevated INR of 7.3 approximately 2 weeks after initiating leflunomide (100 mg daily for 3 days, then 20 mg daily).(1) In another case report, a 49 year-old male who had stable INR values for 1 year developed gross hematuria two days after initiating leflunomide (100 mg daily for 3 days, then 20 mg daily).(2) Four cases of elevated INR during concurrent warfarin and leflunomide have been reported to the UK Committee on Safety of Medicines.(2,3)

Warfarin/Lomitapide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Lomitapide is a weak CYP2C9 inhibitor and a weak CYP3A inhibitor which may decrease the metabolism of both the S-enantiomer and R-enantiomer of warfarin, respectively.(2-4)

CLINICAL EFFECTS: Concurrent use of lomitapide may result in elevated levels of warfarin and INR.(1) Concurrent use of warfarin and lomitapide may increase the risk for bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Pharmacogenomic information: patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective and safe anticoagulation than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: Monitor INRs frequently until stable in patients who start lomitapide therapy, or have the lomitapide dose adjusted.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. Discontinue anticoagulation in patients with active pathologic bleeding.

DISCUSSION: Administration of lomitapide (60 mg daily for 7 days) increased the area-under-curve (AUC) and maximum concentration (Cmax) of a R-warfarin by 28% and 14%, respectively, following the administration of a single dose of warfarin (10 mg). The AUC and Cmax of S-warfarin increased by 30% and 15%, respectively. INR values increased by 22%.(1) In clinical trials for lomitapide, one of five patients receiving concurrent warfarin had to withdraw from the trial as a result of difficulty in controlling INR values.(1)

Warfarin/Milk Thistle

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Milk thistle may inhibit the metabolism of warfarin through CYP2C9.(1)

CLINICAL EFFECTS: Concurrent use of warfarin and milk thistle may result in elevated INR values and increased risk of bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Advise patients against using milk thistle products with warfarin and to report the initiation or discontinuation of any alternative therapy agents. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit,fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black,tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: A review of in vivo and in vitro drug interaction studies with milk thistle suggests there is the possibility of significant CYP2C9 inhibition by milk thistle. In one case study, an individual stable on a warfarin dose of 36.5 mg per week for 8 months began taking a supplement containing 200 mg of milk thistle. At a 4-week follow up, the patient's INR had increased from 2.64 to 4.12. The patient was instructed to stop the supplement, hold one dose of warfarin, and then continue his previous dose. At a 1-week follow-up, his INR was slightly sub-therapeutic at 2.37, but repeat INRs were therapeutic at 3.24 and 2.98 at 4 and 8 weeks.(2) A study was conducted to investigate the effects of milk thistle on the pharmacokinetics of losartan (a CYP2C9 substrate) and its active metabolite E-3147, and its relationship with CYP2C9 genotypes. The AUC of losartan increased significantly following a 14-day milk thistle treatment in subjects with CYP2C9*1/*1 genotype. The results showed that milk thistle inhibits the metabolism of losartan to E-3147, with the magnitude of the interaction differing in individuals with different CYP2C9 genotypes.(3)

Warfarin/Norethindrone (>= 5 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Norethindrone is a weak CYP2C9 inhibitor(1) which may decrease the metabolism of the S-enantiomer of warfarin.(1,2)

CLINICAL EFFECTS: Concurrent use of norethindrone may result in elevated levels of warfarin and increased INR.(1-3)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Pharmacogenomic information: patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective and safe anticoagulation than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: Monitor INRs more frequently until stable in patients who start norethindrone therapy.(2,3) Monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. Discontinue anticoagulation in patients with active pathologic bleeding.

DISCUSSION: A case series of 3 adolescent females with a history of mechanical mitral valve replacement who developed heavy menstrual bleeding (HMB) found that starting norethindrone in combination with warfarin resulted in increased INRs.(3) -Patient 1, a 12-year-old female, who was stable on 42 mg warfarin weekly, started norethindrone 10 mg daily for HMB. The patient's INR became supratherapeutic (INR 4-6) and required a decrease in warfarin dose to 21 mg weekly (50% reduction).(3) -Patient 2, a 14-year-old female, who was stable on 35 mg warfarin weekly, started norethindrone for HMB (10 mg four times daily for 4 days followed by a maintenance dose of 15 mg daily). The patient required a 43% dose reduction of warfarin to 28 mg weekly.(3) -Patient 3, a 15-year-old female, was stable on 24.5 mg of warfarin weekly. After starting norethindrone 5 mg for 1 month and increasing norethindrone to 10 mg daily, the patient's warfarin requirement decreased to 17.5 mg weekly and eventually stabilized at 19 mg weekly (29% dose reduction). One year later, an intrauterine device was placed and norethindrone was tapered and discontinued over 2 months. The patient's warfarin requirement increased to 28 mg weekly once norethindrone was discontinued (47% increase).(3)

Warfarin/Noscapine; Oxolamine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Noscapine may inhibit the metabolism of warfarin by CYP2C9.(1,2) The mechanism for the interaction between oxolamine and warfarin is unknown.(3)

CLINICAL EFFECTS: Concurrent use of noscapine(1,2) or oxolamine(3) may result in increased warfarin effects.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Pharmacogenomic information: patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective and safe anticoagulation than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: Monitor patients maintained on warfarin if noscapine or oxolamine is initiated or discontinued. Consider decreasing the dosage of warfarin by 50% in patients during oxolamine therapy.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. Discontinue anticoagulation in patients with active pathologic bleeding.

DISCUSSION: Eight cases of increased warfarin effects, 7 involving increased INR and one involving bleeding have been reported to the Swedish Adverse Drug Interactions Register (SWEDIS).(1) There are another four cases reported elsewhere in the medical literature.(2) A retrospective review examined 11 patients maintained on warfarin who received concurrent oxolamine. In the six patients who did not receive a warfarin dosage adjustment at the start of oxolamine therapy, INR increased by 70% to 190%. Two patients developed hematoma and were treated with phytonadione. In the 5 subjects whose warfarin dose was decreased by 30%-40% at the initiation of oxolamine, 4 had increased INR values up to 36%.(3) In a prospective follow-up to this review, 6 female patients maintained on warfarin with stable INR values were given oxolamine (range 100-600 mg daily for an average of 6.2 days). At the initiation of oxolamine, warfarin dosages were reduced by 50% and returned to previous dosages at the discontinuation of oxolamine. At the completion of oxolamine therapy, all patients had INR levels in or slightly below the target range and no patient required any further adjustments. INRs remained in the target range 1-8 weeks after the completion of oxolamine therapy in all but 1 subject who began prednisolone therapy at the end of oxolamine therapy.(3)

Warfarin/Oral Contraceptives

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The more potent warfarin S-enantiomer is metabolized by CYP2C9 while the weaker R-enantiomer is metabolized by several CYP enzymes including CYP1A2, CYP2C19, and CYP3A4.(1) Oral contraceptives are moderate inhibitors of CYP1A2 and weak inhibitors of CYP3A4.(2) Oral contraceptives (OC) have been shown to induce the activity of CYP2C9.(7)

CLINICAL EFFECTS: Concurrent use of oral contraceptives may result in increased or decreased levels of warfarin which may increase the risk of clotting or bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Pharmacogenomic information: patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective and safe anticoagulation than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: Monitor INRs more frequently until stable in patients who start oral contraceptive therapy. Monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. Discontinue anticoagulation in patients with active pathologic bleeding.

DISCUSSION: A case series of 3 adolescent females with a history of mechanical mitral valve replacement who developed heavy menstrual bleeding (HMB) found that starting norethindrone in combination with warfarin resulted in increased INRs.(3) -Patient 1, a 12-year-old female, who was stable on 42 mg warfarin weekly, started norethindrone 10 mg daily for HMB. The patient's INR became supratherapeutic (INR 4-6) and required a decrease in warfarin dose to 21 mg weekly (50% reduction).(3) -Patient 2, a 14-year-old female, who was stable on 35 mg warfarin weekly, started norethindrone for HMB (10 mg four times daily for 4 days followed by a maintenance dose of 15 mg daily). The patient required a 43% dose reduction of warfarin to 28 mg weekly.(3) -Patient 3, a 15-year-old female, was stable on 24.5 mg of warfarin weekly. After starting norethindrone 5 mg for 1 month and increasing norethindrone to 10 mg daily, the patient's warfarin requirement decreased to 17.5 mg weekly and eventually stabilized at 19 mg weekly (29% dose reduction). One year later, an intrauterine device was placed and norethindrone was tapered and discontinued over 2 months. The patient's warfarin requirement increased to 28 mg weekly once norethindrone was discontinued (47% increase).(3) A comparative pharmacokinetic study of 14 women found that administration of oral contraceptive steroids in combination with phenprocoumon resulted in decreased serum phenprocoumon concentrations. There was a significant increase in the mean clearance of phenprocoumon from 1.6 to 2.0 mL/min/kg (p <0.05).(4) A case report of a 33-year-old female on long-term anticoagulation following an aortic valve replacement found that stopping Ortho-Cyclen while on warfarin resulted in decreased INRs. While on warfarin (38.5 mg weekly) with a therapeutic INR, she was transitioned from Ortho-Cyclen to implantable progestin-only contraceptive. 19 days after insertion, her INR decreased to 1.8 and required a 55% warfarin dose increase (60 mg weekly). The patient had the implant removed 10 months later and 9 days following removal, her INR went up to 6.5 and finally returned to therapeutic once her dose was reduced to 55.5 mg weekly.(5) An observational study with 12 patients taking nicoumalone (coumarin derivative) and an OC (Neogynona, Microgynon, Eugynon, or Topasel) were assessed in 2 phases using British comparative thromboplastin (BCT). The therapeutic range for commercial thromboplastin ranges from 1.3-1.8, which corresponds to a PT INR of 2-3. Phase A consisted of patients taking both nicoumalone and an OC, while phase B consisted of patients only taking nicoumalone. The mean thromboplastin in phase A was higher than phase B (1.67 vs 1.50; p<0.01) and statistically significant. These findings coincide with a lesser mean requirement for anticoagulation in phase A (2.05 mg) compared to phase B (2.53 mg).(6) In a randomized crossover study with 10 healthy women, participants were started on the Cooperstown 5+1 cocktail (oral caffeine, oral dextromethorphan, oral omeprazole, IV midazolam, and oral warfarin + vitamin k) in 2 phases. There was a 2 month wash-out period between phase 1 and phase 2, with phase 2 adding oral Ortho-Tricyclen. All women in the study carried at least 1 normal-activity allele for CYP2C9, CYP2C19, and CYP2D6. The study found that CYP2C9 and 2D6 activity was increased when taking oral contraception, while CYP1A2, 2C19, and NAT-2 activity decreased.(7)

Warfarin/Regorafenib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Regorafenib is a CYP2C9 inhibitor(1) which may decrease the metabolism of the S-enantiomer of warfarin.(2-4) Also, regorafenib and warfarin therapy may both increase the risk of bleeding.(1-2)

CLINICAL EFFECTS: Concurrent use of regorafenib may result in elevated levels of warfarin and INR.(1) Concurrent use of warfarin and regorafenib may increase the risk for bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Pharmacogenomic information: patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective and safe anticoagulation than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: Monitor INRs more frequently until stable in patients who start regorafenib therapy.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. Discontinue anticoagulation in patients with active pathologic bleeding.

DISCUSSION: In a study of 8 healthy subjects, regorafenib (160 mg once daily) increased the area-under-the-curve (AUC) of a single dose of warfarin by 25%, compared to warfarin alone.(1) In clinical studies, regorafenib increased the risk of hemorrhage, with an overall incidence of hemorrhage Grades 1-5 of 18.2% compared to 9.5% in the placebo group. The incidence of grade 3 or higher hemorrhage was 3% in patients treated with regorafenib, including an incidence of 0.7% of fatal hemorrhagic events.(1) In a case report of a 76 year old man with liver metastasis of colon cancer, three weeks after starting regorafenib therapy the INR increased significantly. The INR before starting regorafenib was 1.26 and significantly increased to 2.1 on day 8, 2.98 on day 15, and 6.4 on day 22. Both regorafenib and warfarin were stopped, and the INR decreased to 1.31 within one week. Warfarin was resumed at a lower dose and titrated based on INR during subsequent regorafenib therapy without further elevation.(5)

Warfarin/Rivoceranib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Rivoceranib is a CYP2C9 inhibitor(1) which may decrease the metabolism of the S-enantiomer of warfarin.(2)

CLINICAL EFFECTS: Concurrent use of rivoceranib may result in elevated levels of warfarin and increased INR.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Pharmacogenomic information: patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective and safe anticoagulation than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: Monitor INRs more frequently until stable in patients who start rivoceranib therapy, or have the warfarin dose adjusted as indicated.(1) If concurrent therapy is warranted, monitor patients for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: In a clinical study, coadministration with rivoceranib increased the area-under-curve (AUC) and concentration maximum (Cmax) of S-warfarin by 92% (90% CI 1.68-2.18) and 24% (90% CI 1.10-1.39), respectively.(5)

Warfarin/Teriflunomide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Teriflunomide may induce the metabolism of R-warfarin by CYP1A2.(1,2)

CLINICAL EFFECTS: Concurrent use of teriflunomide may result in decreased levels and effectiveness of warfarin, which may increase the risk of clotting.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor INR response closely in patients maintained on warfarin when initiating, titrating, and discontinuing teriflunomide. Patients maintained on teriflunomide may require higher dosages of warfarin.

DISCUSSION: Concurrent teriflunomide and warfarin resulted in a 25% decrease in peak INR values. Teriflunomide was found to have no effect on the pharmacokinetics of S-warfarin, a CYP2C9 substrates. However, it is a weak inducer of CYP1A2.(1) R-warfarin is a substrate of CYP1A2.(2)

Warfarin/Valproic Acid

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The more active S-isomer of warfarin is primarily metabolized by CYP2C9(1) and valproic acid is an inhibitor of CYP2C9.(2-4) In addition, both drugs are highly protein bound and may compete for albumin binding sites.(4-6)

CLINICAL EFFECTS: Valproic acid may increase warfarin concentrations leading to an increase in INR and risk for bleeding.

PREDISPOSING FACTORS: Patients with normal serum albumin and valproic acid concentrations at the higher end of the therapeutic range, or patients with low serum albumin at any valproic acid concentration are at greater risk for a clinically significant interaction. The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Monitor INR response closely in patient maintained on warfarin when initiating, increasing or discontinuing valproic acid. Patients maintained on valproic acid may require lower initial doses of warfarin. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Valproic acid is highly protein bound. At usual therapeutic doses valproic acid is present in high molar concentrations and may saturate albumin binding sites.(4) Further increases in valproic acid dosage lead to a disproportionate increase in free (unbound) valproic acid concentration, increasing the risk for inhibition of CYP2C9 mediated metabolism of warfarin and displacement of warfarin from albumin binding sites. One manufacturer describes an in vitro study in which valproate increased the free fraction of warfarin by up to 32.6%.(5) In a case report, a 71 year-old female patient with glioblastoma multiforme had been maintained on warfarin (5 mg/day on Saturday and Sunday and 2.5 mg/day the other days of the week) with an INR target range of 2-3. Other medications included oral pravastatin 20 mg/day and dexamethasone 2 mg/day. The patient was admitted for complex partial seizures. During transport, she was given intravenous levetiracetam (dose not stated), midazolam 3 mg, and dexamethasone 4 mg. Upon arrival she was given additional 1 gram of intravenous(IV) levetiracetam. Warfarin 2.5mg was administered on the night of admission. Her INR on Day 2 was 3.4 and the warfarin dose was reduced to 0.75 mg due to bleeding concerns. The dose of levetiracetam was increased to 2.5 grams IV twice daily. An IV loading dose of valproic acid of 20 mg/kg (1,100 mg) was administered followed by a maintenance dose of 500 mg IV twice daily (later changed to 250mg every six hours per nasogastric tube). On Day 3, the total valproic acid level was 108 ug/mL (target range: 50-100 ug/mL), free valproic acid level was 20 ug/mL (target range: 4-15 ug/mL), and the INR had increased to 5.5. Eight hours later, the INR had further increased to 7.6. No other hemodynamic or metabolic changes were noted. Valproic acid was stopped, oral vitamin K (dose not stated) was given, and warfarin was held for the following two days. Warfarin was resumed when the INR had decreased to 2.5.(7) In a case report, a 42 year-old female patient was maintained on a regimen of divalproex sodium (1,000 mg/day) and lamotrigine (150 mg/day). She underwent surgery for cardiac valve replacement. Her INR on post-surgery Day 1 was 1.11 and she received warfarin (2.5 mg). On Day 4 her INR had increased to 6.54. Warfarin was held and she was given two units of fresh frozen plasma. Her INR decreased to 3.23. On Day 5, her INR increased to 5.42 without any additional doses of warfarin. Her serum valproate level was 91.7 ug/mL. (therapeutic range: 50-100 ug/mL). Divalproex sodium was held. On Day 6, the INR decreased to 3.27. The divalproex sodium was restarted (250 mg twice daily) on Day 7 and the serum valproate level on Day 8 was 30.2 ug/mL. The patient was discharged on Day 15 with an INR of 1.73, but had INR levels as high as 8.2 associated with epistaxis. Divalproex sodium was discontinued and replaced with another agent two months after surgery.(8)

Warfarin/Venetoclax

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Venetoclax may increase systemic exposure to warfarin. The mechanism of this interaction is not clear.

CLINICAL EFFECTS: Concurrent use of venetoclax with warfarin may increase the risk of bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The manufacturer of venetoclax recommends more frequent monitoring of the INR in patients taking this combination.(1) When initiated, venetoclax dosage gradually increases over 5 or more weeks, thus extended INR monitoring may be required to assess interaction risk and magnitude. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: In a drug-drug interaction study in three healthy subjects, administration of a single 400 mg dose of venetoclax with 5 mg of warfarin increased the maximum concentration (Cmax) and area-under-curve (AUC) of warfarin 18% and 28% respectively.(1) Because only one dose of venetoclax was given in this study, the interaction severity and recommended monitoring duration for the combination of venetoclax and warfarin is not clear.

*Pregnancy, except in patients with mechanical heart valves.

*Patients with hemorrhagic tendencies or blood dyscrasias.

*Recent or contemplated surgery of the eye or CNS and in those undergoing traumatic surgery resulting in large open surfaces.

*Bleeding tendencies associated with active ulceration or overt bleeding of the GI, respiratory, or genitourinary tract; CNS hemorrhage; aneurysms (cerebral, dissecting aorta); pericarditis and pericardial effusions; bacterial endocarditis.

*Threatened abortion, eclampsia, and preeclampsia.

*Unsupervised patients with conditions associated with a potential high level of non-compliance with therapy (e.g., dementia/senility).

*Known hypersensitivity (e.g., anaphylaxis).

*Spinal puncture and other diagnostic or therapeutic procedures associated with the potential for uncontrollable bleeding.

*Major regional or lumbar block anesthesia.

*Malignant hypertension.

• Aortic aneurysm with dissection
• Calciphylaxis
• Cerebral amyloid angiopathy
• Deep peripheral nerve block
• Deep plexus block
• Gastrointestinal hemorrhage
• Gastrointestinal ulcer
• Genitourinary tract hemorrhage
• Hemorrhage
• Increased risk of bleeding due to coagulation disorder
• Intracranial bleeding
• Invasive procedure on spine
• Neuraxial anesthesia
• Pericardial effusion
• Pericarditis
• Placement of indwelling epidural catheter
• Pregnancy
• Respiratory tract hemorrhage
• Severe uncontrolled hypertension
• Threatened abortion

• Bacterial endocarditis
• Brain aneurysm
• Cholesterol embolism
• Gangrene
• Heparin-induced thrombocytopenia
• Increased risk of bleeding
• Invasive surgical procedure
• Major traumatic injury
• Protein C deficiency disease
• Surgical procedure on eye proper
• Vitamin K deficiency

• Anemia
• Biliary obstruction
• Bleeding risk associated with vitamin K epoxide reductase (warfarin-sensitive) gene
• CYp2c9 poor metabolizer
• Disease of liver
• Fever
• Indwelling vascular catheter
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Malignancy
• Polycythemia vera
• Protein-calorie malnutrition
• Severe diarrhea
• Steatorrhea
• Tropical sprue

Most common adverse effects: fatal and nonfatal hemorrhage from any tissue or organ.

More Frequent

• Hemorrhage

Less Frequent

• Leukopenia

Rare or Very Rare

• Abnormal hepatic function tests
• Agranulocytosis
• Allergic dermatitis
• Anaphylaxis
• Anemia
• Anticoagulant-related nephropathy
• Calcification of bronchus
• Calcification of trachea
• Calciphylaxis
• Cholestatic hepatitis
• Cholesterol embolism
• Dermal necrosis
• Gangrene
• Hematuria
• Hepatitis
• Hypersensitivity drug reaction
• Intracerebral hemorrhage
• Jaundice
• Pruritus of skin
• Tissue necrosis
• Urticaria
• Vasculitis

Less Frequent

• Abdominal pain with cramps
• Alopecia
• Diarrhea
• Dysgeusia
• Flatulence
• Nausea
• Vomiting

Rare or Very Rare

• Abdominal distension
• Chills
• Fever
• Pallor
• Purpura
• Skin rash

No enhanced messaging available.

The manufacturer of warfarin states that the optimum dosing, safety, and efficacy in pediatric patients are unknown due to a lack of adequate, well-controlled studies. Pediatric use of warfarin is based on adult data and recommendations, as well as limited pediatric data from observational studies and patient registries. However, the drug has been used in pediatric patients for prevention and treatment of thromboembolic events.

Difficulty achieving and maintaining therapeutic INRs has been reported in pediatric patients, and more frequent assessments of INR are recommended in such patients because of possible changing warfarin requirements due to age, concomitant medications, diet, and comorbid conditions. Variable bleeding rates have been observed in pediatric patients; therefore, such patients should avoid activities or sports that may result in traumatic injury.

Infants may have the highest and adolescents the lowest mg per kg dosage requirements. Human milk-fed children may be more sensitive to warfarin compared to those receiving vitamin-K supplemented nutrition.

Warfarin can cause fetal harm and is contraindicated during pregnancy except in women with mechanical heart valves who are at high risk of thromboembolism and for whom the benefits of warfarin may outweigh the risks.

Major congenital malformations (warfarin embryopathy and fetotoxicity), fatal fetal hemorrhage, and an increased risk of spontaneous abortion and fetal mortality may occur as a result of warfarin exposure during pregnancy. Warfarin embryopathy is characterized by nasal hypoplasia with or without stippled epiphyses (chondrodysplasia punctata) and growth retardation (including low birth weight). CNS 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. Teratogenicity risk is highest during the first trimester, at 6-12 weeks of gestation. However, risk of pregnancy loss or fetal hemorrhage still exists for warfarin exposure in the second and/or third trimester.

The risk of valve thrombosis is much higher with mechanical heart valves because of the hypercoagulable state. Pregnant women with mechanical heart valves should receive therapeutic anticoagulation with frequent monitoring during pregnancy. Despite the risks of warfarin to the fetus, the drug has been used in pregnant women with prosthetic heart valves who are at an increased risk for valve thrombosis. The manufacturer states in these situations, the decision to initiate or continue warfarin should be reviewed with the patient, taking into consideration the specific risks and benefits pertaining to that individual patient's medical situation, as well as the most current medical guidelines. If warfarin is used during pregnancy, or if the patient becomes pregnant while taking warfarin, the patient should be apprised of the potential hazard to a fetus.

The American College of Cardiology/American Heart Association (ACC/AHA) issued guidelines for the management of patients with valvular heart disease, which includes recommendations for the management of women with mechanical heart valves who are pregnant or plan to become pregnant. Multiple strategies to reduce, as well as balance, the maternal (e.g., valve thrombosis, death) and fetal risks (e.g., fetal loss, teratogenicity) are based on factors such as daily warfarin dosage (<= or >5 mg/day), ability to utilize heparin or low molecular weight heparin (LMWH), ability to conduct frequent laboratory monitoring (e.g., INR, anti-Xa levels), and the patient's values and priorities. No single anticoagulation strategy is optimally safe for both the mother and the fetus; maternal and fetal risks can be reduced, but not eliminated. Options include warfarin continuation throughout pregnancy, dose-adjusted heparin or LMWH with frequent anti-Xa level monitoring throughout pregnancy, or sequential therapy with dose-adjusted heparin or LMWH with frequent anti-Xa level monitoring during the first trimester and warfarin during the second and third trimesters. Heparin and LMWH therapy have been associated with an increased maternal risk for valve thrombosis, death, and major bleeding complications in women with prosthetic heart valves.

Other guidance documents (e.g., American College of Obstetricians and Gynecologists (ACOG), American Society of Hematology (ASH)) should be consulted for the management of other warfarin indications in the context of pregnancy.

The timing of anticoagulation discontinuance in anticipation of labor and delivery is important to reduce the risk of maternal and fetal bleeding; women should have an individualized plan that addresses obstetrical, anesthetic, and thrombotic concerns.

Limited data suggest that warfarin is not significantly distributed into human milk, is not detectable in plasma of nursing infants, and has not produced substantial coagulation abnormalities in such infants. Based on limited available data, it is considered unlikely that maternal warfarin therapy would pose a substantial risk to healthy, full-term infants receiving human milk, and ACOG, ASH, American Academy of Pediatrics (AAP), ACCP and other experts consider maternal warfarin therapy to be compatible with breast-feeding. Women should inform their clinician if they are breast-feeding or plan to breast-feed. The manufacturers state that the decision to breast-feed while receiving warfarin anticoagulation should be made only after careful consideration of the mother's clinical need for warfarin, the developmental and health benefits of breastfeeding, and potential adverse effects.

Neonates are particularly sensitive to the effects of warfarin as a result of vitamin K deficiency; monitor infants receiving human milk for bruising and bleeding. The effects of warfarin in premature infants have not been evaluated.

In patients >60 years of age, the manufacturer recommends considering lower initial and maintenance warfarin dosages and more frequent monitoring for bleeding.

Age does not appear to substantially affect the pharmacokinetics of racemic warfarin, and the manufacturer states that the clearance of S-warfarin is similar in geriatric versus younger individuals. However, the clearance of R-warfarin appears to be slightly reduced in geriatric patients compared with that in younger individuals. Patients >60 years of age appear to exhibit a greater than expected INR response to warfarin, and a lower dosage is required to produce a therapeutic level of anticoagulation. Increasing age has been shown to confer a greater risk for bleeding outcomes, and advanced age has been included as a risk factor in both disease and bleeding risk stratification tools. The cause for increased sensitivity in geriatric patients is unknown but may be due to a combination of pharmacokinetic and pharmacodynamic factors. Consider lower initial and maintenance doses for elderly and/or debilitated patients. Conduct more frequent monitoring for bleeding in any situation or with any physical condition where added risk of hemorrhage is present.

A systematic review with meta-analysis of 11 clinical trials involving warfarin and direct oral anticoagulants (DOACs; e.g., dabigatran, apixaban, rivaroxaban, edoxaban) for atrial fibrillation and venous thromboembolism (VTE) compared the benefits and harms of these therapies in patients >=75 years of age. Of the 102,479 patients within the 11 trials, 31,418 were >=75 years of age. In these patients, DOACs were shown to be at least as effective as warfarin in reducing the recurrence of stroke, systemic embolism, and VTE; however, DOAC therapy was associated with a significantly lower risk of intracranial bleeding. When stratified by major bleeding, GI bleeding, and clinically relevant bleeding, comparisons were limited due to trial design and data availability; warfarin or a specific DOAC was favored depending upon the specific bleeding outcome.