Eliquis (apixaban)

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Apixaban is a substrate of cytochrome P-450 (CYP) 3A4, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP).

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/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.

Apixaban/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: 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.

Apixaban;Rivaroxaban/P-Gp & Strong 3A4 Inducers; Phenobarb

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: Apalutamide, carbamazepine, fosphenytoin, phenytoin, rifampin, rifapentine, and St. John's wort may induce the metabolism of apixaban(1-4) and rivaroxaban(5) by both P-gp and CYP3A4. Phenobarbital and primidone may also induce the metabolism of apixaban and rivaroxaban.(1-5)

CLINICAL EFFECTS: Concurrent or recent use of apalutamide, carbamazepine, fosphenytoin, phenobarbital, phenytoin, primidone, rifapentine, rifampin, or St. John's wort may result in decreased levels and effectiveness of apixaban(1-4) or rivaroxaban.(5)

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

PATIENT MANAGEMENT: The manufacturer of apixaban and rivaroxaban states to avoid the concurrent use of agents that are combined P-gp and strong CYP3A4 inducers (such as apalutamide, carbamazepine, fosphenytoin, phenytoin, rifampin, rifapentine, and St. John's wort), phenobarbital, and primidone in patients receiving apixaban or rivaroxaban.

DISCUSSION: Concurrent rifampin decreased the area-under-curve (AUC) and maximum concentration (Cmax) of apixaban by 54% and 42%, respectively.(1-4) In a clinical trial, rifampin (600 mg daily) decreased the AUC and Cmax of a single dose of rivaroxaban (20 mg with food) by 50% and 22%,respectively. Similar decreases in pharmacodynamic effects were seen.(5) 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 rivaroxaban and phenytoin resulted in a ratio of rate ratios (95% CI) of 2.39 (1.33-3.29).(6)

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; 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)

Apixaban/Antiplatelets; Aspirin (> 100 Mg)

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

MECHANISM OF ACTION: Additive effects on hemostasis.(1-4)

CLINICAL EFFECTS: Concurrent use of apixaban with antiplatelets may increase the risk of bleeding.(1-4)

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

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

DISCUSSION: Concurrent administration of enoxaparin (40 mg single dose) and apixaban (5 mg single dose) resulted in additive effects on anti-Factor Xa activity.(1) Concurrent apixaban and aspirin (325 mg daily) resulted in no pharmacokinetic or pharmacodynamic interactions.(1) Concurrent apixaban with clopidogrel (75 mg daily) or with combination clopidogrel (75 mg daily) and aspirin (162 mg daily) produced no relevant increases in bleeding time, platelet aggregation, or clotting tests (PI, INR, and aPTT) compared either clopidogrel alone or clopidogrel with aspirin without apixaban.(1) Significant bleeding risk was reported with the combination of apixaban, aspirin, and clopidogrel in patients with acute coronary syndrome.(1) A self-controlled case study of 1,622 oral anticoagulant-precipitant drug pairs were reviewed and found 14% of drug pairs were associated with a statistically significant elevated risk of thromboembolism. Concurrent use of apixaban and clopidogrel resulted in a ratio of rate ratios (95% CI) of 1.96 (1.53-2.51).(5) 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. 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 clinically relevant non-major 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.(3)

Apixaban/Hiv Protease Inhibitors; Cobicistat

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

MECHANISM OF ACTION: Apixaban is metabolized by CYP3A4 and is a substrate of the P-glycoprotein (P-gp) efflux transport protein.(1-4) HIV protease inhibitors are CYP3A4 and P-gp inhibitors and may increase the absorption and decrease the elimination of apixaban.(1-5)

CLINICAL EFFECTS: Concurrent use of protease inhibitors may result in elevated levels and clinical effects of apixaban, including an increased risk of bleeding.(1-5)

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

PATIENT MANAGEMENT: Recommendations for concurrent use of apixaban and HIV protease inhibitors vary in different regions. The Australian(1) and Canadian(2) manufacturers of apixaban state that the concurrent use of agents that are strong inhibitors of both P-gp and CYP3A4 with apixaban is contraindicated. The UK manufacturer of apixaban states that concurrent use of these agents is not recommended.(3) The US manufacturer of apixaban states that if concurrent use cannot be avoided, the dosage of apixaban should be reduced by 50% except in patients already receiving apixaban 2.5 mg twice daily, for whom concurrent use should be avoided.(4) The US manufacturer of atazanavir states that coadministration of unboosted atazanavir should be closely monitored.(5) 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: Concurrent ketoconazole (400 mg daily), a strong CYP3A4 and P-gp inhibitor, increased the area-under-curve (AUC) and maximum concentration (Cmax) of apixaban by 2-fold and 1.6-fold, respectively.(1) HIV protease inhibitors linked to this monograph are: atazanavir, cobicistat, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir.

Apixaban/Nirmatrelvir-Ritonavir

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

MECHANISM OF ACTION: Nirmatrelvir-ritonavir may inhibit the metabolism of apixaban by CYP3A4 and by P-glycoprotein (P-gp).(1-4)

CLINICAL EFFECTS: Concurrent use of an agent that is both an inhibitor of P-gp and a strong inhibitor of CYP3A4 may result in elevated levels of and clinical effects of apixaban, including an increased risk of bleeding.(1-4)

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

PATIENT MANAGEMENT: The US manufacturer of nirmatrelvir-ritonavir states concurrent use with apixaban may require a dose adjustment based on apixaban indication.(5) The Journal of American College of Cardiology states use of nirmatrelvir-ritonavir with apixaban should be avoided. Use of apixaban cannot be safely adjusted or interrupted in patients on dialysis. If nirmatrelvir-ritonavir is deemed necessary, dose adjustment recommendations based on apixaban indication are recommended.(6) For AF: -If on 5 mg apixaban twice daily: Start nirmatrelvir-ritonavir and decrease dose to 2.5 mg twice daily for a total of 8 days and then resume apixaban at the previous dose. -If on 2.5 mg apixaban twice daily: Avoid nirmatrelvir-ritonavir or withhold apixaban for 12-24 hours before starting nirmatrelvir-ritonavir along with an alternative anticoagulant for a total of 8 days and then resume apixaban at the previous dose. For VTE: -If on 10 mg apixaban twice daily: Start nirmatrelvir-ritonavir and decrease apixaban to 5 mg twice daily for a total of 8 days and then resume apixaban at the previous dose. -If on 5 mg apixaban twice daily: Start nirmatrelvir-ritonavir and decrease apixaban to 2.5 mg twice daily for a total of 8 days and then resume apixaban at the previous dose. -If on 2.5 mg apixaban twice daily for VTE prophylaxis: Can continue the same dose while on nirmatrelvir-ritonavir (will likely achieve therapeutic levels). 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: Concurrent ketoconazole (400 mg daily) increased the area-under-curve (AUC) and maximum concentration (Cmax) of apixaban by 2-fold and 1.6-fold, respectively.(1)

Apixaban/P-Gp And Strong Cyp3a4 Inhibitors

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

MECHANISM OF ACTION: Adagrasib, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, paritaprevir, posaconazole, telaprevir, tucatinib, and telithromycin may inhibit the metabolism of apixaban by CYP3A4 and by P-glycoprotein (P-gp).(1-4)

CLINICAL EFFECTS: Concurrent use of an agent that is both an inhibitor of P-gp and a strong inhibitor of CYP3A4 may result in elevated levels of and clinical effects of apixaban, including an increased risk of bleeding.(1-4)

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

PATIENT MANAGEMENT: The Australian(1) and Canadian(2) manufacturers of apixaban states that the concurrent use of agents that are strong inhibitors of both P-gp and CYP3A4 with apixaban is contraindicated. The UK manufacturer of apixaban states that concurrent use of these agents is not recommended.(3) The US manufacturer of apixaban states that if concurrent use cannot be avoided, the dosage of apixaban should be reduced by 50%. In patients already receiving apixaban 2.5 mg twice daily, avoid the concurrent use of strong inhibitors of both P-gp and CYP3A4.(4) The US manufacturer of itraconazole states that apixaban is not recommended during and two weeks after itraconazole treatment.(5) 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: Concurrent ketoconazole (400 mg daily) increased the area-under-curve (AUC) and maximum concentration (Cmax) of apixaban by 2-fold and 1.6-fold, respectively.(1) P-gp and strong CYP3A4 inhibitors linked to this monograph are: adagrasib, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, paritaprevir, posaconazole, telaprevir, tucatinib and telithromycin.

Apixaban;Betrixaban;Edoxaban;Rivaroxaban/Nsaids;Salicylates

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

MECHANISM OF ACTION: Concurrent use of apixaban(1-4), betrixaban(7), edoxaban(5), or rivaroxaban(6) and nonsteroidal antiinflammatory agents (NSAIDs) or salicylates may result in additive increased risk of bleeding.

CLINICAL EFFECTS: Concurrent use of apixaban(1), betrixaban(7), edoxaban(5), or rivaroxaban(2) with NSAIDs or salicylates may result in unwanted bleeding episodes.

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

PATIENT MANAGEMENT: Approach concurrent therapy with apixaban(1-4), betrixaban(7), edoxaban(5), or rivaroxaban(6) with caution. 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 study, naproxen (500 mg) increased apixaban (10 mg) area-under-curve (AUC) and maximum concentration (Cmax) by 1.5-fold an 1.6-fold, respectively, with corresponding increases in clotting tests. There were no changes in the effect of naproxen on arachidonic acid-induced platelet aggregation, no clinically relevant changes in bleeding times, or naproxen pharmacokinetics.(1) In a single dose study, there were no pharmacokinetic or pharmacodynamic interactions between rivaroxaban and naproxen.(6) Although effects seen in the above studies were limited, NSAIDs are known to increase bleeding and may further increase the risk of bleeding with these agents.(1-6) In edoxaban clinical studies, concomitant use of low-dose aspirin (less than or equal to 100 mg/day) or thienopyridines, and NSAIDs was permitted and resulted in increased rates of clinically relevant bleeding.(5) In a study of 34 healthy subjects administered edoxaban 60 mg daily and naproxen 500 mg daily, bleeding time increased by 2.08-fold from baseline on the combination, compared to a 1.23-fold increase with naproxen alone and 1.7-fold increase on edoxaban alone.(8) 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 apixaban and ibuprofen resulted in a ratio of rate ratios (RR) (95% CI) of 5.16 (3.0-8.85); apixaban and celecoxib ratio of RR 1.8 (1.06-3.06); rivaroxaban and etodolac ratio of RR 2.47 (1.18-4.22); rivaroxaban and naproxen ratio of RR 1.89 (1.12-1.43); and rivaroxaban and ibuprofen ratio of RR 1.68 (1.29-4.44).(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/Mifepristone (Cushing)

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

MECHANISM OF ACTION: 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 or antiplatelets may further increase risk.

CLINICAL EFFECTS: The concurrent use of mifepristone with anticoagulants or antiplatelets may result in endometrium thickening, cystic dilatation of endometrial glands, or excessive vaginal bleeding.

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

PATIENT MANAGEMENT: The manufacturer of mifepristone states that mifepristone should be used with caution in patients receiving concurrent anticoagulant or antiplatelet 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. Women experiencing vaginal bleeding during concurrent use should be referred to a gynecologist for further evaluation.

DISCUSSION: The manufacturer of mifepristone states that mifepristone should be used with caution in patients receiving concurrent anticoagulant or antiplatelet therapy.(1)

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/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.(1-4)

CLINICAL EFFECTS: Concurrent use of apixaban with aspirin may increase the risk of bleeding.(1-4)

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.(5-7) 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 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: Concurrent apixaban and aspirin (325 mg daily) resulted in no pharmacokinetic or pharmacodynamic interactions.(1) In a clinical trial examining the use of apixaban in atrial fibrillation, concurrent use of aspirin increased risk of major bleeding with apixaban from 1.8% per year to 3.4% per year and increased the bleeding risk with warfarin from 2.7% per year to 4.6% per year. Concomitant dual antiplatelet therapy was used in 2.1% of patients.(3,4) In a clinical trial examining the use of apixaban in high-risk post acute coronary syndrome patients with multiple cardiac and non-cardiac comorbidities, who received ASA or the combination of ASA and clopidogrel, the risk of major bleeding (defined by ISTH -International Society on Thrombosis and Haemostasis criteria) was increased for apixaban (5.13% per year) compared to placebo (2.04% per year).(3,4) 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. 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 clinically relevant non-major 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.(8)

Apixaban/Clarithromycin

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

MECHANISM OF ACTION: Clarithromycin is a combined P-glycoprotein (P-gp) and strong CYP3A4 inhibitor.(1) Concurrent use may inhibit the metabolism of apixaban by CYP3A4 and increase its absorption through P-gp.(2-5)

CLINICAL EFFECTS: Concurrent use of clarithromycin may result in elevated levels of and clinical effects of apixaban, including an increased risk of bleeding.(1-5)

PREDISPOSING FACTORS: This interaction may be more clinically significant in patients with decreased renal function.(1-5) The risk for bleeding episodes may be greater in older patients (65 years and over) and patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The Australian(2), Canadian(3), UK(4), and US(5) manufacturers of apixaban state that concurrent use of clarithromycin is expected to increase apixaban levels to a lesser extent than agents that are strong inhibitors of both P-gp and CYP3A4. No dose adjustment of apixaban is necessary. Use caution when administering apixaban with clarithromycin. 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 an open-label non-randomized crossover pharmacokinetic study of 19 healthy volunteers, clarithromycin 500 mg twice daily for 4 days increased the area-under-curve (AUC) and maximum concentration (Cmax) of single-dose apixaban 10 mg by 60% and 30%, respectively, compared to apixaban alone. Adverse events were mild, and the frequency did not increase with the combination.(6) An open-label pharmacokinetic study of 12 healthy volunteers evaluated use of clarithromycin (500 mg twice daily with pre-treatment for 7 days) with therapeutic dose of edoxaban (60 mg) and a microdose cocktail of apixaban (25 mcg), edoxaban (50 mcg), and rivaroxaban (25 mcg). Apixaban AUC increased by 60% and Cmax increased by 30%. Compared to therapeutic doses of edoxaban, microdosed edoxaban over-estimated the effect of clarithromycin on edoxaban exposure; the authors stated that the microdose direct oral anticoagulant (DOAC) interactions with clarithromycin are not expected to be clinically relevant.(7) A cohort from two Belgian health databases examined 193,072 atrial fibrillation patients who were at least 45 years old and newly started on dabigatran, rivaroxaban, apixaban or edoxaban. Patients were classified by whether they had concomitant CYP3A4 and P-gp interacting drugs at baseline. On multivariate analysis, concomitant P-gp/CYP3A4 inhibitor use with DOACs was associated with higher risks of major bleeding (aHR 1.24, 95% CI 1.18-1.30), intracranial bleeding (aHR 1.07, 95% CI 1.02-1.11), GI bleeding [aHR 1.20, 95% CI (1.12-1.28)], and all-cause mortality [aHR 1.07, 95% CI (1.02-1.11)]. Although the specific combination of apixaban with clarithromycin was not evaluated, subgroup analysis found that clarithromycin increased the risks of major bleeding [aHR 1.55, 95% CI (1.14-2.11)] and GI bleeding [aHR 1.52, 95% CI 1.03-2.25)] from DOACs, while concurrent P-gp/CYP3A4 inhibitors increased the risk of major bleeding from apixaban [aHR 1.27, 95% CI 1.07-1.35].(8) An analysis of the FDA Adverse Event Reporting System (FAERS) database looking at hemorrhagic signals associated with coadministration of apixaban, dabigatran, rivaroxaban, or edoxaban with azithromycin, clarithromycin, erythromycin, fluconazole, itraconazole, ketoconazole, posaconazole or voriconazole found 27,544 cases of apixaban-related hemorrhagic events, with 315 cases involving CYP3A4 inhibitors. The combination of apixaban and clarithromycin was associated with increased risk of hemorrhagic events in multiple logistic regression (ROR 1.60, 95% CI 1.16-2.20).(9) A population-based retrospective cohort study examined 24,943 patients aged 66 years and older on concurrent therapy with an anticoagulant [rivaroxaban (40.0%), apixaban (31.9%), or dabigatran (28.1%)] and either azithromycin or clarithromycin. The primary outcome of hospital admission with major hemorrhage on an anticoagulant within 30 days on concurrent therapy was higher in patients on clarithromycin (0.77%) compared to azithromycin (0.43%) with an adjusted hazard ratio of 1.71 (95% CI, 1.20-2.45). Hemorrhage rate was similarly elevated when comparing periods of clarithromycin use with periods of nonuse within the same individual. Although the data was not shown, the outcome did not differ by DOAC type or mean daily dose. There was a high proportion (33%) of patients with baseline eGFR <=60 mL/min/1.73m2, which was the same in the clarithromycin and azithromycin groups but this was accounted for in the adjusted analysis.(10)

Apixaban/Enzalutamide

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

MECHANISM OF ACTION: Enzalutamide may induce the metabolism of apixaban by CYP3A4, but increase their absorption by inhibiting P-glycoprotein (P-gp).(1-7)

CLINICAL EFFECTS: Concurrent or recent use of enzalutamide may increase or decrease apixaban drug levels, potentially increasing the risk of bleeding or reducing anticoagulant efficacy.(1-7)

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: Consider the use of alternative agents for anticoagulation in patients requiring therapy with enzalutamide. Depending on indication and renal function, dabigatran, edoxaban, or warfarin may be alternatives.(6) If concurrent therapy is required, monitor patients for altered response to apixaban. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. 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: Concurrent rifampin (a strong inducer of CYP3A4 and an inducer of P-gp) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of apixaban by 54% and 42%, respectively.(1-4) Concurrent ketoconazole (400 mg daily, a strong inhibitor of CYP3A4 and P-gp) increased the area-under-curve (AUC) and maximum concentration (Cmax) of apixaban by 2-fold and 1.6-fold, respectively.(1) Enzalutamide is a strong inducer of CYP3A4 and an inhibitor of P-gp.(5) A PKPB model study evaluated the effects of enzalutamide as a strong CYP3A4 inducer and P-gp inhibitor on apixaban. The model predicted a decrease in apixaban AUC by 31% with no change in Cmax.(7)

Apixaban/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 apixaban.

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

PREDISPOSING FACTORS: None determined.

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

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.(5) 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.(6) 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.(7) 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.(8) 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.(9)

Apixaban/P-Gp And Moderate Cyp3a4 Inhibitors

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

MECHANISM OF ACTION: Cimetidine, diltiazem, dronedarone, erythromycin, isavuconazonium and verapamil may inhibit the metabolism of apixaban by CYP3A4 and by P-glycoprotein.(1,2)

CLINICAL EFFECTS: Concurrent use of an agent that is both an inhibitor of P-gp and a moderate inhibitor of CYP3A4 may result in elevated levels of and clinical effects of apixaban, including an increased risk of bleeding.(1,2)

PREDISPOSING FACTORS: This interaction may be more clinically significant 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 (e.g. NSAIDs).

PATIENT MANAGEMENT: The Australian(1), Canadian(2), UK(3), and US(4) manufacturers state concurrent use of agents that are P-gp and moderate CYP3A4 inhibitors are expected to increase apixaban levels to a lesser extent than agents that are P-gp and strong CYP3A4 inhibitors. No dose adjustment of apixaban is necessary. Use caution when administering apixaban with moderate inhibitors of CYP3A4. 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: Concurrent ketoconazole (400 mg daily, a strong inhibitor of CYP3A4) increased the area-under-curve (AUC) and maximum concentration (Cmax) of apixaban by 2-fold and 1.6-fold, respectively.(1) A propensity matched cohort evaluated the concurrent use of combined P-gp and moderate CYP3A4 inhibitors with apixaban or rivaroxaban. Combined inhibitors included amiodarone (weak CYP3A4 inhibitor), diltiazem, erythromycin, dronedarone, and verapamil. Bleeding occurred in 26.4% of patients in the inhibitor group compared to 18.4% in the control group (hazard ratio 1.8; 95% CI 1.19-2.73; p=0.006). Although not statistically significant, patients in the inhibitor group also had a higher rate of major bleeding (15% vs 10.3%) and minor bleeding (8.9% vs 5.2%), respectively. This study's sample size was not large enough to evaluate individual drug pairs.(6) A summary of pharmacokinetic interactions with apixaban and calcium-channel blockers, including diltiazem and verapamil, concluded that concurrent use is considered safe based on a lesser increase in apixaban exposure with moderate CYP3A4 inhibitors.(7) A population cohort study of 48,422 patients evaluated overall and gastrointestinal major, moderate or minor bleeding in patients on concurrent therapy with apixaban and diltiazem or verapamil. Concurrent therapy was not associated with increased bleeding rates compared to patients receiving amlodipine or metoprolol.(8) A retrospective study of two propensity matched cohorts of 1681 patients each found a bleeding rate of 1.31 and 2.14 per 100 years at risk with apixaban and warfarin, respectively, when used concurrently with dronedarone in patients with atrial fibrillation. The hazard ratio with apixaban and dronedarone was 0.66 compared to warfarin and dronedarone.(9) An observational study of 29 patients evaluated concurrent administration of apixaban (5 mg) with diltiazem or diltiazem with atorvastatin or rosuvastatin. Administration of apixaban with diltiazem and rosuvastatin resulted in a greater than 1.5-fold increate in apixaban concentrations. Concurrent administration of apixaban with diltiazem alone or diltiazem with atorvastatin did not result in a statistically significant increase in apixaban concentration.(11) P-gp and moderate CYP3A4 inhibitors linked to this monograph are: conivaptan, diltiazem, dronedarone, erythromycin, isavuconazonium and verapamil.(10)

Apixaban/Strong And Moderate Cyp3a4 Inhibitors

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

MECHANISM OF ACTION: Apixaban is a substrate of CYP3A4 and P-glycoprotein (P-gp). It is about 20% metabolized, mainly by CYP3A4.(1-4) Strong and moderate CYP3A4 inhibitors may inhibit the metabolism of apixaban by CYP3A4.

CLINICAL EFFECTS: Concurrent use of a CYP3A4 inhibitor may result in elevated levels of and clinical effects of apixaban, including an increased risk of bleeding, especially in the setting of concurrent therapy with an agent that inhibits P-gp.(1-4)

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

PATIENT MANAGEMENT: The US manufacturer of apixaban provides recommendations regarding concurrent use with strong inhibitors of both CYP3A4 and P-gp, but does not provide guidance for concurrent use with agents that inhibit CYP3A4 alone.(1) The Australian, Canadian, and UK labels for apixaban state that no dose adjustment for apixaban is required when co-administered with agents that are not strong inhibitors of both CYP3A4 and P-gp.(2-4) Expert opinion on the clinical significance of this interaction is varied and depends on the inhibitor. Some experts state that specific agents (i.e., voriconazole, imatinib, and crizotinib) should be contraindicated.(5) Others state that concurrent use is acceptable if there are no other pharmacokinetic interactions; otherwise, a 50% dose reduction of apixaban is suggested.(6) In patients who are also on concurrent P-gp inhibitors, consider the manufacturer recommendations for use with dual CYP3A4 and P-gp inhibitors. The US manufacturer of apixaban states that if concurrent use of strong CYP3A4 and P-gp inhibitors cannot be avoided, the dosage of apixaban should be reduced by 50%. In patients already receiving apixaban 2.5 mg twice daily, avoid the concurrent use of strong inhibitors of both P-gp and CYP3A4.(1) The Australian(2) and Canadian(3) manufacturers of apixaban states that the concurrent use of agents that are strong inhibitors of both P-gp and CYP3A4 with apixaban is contraindicated. The UK manufacturer of apixaban states that concurrent use of these agents is not recommended.(4) Concurrent use of agents that are dual P-gp and moderate CYP3A4 inhibitors are expected to increase apixaban levels to a lesser extent than agents that are P-gp and strong CYP3A4 inhibitors. No dose adjustment of apixaban is necessary. Use caution when administering apixaban with moderate inhibitors of CYP3A4. 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 US manufacturer of apixaban states that apixaban dose reduction is recommended when apixaban exposure increases by more than 50%, while efficacy is maintained when exposure is 25% lower. Therefore, no dose adjustment of apixaban is recommended for drug interactions that affect apixaban exposure by 75% to 150%.(7) In a microdose cocktail study using apixaban 25 mcg, voriconazole 400 mg every 12 hours for 2 doses then 200 mg every 12 hours (strong CYP3A4 inhibitor) had "only a minor interaction," increasing the AUC of apixaban by 1.33-fold (95% CI 1.01-1.75) while the Cmax and half-life remained unchanged.(8) Another microdose cocktail study with apixaban 25 mcg and voriconazole 400 mg twice daily found that apixaban AUC increased by 1.24-fold with a non-significant change in Cmax.(9) A retrospective cohort study of 50 oncology patients on apixaban identified 14 patients on concurrent voriconazole, with 3 of those patients receiving reduced-dose apixaban. No bleeding or thrombosis occurred in any of the patients on concurrent voriconazole.(10) An article evaluating the clinical significance of efflux transporters like P-gp and BCRP in apixaban exposure analyzed pharmacokinetic data from drug-drug interaction studies and concluded that all apixaban interactions can be explained by inhibition of intestinal CYP3A4. The authors explain that apixaban is a highly permeable and soluble compound, so its ability to undergo passive diffusion renders the role of membrane transporters irrelevant, as evidenced by a lack of change in apixaban absorption rate in the presence of drugs known to inhibit P-gp and BCRP.(11) A review article on DOAC drug-drug interactions suggests that the combination of voriconazole, crizotinib or imatinib with apixaban or rivaroxaban is contraindicated due to the potential for significant increases in DOAC AUC. The authors state that data with voriconazole is missing and thus the interactions are unpredictable.(5) Another review article states that apixaban may be used with voriconazole if no other pharmacokinetic inhibitor is present; otherwise, concurrent use requires a 50% apixaban dose reduction. No dose adjustment is recommended with moderate CYP3A4 inhibitors.(6) Strong CYP3A4 inhibitors linked to this monograph include: boceprevir, ceritinib, ensitrelvir, idelalisib, mibefradil, nefazodone, relacorilant, ribociclib, troleandomycin, and voriconazole.(12,13) Moderate CYP3A4 inhibitors linked to this monograph include: aprepitant, avacopan, berotralstat, clofazimine, crizotinib, duvelisib, fedratinib, fosnetupitant, imatinib, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and voxelotor.(12,13)

Apixaban/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 apixaban.

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

PREDISPOSING FACTORS: None determined.

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

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.(5) 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.(6)

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)

Apixaban; Rivaroxaban/Fluvoxamine

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

MECHANISM OF ACTION: Apixaban and rivaroxaban are substrates of CYP3A4. Apixaban is about 20% metabolized and rivaroxaban is about 18% metabolized, mainly by CYP3A4.(1-8) Fluvoxamine is a moderate CYP3A4 inhibitor and may inhibit the metabolism of apixaban and rivaroxaban by CYP3A4.(9) Serotonin release by platelets plays a role in hemostasis.(9) Fluvoxamine may cause a decrease in serotonin reuptake by platelets, resulting in an additive risk of bleeding with anticoagulants.

CLINICAL EFFECTS: Concurrent use of fluvoxamine 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 a higher risk of rivaroxaban levels and an elevated risk of GI bleed in patients on SSRIs.(10) Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Concurrent therapy of fluvoxamine with apixaban or rivaroxaban should be undertaken with caution. The manufacturers of apixaban and rivaroxaban do not provide guidance for concurrent use with agents that inhibit CYP3A4 alone, while international manufacturer recommendations vary but generally state that such interactions are of low to no clinical significance.(1-8) Use caution with concurrent use of moderate CYP3A4 inhibitors. 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, anti Factor Xa inhibition) 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: Fluvoxamine is a moderate CYP3A4 inhibitor and a serotonin reuptake inhibitor. Concurrent use with apixaban and rivaroxaban may increase levels of the anticoagulants and result in an additive risk of bleeding. There are no studies or reports on the combination of apixaban and rivaroxaban with moderate CYP3A4 inhibitors like fluvoxamine. In a microdose cocktail study using apixaban 25 mcg or rivaroxaban 25 mcg, voriconazole 400 mg every 12 hours for 2 doses then 200 mg every 12 hours (strong CYP3A4 inhibitor) had "only a minor interaction," increasing the AUC of both apixaban and rivaroxaban by 1.33-fold (p<0.05) while the Cmax and half-life remained unchanged.(11) Another microdose cocktail study with apixaban 25 mcg or rivaroxaban 25 mcg and voriconazole 400 mg twice daily found that apixaban AUC increased by 1.24-fold and rivaroxaban AUC increased by 1.16-fold with a non-significant change in Cmax.(12) A review article on DOAC drug-drug interactions suggests that the combination of voriconazole, crizotinib or imatinib with apixaban or rivaroxaban is contraindicated due to the potential for significant increases in DOAC AUC. The authors state that data with voriconazole is missing and thus the interactions are unpredictable.(13) Another review article states that apixaban and rivaroxaban may be used with voriconazole if no other pharmacokinetic inhibitor is present. No dose adjustment is recommended with moderate CYP3A4 inhibitors.(14) A systemic review and meta-analysis evaluated the risk of bleeding associated with the combination of SSRIs or SNRIs and DOACs. Concurrent use had a significantly higher risk of major bleeding than use of DOACs alone (RR 1.25, 95% CI 1.07-1.47 among cohort studies; OR 1.4, 95% CI 1.24-1.66 for case-control studies).(15) 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.(16) 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).(17)

Apixaban; Rivaroxaban/Strong & Moderate Cyp3a4 Inducers

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

MECHANISM OF ACTION: Apixaban and rivaroxaban are both substrates of CYP3A4 and P-glycoprotein (P-gp). Apixaban is about 20% metabolized and rivaroxaban is about 18% metabolized, mainly by CYP3A4.(1-8) Strong and moderate CYP3A4 inducers may induce the metabolism of apixaban and rivaroxaban by CYP3A4.

CLINICAL EFFECTS: Concurrent or recent use of a CYP3A4 inducer may result in decreased levels and effectiveness of apixaban(1-4) or rivaroxaban,(5-8) especially in the setting of concurrent therapy with an agent that induces P-gp.

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. Drug-associated risk factors include concurrent use of P-gp inducers.

PATIENT MANAGEMENT: The US, Australian, Canadian, and UK manufacturers of apixaban provide recommendations regarding concurrent use with strong inducers of both CYP3A4 and P-gp, but do not provide guidance for concurrent use with agents that induce CYP3A4 alone.(1) The US manufacturer of rivaroxaban provides recommendations regarding concurrent use with strong inducers of both CYP3A4 and P-gp, but does not provide guidance for concurrent use with agents that induce CYP3A4 alone.(5) The Australian manufacturer of rivaroxaban states that concurrent use of strong CYP3A4 inducers should be approached with caution.(6) The Canadian and UK labels for rivaroxaban state that concurrent use of strong CYP3A4 inducers should be avoided.(7-8) When considering concurrent therapy with a strong or moderate CYP3A4 inducer with either apixaban or rivaroxaban, evaluate the patient's other concurrent therapy for CYP3A4 and P-gp effects. In patients who are taking strong CYP3A4 inducers and are also on concurrent P-gp inducers, consider the manufacturer recommendations for use with dual CYP3A4 and P-gp inducers. The US manufacturers of apixaban and rivaroxaban both state to avoid the concurrent use of agents that are combined P-gp and strong CYP3A4 inducers in patients receiving apixaban or rivaroxaban.(1-8) In patients who are taking moderate CYP3A4 inducers and are also on concurrent P-gp inducers, it may be prudent to consider alternative therapy or monitor the patient closely. For patients taking efavirenz or etravirine, the US and European HIV guidelines recommend considering alternative therapies or performing additional monitoring.(9-10)

DISCUSSION: The concurrent use of apixaban or rivaroxaban with strong CYP3A4 inducers that are not also P-gp inducers has not been studied. Apixaban and rivaroxaban are metabolized primarily by CYP3A4. Strong CYP3A4 inducers may decrease the levels and effectiveness of apixaban and rivaroxaban. The US manufacturer of apixaban states that apixaban dose reduction is recommended when apixaban exposure increases by more than 50%, while efficacy is maintained when exposure is 25% lower. Therefore, no dose adjustment of apixaban is recommended for drug interactions that affect apixaban exposure by 75% to 150%.(11) An article evaluating the clinical significance of efflux transporters like P-gp and BCRP in apixaban exposure analyzed pharmacokinetic data from drug-drug interaction studies and concluded that all apixaban interactions can be explained by inhibition of intestinal CYP3A4. The authors explain that apixaban is a highly permeable and soluble compound, so its ability to undergo passive diffusion renders the role of membrane transporters irrelevant, as evidenced by a lack of change in apixaban absorption rate in the presence of drugs known to inhibit P-gp and BCRP.(12) Strong CYP3A4 inducers linked to this monograph include: barbiturates, encorafenib, ivosidenib, lumacaftor, and mitotane.(13,14) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(13,14)

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.

*Severe hypersensitivity reaction (e.g., anaphylactic reactions) to apixaban.

• Antiphospholipid syndrome
• Cerebral amyloid angiopathy
• Deep peripheral nerve block
• Deep plexus block
• Hemorrhage
• Intracranial bleeding
• Invasive procedure on spine
• Lactation
• Mechanical prosthetic heart valve present
• Neuraxial anesthesia
• Placement of indwelling epidural catheter

• Child-pugh class B hepatic impairment
• Child-pugh class C hepatic impairment
• Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min
• Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Increased risk of bleeding
• Pregnancy
• Severe hepatic disease
• Surgical procedure on eye proper
• Thrombocytopenic disorder

• Kidney disease with likely reduction in glomerular filtration rate (GFr)

The most common adverse reactions reported in adults receiving apixaban (>1%) were related to bleeding.

The most common adverse reactions (>=10%) in pediatric patients receiving apixiban were headache, vomiting, and excessive menstrual bleeding.

More Frequent

• Hemorrhage

Less Frequent

• Anemia
• Hemoptysis
• Rectal bleeding

Rare or Very Rare

• Abnormal hepatic function tests
• Anaphylaxis
• Anticoagulant-related nephropathy
• Bleeding from wound
• Bleeding hemorrhoids
• Bloody stools
• Bloody vomit
• Gastrointestinal hemorrhage
• Hemorrhage of muscle
• Hemorrhagic stroke
• Hyperbilirubinemia
• Hypotension
• Increased alanine transaminase
• Increased aspartate transaminase
• Intracranial bleeding
• Ocular hemorrhage
• Periorbital hematoma
• Postsurgical hemorrhage
• Retinal hemorrhage
• Retroperitoneal hemorrhage
• Spinal epidural hematoma
• Thrombocytopenic disorder

More Frequent

• Headache disorder

Less Frequent

• Bruising
• Epistaxis
• Gingival bleeding
• Hematoma
• Hematuria
• Injection site sequelae
• Menorrhagia
• Nausea
• Vomiting

Rare or Very Rare

• Abnormal vaginal bleeding
• Black tarry stools
• Conjunctival hemorrhage
• Ecchymosis
• Edema
• Petechiae
• Skin rash
• Syncope

No enhanced messaging available.

Safety and effectiveness of apixaban have been established in pediatric patients for the treatment of VTE and reduction in risk of recurrent VTE. Use of apixaban in pediatric patients is supported by evidence from adequate and well-controlled studies in adults, and additional pharmacokinetic, safety, and efficacy data in pediatric patients including data from a randomized, active controlled, open-label, descriptive study.

The manufacturer states the limited available data on apixaban use in pregnant women are insufficient to inform drug-associated risks of major birth defects, miscarriage, or adverse developmental outcomes. Animal studies have not demonstrated any evidence of fetotoxic effects; however, increased maternal bleeding was observed when apixaban was administered to pregnant animals at doses ranging from 1-19 times the human exposure at the maximum recommended dose. All patients receiving anticoagulants, including pregnant women, are at risk for bleeding.

Consider use of a shorter acting anticoagulant as delivery approaches. Based on the pharmacologic activity of factor Xa inhibitors, bleeding may occur at any site in the fetus and/or neonate. Apixaban use during labor or delivery in women who are receiving neuraxial anaesthesia may result in epidural or spinal hematomas.

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

Apixaban is distributed into milk in rats; it is not known whether the drug is distributed into human milk. The effects of apixaban on the breast-fed infant or on milk production are unknown. The manufacturer states that breast-feeding is not recommended during treatment with apixaban. ACCP, ACOG, and ASH recommend that anticoagulants other than apixaban be used in nursing women.

The manufacturer states that dosage adjustment based solely on age is not necessary in geriatric patients >=65 years of age; however, a reduced dosage of 2.5 mg twice daily is recommended in patients >=80 years of age with nonvalvular atrial fibrillation if they also weigh <=60 kg and/or have a serum creatinine concentration >=1.5 mg/dL.

No substantial differences in efficacy and safety were observed in geriatric patients >=65 years relative to younger adults in clinical trials. In clinical trials of apixaban in patients with nonvalvular atrial fibrillation or DVT/PE, no clinically important differences in efficacy or safety were observed among different age groups. Pharmacokinetic effects (systemic exposure and peak plasma concentrations) of apixaban were similar in patients >=65 years and younger adults (18-40 years of age) receiving the drug.