Pradaxa (dabigatran etexilate mesylate)

Dosage of dabigatran, which is commercially available as dabigatran etexilate mesylate, is expressed in terms of the prodrug, dabigatran etexilate.

Administer dabigatran orally (as capsules or oral pellets).

Dabigatran is not a substrate, inducer, or inhibitor of cytochrome P-450 (CYP) isoenzymes. Dabigatran is a substrate for the P-glycoprotein (P-gp) transport system.

The manufacturer states no clinical drug interaction studies have been conducted in pediatric subjects.

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/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.

Dabigatran/Anticoagulants; Thrombolytics

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.

Dabigatran/Cobicistat

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 etexilate is a substrate for the P-glycoprotein (P-gp) system. Cobicistat may inhibit intestinal P-gp, leading to increased absorption of dabigatran.(1-4)

CLINICAL EFFECTS: The concurrent use of dabigatran with cobicistat may lead to elevated plasma levels of dabigatran, increasing the risk for bleeding.

PREDISPOSING FACTORS: Factors associated with an increased risk for bleeding include renal impairment, 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.(1-2)

PATIENT MANAGEMENT: The UK manufacturers of products containing cobicistat state that dabigatran is contraindicated with cobicistat-containing products.(4-7) The US manufacturers of cobicistat(3) and of the combination products containing atazanavir-cobicistat(8) and elvitegravir-cobicistat(9) state that dosing recommendations for dabigatran depend on indication and renal function. If coadministration is necessary, assess renal function and evaluate the patient for other pre-existing risk factors for bleeding prior to initiating concomitant therapy. The combination of dabigatran and cobicistat should be avoided in atrial fibrillation patients with severe renal impairment (CrCl less than 30 ml/min) and in patients with moderate renal impairment (CrCl less than 50 ml/min) being treated for or undergoing prophylaxis for deep vein thrombosis (DVT) or pulmonary embolism (PE). The US manufacturer of the combination of darunavir-cobicistat states that concurrent use with dabigatran should be monitored closely. Refer to dabigatran prescribing information for specific recommendations depending on the indication for dabigatran and patient's renal function.(10) The US Department of Health and Human Services guidelines for the use of antiretroviral agents in HIV state that there is no data on the concomitant use of darunavir-cobicistat with dabigatran, and alternative agents should be considered.(11) 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. Consider regular monitoring of hemoglobin, platelet levels, and/or activated partial thromboplastin time (aPTT) or ecarin clotting time (ECT). 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: In healthy volunteers, simultaneous administration and separation of administration by 2 hours of cobicistat (150 mg daily) with dabigatran (150 mg single dose) increased dabigatran area-under-curve (AUC) by 127% and 110%, respectively. Thrombin time (TT) at 24 hours post-dabigatran dose was also increased with simultaneous and separation of dose by 2 hours by 51% and 46%, respectively.(12) In healthy volunteers, a single dose of darunavir 800 mg-cobicistat 150 mg daily increased dabigatran maximum concentration (Cmax) by 2.64-fold and AUC by 2.64-fold. In healthy volunteers, darunavir 800 mg-cobicistat 150 mg daily (administered for 14 days before dabigatran) increased dabigatran Cmax by 1.99-fold and AUC by 1.88-fold.(10)

Dabigatran/Heparins

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: Heparin inhibits thrombosis by inactivating activated Factor X and inhibiting the conversion of prothrombin to thrombin. Dabigatran is a direct thrombin inhibitor.(1,2)

CLINICAL EFFECTS: Concurrent use of anticoagulants with heparin can enhance the effects of heparin and may increase the risk of bleeding.(1,2)

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. 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 dabigatran in patients with active pathological bleeding.(2) The UK manufacturer states that the use of unfractionated heparin, heparin derivatives, and low molecular weight heparins with concomitant dabigatran therapy is contraindicated unless switching treatment to or from dabigatran or when unfractionated heparin is given at doses appropriate to maintain open central venous or arterial catheter.(1) When converting from parenteral anticoagulant to dabigatran, administer dabigatran 0-2 hours before the next dose of the parenteral drug is due or at time of discontinuation of a continuously infused anticoagulant.(2) When converting from dabigatran to a parenteral anticoagulant, begin parenteral anticoagulant: -----12 hours after last dose of dabigatran in patients with CrCl greater than or equal to 30ml/min, -----24 hours after last dose of dabigatran in patients with CrCl less than 30 ml/min.(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.

DISCUSSION: The use of both agents is likely to increase the frequency and occurrence of unwanted bleeding episodes. The use of heparin to maintain catheter patency is acceptable with the use of these agents together.(1,2)

Dabigatran/P-Glycoprotein (P-GP) Inducers

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 substrate of the intestinal efflux transporter P-glycoprotein (P-gp), and has a low oral bioavailability of 3-7%.

CLINICAL EFFECTS: Concurrent or recent use of apalutamide, carbamazepine, fosphenytoin, lorlatinib, phenytoin, rifampin, rifapentine, or St. John's wort may result in decreased levels and effectiveness of dabigatran.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concurrent use of an inducer of P-gp such as apalutamide, carbamazepine, fosphenytoin, lorlatinib, phenytoin, rifampin, rifapentine or St. John's wort in patients maintained on dabigatran.(1) Consider alternatives to these agents in patients maintained on dabigatran. If therapy with an inducer of P-gp is required, alternatives to dabigatran may need to be considered. If a P-gp inducer is discontinued, dabigatran exposure will remain impaired for at least one week after the completion of therapy.(1,2)

DISCUSSION: Pretreatment with rifampin (an inducer of P-gp, 600 mg daily for 7 days) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of dabigatran by 66% and 67%, respectively.(1-3) One week after rifampin discontinuation, exposure to dabigatran was close to normal.(1,2) In a case report, a patient taking concomitant dabigatran (150 mg twice a day) and phenytoin (100 mg three times a day) had no detectable serum concentration of dabigatran 10 hours after the morning dabigatran dose.(6) Other inducers of P-glycoprotein include apalutamide, carbamazepine, fosphenytoin, lorlatinib, phenytoin, rifampin, rifapentine, and St. John's wort.(2-5)

Dabigatran/Risdiplam

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: Risdiplam may inhibit the renal excretion of substrates of Multidrug and Toxin Extrusion (MATE) protein transporters in the kidneys.(1) Dabigatran is a MATE substrate.

CLINICAL EFFECTS: Concurrent use of risdiplam may result in increased levels of and toxicity from dabigatran (a MATE substrate), including increased risk of bleeding.(1)

PREDISPOSING FACTORS: Factors associated with an increased risk for bleeding include renal impairment, concomitant use of P-gp inhibitors, patient age greater than 74 years, coexisting conditions (e.g. recent trauma) or use of drugs (e.g. NSAIDs) associated with bleeding risk, and patient weight less than 50 kg.(2-5)

PATIENT MANAGEMENT: Avoid concurrent use of dabigatran, a MATE substrate, with risdiplam. If concurrent use cannot be avoided, monitor for toxicities of dabigatran or consider alternative anticoagulant therapy.(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. Consider regular monitoring of hemoglobin, platelet levels, and/or activated partial thromboplastin time (aPTT) or ecarin clotting time (ECT). 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: Based upon in vitro data, risdiplam is expected to produce clinically significant inhibition of MATE1 and MATE2-K transporters at clinically relevant concentrations.(1)

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

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/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)

Betrixaban; Dabigatran/P-Gp Inhibitors That Cause Bleeding

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

MECHANISM OF ACTION: This combination may interact via both a pharmacodynamic and a pharmacokinetic mechanism. Pharmacodynamically, serotonin release by platelets plays a role in hemostasis.(1) Fluvoxamine may cause a decrease in serotonin reuptake by platelets, resulting in an additive risk of bleeding with oral anticoagulants.(1) 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 anticoagulants may further increase risk.(2) Pharmacokinetically, fluvoxamine and mifepristone are inhibitors of the P-glycoprotein (P-gp) transporter and may increase the absorption of betrixaban and dabigatran.(3)

CLINICAL EFFECTS: Concurrent use of P-gp inhibitors with betrixaban or dabigatran may result in bleeding. The concurrent use of mifepristone with anticoagulants may result in endometrium thickening, cystic dilatation of endometrial glands, or excessive vaginal bleeding.(2)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia, recent trauma). Renal impairment has been associated with an elevated risk of GI bleed in patients on SSRIs.(4) Patient-associated risk factors include age greater than 74 years and weight less than 50 kg.(5,6) Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet transport or metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Concurrent therapy of P-gp inhibitors with betrixaban or dabigatran should be undertaken with caution. Assess renal function and evaluate the patient for other pre-existing risk factors for bleeding prior to initiating concurrent therapy. The concurrent use of betrixaban and P-gp inhibitors should be avoided in patients with severe renal impairment (CrCl less than 30 ml/min). The recommended dose of betrixaban for patients receiving or starting concomitant P-gp inhibitors is an initial single dose of 80 mg followed by 40 mg once daily. The recommended duration of treatment is 35 to 42 days.(5) The US manufacturer of dabigatran states that the concurrent use of dabigatran and P-gp inhibitors should be avoided in atrial fibrillation patients with severe renal impairment (CrCl less than 30 ml/min) and in patients being treated for or undergoing prophylaxis for deep vein thrombosis (DVT) or pulmonary embolism (PE) who have moderate renal impairment (CrCl less than 50 ml/min). The interaction with P-gp inhibitors can be minimized by taking dabigatran several hours apart from the P-gp inhibitor dose.(6) The manufacturer of mifepristone states that mifepristone should be used with caution in patients receiving concurrent anticoagulant therapy.(2) Women experiencing vaginal bleeding during concurrent use should be referred to a gynecologist for further evaluation. 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. 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: In the APEX randomized, double-blind study the incidence of major or clinically relevant non-major bleeds (CRNM) in the betrixaban 40mg and 80 mg group was higher in patients taking concomitant P-gp inhibitors (2.8% vs. 4.1% vs. 4.7%).(7) In a study in 12 subjects, concomitant administration of betrixaban (40 mg) following a 5-day regimen of ketoconazole (200 mg twice daily) resulted in an increase in betrixaban's maximum concentration (Cmax) and area-under-the-curve (AUC) of 2.3-fold and 2.3-fold, respectively.(8) An open-label study, concomitant administration of a single dose of betrixaban with verapamil resulted in an increase in betrixaban's Cmax and AUC of approximately 4.7-fold and 3-fold, respectively.(8) Coadministration with amiodarone resulted in an increase in betrixaban's Cmax by 143%.(8) When dabigatran was co-administered with amiodarone, dabigatran AUC and Cmax were increased by about 60% and 50%, respectively.(9) Chronic administration of verapamil one hour prior to dabigatran increased dabigatran AUC by 154%.(11) Administration of dabigatran two hours before verapamil results in a negligible increase in dabigatran AUC.(9) A retrospective cohort study evaluated adverse bleeding rates with standard doses of oral anticoagulants with concurrent verapamil or diltiazem in patients with normal kidney function. Concomitant dabigatran use with verapamil or diltiazem was associated with increased overall bleeding (hazard ratio (HR) 1.52; HR 1.43) and increased overall GI bleeding (HR 2.16; HR 2.32) when compared to amlodipine and metoprolol, respectively. No association was found between increased bleeding of any kind and concurrent use of rivaroxaban or apixaban with verapamil or diltiazem.(14) A retrospective cohort study examined 24,943 patients with concurrent therapy of an anticoagulant, either rivaroxaban (40.0%), apixaban (31.9%), or dabigatran (28.1%), with either azithromycin or clarithromycin. The primary outcome of hospital admission with major hemorrhage within 30 days on concurrent therapy was higher in patients on clarithromycin (0.77%) compared to azithromycin (0.43%) with an adjusted HR of 1.71.(12) 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. Concurrent use of a selective serotonin reuptake inhibitor with NSAIDs or low-dose aspirin increased the risk of bleeding to 12.2 and 5.2, respectively.(13) In a case-control study conducted in users of acenocoumarol or phenprocoumon, 1,848 patients who had been hospitalized with abnormal bleeding were each matched to 4 control patients. When patients took both a SSRI and a coumarin, an increased risk of hospitalization due to major non-gastrointestinal bleeding was observed (adjusted OR 1.7), but not due to gastrointestinal bleeding (adjusted OR 0.8).(15) A retrospective review examined patients discharged from a hospital with antiplatelet therapy following a myocardial infarction. When compared to aspirin therapy alone, both aspirin therapy with a SSRI and aspirin, clopidogrel, and SSRI therapy were associated with an increased risk of bleeding (HR 1.42 and 2.35, respectively). Compared with dual antiplatelet therapy (aspirin and clopidogrel), use of aspirin and clopidogrel and a SSRI was also associated with increased risk of bleeding (HR 1.57).(16) In The Rotterdam Study, fluvoxamine increased the risk of over anticoagulation (HR 2.63). Paroxetine was not associated with an increased risk. There were insufficient numbers of patients taking other SSRIs to assess increased risk.(17) 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 dabigatran and citalopram resulted in a ratio of rate ratios (95% CI) of 1.69 (1.11-2.57).(18)

Dabigatran/Antiplatelets; Aspirin (> 100 MG)

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

MECHANISM OF ACTION: Dabigatran is a direct thrombin inhibitor and when taken with agents that effect platelet aggregation increased bleeding episodes can occur.(1,2)

CLINICAL EFFECTS: Concurrent use of dabigatran with antiplatelet agents may result in additive or synergistic effects resulting in unwanted bleeding episodes.(1,2)

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: Patients requiring concurrent therapy with dabigatran and an antiplatelet agent should be closely monitored for signs of 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. 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 dabigatran in patients with active bleeding.

DISCUSSION: Dabigatran is a direct thrombin inhibitor and when taken with agents that effect platelet aggregation and/or other clotting factors increased bleeding episodes can occur.(1,2) In the RE-LY trial, 40% of patients were on aspirin at baseline.(1) In the RE-MEDY trial, 7.7% of patients were on aspirin at baseline.(1) In the RE-DUAL PCI trial, patients were randomly assigned to one of three treatments: (A) dual therapy with dabigatran 110 mg twice daily plus either clopidogrel or ticagrelor, (B) dual therapy with dabigatran 150 mg twice daily plus either clopidogrel or ticagrelor, or (C) triple therapy with warfarin (goal INR 2-3) plus aspirin (< or = 100 mg daily) plus either clopidogrel or ticagrelor. The incidence of the first major or clinically relevant non-major (CRNM) bleeding event was 15.4% in group A compared with 26.9% in group C (hazard ratio, 0.52; 95% CI 0.42 to 0.63; p<0.001 for noninferiority; p<0.001 for superiority) and 20.2% in group B compared to 25.7% in corresponding group C (hazard ratio, 0.72; 95% CI 0.58 to 0.88; p<0.001 for noninferiority). For major bleeding as defined by Thrombolysis in Myocardial Infarction (TIMI) criteria, the rate was lower in both dual-therapy groups than in the triple-therapy group: 1.4% in group A compared to 3.8% in group C (hazard ratio, 0.37; 95% CI 0.2 to 0.68; p=0.002) and 2.1% in group B compared to 3.9% in corresponding group C (hazard ratio, 0.51; 95% CI 0.28 to 0.93; p=0.03). Incidence of composite efficacy end point of thromboembolic events (myocardial infarction, stroke, or systemic embolism), death, or unplanned revascularization was 13.7% in groups A and B compared to 13.4% in group C (hazard ratio, 1.04; 95% CI 0.84 to 1.29; p=0.005 for noninferiority).(4) A meta-analysis of 9 studies identified 13,459 patients taking direct oral anticoagulants (DOACs), 1,692 of whom also took an antiplatelet agent. Of the patients on antiplatelet agents, 1,254 took aspirin while the rest was unspecified. Most of the trials restricted patients to use of low-dose aspirin, with the highest allowable dose being 165 mg/day. Compared with DOACs alone, the use of DOACs with antiplatelet agents was associated with an increased risk of major bleeding (OR 1.89; 95% CI, 1.04-3.44) and CRNM bleeding (OR 1.82; 95% CI, 1.50-2.22). There was no difference between groups in the efficacy outcome of symptomatic recurrent venous thromboembolism (VTE) or VTE-related death.(5)

Dabigatran/Dronedarone, Ketoconazole

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

MECHANISM OF ACTION: Oral dronedarone and ketoconazole are inhibitors of intestinal P-glycoprotein (P-gp) and dabigatran etexilate is a substrate for this system.(1-3) Inhibition of intestinal P-glycoprotein leads to increased absorption of dabigatran.

CLINICAL EFFECTS: The concurrent use of dabigatran with dronedarone or systemic ketoconazole may result in elevated plasma levels of dabigatran, increasing the risk for bleeding. Dronedarone or systemic ketoconazole increases exposure to dabigatran by 1.7 - 2 fold, or 2.5 fold respectively.(2,4)

PREDISPOSING FACTORS: Factors associated with an increased 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.(1,3,4) 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).

PATIENT MANAGEMENT: Evaluate renal function as this is the primary route of dabigatran elimination.(1-3) US manufacturer dosage recommendations for dabigatran patients also receiving dronedarone or oral ketoconazole are indication specific.(2) Non-valvular atrial fibrillation - stroke and systemic embolism risk reduction: - If creatinine clearance (CrCl) is 30 to 50 mL/min, then consider reducing dabigatran dose to 75 mg twice daily during concomitant therapy with oral ketoconazole or dronedarone. - If estimated CrCl is less than 30 mL/min, then treatment with oral ketoconazole or dronedarone should be avoided due to the additive risk for bleeding. Deep vein thrombosis (DVT) or Pulmonary embolism (PE)- treatment or secondary prophylaxis: - No dose reduction is needed for concomitant therapy if CrCl is greater than or equal to 50 mL/min. - If CrCl is less than 50 mL/min, then concomitant treatment with oral ketoconazole or dronedarone should be avoided due to the additive risk for bleeding. Hip replacement surgery - DVT and PE prophylaxis: - No dose reduction for concomitant therapy is needed if CrCl is greater than or equal to 50 mL/min. - If CrCl is less than 50 mL/min, then concomitant treatment with oral ketoconazole or dronedarone should be avoided due to the additive risk for bleeding. In patients receiving concomitant therapy with dabigatran and dronedarone, stagger dosing if possible. Patients who took dronedarone 2 hours after dabigatran dose had approximately 30% lower excess exposure to dabigatran than patients who took dabigatran and dronedarone concurrently.(2) If dabigatran is to be discontinued, then consider coverage with another anticoagulant. The FDA boxed warning for dabigatran states discontinuing dabigatran in patients without adequate continuous anticoagulation increases the risk for stroke.(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. 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. When concurrent treatment of dabigatran with dronedarone or ketoconazole is discontinued, dabigatran dose may need to be increased based upon reevaluation of patient risk factors and existing dabigatran dosage. Canadian and United Kingdom prescribing information state the use of systemic ketoconazole with dabigatran is contraindicated.(1,3) United Kingdom prescribing information states the use of dabigatran with dronedarone is contraindicated.(1,5)

DISCUSSION: Simultaneous administration of dronedarone increased dabigatran exposure by 70% and 140% when dronedarone was administered one or twice daily, respectively. This exposure is 30% to 60% higher compared to administration of dabigatran alone when dronedarone is administered 2 hours after dabigatran.(2) A single dose of ketoconazole increased dabigatran maximum concentration (Cmax) and area-under-curve (AUC) by 135% and 138%, respectively.(2) Multiple daily doses of ketoconazole increased dabigatran Cmax and AUC 149% and 153%, respectively.(2) Simultaneous administration of dabigatran 150 mg once daily with dronedarone 400 mg twice daily increased the dabigatran AUC and Cmax by 100% and 70%, respectively.(5) A summary of pharmacokinetic interactions with dabigatran and dronedarone concluded that if concurrent therapy is warranted, dabigatran should be given 2 hours before dronedarone. In patients with CrCl 30-50 ml/min, reduce does to 75 mg twice daily and avoid use if CrCl < 30 ml/min.(6)

Dabigatran/Nirmatrelvir-Ritonavir

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

MECHANISM OF ACTION: Dabigatran etexilate is a substrate for the P-glycoprotein (P-gp) system. Inhibition of intestinal P-gp leads to increased absorption of dabigatran.(1-3)

CLINICAL EFFECTS: The concurrent use dabigatran with P-gp inhibitors may lead to elevated plasma levels of dabigatran, increasing the risk for bleeding.

PREDISPOSING FACTORS: Factors associated with an increased risk for bleeding include renal impairment, concomitant use of P-gp 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.(1-4)

PATIENT MANAGEMENT: The US manufacturer of nirmatrelvir-ritonavir states concurrent use with dabigatran should be avoided or may require a dose adjustment based on dabigatran indication and renal function.(5) The Journal of American College of Cardiology states use of nirmatrelvir-ritonavir with dabigatran should be avoided. Use of dabigatran cannot be safely adjusted or interrupted. If nirmatrelvir-ritonavir is deemed necessary, dose adjustment is recommended based on the dabigatran indication.(6) For AF: -If CrCl > 50 mL/min: Decrease dose to 110 mg twice daily for 8 days from the start of nirmatrelvir-ritonavir and then resume dabigatran at the previous dose (this dosage is not available in the United States). -If CrCl 30-5 0mL/min: Decrease dose to 75 mg twice daily for 8 days from the start of nirmatrelvir-ritonavir and then resume dabigatran at the previous dose. -If CrCl < 30 mL/min: Avoid co-administration of nirmatrelvir-ritonavir with dabigatran; consider switching to an alternative anticoagulant. For VTE: -If on 150 mg dabigatran twice daily: Co-administration with nirmatrelvir-ritonavir is not recommended. Withhold dabigatran for 12-24 hours and then start nirmatrelvir-ritonavir with an alternative anticoagulant (eg, enoxaparin) for a total of 8 days, and then resume dabigatran at previous dose. Assess renal function and evaluate patient for other pre-existing risk factors for bleeding prior to initiating concurrent therapy. 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. Consider regular monitoring of hemoglobin, platelet levels, and/or activated partial thromboplastin time (aPTT) or ecarin clotting time (ECT). 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: When dabigatran was co-administered with amiodarone, the extent and rate of absorption of amiodarone and its active metabolite DEA were essentially unchanged. The dabigatran area-under-curve (AUC) and maximum concentration (Cmax) were increased by about 60% and 50%, respectively;(1,2) however, dabigatran clearance was increased by 65%.(1) Pretreatment with quinidine (200 mg every 2 hours to a total dose of 1000 mg) increased the AUC and Cmax of dabigatran by 53% and 56%, respectively.(1,2) Chronic administration of immediate release verapamil one hour prior to dabigatran dose increased dabigatran AUC by 154%.(4) Administration of dabigatran two hours before verapamil results in a negligible increase in dabigatran AUC.(1) Administration of sofosbuvir-velpatasvir-voxilaprevir (400/100/200 mg daily) increased the Cmax and AUC of a single dose of dabigatran (75 mg) by 2.87-fold and 2.61-fold, respectively.(7) Simultaneous administration of glecaprevir-pibrentasvir (300/120 mg daily) with a single dose of dabigatran (150 mg) increased the Cmax and AUC by 2.05-fold and 2.38-fold, respectively.(8) A retrospective comparative effectiveness cohort study including data from 9,886 individuals evaluated adverse bleeding rates with standard doses of oral anticoagulants with concurrent verapamil or diltiazem in patients with nonvalvular atrial fibrillation and normal kidney function. The study compared rates of bleeding following co-administration of either dabigatran, rivaroxaban, or apixaban with verapamil or diltiazem, compared to co-administration with amlodipine or metoprolol. Results of the study found that concomitant dabigatran use with verapamil or diltiazem was associated with increased overall bleeding (hazard ratio (HR) 1.52; 95% confidence interval (CI), 1.05-2.20, p<0.05) and increased overall GI bleeding (HR 2.16; 95% CI, 1.30-3.60, p<0.05) when compared to amlodipine. When compared to metoprolol, concomitant dabigatran use with verapamil or diltiazem was also associated with increased overall bleeding (HR, 1.43; 95% CI, 1.02-2.00, p<0.05) and increased overall GI bleeding (HR, 2.32; 95% CI, 1.42-3.79, p<0.05). No association was found between increased bleeding of any kind and concurrent use of rivaroxaban or apixaban with verapamil or diltiazem.(9) A summary of pharmacokinetic interactions with dabigatran and amiodarone or verapamil concluded that concurrent use is considered safe if CrCl is greater than 50 ml/min but should be avoided if CrCl is less than 50 ml/min in VTE and less than 30 ml/min for NVAF. Concurrent use with diltiazem was considered safe.(10) In a pharmacokinetic study in 12 healthy subjects, concurrent use of dabigatran with nirmatrelvir-ritonavir increased the geometric mean AUC and Cmax by 1.9-fold and 2.3-fold, respectively. Concurrent use of dabigatran with ritonavir alone increased the mean AUC and Cmax by 1.7-fold and 1.7-fold, respectively.(11)

Dabigatran/Nsaids; Salicylates

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

MECHANISM OF ACTION: Dabigatran is a direct thrombin inhibitor and when taken with agents that effect platelet aggregation and/or other clotting factors increased bleeding episodes can occur.(1,2)

CLINICAL EFFECTS: Concurrent use of dabigatran with NSAIDs or salicylates may result in additive or synergistic effects resulting in unwanted bleeding episodes.(1)

PREDISPOSING FACTORS: Factors associated with an increased risk for bleeding include renal impairment, concomitant use of P-glycoprotein inhibitors, patient older than 74 years, coexisting conditions (e.g. recent trauma, thrombocytopenia, advanced liver disease), use of drugs associated with bleeding risk (e.g. other anticoagulants, antiplatelets, corticosteroids, selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs)), and patient weight less than 50 kg. (1-3) Risk of GI bleed may be increased in patients who are of older age, in poor health status, who use alcohol or smoke, with longer duration of NSAID use, and with prior history of peptic ulcer disease and/or GI bleeding.

PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy for signs of blood loss and promptly evaluate patients with any symptoms. Discontinue dabigatran in patients with active pathological 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 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: Dabigatran is a direct thrombin inhibitor and when taken with agents that effect platelet aggregation and/or other clotting factors increased bleeding episodes can occur.(1,2) 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)

Dabigatran/Selected P-Glycoprotein (P-GP) Inhibitors

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

MECHANISM OF ACTION: Dabigatran etexilate is a substrate for the P-glycoprotein (P-gp) system. Inhibition of intestinal P-gp leads to increased absorption of dabigatran.(1-3)

CLINICAL EFFECTS: The concurrent use dabigatran with P-gp inhibitors may lead to elevated plasma levels of dabigatran, increasing the risk for bleeding.

PREDISPOSING FACTORS: Factors associated with an increased risk for bleeding include renal impairment, concomitant use of P-gp 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.(1-4)

PATIENT MANAGEMENT: Assess renal function and evaluate patient for other pre-existing risk factors for bleeding prior to initiating concurrent therapy. The US manufacturer of dabigatran states that the concurrent use of dabigatran and P-gp inhibitors should be avoided in atrial fibrillation patients with severe renal impairment (CrCl less than 30 ml/min) and in patients with moderate renal impairment (CrCl less than 50 ml/min) being treated for or undergoing prophylaxis for deep vein thrombosis (DVT) or pulmonary embolism (PE). The interaction with P-gp inhibitors can be minimized by taking dabigatran several hours apart from the P-gp inhibitor dose.(1) The concomitant use of dabigatran with P-gp inhibitors has not been studied in pediatric patients but may increase exposure to dabigatran.(1) While the US manufacturer of dabigatran states that no dosage adjustment is necessary in other patients,(1) the Canadian manufacturer of dabigatran states that concomitant use of strong P-gp inhibitors (e.g., glecaprevir-pibrentasvir) is contraindicated. When dabigatran is used for the prevention of venous thromboembolism (VTE) after total hip or knee replacement concurrently with amiodarone, quinidine, or verapamil, the dose of dabigatran should be reduced from 110 mg twice daily to 150 mg once daily. For patients with CrCl less than 50 ml/min on verapamil, a further dabigatran dose reduction to 75 mg once daily should be considered. Verapamil should be given at least 2 hours after dabigatran to minimize the interaction.(2) The UK manufacturer of dabigatran also states the use of dabigatran with strong P-gp inhibitors (e.g., cyclosporine, glecaprevir-pibrentasvir or itraconazole) is contraindicated. Concurrent use of ritonavir is not recommended. When dabigatran is used in atrial fibrillation patients and for treatment of DVT and PE concurrently with verapamil, the UK manufacturer recommends reducing the dose of dabigatran from 150 mg twice daily to 110 mg twice daily, taken simultaneously with verapamil. When used for VTE prophylaxis after orthopedic surgery concurrently with amiodarone, quinidine, or verapamil, the dabigatran loading dose should be reduced from 110 mg to 75 mg, and the maintenance dose should be reduced from 220 mg daily to 150 mg daily, taken simultaneously with the P-gp inhibitor. For patients with CLcr 30-50 mL/min on concurrent verapamil, consider further lowering the dabigatran dose to 75 mg daily.(3) 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. Consider regular monitoring of hemoglobin, platelet levels, and/or activated partial thromboplastin time (aPTT) or ecarin clotting time (ECT). 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 manufacturer of daraxonrasib states P-gp substrates should be administered at least 4 hours apart from daraxonrasib.(10)

DISCUSSION: When dabigatran was co-administered with amiodarone, the extent and rate of absorption of amiodarone and its active metabolite DEA were essentially unchanged. The dabigatran area-under-curve (AUC) and maximum concentration (Cmax) were increased by about 60% and 50%, respectively;(1,2) however, dabigatran clearance was increased by 65%.(1) Pretreatment with quinidine (200 mg every 2 hours to a total dose of 1000 mg) increased the AUC and Cmax of dabigatran by 53% and 56%, respectively.(1,2) Chronic administration of immediate release verapamil one hour prior to dabigatran dose increased dabigatran AUC by 154%.(4) Administration of dabigatran two hours before verapamil results in a negligible increase in dabigatran AUC.(1) Administration of sofosbuvir-velpatasvir-voxilaprevir (400/100/200 mg daily) increased the Cmax and AUC of a single dose of dabigatran (75 mg) by 2.87-fold and 2.61-fold, respectively.(5) Simultaneous administration of glecaprevir-pibrentasvir (300/120 mg daily) with a single dose of dabigatran (150 mg) increased the Cmax and AUC by 2.05-fold and 2.38-fold, respectively.(6) A retrospective comparative effectiveness cohort study including data from 9,886 individuals evaluated adverse bleeding rates with standard doses of oral anticoagulants with concurrent verapamil or diltiazem in patients with nonvalvular atrial fibrillation and normal kidney function. The study compared rates of bleeding following co-administration of either dabigatran, rivaroxaban, or apixaban with verapamil or diltiazem, compared to co-administration with amlodipine or metoprolol. Results of the study found that concomitant dabigatran use with verapamil or diltiazem was associated with increased overall bleeding (hazard ratio (HR) 1.52; 95% confidence interval (CI), 1.05-2.20, p<0.05) and increased overall GI bleeding (HR 2.16; 95% CI, 1.30-3.60, p<0.05) when compared to amlodipine. When compared to metoprolol, concomitant dabigatran use with verapamil or diltiazem was also associated with increased overall bleeding (HR, 1.43; 95% CI, 1.02-2.00, p<0.05) and increased overall GI bleeding (HR, 2.32; 95% CI, 1.42-3.79, p<0.05). No association was found between increased bleeding of any kind and concurrent use of rivaroxaban or apixaban with verapamil or diltiazem.(7) A summary of pharmacokinetic interactions with dabigatran and amiodarone or verapamil concluded that concurrent use is considered safe if CrCl is greater than 50 ml/min but should be avoided if CrCl is less than 50 ml/min in VTE and less than 30 ml/min for NVAF. Concurrent use with diltiazem was considered safe.(9) P-gp inhibitors include amiodarone, asunaprevir, aumolertinib, belumosudil, capmatinib, carvedilol, cimetidine, conivaptan, cyclosporine, daclatasvir, danicopan, daraxonrasib, daridorexant, diosmin, erythromycin, flibanserin, fostamatinib, ginseng, glecaprevir, imlunestrant, indinavir, itraconazole, ivacaftor, josamycin, lapatinib, ledipasvir, lonafarnib, mavorixafor, neratinib, osimertinib, pibrentasvir, posaconazole, propafenone, quinidine, ranolazine, ritonavir, selpercatinib, sotorasib, telaprevir, telithromycin, tepotinib, tezacaftor, tucatinib, valbenazine, velpatasvir, vemurafenib, vepdegestrant, verapamil, vimseltinib, voclosporin, and voxilaprevir.(1-9)

Dabigatran/Sulfinpyrazone

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

MECHANISM OF ACTION: Dabigatran is a direct thrombin inhibitor and when taken with agents that effect platelet aggregation and/or other clotting factors increased bleeding episodes can occur.

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

PREDISPOSING FACTORS: Factors associated with an increase risk of 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: 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 UK manufacturer of dabigatran states the use of dabigatran and sulfinpyrazone is not recommended.(1)

DISCUSSION: Dabigatran is a direct thrombin inhibitor and when taken with agents that effect platelet aggregation and/or other clotting factors increased bleeding episodes can occur.(1)

Selected P-Glycoprotein (P-GP) Substrates/Venetoclax

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

MECHANISM OF ACTION: Venetoclax is an inhibitor of the P-glycoprotein (P-gp) system and may increase the absorption of P-gp substrates.(1)

CLINICAL EFFECTS: Concurrent use of venetoclax with P-gp substrates may result in elevated levels and toxicities of the substrate.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of venetoclax states that the concurrent use of P-gp substrates should be avoided. If concurrent therapy cannot be avoided, the P-gp substrate should be taken at least 6 hours before venetoclax.(1) If concurrent therapy with afatinib is unavoidable and not tolerated, the US manufacturer of afatinib states that the afatinib dose should be reduced by 10 mg. Resume the previous dose of afatinib if venetoclax is discontinued.(2) The manufacturer of ubrogepant recommends a dosage adjustment of ubrogepant when coadministered with P-gp inhibitors. The initial dose of ubrogepant should not exceed 50 mg. If a second dose of ubrogepant is needed, the dose should not exceed 50 mg.(8)

DISCUSSION: In vitro data suggests venetoclax is a P-gp inhibitor at therapeutic doses in the gut.(1) Administration of a single venetoclax 100 mg dose with digoxin increased the maximum concentration (Cmax) and area-under-the-curve of digoxin by 35% and 9%, respectively.(1) Selected P-gp substrates linked to this monograph include: afatinib, aliskiren, betrixaban, bilastine, cyclosporine, dabigatran, digoxin, edoxaban, everolimus, loperamide, sirolimus, talazoparib, topotecan, and ubrogepant.(1-9)

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/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; 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)

Apixaban; Dabigatran; Rivaroxaban/Fluconazole

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

MECHANISM OF ACTION: Fluconazole may inhibit the metabolism of apixaban, dabigatran, and rivaroxaban.(1)

CLINICAL EFFECTS: Concurrent use of fluconazole with apixaban, dabigatran, or rivaroxaban may result in elevated levels of and clinical effects of apixaban, dabigatran, or rivaroxaban, including an increased risk of bleeding, in patients.(1)

PREDISPOSING FACTORS: This interaction may be more severe in patients with decreased renal function.(1) 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 (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.

DISCUSSION: A retrospective cohort study of patients from the Taiwan National Health Insurance database examined 91,330 patients with nonvalvular atrial fibrillation who received therapy with apixaban, dabigatran, or rivaroxaban for major bleeding (hospitalization or emergency department visit with a primary diagnosis of intracranial hemorrhage, gastrointestinal/urogenital/other bleeding) and compared the differences in bleeding between patients taking TSOAs with or without concurrent therapy. Exact fluconazole dosages were not stated.(1) The adjusted rate ratio of bleeding with concurrent apixaban and fluconazole was 3.36 (range 1.69-6.68, p<0.01). There were 16 incidences of bleeding in 199 patient-quarters of concurrent therapy with apixaban and fluconazole, compared with 432 incidences of bleeding in 36,733 patient-quarters of apixaban without fluconazole.(1) The adjusted rate ratio of bleeding with concurrent dabigatran and fluconazole was 2.26 (range 1.44-3.55, p<0.01). There were 47 incidences of bleeding in 705 patient-quarters of concurrent therapy with dabigatran and fluconazole, compared with 1884 incidences of bleeding in 199,433 patient-quarters of dabigatran without fluconazole.(1) The adjusted rate ratio of bleeding with concurrent rivaroxaban and fluconazole was 2.25 (range 1.54-3.30, p<0.01). There were 63 incidences of bleeding in 1185 patient-quarters of concurrent therapy with rivaroxaban and fluconazole, compared with 2499 incidences of bleeding in 222,604 patient-quarters of rivaroxaban without fluconazole.(1) In a randomized, open-label cross-over study, fluconazole (400 mg daily) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of rivaroxaban (20 mg) by 1.28-fold and 1.42-fold, respectively. FDA reviewers concluded no dose adjustments were warranted.(2) In a case-crossover study, the cross-over odds ratio of bleeding with concurrent apixaban and fluconazole was 3.5 (range 1.4-10.6) in the 30-day exposure window. The cross-over odds ratio of bleeding with concurrent rivaroxaban (OR 0.9, 0.2.-3.0) or dabigatran (OR 1.7, 0.5-5.6) with fluconazole was not significantly elevated in the 30-day exposure window. Concurrent use of topical azole antifungals among apixaban (OR 0.8, 0.5-1.3), rivaroxaban (OR 1.3, 0.9-2.1), or dabigatran (OR 1.2, 0.8-1.8) users did not have a corresponding association with bleeding risk in the 30-day exposure window. The study authors noted not many patients were exposed to systemic fluconazole, resulting in large confidence intervals, making interpretation of the results difficult. Further studies with narrow confidence intervals are needed to conclude that no association exists with rivaroxaban or dabigatran.(3) In a retrospective observational cohort study, the effect of concurrent administration of fluconazole with either apixaban or rivaroxaban on bleeding risk was assessed. Initial results revealed more patients on concurrent fluconazole with apixaban or rivaroxaban experienced a statistically significant increase in the risk of bleeding at 30 days than the group treated with apixaban or rivaroxaban alone [32% vs. 19%, respectively). However, when accounting for confounding variables, the higher bleeding risk observed with concurrent fluconazole was not found to be statistically significant (adjusted odds ratio 1.71, 95% CI 0.85-3.4).(4)

Betrixaban; Dabigatran; Edoxaban/Lovastatin; Simvastatin

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

MECHANISM OF ACTION: Betrixaban, dabigatran etexilate, and edoxaban are substrates for the P-glycoprotein (P-gp) system. Inhibition of intestinal P-gp leads to increased absorption of betrixaban, dabigatran, and edoxaban.(1-6) Lovastatin and simvastatin are inhibitors of intestinal P-gp.(7,8)

CLINICAL EFFECTS: The concurrent use of betrixaban, dabigatran, and edoxaban with lovastatin or simvastatin may lead to elevated plasma levels of betrixaban, dabigatran, and edoxaban, increasing the risk for bleeding.

PREDISPOSING FACTORS: Factors associated with an increased risk for bleeding include renal impairment, concomitant use of P-gp 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.(1-6) 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: Assess renal function and evaluate patient for other pre-existing risk factors for bleeding prior to initiating concurrent therapy. The concurrent use of betrixaban, dabigatran, and edoxaban with lovastatin or simvastatin should be monitored closely. Consider alternate therapy such as atorvastatin, fluvastatin, pravastatin, or rosuvastatin that are not known to inhibit P-gp.(7,8) Careful monitoring for signs and symptoms of bleeding is warranted during concurrent therapy. Consider regular monitoring of hemoglobin, platelet levels, and/or activated partial thromboplastin time (aPTT) or ecarin clotting time (ECT). Instruct patients to report any signs and symptoms of bleeding, such as bleeding from the eyes, gums or nose; unusual bruising; dark stools; red or dark brown urine; and/or abdominal pain or swelling.

DISCUSSION: A population-based, nested case-control study of 45,991 patients taking dabigatran aged 66 years or older were screened for ischemic stroke or major hemorrhage with a single statin prescription in the 60 days preceding the index date. Each case was matched with up to 4 controls by age and sex. The use of lovastatin or simvastatin was not associated with an increased risk of stroke or transient ischemic attack relative to other statins in patients receiving dabigatran (adjusted OR 1.33, 95% CI 0.88-2.01). However, the use of lovastatin or simvastatin was associated with a higher risk of major hemorrhage than comparator statins (adjusted OR 1.46, 95% CI 1.17-1.82).(7) In the APEX randomized, double-blind study the incidence of major or clinically relevant non-major bleeds (CRNM) in the betrixaban 40 mg and 80 mg group was higher in patients taking concomitant P-gp inhibitors (2.8% vs. 4.1% vs. 4.7%).(9) In a study in 12 subjects, concomitant administration of a single dose of betrixaban (40 mg) following a 5-day regimen of ketoconazole (200 mg twice daily) resulted in an increase in betrixaban's maximum concentration (Cmax) and area-under-the-curve (AUC) of 2.3-fold and 2.3-fold, respectively.(10) An open-label study looking at concomitant administration of a single dose of betrixaban with verapamil in 18 subjects found an increase in betrixaban's Cmax and AUC of approximately 4.7-fold and 3-fold, respectively.(11) In a study, concomitant administration of betrixaban (80 mg) with amiodarone resulted in an increase in betrixaban's Cmax by 143%.(10) A summary of pharmacokinetic interactions with betrixaban and amiodarone, diltiazem, or verapamil concluded that if concurrent use is warranted, the betrixaban dose should be reduced to 80 mg once then 40 mg daily. Use should be avoided if CrCl is less than 30 ml/min.(11) When dabigatran was co-administered with amiodarone, a P-gp inhibitor, the extent and rate of absorption of amiodarone and its active metabolite DEA were essentially unchanged. The dabigatran area-under-curve (AUC) and maximum concentration (Cmax) were increased by about 60% and 50%, respectively;(2,3) however, dabigatran clearance was increased by 65%.(2) Pretreatment with quinidine (200 mg every 2 hours to a total dose of 1000 mg), and a P-gp inhibitor, increased the AUC and Cmax of dabigatran by 53% and 56%, respectively.(2,3) Chronic administration of immediate release verapamil, a P-gp inhibitor, one hour prior to dabigatran dose increased dabigatran AUC by 154%.(6) Administration of dabigatran two hours before verapamil results in a negligible increase in dabigatran AUC.(2) In an interaction study, the effect of repeat administration of quinidine (300 mg TID) on a single oral dose of edoxaban 60 mg was evaluated in healthy subjects. Both peak (Cmax) and total systemic exposure (AUC) to edoxaban and to the active M4 metabolite increased approximately 1.75-fold.(5) In an interaction study, the effect of repeat administration of verapamil (240 mg Verapamil SR Tablets (Calan SR) QD for 11 Days) on a single oral dose of edoxaban 60 mg on the morning of Day 10 was evaluated in healthy subjects. Total and peak systemic exposure to edoxaban increased 1.53-fold and 1.53-fold, respectively. Total and peak systemic exposure to the active M4 metabolite increased 1.31-fold and 1.28-fold, respectively.(5) Based upon the above results, patients in the DVT/PE trial had a 50% dose reduction (from 60 mg to 30 mg) during concomitant therapy with P-glycoprotein inhibitors. Approximately 0.5% of these patients required a dose reduction solely due to P-gp inhibitor use. This low rate of concurrent therapy was too small to allow for detailed statistical evaluation. Almost all of these patients were receiving quinidine or verapamil. In these patients, both trough edoxaban concentrations (Ctrough) used to evaluate bleeding risk, and total edoxaban exposure (AUC or area-under-curve) used to evaluate treatment efficacy, were lower than patients who did not require any edoxaban dose adjustment. In this DVT/PE comparator trial, subgroup analysis revealed that warfarin had numerically better efficacy than edoxaban in patients receiving P-gp inhibitors. Based upon the overall lower exposure to edoxaban in P-gp dose adjusted subjects, both EMA and FDA Office of Clinical Pharmacology (OCP) concluded that the edoxaban 50% dose reduction overcorrected for the difference in exposure.(5,12) Consequently, EMA recommended no edoxaban dose adjustments for patients receiving concomitant therapy with quinidine or verapamil.(12,13)

Dabigatran/Abciximab

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

MECHANISM OF ACTION: Direct thrombin inhibitors decrease plasma fibrinogen levels.(1) When direct thrombin inhibitors are administered with abciximab, there is enhanced inhibition of platelet aggregation.

CLINICAL EFFECTS: Concurrent use of abciximab and dabigatran may result in greater inhibition of platelet aggregation which may lead to an increased risk of bleeding.(2,3)

PREDISPOSING FACTORS: Active internal bleed, thrombocytopenia, recent major surgery or trauma, severe uncontrolled hypertension, use of IV dextran before PCI, and history of cerebrovascular accident within two years.(2) Additional factors associated with an increased risk for bleeding include renal impairment, concomitant use of P-glycoprotein inhibitors, patient age >74 years, use of other drugs associated with bleeding risk (e.g. NSAIDs), and patient weight <50 kg. (3-5)

PATIENT MANAGEMENT: The UK manufacturer states that the use of unfractionated heparin, heparin derivatives, and low molecular weight heparins with concomitant dabigatran therapy is not recommended.(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.

DISCUSSION: The concurrent use of both agents is likely to increase the frequency and occurrence of unwanted bleeding episodes.(1,2,3)

Dabigatran/Aspirin (< OR = 100 MG)

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

MECHANISM OF ACTION: Additive effects on hemostasis.(1-3)

CLINICAL EFFECTS: Concurrent use of dabigatran with aspirin may increase the risk of bleeding.(1-3)

PREDISPOSING FACTORS: Factors associated with an increase risk for bleeding may include renal impairment, concomitant use of P-glycoprotein inhibitors, patient age greater than 74 years, coexisting conditions (e.g. recent trauma) or use of drugs (e.g. NSAIDs) associated with bleeding risk, and patient weight less than 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 anticoagulants/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or 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 Phase II study in patients with atrial fibrillation examined the effects of dabigatran and concurrent aspirin on the risk of major bleeds. Concurrent use of aspirin and dabigatran etexilate (150 mg twice daily) increased the risk for any bleeding from 12 % to 18 % and 24 % with 81 mg and 325 mg ASA, respectively, when compared to dabigatran alone.(3) In the RE-DUAL PCI trial, patients were randomly assigned to one of three treatments: (A) dual therapy with dabigatran 110 mg twice daily plus either clopidogrel or ticagrelor, (B) dual therapy with dabigatran 150 mg twice daily plus either clopidogrel or ticagrelor, or (C) triple therapy with warfarin (goal INR 2-3) plus aspirin (less than or equal to 100 mg daily) plus either clopidogrel or ticagrelor. The incidence of the first major or clinically relevant non-major (CRNM) bleeding event was 15.4% in group A compared with 26.9% in group C (hazard ratio, 0.52; 95% CI 0.42 to 0.63; p<0.001 for noninferiority; p<0.001 for superiority) and 20.2% in group B compared to 25.7% in corresponding group C (hazard ratio, 0.72; 95% CI 0.58 to 0.88; p<0.001 for noninferiority). Major bleeding as defined by Thrombolysis in Myocardial Infarction (TIMI) criteria, the rate was lower in both dual-therapy groups than in the triple-therapy group: 1.4% in group A compared to 3.8% in group C (hazard ratio, 0.37; 95% CI 0.2 to 0.68; p=0.002) and 2.1% in group B compared to 3.9% in corresponding group C (hazard ratio, 0.51; 95% CI 0.28 to 0.93; p=0.03). Incidence of composite efficacy end point of thromboembolic events (myocardial infarction, stroke, or systemic embolism), death, or unplanned revascularization was 13.7% in groups A and B compared to 13.4% in group C (hazard ratio, 1.04; 95% CI 0.84 to 1.29; p=0.005 for noninferiority).(4) A meta-analysis of 9 studies identified 13,459 patients taking direct oral anticoagulants (DOACs), 1,692 of whom also took an antiplatelet agent. Of the patients on antiplatelet agents, 1,254 took aspirin while the rest was unspecified. Most of the trials restricted patients to use of low-dose aspirin, with the highest allowable dose being 165 mg/day. Compared with DOACs alone, the use of DOACs with antiplatelet agents was associated with an increased risk of major bleeding (OR 1.89; 95% CI, 1.04-3.44) and CRNM bleeding (OR 1.82; 95% CI, 1.50-2.22). There was no difference between groups in the efficacy outcome of symptomatic recurrent venous thromboembolism (VTE) or VTE-related death.(5)

Dabigatran/Clarithromycin

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

MECHANISM OF ACTION: Dabigatran is a substrate for the P-glycoprotein (P-gp) transporter. Inhibition of intestinal P-gp leads to increased absorption of dabigatran. Clarithromycin is a P-gp inhibitor.

CLINICAL EFFECTS: The concurrent use of dabigatran with P-gp inhibitors, like clarithromycin, may lead to elevated plasma levels of dabigatran, increasing the risk for bleeding.

PREDISPOSING FACTORS: Factors associated with an increased risk for bleeding include renal impairment, concomitant use of P-gp 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.

PATIENT MANAGEMENT: Assess renal function and evaluate other pre-existing risk factors for bleeding prior to initiating concurrent therapy. The US and and Canadian manufacturers of dabigatran state that no dosage adjustment is necessary with clarithromycin.(1-2) The UK and Australian manufacturers state that dabigatran should be used with caution with clarithromycin.(3-4) 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. Consider regular monitoring of hemoglobin, platelet levels, and/or activated partial thromboplastin time (aPTT) or ecarin clotting time (ECT). 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: When clarithromycin (500 mg twice daily) was administered together with dabigatran etexilate in healthy volunteers, an increase of dabigatran area-under-curve (AUC) by about 1.19-fold and maximum concentration (Cmax) by about 1.15-fold were observed.(1-4) In an evaluation with healthy male volunteers on dabigatran and clarithromycin, clarithromycin increased Cmax and AUC of dabigatran by 60.2% and 49.1%, respectively. In another evaluation of the PK relationship between dabigatran and clarithromycin, a 68% increase in Cmax was observed, which was consistent with predicted PK models.(5-6) In a population-based retrospective cohort study, coprescribing clarithromycin vs azithromycin with a DOAC was associated with a higher risk of a hospital admission with major hemorrhage (51 of 6,592 patients [0.77%] taking clarithromycin vs 79 of 18,351 patients [0.43%] taking azithromycin; adjusted hazard ratio, 1.71 [95% CI, 1.20-2.45]; absolute risk difference, 0.34%).(7) In a case report, a 75 year old female on dabigatran for atrial fibrillation who was started on clarithromycin for bronchitis. After 3 days of concomitant treatment, she experienced severe coughing and bruising on the left side of her waist. The patient was switched from clarithromycin to levofloxacin and bruising was resolved.(8)

Dabigatran/Diltiazem

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

MECHANISM OF ACTION: Dabigatran etexilate is a substrate for the P-glycoprotein (P-gp) system. Diltiazem is a P-gp inhibitor. Inhibition of intestinal P-gp leads to increased absorption of dabigatran.(1-3)

CLINICAL EFFECTS: The concurrent use dabigatran with diltiazem may lead to elevated plasma levels of dabigatran, increasing the risk for bleeding.

PREDISPOSING FACTORS: Factors associated with an increased risk for bleeding include renal impairment, concomitant use of P-gp 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.(1-4)

PATIENT MANAGEMENT: Assess renal function and evaluate patient for other pre-existing risk factors for bleeding prior to initiating concurrent therapy. Caution and close monitoring is warranted with concurrent use of dabigatran and diltiazem. The US manufacturer of dabigatran states that the concurrent use of dabigatran and P-gp inhibitors should be avoided in atrial fibrillation patients with severe renal impairment (CrCl less than 30 ml/min) and in patients with moderate renal impairment (CrCl less than 50 ml/min) being treated for or undergoing prophylaxis for deep vein thrombosis (DVT) or pulmonary embolism (PE). The interaction with P-gp inhibitors can be minimized by taking dabigatran several hours apart from the P-gp inhibitor dose.(1) The concomitant use of dabigatran with P-gp inhibitors has not been studied in pediatric patients but may increase exposure to dabigatran.(1) While the US manufacturer of dabigatran states that no dosage adjustment is necessary in other patients,(1) the Canadian manufacturer of dabigatran states that concomitant use of strong P-gp inhibitors such as but not limited to cyclosporine, itraconazole, nelfinavir, posaconazole, ritonavir, saquinavir, tacrolimus and tipranavir may be expected to increase systemic exposure to dabigatran and should be used with caution.(2) The UK manufacturer of dabigatran also states when dabigatran is used in atrial fibrillation patients and for treatment of DVT and PE concurrently with mild to moderate P-gp inhibitors, the dose of dabigatran should be reduced from 150 mg twice daily to 110 mg twice daily, taken simultaneously with the P-gp inhibitor. When used for VTE prophylaxis after orthopedic surgery concurrently with amiodarone, quinidine, or verapamil, the dabigatran loading dose should be reduced from 110 mg to 75 mg, and the maintenance dose should be reduced from 220 mg daily to 150 mg daily, taken simultaneously with the P-gp inhibitor. For patients with CLcr 30-50 mL/min on concurrent verapamil or other moderate P-gp inhibitor, consider further lowering the dabigatran dose to 75 mg daily.(3) Concomitant administration of P-gp inhibitors is expected to result in increased dabigatran plasma concentrations. If not otherwise specifically described, close clinical surveillance is required when dabigatran is co-administered with strong P-gp inhibitors. Dose reductions may be required in combination with some P-gp inhibitors.(3) 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. Consider regular monitoring of hemoglobin, platelet levels, and/or activated partial thromboplastin time (aPTT) or ecarin clotting time (ECT). 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 cohort study included data from 9,886 individuals evaluating rates of adverse bleeding with standard doses of oral anticoagulants with concurrent verapamil or diltiazem in patients with nonvalvular atrial fibrillation and normal kidney function. Concurrent dabigatran use with verapamil or diltiazem was associated with increased overall bleeding (hazard ratio (HR) 1.52; 95% confidence interval (CI), 1.05-2.20, p<0.05) and increased overall gastrointestinal (GI) bleeding (HR 2.16; 95% CI, 1.30-3.60, p<0.05) when compared to amlodipine. When compared to metoprolol, concomitant dabigatran use with verapamil or diltiazem was also associated with increased overall bleeding (HR, 1.43; 95% CI, 1.02-2.00, p<0.05) and increased overall GI bleeding (HR, 2.32; 95% CI, 1.42-3.79, p<0.05). No association was found between increased bleeding of any kind and concurrent use of rivaroxaban or apixaban with verapamil or diltiazem.(5) A summary of pharmacokinetic interactions with dabigatran and amiodarone or verapamil concluded that concurrent use is considered safe if CrCl is greater than 50 ml/min but should be avoided if CrCl is less than 50 ml/min in VTE and less than 30 ml/min for NVAF. Concurrent use with diltiazem was considered safe.(6) In a study of 4,544 patients with atrial fibrillation, the association between the concomitant use of diltiazem and direct oral anticoagulants (DOACs) (rivaroxaban, apixaban, and dabigatran) with bleeding was evaluated. The study reported that DOAC patients taking diltiazem were associated with a higher risk of any bleeding-related hospitalizations (unadjusted risk difference, 2.4; 95% CI, 0.6-4.2 events per 100 person-years; adjusted HR, 1.56, 95% CI, 1.15-2.12), as well as major bleeding (unadjusted risk difference, 1.4 [95% CI, 0.1-2.6 events per 100 person-years]; adjusted HR, 1.84 [95% CI, 1.18-2.85]). Increased risk of bleeding with diltiazem was observed in both patients with and without chronic kidney disease (estimated glomerular filtration rate <60 mL/min per 1.73 m2).(7) In a retrospective cohort study, the association of novel oral anticoagulants (NOACs) with or without concomitant medication with risk of major bleeding was assessed in 91,330 patients with nonvalvular atrial fibrillation. Concurrent use of amiodarone, fluconazole, rifampin, and phenytoin with NOACs had a significant increase in adjusted incidence rates per 1000 person-years of major bleeding than NOACs alone. Compared with NOAC use alone, the adjusted incidence rate for major bleeding was significantly lower for concurrent use of atorvastatin, digoxin, and erythromycin or clarithromycin and was not significantly different for concurrent use of verapamil; diltiazem; cyclosporine; ketoconazole, itraconazole, voriconazole, or posaconazole; and dronedarone.(8) A retrospective cohort study included patients taking DOACs (dabigatran, apixaban, rivaroxaban) who were prescribed amiodarone, verapamil, or diltiazem compared to amlodipine or metoprolol. The study evaluated the association between hospitalization or emergency room visit due to major hemorrhage and concomitant administration of DOACs with either a moderate P-gp inhibitor or agents with no P-gp activity. Results of the study show the weighted risk of major hemorrhage was not increased with amiodarone, verapamil, or diltiazem initiation in DOAC users, compared to metoprolol or amlodipine, during the full follow-up period (HR; 95% confidence interval]: amiodarone HR 0.77 [0.61-0.97]; verapamil HR 1.32 [0.88-1.98]; diltiazem HR 0.99 [0.85-1.15], respectively).(9)

Dabigatran/Levetiracetam

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

MECHANISM OF ACTION: The mechanism of the interaction is unknown. Levetiracetam may decrease the efficacy of dabigatran.

CLINICAL EFFECTS: Concurrent use of levetiracetam may result in decreased effectiveness of dabigatran.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of levetiracetam in patients receiving dabigatran should be approached with caution. Consider alternative anticonvulsants in patients maintained on dabigatran. If concurrent use is warranted, monitor patients closely for decreased response to dabigatran.

DISCUSSION: A nested case-control study of 100,168 patients on apixaban, dabigatran, edoxaban, or rivaroxaban were reviewed for stroke (CVA)/systemic emboli in patients with atrial fibrillation or recurrent thromboembolism in patients with thromboembolism. The primary outcome of CVA/systemic embolism with concurrent use of levetiracetam resulted in an odds ratio (95% CI) of 2.38 (1.19-4.75) and a propensity score adjusted odds ratio (95% CI) of 2.26 (1.13-4.54) compared to controls.(4) A population-based retrospective cohort study of 8746 patients on apixaban, dabigatran, edoxaban, or rivaroxaban were evaluated for occurrence of first ischemic stroke with concurrent antiseizure medications. Antiseizure medications that induce CYP3A4 or P-gp were associated with an increased risk of ischemic stroke (annual incidence rate of 5.5% vs 3.9%, adjusted hazard ratio 1.28). The annual incidence rates of ischemic stroke (valproate: 5.1%; levetiracetam: 6.0%; control: 3.9%) and venous thromboembolism (valproate: 3.7%; levetiracetam: 3.8%; control: 3.0%) were higher among valproate and levetiracetam users but were not statistically different from controls.(5) In a case report, a 54 year old man with a complicated medical history including paroxysmal atrial fibrillation, heart failure, and epilepsy who was on levetiracetam 500 mg twice daily was started on dabigatran 150 mg twice daily, taken simultaneously with levetiracetam. On day 10 of dabigatran, trough levels were normal but Cmax was subtherapeutic. Separation of dabigatran administration to 4 hours before levetiracetam resulted in an increase of Cmax from 88 ng/mL to 101 ng/mL. Over 32 months of follow-up, no hemorrhagic or ischemic events occurred.(6) A retrospective study of 320 patients with atrial fibrillation on DOAC therapy for secondary stroke prevention compared the incidence of ischemic stroke or TIA in patients on concomitant CYP3A4 and P-gp inducing medications (n=43), P-gp inducing medications (n=13), or no interacting medications (n=264). Twenty of the patients were on levetiracetam. There was no statistically significant difference between any of the groups.(7) A small prospective cohort study of 19 patients on the combination of levetiracetam and DOACs (8 patients on dabigatran, 9 patients on apixaban, 4 patients on rivaroxaban) did not find a significant correlation between levetiracetam and DOAC concentrations. One patient who was on low-dose apixaban had low apixaban levels, and there were no thromboembolic events in the 1388 +/- 994 days of follow-up.(8)

Dabigatran/Valproate Derivatives

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

MECHANISM OF ACTION: The mechanism of the interaction is unknown. Valproate derivatives may decrease the efficacy of dabigatran.

CLINICAL EFFECTS: Concurrent use of valproate derivatives may result in decreased effectiveness of dabigatran.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of valproate derivatives in patients receiving dabigatran should be approached with caution. Consider alternative anticonvulsants in patients maintained on dabigatran. If concurrent use is warranted, monitor patients closely for decreased response to dabigatran.

DISCUSSION: A nested case-control study of 100,168 patients on apixaban, dabigatran, edoxaban, or rivaroxaban were reviewed for stroke (CVA)/systemic emboli in patients with atrial fibrillation or recurrent thromboembolism in patients with thromboembolism. The primary outcome of CVA/systemic embolism with concurrent use of valproic acid resulted in an odds ratio (95% CI) of 2.58 (1.50-4.45) and a propensity score adjusted odds ratio (95% CI) of 2.38 (1.37-4.12) compared to controls.(4) A population-based retrospective cohort study of 8746 patients on apixaban, dabigatran, edoxaban, or rivaroxaban were evaluated for occurrence of first ischemic stroke with concurrent antiseizure medications. Antiseizure medications that induce CYP3A4 or P-gp were associated with an increased risk of ischemic stroke (annual incidence rate of 5.5% vs 3.9%, adjusted hazard ratio 1.28). The annual incidence rates of ischemic stroke (valproate: 5.1%; levetiracetam: 6.0%; control: 3.9%) and venous thromboembolism (valproate: 3.7%; levetiracetam: 3.8%; control: 3.0%) were higher among valproate and levetiracetam users but were not statistically different from controls.(5)

Selected Anticoagulants/Pentosan

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

MECHANISM OF ACTION: Pentosan is a weak anticoagulant with 1/15 the activity of heparin. Concurrent use with anticoagulants may result in additive effects.(1)

CLINICAL EFFECTS: Concurrent use of pentosan and anticoagulants 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 pentosan and anticoagulants should be evaluated for hemorrhage.(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: Pentosan is a weak anticoagulant with 1/15 the activity of heparin.(1) In a study in 41 patients with interstitial cystitis, the concurrent use of pentosan and heparin (5000 units 3 times daily for 2 days, 5000 units 2 times daily for 12 days, then 5000 units daily as maintenance) resulted in increased response rates at 3 and 9 months, compared with 17 controls receiving pentosan alone.(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)

Slt Anticoagulants;Antiplatelets;Thrombolytics/Ssris;Snris

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

MECHANISM OF ACTION: Serotonin release by platelets plays a role in hemostasis.(1,2) The increased risk of bleeding may be a result of a decrease in serotonin reuptake by platelets.

CLINICAL EFFECTS: Concurrent use of a selective serotonin reuptake inhibitor(1-6) or a serotonin-norepinephrine reuptake inhibitor(7-9) and agents that affect coagulation may result in 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.(15) 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: Selective serotonin reuptake inhibitors(1-6) or serotonin-norepinephrine reuptake inhibitors(7-9) and agents that affect coagulation should be used concurrently with caution. 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: 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 ration was 4.5 and in a patient using low-dose aspirin only was 2.5. Concurrent use of a selective serotonin reuptake inhibitor with NSAIDs or low-dose aspirin increased the risk of bleeding to 12.2 and 5.2, respectively.(10) In another study, there were 16 cases of upper gastrointestinal bleeding in patients receiving concurrent therapy with selective serotonin reuptake inhibitors and NSAIDs. Adjusted relative risk of bleeding with NSAIDs, selective serotonin reuptake inhibitors, or both were 3.7, 2.6, or 15.6, respectively.(11) In a case-control study conducted in users of acenocoumarol or phenprocoumon, 1848 patients who had been hospitalized with abnormal bleeding were each matched to 4 control patients. When patients took both a SSRI and a coumarin, an increased risk of hospitalization due to major non-gastrointestinal bleeding was observed (adjusted OR 1.7), but not due to gastrointestinal bleeding (adjusted OR 0.8).(12) A retrospective review examined patients discharged from a hospital with antiplatelet therapy following a myocardial infarction. When compared to aspirin therapy alone, both aspirin therapy with a SSRI and aspirin, clopidogrel, and SSRI therapy were associated with an increased risk of bleeding (hazard ratios 1.42 and 2.35, respectively.) Compared with dual antiplatelet therapy (aspirin and clopidogrel), use of aspirin and clopidogrel and a SSRI was also associated with increased risk of bleeding (hazard ratio 1.57).(13) In The Rotterdam Study, fluvoxamine increased the risk of over anticoagulation (hazard ratio 2.63). Paroxetine was not associated with an increased risk. There were insufficient numbers of patients taking other SSRIs to assess increased risk.(14) 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 dabigatran and citalopram resulted in a ratio of rate ratios (95% CI) of 1.69 (1.11-2.57).(16) A systematic review and meta-analysis of 22 cohort and case-controlled studies including over 1 million patients found 1.55-fold higher odds of upper gastrointestinal (GI) bleeding in SSRI users compared with non-SSRI users (95% CI, 1.35-1.78). In subgroup analyses, the risk was found to be greatest among participants taking SSRIs concurrently with NSAIDs or antiplatelet medications.(17)

*Active pathologic bleeding.

*History of serious hypersensitivity reaction.

*Mechanical prosthetic heart valve.

• Antiphospholipid syndrome
• Cerebral amyloid angiopathy
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Deep peripheral nerve block
• Deep plexus block
• Intracranial bleeding
• Invasive procedure on spine
• Mechanical prosthetic heart valve present
• Neuraxial anesthesia
• Placement of indwelling epidural catheter

• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Hemorrhage
• Increased risk of bleeding
• Increased risk of bleeding due to coagulation disorder
• Pregnancy

There are no moderate contraindications for this drug.

Adverse effects reported in >15% of patients receiving dabigatran in clinical studies include GI adverse reactions and bleeding.

More Frequent

• Bruising
• Gastritis
• Gastrointestinal hemorrhage
• Gastrointestinal ulcer
• Hemorrhage

Rare or Very Rare

• Agranulocytosis
• Anaphylaxis
• Angioedema
• Anticoagulant-related nephropathy
• Erosive esophagitis
• Esophageal ulcer
• Hemorrhagic stroke
• Hypersensitivity drug reaction
• Intracranial bleeding
• Neutropenic disorder
• Ocular hemorrhage
• Retroperitoneal hemorrhage
• Spinal epidural hematoma
• Thrombocytopenic disorder
• Urticaria

More Frequent

• Abdominal distension
• Diarrhea
• Epistaxis
• Gastroesophageal reflux disease
• Upper abdominal pain

Less Frequent

• Dyspepsia
• Esophagitis
• Menorrhagia
• Nausea
• Vomiting

Rare or Very Rare

• Alopecia
• Edema
• Pruritus of skin
• Skin rash

No enhanced messaging available.

Safety and efficacy of dabigatran for treatment of venous thromboembolism (VTE) and reduction in the risk of recurrent VTE have been established in pediatric patients <12 years of age (oral pellets) and 8 to <18 years of age (oral capsules).

Safety and efficacy of dabigatran have not been established in pediatric patients for other indications.

There is insufficient data to inform the associated risks for adverse developmental outcomes following use of dabigatran during pregnancy. In animal studies, decreased implantation, fetal loss, and excess vaginal/uterine bleeding close to parturition have been observed. When administered to rats in maternally toxic doses during organogenesis, abnormal fetal skull bone and vertebrae ossification was observed, but no other major malformations were induced.

Dabigatran use during labor or delivery in women receiving neuraxial anesthesia may result in epidural or spinal hematomas. Consider discontinuation of dabigatran or use of a shorter acting anticoagulant agent as delivery approaches. Based on the pharmacologic activity of anticoagulants, bleeding risk may be increased in the fetus and neonate. Monitor neonates for signs/symptoms of bleeding.

The American College of Chest Physicians (ACCP) and the American College of Obstetricians and Gynecologists (ACOG) recommend avoiding dabigatran in pregnant women due to insufficient safety data; the American Society of Hematology (ASH) states that more data are necessary in their most recent guidelines for the management of VTE in the context of pregnancy.

It is not known whether dabigatran is distributed into human milk; dabigatran and/or its metabolites are found in rat milk. The manufacturer does not recommend breastfeeding during dabigatran treatment. ACCP, ACOG, and ASH recommend that anticoagulants other than dabigatran be used in nursing women.

The manufacturer makes no specific dosage recommendations for geriatric patients.

In the RE-LY study, 82% of patients were >=65 years of age, and 40% were >=75 years of age. Risk of bleeding increases with age, but the risk-benefit profile is favorable in all age groups.