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Drug overview for SAVAYSA (edoxaban tosylate):
Generic name: EDOXABAN TOSYLATE (e-DOX-a-ban)
Drug class: Oral Anticoagulants
Therapeutic class: Hematological Agents
Edoxaban tosylate, an oral, direct, activated factor X (Xa) inhibitor, is an anticoagulant.
No enhanced Uses information available for this drug.
Generic name: EDOXABAN TOSYLATE (e-DOX-a-ban)
Drug class: Oral Anticoagulants
Therapeutic class: Hematological Agents
Edoxaban tosylate, an oral, direct, activated factor X (Xa) inhibitor, is an anticoagulant.
No enhanced Uses information available for this drug.
DRUG IMAGES
SAVAYSA 15 MG TABLET
SAVAYSA 30 MG TABLET
SAVAYSA 60 MG TABLET
The following indications for SAVAYSA (edoxaban tosylate) have been approved by the FDA:
Indications:
Deep venous thrombosis
Prevention of thromboembolism in chronic atrial fibrillation
Pulmonary thromboembolism
Professional Synonyms:
Deep vein thrombosis
Pulmonary embolism
Indications:
Deep venous thrombosis
Prevention of thromboembolism in chronic atrial fibrillation
Pulmonary thromboembolism
Professional Synonyms:
Deep vein thrombosis
Pulmonary embolism
The following dosing information is available for SAVAYSA (edoxaban tosylate):
Dosage of edoxaban tosylate monohydrate is expressed in terms of edoxaban.
Edoxaban is administered orally without regard to food. (See Description.) Edoxaban can be crushed and mixed with 2-3 ounces of water and immediately administered orally or through a gastric tube in patients unable to swallow whole tablets. Crushed tablets can also be mixed into applesauce and immediately administered orally. If a dose of edoxaban is missed, the missed dose should be taken as soon as possible on the same day, followed by resumption of the regular schedule; the dose should not be doubled to make up for the missed dose.
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| SAVAYSA 15 MG TABLET | Maintenance | Adults take 2 tablets (30 mg) by oral route once daily |
| SAVAYSA 30 MG TABLET | Maintenance | Adults take 1 tablet (30 mg) by oral route once daily |
| SAVAYSA 60 MG TABLET | Maintenance | Adults take 1 tablet (60 mg) by oral route once daily |
No generic dosing information available.
The following drug interaction information is available for SAVAYSA (edoxaban tosylate):
There are 5 contraindications.
These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.
| Drug Interaction | Drug Names |
|---|---|
| Mifepristone/Anticoagulants; Antiplatelets 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) |
MIFEPREX, MIFEPRISTONE |
| Edoxaban/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 edoxaban with anticoagulants or thrombolytics may increase the risk of bleeding. PREDISPOSING FACTORS: Bleeding risk may be increased in patients with renal impairment and in patients > 75 years of age. Use of multiple agents which affect hemostasis increases the risk for bleeding. PATIENT MANAGEMENT: The long-term use of concurrent therapy with direct oral anticoagulants (DOACs) and other anticoagulants is generally considered contraindicated. However, overlap may be necessary when switching therapy from one agent to another in order to prevent thrombotic events. Manufacturer recommendations concerning overlap (if any) and timing of discontinuation versus initiation vary depending upon which agent is being discontinued and initiated. Refer to current prescribing information for both agents for additional details. Specific recommendations for converting between anticoagulants: - When converting from other (non-vitamin K antagonist) oral anticoagulants to edoxaban, discontinue current oral anticoagulant and start edoxaban at the time of the next scheduled dose of the old oral anticoagulant. - When converting from a low molecular weight heparin (LMWH) to edoxaban, start edoxaban at the time of the next scheduled administration of LMWH. - When converting from unfractionated heparin to edoxaban, discontinue the infusion and start edoxaban 4 hours later. - When converting from edoxaban to another DOAC, discontinue edoxaban and begin the new oral anticoagulant at the time of the next scheduled dose of edoxaban. - When converting from edoxaban to parenteral anticoagulation, start the parenteral anticoagulant at the time of the next dose of edoxaban. - When converting from warfarin to edoxaban, discontinue warfarin and start edoxaban when the INR is < or = to 2.5. - When converting from edoxaban to warfarin, for patients taking 60 mg of edoxaban, reduce the dose to 30 mg and begin warfarin concomitantly. For patients receiving 30 mg of edoxaban, reduce the dose to 15 mg and begin warfarin concomitantly. INR must be measured at least weekly and just prior to the daily dose of edoxaban to minimize the effects of edoxaban on INR measurement. Once a stable INR = or > 2.0 is achieved, edoxaban should be discontinued and the warfarin continued. - A second edoxaban to warfarin conversion option: Discontinue edoxaban and administer a parenteral anticoagulant and warfarin at the time of the next scheduled edoxaban dose. Once a stable INR = or > 2.0 is achieved, the parenteral anticoagulant should be discontinued and the warfarin continued. The use of concurrent therapy with Direct Oral Anticoagulants (DOACs) and thrombolytics is generally considered contraindicated. The manufacturer of alteplase states that the use of alteplase for an indication of acute ischemic stroke is contraindicated in patients receiving anticoagulants. Concurrent use of alteplase and anticoagulants is dependent on the therapeutic indication. In Acute Ischemic Stroke: - Clinical practice guidelines for acute ischemic stroke state the use of thrombolytic therapy for an indication of acute ischemic stroke is contraindicated in patients who have received thrombin inhibitors or factor Xa inhibitors in the previous 48 hours (in normal renal function) and have abnormal laboratory tests such as activated partial thromboplastin time (aPTT), INR, platelet count, ecarin clotting time (ECT), thrombin time, or direct factor Xa assays at presentation. In Acute Myocardial Infarction: - Patients who are receiving thrombolytics for an indication of acute myocardial infarction should be carefully monitored for signs of bleeding, especially at arterial puncture sites, if edoxaban is used concurrently. - The use of thrombolytics in patients with acute myocardial infarction should follow standard management of myocardial infarction, including minimizing arterial and venous puncture; avoid noncompressible arterial puncture; and minimize internal jugular and subclavian venous punctures to decrease bleeding from the noncompressible sites. For all indications: - In the event of serious bleeding, anticoagulants should be discontinued immediately. - If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. - When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. - Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. DISCUSSION: Limited overlap of DOACs with other anticoagulants may be required when initiating or discontinuing DOACs in order to prevent thrombotic events. However, long-term concomitant treatment is not recommended because of increased risk of bleeding. Patients who are receiving thrombolytics should be carefully monitored for signs of bleeding if anticoagulants are being used concurrently or have recently been used. |
ACD-A, ACTIVASE, ANISINDIONE, ARGATROBAN, ARGATROBAN-0.9% NACL, ARIXTRA, BIVALIRUDIN, CATHFLO ACTIVASE, CITRATE PHOSPHATE DEXTROSE, DEFITELIO, DICUMAROL, ENOXAPARIN SODIUM, ENOXILUV, FONDAPARINUX SODIUM, FRAGMIN, HEPARIN SODIUM, HEPARIN SODIUM IN 0.45% NACL, HEPARIN SODIUM-0.45% NACL, HEPARIN SODIUM-0.9% NACL, HEPARIN SODIUM-D5W, JANTOVEN, LMD 10% WITH 0.9% SOD CHLORIDE, LMD 10% WITH 5% DEXTROSE, LOVENOX, PHENINDIONE, TNKASE, WARFARIN SODIUM |
| 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. |
ELIQUIS |
| Dabigatran/Anticoagulants; Thrombolytics SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Dabigatran is a direct thrombin inhibitor. When taken with agents that affect clotting factors, increased bleeding episodes can occur. CLINICAL EFFECTS: Concurrent use of dabigatran with anticoagulants or thrombolytics may result in additive or synergistic effects resulting in unwanted bleeding episodes. PREDISPOSING FACTORS: Factors associated with an increase risk for bleeding include renal impairment, concomitant use of P-glycoprotein inhibitors, patient age >74 years, coexisting conditions (e.g. recent trauma) or use of drugs (e.g. NSAIDs) associated with bleeding risk, and patient weight <50 kg.(1-3) The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: The long-term use of concurrent therapy with direct oral anticoagulants (DOACs) and other anticoagulants is generally considered contraindicated. However, overlap may be necessary when switching therapy from one agent to another in order to prevent thrombotic events. Manufacturer recommendations concerning overlap (if any) and timing of discontinuation versus initiation vary depending upon which agent is being discontinued and initiated. Refer to current prescribing information for both agents for additional details. Specific recommendations for converting between anticoagulants: - When converting from parenteral anticoagulants to dabigatran, administer dabigatran 0-2 hours before the next dose of the parenteral drug is due. - When converting from dabigatran to a parenteral anticoagulant in adults, begin parenteral anticoagulant: --12 hours after last dose of dabigatran in patients with CrCl greater than or equal to 30 ml/min, --24 hours after last dose of dabigatran in patients with CrCl less than 30 ml/min. - When converting from dabigatran to a parenteral anticoagulant in pedatrics, begin the parenteral anticoagulant 12 hours after the last dose of dabigatran. - When converting from warfarin to dabigatran, discontinue warfarin and begin dabigatran when the patient's INR is below 2.0. - When converting from dabigatran to warfarin in adults, start warfarin: --3 days before discontinuing dabigatran in patients with CrCl greater than 50 ml/min, --2 days before discontinuing dabigatran in patients with CrCl of 30 ml/min to 50 ml/min, --1 day before discontinuing dabigatran in patients with CrCl of 15 ml/min to 30 ml/min. --There is no recommendation available for converting dabigatran to warfarin in patients with CrCl less than 15 ml/min. - When converting from dabigatran to warfarin in pediatrics, start warfarin: --3 days before discontinuing dabigatran in patient with eGFR >= 50 ml/min/1.73 m2. --There is no data on using dabigatran in pediatric patients with eGFR < 50 ml/min/1.73 m2. - Dabigatran affects INR. Therefore the INR will better reflect warfarin's effect only after stopping dabigatran for at least 2 days. The use of concurrent therapy with Direct Oral Anticoagulants (DOACs) and thrombolytics is generally considered contraindicated. The manufacturer of alteplase states that the use of alteplase for an indication of acute ischemic stroke is contraindicated in patients receiving anticoagulants. Concurrent use of alteplase and anticoagulants is dependent on the therapeutic indication. In Acute Ischemic Stroke: - Clinical practice guidelines for acute ischemic stroke state the use of thrombolytic therapy for an indication of acute ischemic stroke is contraindicated in patients who have received thrombin inhibitors or factor Xa inhibitors in the previous 48 hours (in normal renal function) and have abnormal laboratory tests such as activated partial thromboplastin time (aPTT), INR, platelet count, ecarin clotting time (ECT), thrombin time, or direct factor Xa assays at presentation. In Acute Myocardial Infarction: - Patients who are receiving thrombolytics for an indication of acute myocardial infarction should be carefully monitored for signs of bleeding, especially at arterial puncture sites, if dabigatran is used concurrently. - The use of thrombolytics in patients with acute myocardial infarction should follow standard management of myocardial infarction, including minimizing arterial and venous puncture; avoid noncompressible arterial puncture; and minimize internal jugular and subclavian venous punctures to decrease bleeding from the noncompressible sites. For all indications: - In the event of serious bleeding, anticoagulants should be discontinued immediately. - If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. - When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. - Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. DISCUSSION: Patients who are receiving thrombolytics should be carefully monitored for signs of bleeding if anticoagulants are being used concurrently or have recently been used. |
DABIGATRAN ETEXILATE, PRADAXA |
| Rivaroxaban/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 rivaroxaban with anticoagulants or thrombolytics may increase the risk of bleeding. PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: The long-term use of concurrent therapy with direct oral anticoagulants (DOACs) and other anticoagulants is generally considered contraindicated. However, overlap may be necessary when switching therapy from one agent to another in order to prevent thrombotic events. Manufacturer recommendations concerning overlap (if any) and timing of discontinuation versus initiation vary depending upon which agent is being discontinued and initiated. Refer to current prescribing information for both agents for additional details. Specific recommendations for converting between anticoagulants: - When converting from rivaroxaban to anticoagulants other than warfarin and switching to an anticoagulant with rapid onset, discontinue rivaroxaban and begin new anticoagulant when next dose of rivaroxaban is due. - When converting from anticoagulants other than warfarin to rivaroxaban, discontinue current anticoagulant and begin rivaroxaban between 0-2 hours before next evening dose of the drug is due. For patients receiving continuous infusion of unfractionated heparin, simultaneously stop the infusion and administer rivaroxaban. - When converting from warfarin to rivaroxaban, discontinue warfarin and begin rivaroxaban once international normalized ratio (INR) is below 3.0 in adults and below 2.5 in pediatric patients. - When converting from rivaroxaban to warfarin in adults, rivaroxaban affects INR. Therefore concurrent administration with warfarin is not useful in determining target warfarin dose. If continuous anticoagulation is warranted, discontinue rivaroxaban and begin both warfarin and a parenteral anticoagulant when the next dose of rivaroxaban is due. Once INR is within range, discontinue the parenteral anticoagulant. - When converting from rivaroxaban to warfarin in pediatrics, continue rivaroxaban for at least 2 days after the first dose of warfarin. After two days, INR should be measured just prior to the next scheduled dose of rivaroxaban. Once a stable INR = or > 2.0 is achieved, rivaroxaban should be discontinued and warfarin continued. The use of concurrent therapy with Direct Oral Anticoagulants (DOACs) and thrombolytics is generally considered contraindicated. The manufacturer of alteplase states that the use of alteplase for an indication of acute ischemic stroke is contraindicated in patients receiving anticoagulants. Concurrent use of alteplase and anticoagulants is dependent on the therapeutic indication. In Acute Ischemic Stroke: - Clinical practice guidelines for acute ischemic stroke state the use of thrombolytic therapy for an indication of acute ischemic stroke is contraindicated in patients who have received thrombin inhibitors or factor Xa inhibitors in the previous 48 hours (in normal renal function) and have abnormal laboratory tests such as activated partial thromboplastin time (aPTT), INR, platelet count, ecarin clotting time (ECT), thrombin time, or direct factor Xa assays at presentation. In Acute Myocardial Infarction: - Patients who are receiving thrombolytics for an indication of acute myocardial infarction should be carefully monitored for signs of bleeding, especially at arterial puncture sites, if rivaroxaban is used concurrently. - The use of thrombolytics in patients with acute myocardial infarction should follow standard management of myocardial infarction, including minimizing arterial and venous puncture; avoid noncompressible arterial puncture; and minimize internal jugular and subclavian venous punctures to decrease bleeding from the noncompressible sites. For all indications: - In the event of serious bleeding, anticoagulants should be discontinued immediately. - If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. - When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. - Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. DISCUSSION: Patients who are receiving thrombolytics should be carefully monitored for signs of bleeding if anticoagulants are being used concurrently or have recently been used. |
RIVAROXABAN, XARELTO |
There are 13 severe interactions.
These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.
| Drug Interaction | Drug Names |
|---|---|
| Tipranavir/Anticoagulants; Antiplatelets SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Tipranavir has been shown to inhibit platelet aggregation in vitro in human platelets(1-3) and in rodents.(1,2) The mechanism behind this platelet aggregation is unknown.(1,2) CLINICAL EFFECTS: Concurrent use of tipranavir with anticoagulants and/or antiplatelet agents may result in additive or synergistic effects, including fatal and non-fatal intracranial hemorrhage.(1-3) PREDISPOSING FACTORS: The risk of intracranial hemorrhage may be increased by CNS lesions, head trauma, neurosurgery, coagulopathy, hypertension, or alcohol abuse.(1-3) The risk for bleeding episodes may also be greater in patients with other disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: Tipranavir should be administered with caution in patients receiving anticoagulants and/or antiplatelet agents. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Patients should be warned that tipranavir has been associated with fatal and non-fatal intracranial hemorrhage and instructed to report any unusual or unexplained bleeding to their physician.(1-3) Signs or symptoms of bleeding may include unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. DISCUSSION: As of June 7, 2006,(3) the manufacturer of tipranavir has has identified 14 cases of intracranial hemorrhage, including 8 fatalities, in 13 out of 6,840 HIV+ subjects in clinical trials.(1,3) No pattern of abnormal coagulation parameters has been noted in patients receiving tipranavir in general or preceding the development of intracranial hemorrhage.(1-3) In vitro tests showed that tipranavir inhibits human platelet aggregation at concentrations consistent with normal exposure during therapy. In rodents, tipranavir resulted in increased prothrombin and activated partial thromboplastin times. At higher doses and in extreme cases, these changes resulted in bleeding in multiple organs and death. This effect was not seen in studies in dogs.(1,2) |
APTIVUS |
| 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) |
ANAPROX DS, ANJESO, ARTHROTEC 50, ARTHROTEC 75, BISMUTH SUBSALICYLATE, BROMFENAC SODIUM, CALDOLOR, CAMBIA, CELEBREX, CELECOXIB, CHOLINE MAGNESIUM TRISALICYLAT, COMBOGESIC, COMBOGESIC IV, CONSENSI, COXANTO, DAYPRO, DICLOFENAC, DICLOFENAC POTASSIUM, DICLOFENAC SODIUM, DICLOFENAC SODIUM ER, DICLOFENAC SODIUM MICRONIZED, DICLOFENAC SODIUM-MISOPROSTOL, DIFLUNISAL, DISALCID, DOLOBID, EC-NAPROSYN, ELYXYB, ETODOLAC, ETODOLAC ER, FELDENE, FENOPROFEN CALCIUM, FENOPRON, FLURBIPROFEN, HYDROCODONE-IBUPROFEN, IBU, IBUPAK, IBUPROFEN, IBUPROFEN LYSINE, IBUPROFEN-FAMOTIDINE, INDOCIN, INDOMETHACIN, INDOMETHACIN ER, INFLAMMACIN, INFLATHERM(DICLOFENAC-MENTHOL), KETOPROFEN, KETOPROFEN MICRONIZED, KETOROLAC TROMETHAMINE, KIPROFEN, LODINE, LOFENA, LURBIPR, MECLOFENAMATE SODIUM, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NABUMETONE MICRONIZED, NALFON, NAPRELAN, NAPROSYN, NAPROTIN, NAPROXEN, NAPROXEN SODIUM, NAPROXEN SODIUM CR, NAPROXEN SODIUM ER, NAPROXEN-ESOMEPRAZOLE MAG, NEOPROFEN, OXAPROZIN, PHENYL SALICYLATE, PHENYLBUTAZONE, PIROXICAM, RELAFEN DS, SALSALATE, SODIUM SALICYLATE, SULINDAC, SUMATRIPTAN SUCC-NAPROXEN SOD, SYMBRAVO, TOLECTIN 600, TOLMETIN SODIUM, TORONOVA II SUIK, TORONOVA SUIK, TRESNI, TREXIMET, VIMOVO, VIVLODEX, ZIPSOR, ZORVOLEX, ZYNRELEF |
| Edoxaban/Antiplatelets; Aspirin (Greater Than 100 mg) SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Anticoagulants and antiplatelet agents have additive effects on hemostasis.(1) In addition, aspirin doses greater than or equal to 325 mg daily increase edoxaban exposure.(1) CLINICAL EFFECTS: Concurrent use of edoxaban with antiplatelets may increase the risk of bleeding.(1) PREDISPOSING FACTORS: Bleeding risk may be increased in patients with renal impairment and in patients > 75 years of age.(1) Use of multiple agents which affect hemostasis increases the risk for bleeding. The risk for bleeding episodes may be greater in patient 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 edoxaban and an antiplatelet agent should be closely monitored for signs of bleeding. Edoxaban and aspirin at dosages of 100 mg or less may be coadministered.(2,3) Monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. 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 edoxaban in patients with active bleeding. DISCUSSION: Concomitant use of edoxaban and antiplatelet agents may increase the risk of bleeding. In edoxaban clinical trials concomitant use of low dose aspirin (< or = 100 mg daily), thienopyridines, and NSAIDs was permitted and resulted in increased rates of clinically relevant bleeding. The rates of major bleeding on edoxaban and warfarin were generally consistent among subgroups. Bleeding rates appeared higher in both treatment arms (edoxaban and warfarin) in patients taking aspirin. Co-administration of aspirin (100 mg or 325 mg) and edoxaban increased bleeding time relative to that seen with either drug alone.(1) About 30% of the population in ENGAGE-AF received concomitant therapy with aspirin because of co-morbid conditions. While aspirin is known to increase risk for bleeds and the annualized event rate for major bleeds was higher than that in patients not receiving aspirin (3.87% vs. 2.13%), the risk for bleeds in patients receiving edoxaban 60 mg on a background of aspirin was lower than that for warfarin on a background of aspirin (HR 0.78 (95%CI 0.65,0.94). Based on these data no dose adjustments/contraindications are required.(4) Edoxaban and aspirin at dosages of 100 mg or less may be coadministered.(2,3) 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.(5) |
ACETYL SALICYLIC ACID, AGGRASTAT, ASA-BUTALB-CAFFEINE-CODEINE, ASCOMP WITH CODEINE, ASPIRIN, ASPIRIN-DIPYRIDAMOLE ER, BRILINTA, BUTALBITAL-ASPIRIN-CAFFEINE, CARISOPRODOL-ASPIRIN, CARISOPRODOL-ASPIRIN-CODEINE, CILOSTAZOL, CLOPIDOGREL, CLOPIDOGREL BISULFATE, DIPYRIDAMOLE, DURLAZA, EFFIENT, EPTIFIBATIDE, KENGREAL, NORGESIC, NORGESIC FORTE, ORPHENADRINE-ASPIRIN-CAFFEINE, ORPHENGESIC FORTE, PLAVIX, PRASUGREL HCL, TICAGRELOR, TIROFIBAN HCL, YOSPRALA, ZONTIVITY |
| Edoxaban (Greater Than 30 mg)/Selected P-gp Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Edoxaban is a substrate for P-glycoprotein (P-gp). Inhibitors of P-gp may increase intestinal absorption and decrease renal tubular elimination of edoxaban.(1,2) CLINICAL EFFECTS: Concurrent use with selected P-gp inhibitors may result in higher systemic concentrations of edoxaban which may increase the risk for bleeding.(1-5) P-gp inhibitors linked to this interaction are: cyclosporine, dronedarone, erythromycin, and ketoconazole. PREDISPOSING FACTORS: Bleeding risk may be increased in patients with creatinine clearance 15mL - 50 mL per minute(1) or weight < or = 60 kg.(2) Use of multiple agents which increase edoxaban exposure or affect hemostasis would be expected to increase the risk for bleeding. The risk for bleeding episodes may be greater in patients with disease-associated factors (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: Management recommendations vary depending upon the approving regulatory agency (FDA or European Medicines Agency, EMA). US FDA recommendations are based upon the edoxaban indication: - For treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE), the edoxaban dose should be reduced to 30 mg daily when used concomitantly with erythromycin or oral ketoconazole.(3) - For prevention of stroke or embolic events due to nonvalvular atrial fibrillation, no edoxaban dose adjustments are recommended during concomitant therapy with P-glycoprotein inhibitors.(1,3) - Concurrent use of cyclosporine was not allowed in edoxaban clinical trials (atrial fibrillation or DVT/PE). US prescribing information does not provide specific management information for concurrent use of cyclosporine with edoxaban.(3) EMA dosage adjustments are the same, regardless of indication: - Reduce edoxaban dose to 30 mg daily in patients receiving concomitant treatment with cyclosporine, dronedarone, erythromycin or oral ketoconazole.(4) 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. 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. Discontinue edoxaban in patients with active bleeding. DISCUSSION: Edoxaban in vivo interaction studies have been performed for P-gp inhibitors linked to this monograph: In an interaction study, the effect of single oral dose of cyclosporine 500 mg on a single oral dose of edoxaban 60 mg was evaluated in healthy subjects. Total and peak systemic exposure to edoxaban increased 1.73-fold and 1.74-fold, respectively. Total and peak systemic exposure to the active M4 metabolite increased 6.87-fold and 8.71-fold respectively, likely due to cyclosporine inhibition of OATP1B1.(1) In the absence of OATP1B1 inhibition, M4 concentrations are generally < or = 10% of edoxaban exposure,(1) but the approximately 7-fold increase in active metabolite exposure may result in clinically meaningful concentrations of M4. In an interaction study, the effect of repeat administration of dronedarone (400 mg bid) on a single oral dose of edoxaban 60 mg was evaluated in healthy subjects. Total and peak systemic exposure to edoxaban increased 1.84-fold and 1.45-fold, respectively. Plasma edoxaban concentrations 24 hours post dose (Ctrough) following coadministration edoxaban and dronedarone were 2.6-fold higher compared with administration of edoxaban alone.(1) In an interaction study, the effect of repeat administration of erythromycin (oral dose of 500 mg four times daily for 8 days) on a single oral dose of edoxaban 60 mg on on study day 7 was evaluated in healthy subjects. Total and peak systemic exposure to edoxaban increased 1.85-fold and 1.68-fold, respectively. Total and peak systemic exposure to the M4 metabolite increased 1.78-fold and 1.75-fold, respectively.(1) In an interaction study, the effect of repeat administration of ketoconazole (oral dose of 400 mg QD for 7 days) on a single oral dose of edoxaban (60 mg) was evaluated in healthy subjects. Total and peak systemic exposure to edoxaban increased 1.87-fold and 1.89-fold, respectively. Total and peak systemic exposure to the M4 metabolite increased 1.46-fold and 1.56-fold, respectively.(1) A summary of pharmacokinetic interactions with edoxaban and dronedarone concluded that if concurrent use is warranted, the edoxaban dose should be reduced by 50%.(6) |
CYCLOSPORINE, CYCLOSPORINE MODIFIED, E.E.S. 200, E.E.S. 400, ERY-TAB, ERYPED 200, ERYPED 400, ERYTHROCIN LACTOBIONATE, ERYTHROCIN STEARATE, ERYTHROMYCIN, ERYTHROMYCIN ESTOLATE, ERYTHROMYCIN ETHYLSUCCINATE, ERYTHROMYCIN LACTOBIONATE, GENGRAF, KETOCONAZOLE, MULTAQ, NEORAL, SANDIMMUNE |
| Edoxaban/Rifampin SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Edoxaban is a P-glycoprotein (P-gp) substrate. Rifampin induces production of P-gp which may reduce systemic absorption of edoxaban.(1) CLINICAL EFFECTS: Concurrent or recent use of rifampin may result in decreased levels and effectiveness of edoxaban.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid concurrent use of an inducer of P-gp such as rifampin in patients maintained on edoxaban.(1) When possible use an alternative to rifampin in patients maintained on edoxaban. If therapy with rifampin is required an alternative to edoxaban may need to be considered. If rifampin is discontinued, edoxaban exposure will remain impaired for at least one week after the completion of therapy.(1) DISCUSSION: Co-administration of rifampin (600 mg QD for 7 days) and edoxaban (60 mg single dose on Day 7) decreased total systemic exposure to edoxaban by 40% without having an apparent effect on peak exposure. Total and peak systemic exposure to the active M4 metabolite increased 2.86-fold and 5.06-fold, respectively. Metabolite to parent ratios increased approximately 4.5-fold from approximately 9 to 40% for area-under-curve (AUC) and from approximately 10 to 45% for maximum concentration (Cmax). While an increase in systemic exposure to its equipotent active M4 metabolite makes up for this loss in total systemic exposure, it is driven by an increase in peak systemic exposure (Cmax) to M4. At trough (end of inter-dosing interval), there still exists a approximately 80% reduction in exposure to both edoxaban and the active metabolite combined.(2) |
RIFADIN, RIFAMPIN |
| Edoxaban/Selected P-glycoprotein (P-gp) Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Edoxaban is a P-glycoprotein (P-gp) substrate. P-gp induction may reduce systemic exposure to edoxaban.(1) CLINICAL EFFECTS: Concurrent or recent use of apalutamide, carbamazepine, efavirenz, fosphenytoin, lorlatinib, phenytoin, rifapentine, or St. John's wort may result in decreased effectiveness of edoxaban.(1-3) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of edoxaban states that concomitant use of rifampin should be avoided. Although there are no recommendations for other P-gp inducers, a similar precaution is reasonable.(4) The UK manufacturer of edoxaban recommends caution with co-administration of P-gp inducers such as carbamazepine, phenytoin, or St. John's wort.(1,3) Consider alternatives to the P-gp inducing agent. If therapy with an inducer of P-gp is required, alternatives to edoxaban may need to be considered. If a P-gp inducer is discontinued, edoxaban exposure will remain impaired for at least one week after the completion of therapy. DISCUSSION: Co-administration of another P-gp inducer, rifampin 600 mg QD for 7 days with a single dose of edoxaban 60 mg on Day 7, decreased total systemic exposure to edoxaban by 40% without having an apparent effect on peak exposure.(5) A 76-year-old male on apixaban for atrial fibrillation s/p pulmonary embolism 1 month prior was started on rifabutin 300 mg daily for tuberculosis. Apixaban was switched to edoxaban due to a drug interaction with rifabutin. At 1 month, rifabutin was increased to 450 mg daily. After another 8 weeks, the patient suffered a DVT that was thought to be a result of a drug-drug interaction with rifabutin.(6) Other inducers of P-glycoprotein linked to this monograph include apalutamide, carbamazepine, fosphenytoin, lorlatinib, phenytoin, rifabutin, rifapentine, and St. John's wort.(2,3) |
CARBAMAZEPINE, CARBAMAZEPINE ER, CARBATROL, CEREBYX, DILANTIN, DILANTIN-125, EPITOL, EQUETRO, ERLEADA, FOSPHENYTOIN SODIUM, LORBRENA, PHENYTEK, PHENYTOIN, PHENYTOIN SODIUM, PHENYTOIN SODIUM EXTENDED, PRIFTIN, RIFABUTIN, TALICIA, TEGRETOL, TEGRETOL XR |
| Selected P-glycoprotein (P-gp) Substrates/Sotorasib SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Sotorasib is an inhibitor of the P-glycoprotein (P-gp) system. P-gp substrates with a narrow therapeutic index may be increased.(1) CLINICAL EFFECTS: Concurrent use of sotorasib with narrow therapeutic index P-gp substrates may result in elevated levels of the substrate, increasing the risk for adverse effects.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of sotorasib states that the concurrent use of narrow therapeutic index P-gp substrates should be avoided. If concurrent therapy cannot be avoided, the dosage of the narrow therapeutic index P-gp substrate should be decreased according to the substrate prescribing information.(1) DISCUSSION: In a study, sotorasib increased digoxin's area-under-curve (AUC) by 21% and maximum concentration (Cmax) by 91%.(1) Selected narrow therapeutic index P-gp substrates include: afatinib, betrixaban, digoxin, edoxaban, etoposide, and loperamide.(1,2) |
LUMAKRAS |
| Caplacizumab/Anticoagulants; Antiplatelets 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 either anticoagulants or antiplatelets 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 and antiplatelets. 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) |
CABLIVI |
| Selected P-glycoprotein (P-gp) Substrates/Selpercatinib SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Selpercatinib is an inhibitor of the P-glycoprotein (P-gp) transporter and may increase the plasma concentrations of P-gp substrates.(1) CLINICAL EFFECTS: Concurrent use of selpercatinib with P-gp substrates may result in elevated levels of the substrate, increasing the risk for adverse effects.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of selpercatinib states that the concurrent use of narrow therapeutic index P-gp substrates should be avoided. If concurrent therapy cannot be avoided, follow recommendations for the narrow therapeutic index P-gp substrate according to the substrate's prescribing information.(1) DISCUSSION: In a study, selpercatinib increased dabigatran's area-under-curve (AUC) by 38% and maximum concentration (Cmax) by 43%.(1) Selected narrow therapeutic index P-gp substrates include: afatinib, betrixaban, bilastine, dabigatran, digoxin, edoxaban, etoposide, everolimus, loperamide, rimegepant, rivaroxaban, sirolimus, and ubrogepant.(1,2) |
RETEVMO |
| Edoxaban/Nirmatrelvir-Ritonavir SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Edoxaban is a substrate for P-glycoprotein (P-gp). Inhibitors of P-gp may increase intestinal absorption and decrease renal tubular elimination of edoxaban.(1-4) CLINICAL EFFECTS: Concurrent use with P-gp inhibitors may result in higher systemic concentrations of edoxaban which may increase the risk for bleeding.(1-4) PREDISPOSING FACTORS: Bleeding risk may be increased in patients with creatinine clearance below 50 mL per minute and in patients greater than 75 years of age.(1-2). Use of multiple agents which increase edoxaban exposure or affect hemostasis would be expected to increase the risk for bleeding. The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: The Journal of American College of Cardiology states concurrent use of nirmatrelvir-ritonavir with edoxaban should be avoided. Use of edoxaban cannot be safely adjusted or interrupted. If nirmatrelvir-ritonavir is deemed necessary, dose adjustment recommendations based on edoxaban dose are recommended.(5) -If on 60 mg edoxaban daily: Decrease dose of edoxaban by 50% for a total of 8 days from the start of nirmatrelvir-ritonavir and then resume edoxaban at the previous dose. -If on 30 mg edoxaban daily: Withhold edoxaban when starting nirmatrelvir-ritonavir. Use an alternative anticoagulant (eg, enoxaparin) for 8 days and then resume edoxaban. 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. 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. Discontinue edoxaban in patients with active bleeding. DISCUSSION: Edoxaban interaction studies have not been performed for nirmatrelvir-ritonavir(1) and so the magnitude of any interaction with these agents is not known. |
PAXLOVID |
| Lecanemab/Anticoagulants 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. |
LEQEMBI |
| Donanemab/Anticoagulants 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) |
KISUNLA |
| Hemin/Anticoagulants SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. 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) |
PANHEMATIN |
There are 19 moderate interactions.
The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.
| Drug Interaction | Drug Names |
|---|---|
| SSRIs;SNRIs/Slt Anticoagulants;Antiplatelets;Thrombolytics 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) |
CELEXA, CITALOPRAM HBR, CYMBALTA, DESVENLAFAXINE ER, DESVENLAFAXINE SUCCINATE ER, DRIZALMA SPRINKLE, DULOXETINE HCL, DULOXICAINE, EFFEXOR XR, ESCITALOPRAM OXALATE, FETZIMA, FLUOXETINE DR, FLUOXETINE HCL, LEXAPRO, OLANZAPINE-FLUOXETINE HCL, PAROXETINE CR, PAROXETINE ER, PAROXETINE HCL, PAROXETINE MESYLATE, PAXIL, PAXIL CR, PRISTIQ, PROZAC, SAVELLA, SERTRALINE HCL, TRINTELLIX, VENLAFAXINE BESYLATE ER, VENLAFAXINE HCL, VENLAFAXINE HCL ER, VIIBRYD, VILAZODONE HCL, ZOLOFT |
| Edoxaban (Greater Than 30 mg)/Select P-gp Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Edoxaban is a substrate for P-glycoprotein (P-gp). Inhibitors of P-gp may increase intestinal absorption and decrease renal tubular elimination of edoxaban.(1,2) CLINICAL EFFECTS: Concurrent use with selected P-gp inhibitors may result in higher systemic concentrations of edoxaban which may increase the risk for bleeding.(1,2) PREDISPOSING FACTORS: Bleeding risk may be increased in patients with creatinine clearance below 50 mL per minute(1-4). Use of multiple agents which increase edoxaban exposure or affect hemostasis would be expected to increase the risk for bleeding. The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: Management recommendations between approving regulatory agencies (FDA or European Medicines Agency, EMA) are conflicting. EMA approved prescribing information specifically states that dosage adjustments are not required solely for concomitant use with amiodarone, quinidine, or verapamil regardless of indication.(3,4) Potential interactions with azithromycin, clarithromycin, or oral itraconazole are not described.(3) FDA approved prescribing recommendations for edoxaban are indication specific:(2) - For prevention of stroke or embolic events due to nonvalvular atrial fibrillation, no edoxaban dose adjustments are recommended during concomitant therapy with P-glycoprotein inhibitors. - For treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE), the edoxaban dose should be reduced to 30 mg daily during concomitant use with azithromycin, clarithromycin, oral itraconazole, quinidine or verapamil. The manufacturer of vimseltinib states concurrent use with P-gp substrates should be avoided. If concurrent use cannot be avoided, take vimseltinib at least 4 hours prior to edoxaban.(6) Monitor patients receiving anticoagulant 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. 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. Discontinue edoxaban in patients with active bleeding. DISCUSSION: Edoxaban in vivo interaction studies have been performed for quinidine and verapamil. In vivo interaction studies have not been conducted for the remaining P-gp inhibitors linked to this monograph.(1,4) In an interaction study, the effect of repeat administration of quinidine (300 mg TID) on a single oral dose of edoxaban 60 mg was evaluated in healthy subjects. Both peak (Cmax) and total systemic exposure (AUC) to edoxaban and to the active M4 metabolite increased approximately 1.75-fold.(1) In an interaction study, the effect of repeat administration of verapamil (240 mg Verapamil SR Tablets (Calan SR) QD for 11 Days) on a single oral dose of edoxaban 60 mg on the morning of Day 10 was evaluated in healthy subjects. Total and peak systemic exposure to edoxaban increased 1.53-fold and 1.53-fold, respectively. Total and peak systemic exposure to the active M4 metabolite increased 1.31-fold and 1.28-fold, respectively.(1) Based upon the above results, patients in the DVT/PE trial had a 50% dose reduction (from 60 mg to 30 mg) during concomitant therapy with P-glycoprotein inhibitors. Approximately 0.5% of these patients required a dose reduction solely due to P-gp inhibitor use. This low rate of concurrent therapy was too small to allow for detailed statistical evaluation. Almost all of these patients were receiving quinidine or verapamil. In these patients, both trough edoxaban concentrations (Ctrough) used to evaluate bleeding risk, and total edoxaban exposure (AUC or area-under-curve) used to evaluate treatment efficacy, were lower than patients who did not require any edoxaban dose adjustment. In this DVT/PE comparator trial, subgroup analysis revealed that warfarin had numerically better efficacy than edoxaban in patients receiving P-gp inhibitors. Based upon the overall lower exposure to edoxaban in P-gp dose adjusted subjects, both EMA and FDA Office of Clinical Pharmacology (OCP) concluded that the edoxaban 50% dose reduction overcorrected for the difference in exposure.(1,4) Consequently, EMA recommended no edoxaban dose adjustments for patients receiving concomitant therapy with quinidine or verapamil.(3,4) A summary of pharmacokinetic interactions with edoxaban and verapamil concluded that if concurrent use is considered safe.(7) P-gp inhibitors linked to this interaction are: amiodarone, asunaprevir, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, clarithromycin, cobicistat, conivaptan, daclatasvir, danicopan, daridorexant, diltiazem, diosmin, flibanserin, fostamatinib, ginseng, glecaprevir/pibrentasvir, hydroquinidine, oral itraconazole, indinavir, ivacaftor, josamycin, ledipasvir, lonafarnib, neratinib, osimertinib, pirtobrutinib, propafenone, quinidine, ranolazine, telaprevir, telithromycin, tezacaftor, tepotinib, tucatinib, valbenazine, velpatasvir, vemurafenib, verapamil, vimseltinib, and voclosporin.(8) |
ADDYI, ALYFTREK, AMIODARONE HCL, AMIODARONE HCL-D5W, ASPRUZYO SPRINKLE, AZITHROMYCIN, CARDIZEM, CARDIZEM CD, CARDIZEM LA, CARTIA XT, CARVEDILOL, CARVEDILOL ER, CIMETIDINE, CLARITHROMYCIN, CLARITHROMYCIN ER, CONIVAPTAN-D5W, COREG, COREG CR, DILT-XR, DILTIAZEM 12HR ER, DILTIAZEM 24HR ER, DILTIAZEM 24HR ER (CD), DILTIAZEM 24HR ER (LA), DILTIAZEM 24HR ER (XR), DILTIAZEM HCL, DILTIAZEM HCL-0.7% NACL, DILTIAZEM HCL-0.9% NACL, DILTIAZEM HCL-NACL, DILTIAZEM-D5W, EPCLUSA, EVOTAZ, FLIBANSERIN, GENVOYA, HARVONI, INGREZZA, INGREZZA INITIATION PK(TARDIV), INGREZZA SPRINKLE, ITRACONAZOLE, ITRACONAZOLE MICRONIZED, JAYPIRCA, KALYDECO, LANSOPRAZOL-AMOXICIL-CLARITHRO, LEDIPASVIR-SOFOSBUVIR, LUPKYNIS, MATZIM LA, MAVYRET, NERLYNX, NEXTERONE, NUEDEXTA, OMECLAMOX-PAK, PACERONE, PREZCOBIX, PROPAFENONE HCL, PROPAFENONE HCL ER, QUINIDINE GLUCONATE, QUINIDINE SULFATE, QUVIVIQ, RANOLAZINE ER, REZUROCK, ROMVIMZA, SOFOSBUVIR-VELPATASVIR, SPORANOX, STRIBILD, SYMDEKO, SYMTUZA, TABRECTA, TAGRISSO, TAVALISSE, TEPMETKO, TIADYLT ER, TIAZAC, TOLSURA, TRANDOLAPRIL-VERAPAMIL ER, TRIKAFTA, TUKYSA, TYBOST, VAPRISOL-5% DEXTROSE, VERAPAMIL ER, VERAPAMIL ER PM, VERAPAMIL HCL, VERAPAMIL SR, VOQUEZNA TRIPLE PAK, VOSEVI, VOYDEYA, XOLREMDI, ZELBORAF, ZITHROMAX, ZITHROMAX TRI-PAK, ZOKINVY |
| Edoxaban (Greater Than 30 mg)/Lapatinib; Ritonavir SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Edoxaban is a substrate for P-glycoprotein (P-gp). Inhibitors of P-gp may increase intestinal absorption and decrease renal tubular elimination of edoxaban.(1,2) CLINICAL EFFECTS: Concurrent use with P-gp inhibitors may result in higher systemic concentrations of edoxaban which may increase the risk for bleeding.(1,2) P-gp inhibitors linked to this interaction are: lapatinib, lopinavir-ritonavir, ombitasvir-paritaprevir-ritonavir, ombitasvir-paritaprevir-ritonavir-dasabuvir, and ritonavir. PREDISPOSING FACTORS: Bleeding risk may be increased in patients with creatinine clearance below 50 mL per minute(1-2). Use of multiple agents which increase edoxaban exposure or affect hemostasis would be expected to increase the risk for bleeding. The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: Interaction studies between edoxaban and lapatinib, lopinavir-ritonavir, ombitasvir-paritaprevir-ritonavir, ombitasvir-paritaprevir-ritonavir-dasabuvir, and ritonavir have not been performed. Concurrent use of these agents were not allowed in edoxaban clinical trials. FDA approved prescribing recommendations for edoxaban are indication specific:(2) - For prevention of stroke or embolic events due to nonvalvular atrial fibrillation, no edoxaban dose adjustments are recommended during concomitant therapy with P-glycoprotein inhibitors. - For treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE), the edoxaban dose should be reduced to 30 mg daily during concomitant use with azithromycin, clarithromycin, oral itraconazole, quinidine or verapamil. No recommendations were made regarding concomitant lapatinib, ritonavir or lopinavir-ritonavir therapy. Monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. 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. Discontinue edoxaban in patients with active bleeding. DISCUSSION: Edoxaban interaction studies have not been performed for lapatinib, lopinavir-ritonavir, ombitasvir-paritaprevir-ritonavir, ombitasvir-paritaprevir-ritonavir-dasabuvir, and ritonavir(1) and so the magnitude of any interaction with these agents is not known. |
KALETRA, LAPATINIB, LOPINAVIR-RITONAVIR, NORVIR, RITONAVIR, TYKERB |
| Ibrutinib/Selected Anticoagulants; Antiplatelets 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) |
IMBRUVICA |
| Betrixaban; Dabigatran; Edoxaban/Lovastatin; Simvastatin SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Betrixaban, dabigatran etexilate, and edoxaban are substrates for the P-glycoprotein (P-gp) system. Inhibition of intestinal P-gp leads to increased absorption of betrixaban, dabigatran, and edoxaban.(1-6) Lovastatin and simvastatin are inhibitors of intestinal P-gp.(7,8) CLINICAL EFFECTS: The concurrent use of betrixaban, dabigatran, and edoxaban with lovastatin or simvastatin may lead to elevated plasma levels of betrixaban, dabigatran, and edoxaban, increasing the risk for bleeding. PREDISPOSING FACTORS: Factors associated with an increased risk for bleeding include renal impairment, concomitant use of P-gp inhibitors, patient age >74 years, coexisting conditions (e.g. recent trauma) or use of drugs (e.g. NSAIDs) associated with bleeding risk, and patient weight < 50 kg.(1-6) The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: Assess renal function and evaluate patient for other pre-existing risk factors for bleeding prior to initiating concurrent therapy. The concurrent use of betrixaban, dabigatran, and edoxaban with lovastatin or simvastatin should be monitored closely. Consider alternate therapy such as atorvastatin, fluvastatin, pravastatin, or rosuvastatin that are not known to inhibit P-gp.(7,8) Careful monitoring for signs and symptoms of bleeding is warranted during concurrent therapy. Consider regular monitoring of hemoglobin, platelet levels, and/or activated partial thromboplastin time (aPTT) or ecarin clotting time (ECT). Instruct patients to report any signs and symptoms of bleeding, such as bleeding from the eyes, gums or nose; unusual bruising; dark stools; red or dark brown urine; and/or abdominal pain or swelling. DISCUSSION: A population-based, nested case-control study of 45,991 patients taking dabigatran aged 66 years or older were screened for ischemic stroke or major hemorrhage with a single statin prescription in the 60 days preceding the index date. Each case was matched with up to 4 controls by age and sex. The use of lovastatin or simvastatin was not associated with an increased risk of stroke or transient ischemic attack relative to other statins in patients receiving dabigatran (adjusted OR 1.33, 95% CI 0.88-2.01). However, the use of lovastatin or simvastatin was associated with a higher risk of major hemorrhage than comparator statins (adjusted OR 1.46, 95% CI 1.17-1.82).(7) In the APEX randomized, double-blind study the incidence of major or clinically relevant non-major bleeds (CRNM) in the betrixaban 40 mg and 80 mg group was higher in patients taking concomitant P-gp inhibitors (2.8% vs. 4.1% vs. 4.7%).(9) In a study in 12 subjects, concomitant administration of a single dose of betrixaban (40 mg) following a 5-day regimen of ketoconazole (200 mg twice daily) resulted in an increase in betrixaban's maximum concentration (Cmax) and area-under-the-curve (AUC) of 2.3-fold and 2.3-fold, respectively.(10) An open-label study looking at concomitant administration of a single dose of betrixaban with verapamil in 18 subjects found an increase in betrixaban's Cmax and AUC of approximately 4.7-fold and 3-fold, respectively.(11) In a study, concomitant administration of betrixaban (80 mg) with amiodarone resulted in an increase in betrixaban's Cmax by 143%.(10) A summary of pharmacokinetic interactions with betrixaban and amiodarone, diltiazem, or verapamil concluded that if concurrent use is warranted, the betrixaban dose should be reduced to 80 mg once then 40 mg daily. Use should be avoided if CrCl is less than 30 ml/min.(11) When dabigatran was co-administered with amiodarone, a P-gp inhibitor, the extent and rate of absorption of amiodarone and its active metabolite DEA were essentially unchanged. The dabigatran area-under-curve (AUC) and maximum concentration (Cmax) were increased by about 60% and 50%, respectively;(2,3) however, dabigatran clearance was increased by 65%.(2) Pretreatment with quinidine (200 mg every 2 hours to a total dose of 1000 mg), and a P-gp inhibitor, increased the AUC and Cmax of dabigatran by 53% and 56%, respectively.(2,3) Chronic administration of immediate release verapamil, a P-gp inhibitor, one hour prior to dabigatran dose increased dabigatran AUC by 154%.(6) Administration of dabigatran two hours before verapamil results in a negligible increase in dabigatran AUC.(2) In an interaction study, the effect of repeat administration of quinidine (300 mg TID) on a single oral dose of edoxaban 60 mg was evaluated in healthy subjects. Both peak (Cmax) and total systemic exposure (AUC) to edoxaban and to the active M4 metabolite increased approximately 1.75-fold.(5) In an interaction study, the effect of repeat administration of verapamil (240 mg Verapamil SR Tablets (Calan SR) QD for 11 Days) on a single oral dose of edoxaban 60 mg on the morning of Day 10 was evaluated in healthy subjects. Total and peak systemic exposure to edoxaban increased 1.53-fold and 1.53-fold, respectively. Total and peak systemic exposure to the active M4 metabolite increased 1.31-fold and 1.28-fold, respectively.(5) Based upon the above results, patients in the DVT/PE trial had a 50% dose reduction (from 60 mg to 30 mg) during concomitant therapy with P-glycoprotein inhibitors. Approximately 0.5% of these patients required a dose reduction solely due to P-gp inhibitor use. This low rate of concurrent therapy was too small to allow for detailed statistical evaluation. Almost all of these patients were receiving quinidine or verapamil. In these patients, both trough edoxaban concentrations (Ctrough) used to evaluate bleeding risk, and total edoxaban exposure (AUC or area-under-curve) used to evaluate treatment efficacy, were lower than patients who did not require any edoxaban dose adjustment. In this DVT/PE comparator trial, subgroup analysis revealed that warfarin had numerically better efficacy than edoxaban in patients receiving P-gp inhibitors. Based upon the overall lower exposure to edoxaban in P-gp dose adjusted subjects, both EMA and FDA Office of Clinical Pharmacology (OCP) concluded that the edoxaban 50% dose reduction overcorrected for the difference in exposure.(5,12) Consequently, EMA recommended no edoxaban dose adjustments for patients receiving concomitant therapy with quinidine or verapamil.(12,13) |
ALTOPREV, EZETIMIBE-SIMVASTATIN, FLOLIPID, LOVASTATIN, SIMVASTATIN, VYTORIN, ZOCOR |
| Edoxaban/Aspirin (Less Than or Equal To 100 mg) SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Edoxaban and aspirin have additive effects on hemostasis.(1) In addition, aspirin doses greater than or equal to 325 mg daily increase edoxaban exposure.(1) CLINICAL EFFECTS: Concurrent use of edoxaban with aspirin may increase the risk of bleeding compared to either agent alone.(1) PREDISPOSING FACTORS: Bleeding risk may be increased in patients with renal impairment and in patients greater than 75 years of age.(1) Use of multiple agents which affect hemostasis increases the risk for bleeding. The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: Patients requiring concurrent therapy with edoxaban and aspirin should be closely monitored for signs of bleeding. Edoxaban and aspirin at dosages of 100 mg or less may be coadministered.(2,3) Monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. 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 edoxaban in patients with active bleeding. DISCUSSION: Concomitant use of edoxaban and antiplatelet agents may increase the risk of bleeding. In edoxaban clinical trials concomitant use of low dose aspirin (less than or equal to 100 mg daily), thienopyridines, and NSAIDs was permitted and resulted in increased rates of clinically relevant bleeding. The rates of major bleeding on edoxaban and warfarin were generally consistent among subgroups. Bleeding rates appeared higher in both treatment arms (edoxaban and warfarin) in patients taking aspirin. Co-administration of aspirin (100 mg or 325 mg) and edoxaban increased bleeding time relative to that seen with either drug alone.(1) About 30% of the population in ENGAGE-AF received concomitant therapy with aspirin because of co-morbid conditions. While aspirin is known to increase risk for bleeds and the annualized event rate for major bleeds was higher than that in patients not receiving aspirin (3.87% vs. 2.13%), the risk for bleeds in patients receiving edoxaban 60 mg on a background of aspirin was lower than that for warfarin on a background of aspirin (HR 0.78 (95%CI 0.65,0.94). Based on these data no dose adjustments/contraindications are required.(4) Edoxaban and aspirin at dosages of 100 mg or less may be coadministered.(2,3) 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.(5) |
YOSPRALA |
| Edoxaban (Less Than or Equal To 30 mg)/Selected P-gp Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Edoxaban is a substrate for P-glycoprotein (P-gp). Inhibitors of P-gp may increase intestinal absorption and decrease renal tubular elimination of edoxaban.(1,2) CLINICAL EFFECTS: Concurrent use with selected P-gp inhibitors may result in higher systemic concentrations of edoxaban which may increase the risk for bleeding.(1-5) P-gp inhibitors linked to this interaction are: cyclosporine, dronedarone, erythromycin, and ketoconazole. PREDISPOSING FACTORS: Bleeding risk may be increased in patients with creatinine clearance 15mL - 50 mL per minute(1) or weight less than or equal to 60 kg.(2) Use of multiple agents which increase edoxaban exposure or affect hemostasis would be expected to increase the risk for bleeding. The risk for bleeding episodes may be greater in patients with disease-associated factors (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: Management recommendations vary depending upon the approving regulatory agency (FDA or European Medicines Agency, EMA). US FDA recommendations are based upon the edoxaban indication: - For treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE), the edoxaban dose should be reduced to 30 mg daily when used concomitantly with erythromycin or oral ketoconazole.(3) - For prevention of stroke or embolic events due to nonvalvular atrial fibrillation, no edoxaban dose adjustments are recommended during concomitant therapy with P-glycoprotein inhibitors.(1,3) - Concurrent use of cyclosporine was not allowed in edoxaban clinical trials (atrial fibrillation or DVT/PE). US prescribing information does not provide specific management information for concurrent use of cyclosporine with edoxaban.(3) EMA dosage adjustments are the same, regardless of indication: - Reduce edoxaban dose to 30 mg daily in patients receiving concomitant treatment with cyclosporine, dronedarone, erythromycin or oral ketoconazole.(4) 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. 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. Discontinue edoxaban in patients with active bleeding. DISCUSSION: Edoxaban in vivo interaction studies have been performed for P-gp inhibitors linked to this monograph: In an interaction study, the effect of single oral dose of cyclosporine 500 mg on a single oral dose of edoxaban 60 mg was evaluated in healthy subjects. Total and peak systemic exposure to edoxaban increased 1.73-fold and 1.74-fold, respectively. Total and peak systemic exposure to the active M4 metabolite increased 6.87-fold and 8.71-fold respectively, likely due to cyclosporine inhibition of OATP1B1.(1) In the absence of OATP1B1 inhibition, M4 concentrations are generally less than or equal to 10% of edoxaban exposure,(1) but the approximately 7-fold increase in active metabolite exposure may result in clinically meaningful concentrations of M4. In an interaction study, the effect of repeat administration of dronedarone (400 mg bid) on a single oral dose of edoxaban 60 mg was evaluated in healthy subjects. Total and peak systemic exposure to edoxaban increased 1.84-fold and 1.45-fold, respectively. Plasma edoxaban concentrations 24 hours post dose (Ctrough) following coadministration edoxaban and dronedarone were 2.6-fold higher compared with administration of edoxaban alone.(1) In an interaction study, the effect of repeat administration of erythromycin (oral dose of 500 mg four times daily for 8 days) on a single oral dose of edoxaban 60 mg on on study day 7 was evaluated in healthy subjects. Total and peak systemic exposure to edoxaban increased 1.85-fold and 1.68-fold, respectively. Total and peak systemic exposure to the M4 metabolite increased 1.78-fold and 1.75-fold, respectively.(1) In an interaction study, the effect of repeat administration of ketoconazole (oral dose of 400 mg QD for 7 days) on a single oral dose of edoxaban (60 mg) was evaluated in healthy subjects. Total and peak systemic exposure to edoxaban increased 1.87-fold and 1.89-fold, respectively. Total and peak systemic exposure to the M4 metabolite increased 1.46-fold and 1.56-fold, respectively.(1) A summary of pharmacokinetic interactions with edoxaban and dronedarone concluded that if concurrent use is warranted, the edoxaban dose should be reduced by 50%.(6) |
CYCLOSPORINE, CYCLOSPORINE MODIFIED, E.E.S. 200, E.E.S. 400, ERY-TAB, ERYPED 200, ERYPED 400, ERYTHROCIN LACTOBIONATE, ERYTHROCIN STEARATE, ERYTHROMYCIN, ERYTHROMYCIN ESTOLATE, ERYTHROMYCIN ETHYLSUCCINATE, ERYTHROMYCIN LACTOBIONATE, GENGRAF, KETOCONAZOLE, MULTAQ, NEORAL, SANDIMMUNE |
| Edoxaban (Less Than or Equal To 30 mg)/Select P-gp Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Edoxaban is a substrate for P-glycoprotein (P-gp). Inhibitors of P-gp may increase intestinal absorption and decrease renal tubular elimination of edoxaban.(1,2) CLINICAL EFFECTS: Concurrent use with selected P-gp inhibitors may result in higher systemic concentrations of edoxaban which may increase the risk for bleeding.(1,2) PREDISPOSING FACTORS: Bleeding risk may be increased in patients with creatinine clearance below 50 mL per minute(1-4). Use of multiple agents which increase edoxaban exposure or affect hemostasis would be expected to increase the risk for bleeding. The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: Management recommendations between approving regulatory agencies (FDA or European Medicines Agency, EMA) are conflicting. EMA approved prescribing information specifically states that dosage adjustments are not required solely for concomitant use with amiodarone, quinidine, or verapamil regardless of indication.(3,4) Potential interactions with azithromycin, clarithromycin, or oral itraconazole are not described.(3) FDA approved prescribing recommendations for edoxaban are indication specific:(2) - For prevention of stroke or embolic events due to nonvalvular atrial fibrillation, no edoxaban dose adjustments are recommended during concomitant therapy with P-glycoprotein inhibitors. - For treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE), the edoxaban dose should be reduced to 30 mg daily during concomitant use with azithromycin, clarithromycin, oral itraconazole, quinidine or verapamil. The manufacturer of vimseltinib states concurrent use with P-gp substrates should be avoided. If concurrent use cannot be avoided, take vimseltinib at least 4 hours prior to edoxaban.(6) Monitor patients receiving anticoagulant 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. 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. Discontinue edoxaban in patients with active bleeding. DISCUSSION: Edoxaban in vivo interaction studies have been performed for quinidine and verapamil. In vivo interaction studies have not been conducted for the remaining P-gp inhibitors linked to this monograph.(1,4) In an interaction study, the effect of repeat administration of quinidine (300 mg TID) on a single oral dose of edoxaban 60 mg was evaluated in healthy subjects. Both peak (Cmax) and total systemic exposure (AUC) to edoxaban and to the active M4 metabolite increased approximately 1.75-fold.(1) In an interaction study, the effect of repeat administration of verapamil (240 mg Verapamil SR Tablets (Calan SR) QD for 11 Days) on a single oral dose of edoxaban 60 mg on the morning of Day 10 was evaluated in healthy subjects. Total and peak systemic exposure to edoxaban increased 1.53-fold and 1.53-fold, respectively. Total and peak systemic exposure to the active M4 metabolite increased 1.31-fold and 1.28-fold, respectively.(1) Based upon the above results, patients in the DVT/PE trial had a 50% dose reduction (from 60 mg to 30 mg) during concomitant therapy with P-glycoprotein inhibitors. Approximately 0.5% of these patients required a dose reduction solely due to P-gp inhibitor use. This low rate of concurrent therapy was too small to allow for detailed statistical evaluation. Almost all of these patients were receiving quinidine or verapamil. In these patients, both trough edoxaban concentrations (Ctrough) used to evaluate bleeding risk, and total edoxaban exposure (AUC or area-under-curve) used to evaluate treatment efficacy, were lower than patients who did not require any edoxaban dose adjustment. In this DVT/PE comparator trial, subgroup analysis revealed that warfarin had numerically better efficacy than edoxaban in patients receiving P-gp inhibitors. Based upon the overall lower exposure to edoxaban in P-gp dose adjusted subjects, both EMA and FDA Office of Clinical Pharmacology (OCP) concluded that the edoxaban 50% dose reduction overcorrected for the difference in exposure.(1,4) Consequently, EMA recommended no edoxaban dose adjustments for patients receiving concomitant therapy with quinidine or verapamil.(3,4) A summary of pharmacokinetic interactions with edoxaban and verapamil concluded that if concurrent use is considered safe.(7) P-gp inhibitors linked to this interaction are: amiodarone, asunaprevir, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, clarithromycin, cobicistat, conivaptan, daclatasvir, danicopan, daridorexant, diltiazem, diosmin, flibanserin, fostamatinib, ginseng, glecaprevir/pibrentasvir, hydroquinidine, indinavir, oral itraconazole, ivacaftor, josamycin, ledipasvir, lonafarnib, mavorixafor, neratinib, osimertinib, pirtobrutinib, propafenone, quinidine, ranolazine, telaprevir, telithromycin, tezacaftor, tepotinib, tucatinib, valbenazine, velpatasvir, vemurafenib, verapamil vimseltinib, and voclosporin.(8) |
ADDYI, ALYFTREK, AMIODARONE HCL, AMIODARONE HCL-D5W, ASPRUZYO SPRINKLE, AZITHROMYCIN, CARDIZEM, CARDIZEM CD, CARDIZEM LA, CARTIA XT, CARVEDILOL, CARVEDILOL ER, CIMETIDINE, CLARITHROMYCIN, CLARITHROMYCIN ER, CONIVAPTAN-D5W, COREG, COREG CR, DILT-XR, DILTIAZEM 12HR ER, DILTIAZEM 24HR ER, DILTIAZEM 24HR ER (CD), DILTIAZEM 24HR ER (LA), DILTIAZEM 24HR ER (XR), DILTIAZEM HCL, DILTIAZEM HCL-0.7% NACL, DILTIAZEM HCL-0.9% NACL, DILTIAZEM HCL-NACL, DILTIAZEM-D5W, EPCLUSA, EVOTAZ, FLIBANSERIN, GENVOYA, HARVONI, INGREZZA, INGREZZA INITIATION PK(TARDIV), INGREZZA SPRINKLE, ITRACONAZOLE, ITRACONAZOLE MICRONIZED, JAYPIRCA, KALYDECO, LANSOPRAZOL-AMOXICIL-CLARITHRO, LEDIPASVIR-SOFOSBUVIR, LUPKYNIS, MATZIM LA, MAVYRET, NERLYNX, NEXTERONE, NUEDEXTA, OMECLAMOX-PAK, PACERONE, PREZCOBIX, PROPAFENONE HCL, PROPAFENONE HCL ER, QUINIDINE GLUCONATE, QUINIDINE SULFATE, QUVIVIQ, RANOLAZINE ER, REZUROCK, ROMVIMZA, SOFOSBUVIR-VELPATASVIR, SPORANOX, STRIBILD, SYMDEKO, SYMTUZA, TABRECTA, TAGRISSO, TAVALISSE, TEPMETKO, TIADYLT ER, TIAZAC, TOLSURA, TRANDOLAPRIL-VERAPAMIL ER, TRIKAFTA, TUKYSA, TYBOST, VAPRISOL-5% DEXTROSE, VERAPAMIL ER, VERAPAMIL ER PM, VERAPAMIL HCL, VERAPAMIL SR, VOQUEZNA TRIPLE PAK, VOSEVI, VOYDEYA, XOLREMDI, ZELBORAF, ZITHROMAX, ZITHROMAX TRI-PAK, ZOKINVY |
| Edoxaban (Less Than or Equal To 30 mg)/Lapatinib; Ritonavir SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Edoxaban is a substrate for P-glycoprotein (P-gp). Inhibitors of P-gp may increase intestinal absorption and decrease renal tubular elimination of edoxaban.(1,2) CLINICAL EFFECTS: Concurrent use with P-gp inhibitors may result in higher systemic concentrations of edoxaban which may increase the risk for bleeding.(1,2) P-gp inhibitors linked to this interaction are: lapatinib, lopinavir-ritonavir, ombitasvir-paritaprevir-ritonavir, ombitasvir-paritaprevir-ritonavir-dasabuvir, and ritonavir. PREDISPOSING FACTORS: Bleeding risk may be increased in patients with creatinine clearance below 50 mL per minute(1-2). Use of multiple agents which increase edoxaban exposure or affect hemostasis would be expected to increase the risk for bleeding. The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: Interaction studies between edoxaban and lapatinib, lopinavir-ritonavir, ombitasvir-paritaprevir-ritonavir, ombitasvir-paritaprevir-ritonavir-dasabuvir, and ritonavir have not been performed. Concurrent use of these agents were not allowed in edoxaban clinical trials. FDA approved prescribing recommendations for edoxaban are indication specific:(2) - For prevention of stroke or embolic events due to nonvalvular atrial fibrillation, no edoxaban dose adjustments are recommended during concomitant therapy with P-glycoprotein inhibitors. - For treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE), the edoxaban dose should be reduced to 30 mg daily during concomitant use with azithromycin, clarithromycin, oral itraconazole, quinidine or verapamil. No recommendations were made regarding concomitant lapatinib, ritonavir or lopinavir-ritonavir therapy. Monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. 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. Discontinue edoxaban in patients with active bleeding. DISCUSSION: Edoxaban interaction studies have not been performed for lapatinib, lopinavir-ritonavir, ombitasvir-paritaprevir-ritonavir, ombitasvir-paritaprevir-ritonavir-dasabuvir, and ritonavir(1) and so the magnitude of any interaction with these agents is not known. |
KALETRA, LAPATINIB, LOPINAVIR-RITONAVIR, NORVIR, RITONAVIR, TYKERB |
| Icosapent Ethyl/Anticoagulant;Antiplatelet;Thrombolytic 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) |
ICOSAPENT ETHYL, VASCEPA |
| Edoxaban (Greater Than 30 mg)/P-gp Inhibitors that Cause Bleeding SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: This combination may interact via both a pharmacodynamic and a pharmacokinetic mechanism. Pharmacodynamically, serotonin release by platelets plays a role in hemostasis.(1) Fluvoxamine may cause a decrease in serotonin reuptake by platelets, resulting in an additive risk of bleeding with oral anticoagulants.(1) Mifepristone is an antagonist at the progesterone receptor which can result in endometrium thickening, cystic dilatation of endometrial glands, or excessive vaginal bleeding. Concurrent use with anticoagulants may further increase risk.(2) Pharmacokinetically, fluvoxamine, and mifepristone are inhibitors of the P-glycoprotein (P-gp) transporter and may increase the absorption of edoxaban.(3) CLINICAL EFFECTS: Concurrent use of P-gp inhibitors and edoxaban may result in bleeding.(4,5) The concurrent use of mifepristone with anticoagulants may result in endometrium thickening, cystic dilatation of endometrial glands, or excessive vaginal bleeding.(2) PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Bleeding risk may be increased in patients with creatinine clearance below 50 mL per minute and in patients greater than 75 years of age.(4,5) Use of multiple agents which increase edoxaban exposure or affect hemostasis would be expected to increase the risk for bleeding. PATIENT MANAGEMENT: The combination of P-gp inhibitors and edoxaban should be used with caution. Fluvoxamine and mifepristone are P-gp inhibitors. FDA approved prescribing recommendations for edoxaban are indication specific: - For prevention of stroke or embolic events due to nonvalvular atrial fibrillation, no edoxaban dose adjustments are recommended during concomitant therapy with P-gp inhibitors. - For treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE), the edoxaban dose is recommended to be reduced to 30 mg daily when used concurrently with specific P-gp inhibitors (azithromycin, clarithromycin, oral itraconazole, quinidine and verapamil).(5) The manufacturer of mifepristone states that mifepristone should be used with caution in patients receiving concurrent anticoagulant therapy. Women experiencing vaginal bleeding during concurrent use should be referred to a gynecologist for further evaluation.(2) Monitor patients receiving anticoagulant 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. 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. Discontinue edoxaban in patients with active bleeding. DISCUSSION: Edoxaban in vivo interactions studies have not been conducted with fluvoxamine and there is no recommendation on the appropriate dose of edoxaban with concomitant fluvoxamine. In an edoxaban DVT/PE trial, patients who had a 50% dose reduction (from 60 mg to 30 mg) during concomitant therapy with P-gp inhibitors (mostly verapamil and quinidine) had lower trough edoxaban concentrations (Ctrough) and lower total edoxaban exposure (AUC or area-under-curve) than patients who did not require any edoxaban dose adjustment. In this DVT/PE comparator trial, subgroup analysis revealed that warfarin had numerically better efficacy than edoxaban in patients receiving P-gp inhibitors. Based upon the overall lower exposure to edoxaban in P-gp dose adjusted subjects, both EMA and FDA Office of Clinical Pharmacology (OCP) concluded that the edoxaban 50% dose reduction overcorrected for the difference in exposure.(4,6) Consequently, EMA recommended no edoxaban dose adjustments for patients receiving concomitant therapy with quinidine or verapamil.(6,7) In a retrospective review of 5 years of data from the Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper gastro-intestinal bleeding in antidepressant users were compared to those in non-antidepressant users. The risk of a bleed in a patient using an NSAID only based on an observed-expected 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.(8) 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.(9) 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).(10) 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).(11) 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.(12) 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).(13) |
FLUVOXAMINE MALEATE, FLUVOXAMINE MALEATE ER, KORLYM, MIFEPRISTONE |
| Edoxaban (Less Than or Equal To 30 mg)/P-gp Inhibitors that Cause Bleeding SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: This combination may interact via both a pharmacodynamic and a pharmacokinetic mechanism. Pharmacodynamically, serotonin release by platelets plays a role in hemostasis.(1) Fluvoxamine may cause a decrease in serotonin reuptake by platelets, resulting in an additive risk of bleeding with oral anticoagulants.(1) Mifepristone is an antagonist at the progesterone receptor which can result in endometrium thickening, cystic dilatation of endometrial glands, or excessive vaginal bleeding. Concurrent use with anticoagulants may further increase risk.(2) Pharmacokinetically, fluvoxamine and mifepristone are inhibitors of the P-glycoprotein (P-gp) transporter and may increase the absorption of edoxaban.(3) CLINICAL EFFECTS: Concurrent use of P-gp inhibitors and edoxaban may result in bleeding.(2) The concurrent use of mifepristone with anticoagulants may result in endometrium thickening, cystic dilatation of endometrial glands, or excessive vaginal bleeding.(2) PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Bleeding risk may be increased in patients with creatinine clearance below 50 mL per minute and in patients greater than 75 years of age.(4,5) Use of multiple agents which increase edoxaban exposure or affect hemostasis would be expected to increase the risk for bleeding. PATIENT MANAGEMENT: The combination of P-gp inhibitors and edoxaban should be used with caution. Fluvoxamine and mifepristone are P-gp inhibitors. FDA approved prescribing recommendations for edoxaban are indication specific: - For prevention of stroke or embolic events due to nonvalvular atrial fibrillation, no edoxaban dose adjustments are recommended during concomitant therapy with P-gp inhibitors. - For treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE), the edoxaban dose is recommended to be reduced to 30 mg daily when used concurrently with specific P-gp inhibitors (azithromycin, clarithromycin, oral itraconazole, quinidine and verapamil).(5) The manufacturer of mifepristone states that mifepristone should be used with caution in patients receiving concurrent anticoagulant therapy. Women experiencing vaginal bleeding during concurrent use should be referred to a gynecologist for further evaluation.(2) Monitor patients receiving anticoagulant 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. 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. Discontinue edoxaban in patients with active bleeding. DISCUSSION: Edoxaban in vivo interactions studies have not been conducted with fluvoxamine and there is no recommendation on the appropriate dose of edoxaban with concomitant fluvoxamine. In an edoxaban DVT/PE trial, patients who had a 50% dose reduction (from 60 mg to 30 mg) during concomitant therapy with P-gp inhibitors (mostly verapamil and quinidine) had lower trough edoxaban concentrations (Ctrough) and lower total edoxaban exposure (AUC or area-under-curve) than patients who did not require any edoxaban dose adjustment. In this DVT/PE comparator trial, subgroup analysis revealed that warfarin had numerically better efficacy than edoxaban in patients receiving P-gp inhibitors. Based upon the overall lower exposure to edoxaban in P-gp dose adjusted subjects, both EMA and FDA Office of Clinical Pharmacology (OCP) concluded that the edoxaban 50% dose reduction overcorrected for the difference in exposure.(4,6) Consequently, EMA recommended no edoxaban dose adjustments for patients receiving concomitant therapy with quinidine or verapamil.(6,7) In a retrospective review of 5 years of data from the Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper gastro-intestinal bleeding in antidepressant users were compared to those in non-antidepressant users. The risk of a bleed in a patient using an NSAID only based on an observed-expected 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.(8) 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.(9) 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).(10) 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).(11) 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.(12) 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).(13) |
FLUVOXAMINE MALEATE, FLUVOXAMINE MALEATE ER, KORLYM, MIFEPRISTONE |
| Fruquintinib; Surufatinib/Anticoagulants; Antiplatelets 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) |
FRUZAQLA |
| Plasminogen/Anticoagulants; Antiplatelets 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) |
RYPLAZIM |
| Tisotumab/Anticoagulants; Antiplatelets 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) |
TIVDAK |
| Edoxaban/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 edoxaban. CLINICAL EFFECTS: Concurrent use of levetiracetam may result in decreased effectiveness of edoxaban. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concurrent use of levetiracetam in patients receiving edoxaban should be approached with caution. Consider alternative anticonvulsants in patients maintained on edoxaban. If concurrent use is warranted, monitor patients closely for decreased response to edoxaban. DISCUSSION: A nested case-control study of 100,168 patients on apixaban, dabigatran, edoxaban, or rivaroxaban were reviewed for stroke (CVA)/systemic emboli in patients with atrial fibrillation or recurrent thromboembolism in patients with thromboembolism. The primary outcome of CVA/systemic embolism with concurrent use of levetiracetam resulted in an odds ratio (95% CI) of 2.38 (1.19-4.75) and a propensity score adjusted odds ratio (95% CI) of 2.26 (1.13-4.54) compared to controls.(4) A population-based retrospective cohort study of 8746 patients on apixaban, dabigatran, edoxaban, or rivaroxaban were evaluated for occurrence of first ischemic stroke with concurrent antiseizure medications. Antiseizure medications that induce CYP3A4 or P-gp were associated with an increased risk of ischemic stroke (annual incidence rate of 5.5% vs 3.9%, adjusted hazard ratio 1.28). The annual incidence rates of ischemic stroke (valproate: 5.1%; levetiracetam: 6.0%; control: 3.9%) and venous thromboembolism (valproate: 3.7%; levetiracetam: 3.8%; control: 3.0%) were higher among valproate and levetiracetam users but were not statistically different from controls.(5) In a case report, a 54 year old man with a complicated medical history including paroxysmal atrial fibrillation, heart failure, and epilepsy who was on levetiracetam 500 mg twice daily was started on dabigatran 150 mg twice daily, taken simultaneously with levetiracetam. On day 10 of dabigatran, trough levels were normal but Cmax was subtherapeutic. Separation of dabigatran administration to 4 hours before levetiracetam resulted in an increase of Cmax from 88 ng/mL to 101 ng/mL. Over 32 months of follow-up, no hemorrhagic or ischemic events occurred.(6) A retrospective study of 320 patients with atrial fibrillation on DOAC therapy for secondary stroke prevention compared the incidence of ischemic stroke or TIA in patients on concomitant CYP3A4 and P-gp inducing medications (n=43), P-gp inducing medications (n=13), or no interacting medications (n=264). Twenty of the patients were on levetiracetam. There was no statistically significant difference between any of the groups.(7) A small prospective cohort study of 19 patients on the combination of levetiracetam and DOACs (8 patients on dabigatran, 9 patients on apixaban, 4 patients on rivaroxaban) did not find a significant correlation between levetiracetam and DOAC concentrations. One patient who was on low-dose apixaban had low apixaban levels, and there were no thromboembolic events in the 1388 +/- 994 days of follow-up.(8) |
ELEPSIA XR, KEPPRA, KEPPRA XR, LEVETIRACETAM, LEVETIRACETAM ER, LEVETIRACETAM-NACL, ROWEEPRA, ROWEEPRA XR, SPRITAM |
| Edoxaban/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 edoxaban. CLINICAL EFFECTS: Concurrent use of valproate derivatives may result in decreased effectiveness of edoxaban. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concurrent use of valproate derivatives in patients receiving edoxaban should be approached with caution. Consider alternative anticonvulsants in patients maintained on edoxaban. If concurrent use is warranted, monitor patients closely for decreased response to edoxaban. DISCUSSION: A nested case-control study of 100,168 patients on apixaban, dabigatran, edoxaban, or rivaroxaban were reviewed for stroke (CVA)/systemic emboli in patients with atrial fibrillation or recurrent thromboembolism in patients with thromboembolism. The primary outcome of CVA/systemic embolism with concurrent use of valproic acid resulted in an odds ratio (95% CI) of 2.58 (1.50-4.45) and a propensity score adjusted odds ratio (95% CI) of 2.38 (1.37-4.12) compared to controls.(4) A population-based retrospective cohort study of 8746 patients on apixaban, dabigatran, edoxaban, or rivaroxaban were evaluated for occurrence of first ischemic stroke with concurrent antiseizure medications. Antiseizure medications that induce CYP3A4 or P-gp were associated with an increased risk of ischemic stroke (annual incidence rate of 5.5% vs 3.9%, adjusted hazard ratio 1.28). The annual incidence rates of ischemic stroke (valproate: 5.1%; levetiracetam: 6.0%; control: 3.9%) and venous thromboembolism (valproate: 3.7%; levetiracetam: 3.8%; control: 3.0%) were higher among valproate and levetiracetam users but were not statistically different from controls.(5) |
DEPAKOTE, DEPAKOTE ER, DEPAKOTE SPRINKLE, DIVALPROEX SODIUM, DIVALPROEX SODIUM ER, SODIUM VALPROATE, VALPROATE SODIUM, VALPROIC ACID |
| Lifileucel/Anticoagulants 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) |
AMTAGVI |
| Pentosan/Selected Anticoagulants 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) |
ELMIRON, PENTOSAN POLYSULFATE SODIUM |
The following contraindication information is available for SAVAYSA (edoxaban tosylate):
Drug contraindication overview.
*Active pathologic bleeding.
*Active pathologic bleeding.
There are 14 contraindications.
Absolute contraindication.
| Contraindication List |
|---|
| Antiphospholipid syndrome |
| Cerebral amyloid angiopathy |
| Chronic kidney disease stage 1 (mild) GFR 90ml/min or higher with signs of kidney damage |
| Chronic kidney disease stage 5 (failure) GFr<15 ml/min |
| 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 |
| Severe hepatic disease |
There are 6 severe contraindications.
Adequate patient monitoring is recommended for safer drug use.
| Severe List |
|---|
| 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 |
| Increased risk of bleeding due to coagulation disorder |
| Kidney disease with likely reduction in glomerular filtration rate (GFr) |
| Pregnancy |
There are 0 moderate contraindications.
The following adverse reaction information is available for SAVAYSA (edoxaban tosylate):
Adverse reaction overview.
In studies in patients with nonvalvular atrial fibrillation, the most common adverse effects of edoxaban were bleeding and anemia. In studies in patients with acute venous thromboembolism, the most common adverse effects of the drug were bleeding, rash, abnormal liver function tests, and anemia.
In studies in patients with nonvalvular atrial fibrillation, the most common adverse effects of edoxaban were bleeding and anemia. In studies in patients with acute venous thromboembolism, the most common adverse effects of the drug were bleeding, rash, abnormal liver function tests, and anemia.
There are 19 severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Anemia Bruising Epistaxis Hemorrhage |
Abnormal hepatic function tests Gastrointestinal hemorrhage Oral hemorrhage |
| Rare/Very Rare |
|---|
|
Angioedema Anticoagulant-related nephropathy Hemorrhagic stroke Hypersensitivity drug reaction Interstitial lung disease Intracranial bleeding Ocular hemorrhage Retroperitoneal hemorrhage Spinal epidural hematoma Stevens-johnson syndrome Thrombocytopenic disorder Urticaria |
There are 6 less severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Abnormal vaginal bleeding |
Hematuria Skin rash |
| Rare/Very Rare |
|---|
|
Acute abdominal pain Dizziness Headache disorder |
The following precautions are available for SAVAYSA (edoxaban tosylate):
Safety and efficacy of edoxaban have not been established in pediatric patients.
Contraindicated
Severe Precaution
Management or Monitoring Precaution
Contraindicated
| None |
Severe Precaution
| None |
Management or Monitoring Precaution
| None |
There are no adequate or well-controlled studies of edoxaban in pregnant women; use of the drug in pregnant women is not recommended. In animal studies, edoxaban was not teratogenic at exposure levels 49 times the maximum recommended human dose based on BSA; however, fetotoxic effects, including gallbladder abnormalities, postimplantation pregnancy loss, spontaneous abortion, decreased live fetuses, and decreased fetal weight, occurred at maternally toxic doses. Edoxaban use during labor or delivery in women receiving neuraxial anesthesia may result in epidural or spinal hematomas.
(See Spinal/Epidural Hematoma under Cautions.) Use of a shorter-acting anticoagulant should be considered as delivery approaches. Edoxaban should be used during pregnancy only if the potential benefits justify the potential risks to the fetus. Edoxaban may increase the risk of bleeding in the fetus or neonate. Careful monitoring for bleeding is recommended.
(See Spinal/Epidural Hematoma under Cautions.) Use of a shorter-acting anticoagulant should be considered as delivery approaches. Edoxaban should be used during pregnancy only if the potential benefits justify the potential risks to the fetus. Edoxaban may increase the risk of bleeding in the fetus or neonate. Careful monitoring for bleeding is recommended.
Edoxaban is distributed into milk in rats; it is not known whether the drug is distributed into human milk. Because of the potential for serious adverse reactions to edoxaban in nursing infants, including hemorrhage, the manufacturer states that breast-feeding is not recommended during treatment with edoxaban.
No substantial differences in efficacy and safety have been observed in geriatric patients >=65 years of age relative to younger adults in clinical trials of edoxaban. In the ENGAGE AF-TIMI 48 trial, 74% of patients were >=65 years of age, and 41% were >=75 years of age. In the Hokusai VTE trial, 32% of patients were >=65 years of age, and 14% were >=75 years of age. In the Hokusai VTE Cancer study, 52% of patients were >=65 years of age, and 17% were >=75 years of age.
The following prioritized warning is available for SAVAYSA (edoxaban tosylate):
WARNING: Your doctor should order a blood test to check your kidney function before you start edoxaban. Edoxaban is affected by the kidneys and may not work well to prevent blood clots from atrial fibrillation in certain people due to their kidney function. Talk to your doctor for more details and to see if this medication is right for you.
Do not stop taking edoxaban unless directed by your doctor. If you stop taking this medication early, you have a higher risk of forming a serious blood clot (such as a stroke, blood clot in the legs/lungs). Your doctor may direct you to take a different "blood thinning" or antiplatelet medication to reduce your risk.
Get medical help right away if you have weakness on one side of the body, trouble speaking, sudden vision changes, confusion, chest pain, trouble breathing, or pain/warmth/swelling in the legs. People taking this medication may bleed near the spinal cord after certain spinal procedures. Bleeding in this area can cause paralysis that lasts a long time or could become permanent.
Before any spinal procedure, ask your doctor about the benefits and risks. The risk of bleeding may be higher if you have a deformed spine, or have had spinal procedures/surgery before (such as epidural catheter placement, difficult epidural/spinal puncture), or are taking other drugs that can cause bleeding/bruising (including antiplatelet drugs such as clopidogrel, "blood thinners" such as warfarin/enoxaparin, nonsteroidal anti-inflammatory drugs-NSAIDs such as ibuprofen). Tell your doctor right away if you notice symptoms such as back pain, leg numbness/tingling/weakness, loss of control of the bowels or bladder (incontinence).
WARNING: Your doctor should order a blood test to check your kidney function before you start edoxaban. Edoxaban is affected by the kidneys and may not work well to prevent blood clots from atrial fibrillation in certain people due to their kidney function. Talk to your doctor for more details and to see if this medication is right for you.
Do not stop taking edoxaban unless directed by your doctor. If you stop taking this medication early, you have a higher risk of forming a serious blood clot (such as a stroke, blood clot in the legs/lungs). Your doctor may direct you to take a different "blood thinning" or antiplatelet medication to reduce your risk.
Get medical help right away if you have weakness on one side of the body, trouble speaking, sudden vision changes, confusion, chest pain, trouble breathing, or pain/warmth/swelling in the legs. People taking this medication may bleed near the spinal cord after certain spinal procedures. Bleeding in this area can cause paralysis that lasts a long time or could become permanent.
Before any spinal procedure, ask your doctor about the benefits and risks. The risk of bleeding may be higher if you have a deformed spine, or have had spinal procedures/surgery before (such as epidural catheter placement, difficult epidural/spinal puncture), or are taking other drugs that can cause bleeding/bruising (including antiplatelet drugs such as clopidogrel, "blood thinners" such as warfarin/enoxaparin, nonsteroidal anti-inflammatory drugs-NSAIDs such as ibuprofen). Tell your doctor right away if you notice symptoms such as back pain, leg numbness/tingling/weakness, loss of control of the bowels or bladder (incontinence).
The following icd codes are available for SAVAYSA (edoxaban tosylate)'s list of indications:
| Deep venous thrombosis | |
| I80.1 | Phlebitis and thrombophlebitis of femoral vein |
| I80.10 | Phlebitis and thrombophlebitis of unspecified femoral vein |
| I80.11 | Phlebitis and thrombophlebitis of right femoral vein |
| I80.12 | Phlebitis and thrombophlebitis of left femoral vein |
| I80.13 | Phlebitis and thrombophlebitis of femoral vein, bilateral |
| I80.2 | Phlebitis and thrombophlebitis of other and unspecified deep vessels of lower extremities |
| I80.20 | Phlebitis and thrombophlebitis of unspecified deep vessels of lower extremities |
| I80.201 | Phlebitis and thrombophlebitis of unspecified deep vessels of right lower extremity |
| I80.202 | Phlebitis and thrombophlebitis of unspecified deep vessels of left lower extremity |
| I80.203 | Phlebitis and thrombophlebitis of unspecified deep vessels of lower extremities, bilateral |
| I80.209 | Phlebitis and thrombophlebitis of unspecified deep vessels of unspecified lower extremity |
| I80.21 | Phlebitis and thrombophlebitis of iliac vein |
| I80.211 | Phlebitis and thrombophlebitis of right iliac vein |
| I80.212 | Phlebitis and thrombophlebitis of left iliac vein |
| I80.213 | Phlebitis and thrombophlebitis of iliac vein, bilateral |
| I80.219 | Phlebitis and thrombophlebitis of unspecified iliac vein |
| I80.22 | Phlebitis and thrombophlebitis of popliteal vein |
| I80.221 | Phlebitis and thrombophlebitis of right popliteal vein |
| I80.222 | Phlebitis and thrombophlebitis of left popliteal vein |
| I80.223 | Phlebitis and thrombophlebitis of popliteal vein, bilateral |
| I80.229 | Phlebitis and thrombophlebitis of unspecified popliteal vein |
| I80.23 | Phlebitis and thrombophlebitis of tibial vein |
| I80.231 | Phlebitis and thrombophlebitis of right tibial vein |
| I80.232 | Phlebitis and thrombophlebitis of left tibial vein |
| I80.233 | Phlebitis and thrombophlebitis of tibial vein, bilateral |
| I80.239 | Phlebitis and thrombophlebitis of unspecified tibial vein |
| I80.24 | Phlebitis and thrombophlebitis of peroneal vein |
| I80.241 | Phlebitis and thrombophlebitis of right peroneal vein |
| I80.242 | Phlebitis and thrombophlebitis of left peroneal vein |
| I80.243 | Phlebitis and thrombophlebitis of peroneal vein, bilateral |
| I80.249 | Phlebitis and thrombophlebitis of unspecified peroneal vein |
| I80.25 | Phlebitis and thrombophlebitis of calf muscular vein |
| I80.251 | Phlebitis and thrombophlebitis of right calf muscular vein |
| I80.252 | Phlebitis and thrombophlebitis of left calf muscular vein |
| I80.253 | Phlebitis and thrombophlebitis of calf muscular vein, bilateral |
| I80.259 | Phlebitis and thrombophlebitis of unspecified calf muscular vein |
| I80.29 | Phlebitis and thrombophlebitis of other deep vessels of lower extremities |
| I80.291 | Phlebitis and thrombophlebitis of other deep vessels of right lower extremity |
| I80.292 | Phlebitis and thrombophlebitis of other deep vessels of left lower extremity |
| I80.293 | Phlebitis and thrombophlebitis of other deep vessels of lower extremity, bilateral |
| I80.299 | Phlebitis and thrombophlebitis of other deep vessels of unspecified lower extremity |
| I82.4 | Acute embolism and thrombosis of deep veins of lower extremity |
| I82.40 | Acute embolism and thrombosis of unspecified deep veins of lower extremity |
| I82.401 | Acute embolism and thrombosis of unspecified deep veins of right lower extremity |
| I82.402 | Acute embolism and thrombosis of unspecified deep veins of left lower extremity |
| I82.403 | Acute embolism and thrombosis of unspecified deep veins of lower extremity, bilateral |
| I82.409 | Acute embolism and thrombosis of unspecified deep veins of unspecified lower extremity |
| I82.41 | Acute embolism and thrombosis of femoral vein |
| I82.411 | Acute embolism and thrombosis of right femoral vein |
| I82.412 | Acute embolism and thrombosis of left femoral vein |
| I82.413 | Acute embolism and thrombosis of femoral vein, bilateral |
| I82.419 | Acute embolism and thrombosis of unspecified femoral vein |
| I82.42 | Acute embolism and thrombosis of iliac vein |
| I82.421 | Acute embolism and thrombosis of right iliac vein |
| I82.422 | Acute embolism and thrombosis of left iliac vein |
| I82.423 | Acute embolism and thrombosis of iliac vein, bilateral |
| I82.429 | Acute embolism and thrombosis of unspecified iliac vein |
| I82.43 | Acute embolism and thrombosis of popliteal vein |
| I82.431 | Acute embolism and thrombosis of right popliteal vein |
| I82.432 | Acute embolism and thrombosis of left popliteal vein |
| I82.433 | Acute embolism and thrombosis of popliteal vein, bilateral |
| I82.439 | Acute embolism and thrombosis of unspecified popliteal vein |
| I82.44 | Acute embolism and thrombosis of tibial vein |
| I82.441 | Acute embolism and thrombosis of right tibial vein |
| I82.442 | Acute embolism and thrombosis of left tibial vein |
| I82.443 | Acute embolism and thrombosis of tibial vein, bilateral |
| I82.449 | Acute embolism and thrombosis of unspecified tibial vein |
| I82.45 | Acute embolism and thrombosis of peroneal vein |
| I82.451 | Acute embolism and thrombosis of right peroneal vein |
| I82.452 | Acute embolism and thrombosis of left peroneal vein |
| I82.453 | Acute embolism and thrombosis of peroneal vein, bilateral |
| I82.459 | Acute embolism and thrombosis of unspecified peroneal vein |
| I82.46 | Acute embolism and thrombosis of calf muscular vein |
| I82.461 | Acute embolism and thrombosis of right calf muscular vein |
| I82.462 | Acute embolism and thrombosis of left calf muscular vein |
| I82.463 | Acute embolism and thrombosis of calf muscular vein, bilateral |
| I82.469 | Acute embolism and thrombosis of unspecified calf muscular vein |
| I82.49 | Acute embolism and thrombosis of other specified deep vein of lower extremity |
| I82.491 | Acute embolism and thrombosis of other specified deep vein of right lower extremity |
| I82.492 | Acute embolism and thrombosis of other specified deep vein of left lower extremity |
| I82.493 | Acute embolism and thrombosis of other specified deep vein of lower extremity, bilateral |
| I82.499 | Acute embolism and thrombosis of other specified deep vein of unspecified lower extremity |
| I82.4Y | Acute embolism and thrombosis of unspecified deep veins of proximal lower extremity |
| I82.4Y1 | Acute embolism and thrombosis of unspecified deep veins of right proximal lower extremity |
| I82.4Y2 | Acute embolism and thrombosis of unspecified deep veins of left proximal lower extremity |
| I82.4Y3 | Acute embolism and thrombosis of unspecified deep veins of proximal lower extremity, bilateral |
| I82.4Y9 | Acute embolism and thrombosis of unspecified deep veins of unspecified proximal lower extremity |
| I82.4Z | Acute embolism and thrombosis of unspecified deep veins of distal lower extremity |
| I82.4Z1 | Acute embolism and thrombosis of unspecified deep veins of right distal lower extremity |
| I82.4Z2 | Acute embolism and thrombosis of unspecified deep veins of left distal lower extremity |
| I82.4Z3 | Acute embolism and thrombosis of unspecified deep veins of distal lower extremity, bilateral |
| I82.4Z9 | Acute embolism and thrombosis of unspecified deep veins of unspecified distal lower extremity |
| I82.5 | Chronic embolism and thrombosis of deep veins of lower extremity |
| I82.50 | Chronic embolism and thrombosis of unspecified deep veins of lower extremity |
| I82.501 | Chronic embolism and thrombosis of unspecified deep veins of right lower extremity |
| I82.502 | Chronic embolism and thrombosis of unspecified deep veins of left lower extremity |
| I82.503 | Chronic embolism and thrombosis of unspecified deep veins of lower extremity, bilateral |
| I82.509 | Chronic embolism and thrombosis of unspecified deep veins of unspecified lower extremity |
| I82.51 | Chronic embolism and thrombosis of femoral vein |
| I82.511 | Chronic embolism and thrombosis of right femoral vein |
| I82.512 | Chronic embolism and thrombosis of left femoral vein |
| I82.513 | Chronic embolism and thrombosis of femoral vein, bilateral |
| I82.519 | Chronic embolism and thrombosis of unspecified femoral vein |
| I82.52 | Chronic embolism and thrombosis of iliac vein |
| I82.521 | Chronic embolism and thrombosis of right iliac vein |
| I82.522 | Chronic embolism and thrombosis of left iliac vein |
| I82.523 | Chronic embolism and thrombosis of iliac vein, bilateral |
| I82.529 | Chronic embolism and thrombosis of unspecified iliac vein |
| I82.53 | Chronic embolism and thrombosis of popliteal vein |
| I82.531 | Chronic embolism and thrombosis of right popliteal vein |
| I82.532 | Chronic embolism and thrombosis of left popliteal vein |
| I82.533 | Chronic embolism and thrombosis of popliteal vein, bilateral |
| I82.539 | Chronic embolism and thrombosis of unspecified popliteal vein |
| I82.54 | Chronic embolism and thrombosis of tibial vein |
| I82.541 | Chronic embolism and thrombosis of right tibial vein |
| I82.542 | Chronic embolism and thrombosis of left tibial vein |
| I82.543 | Chronic embolism and thrombosis of tibial vein, bilateral |
| I82.549 | Chronic embolism and thrombosis of unspecified tibial vein |
| I82.55 | Chronic embolism and thrombosis of peroneal vein |
| I82.551 | Chronic embolism and thrombosis of right peroneal vein |
| I82.552 | Chronic embolism and thrombosis of left peroneal vein |
| I82.553 | Chronic embolism and thrombosis of peroneal vein, bilateral |
| I82.559 | Chronic embolism and thrombosis of unspecified peroneal vein |
| I82.56 | Chronic embolism and thrombosis of calf muscular vein |
| I82.561 | Chronic embolism and thrombosis of right calf muscular vein |
| I82.562 | Chronic embolism and thrombosis of left calf muscular vein |
| I82.563 | Chronic embolism and thrombosis of calf muscular vein, bilateral |
| I82.569 | Chronic embolism and thrombosis of unspecified calf muscular vein |
| I82.59 | Chronic embolism and thrombosis of other specified deep vein of lower extremity |
| I82.591 | Chronic embolism and thrombosis of other specified deep vein of right lower extremity |
| I82.592 | Chronic embolism and thrombosis of other specified deep vein of left lower extremity |
| I82.593 | Chronic embolism and thrombosis of other specified deep vein of lower extremity, bilateral |
| I82.599 | Chronic embolism and thrombosis of other specified deep vein of unspecified lower extremity |
| I82.5Y | Chronic embolism and thrombosis of unspecified deep veins of proximal lower extremity |
| I82.5Y1 | Chronic embolism and thrombosis of unspecified deep veins of right proximal lower extremity |
| I82.5Y2 | Chronic embolism and thrombosis of unspecified deep veins of left proximal lower extremity |
| I82.5Y3 | Chronic embolism and thrombosis of unspecified deep veins of proximal lower extremity, bilateral |
| I82.5Y9 | Chronic embolism and thrombosis of unspecified deep veins of unspecified proximal lower extremity |
| I82.5Z | Chronic embolism and thrombosis of unspecified deep veins of distal lower extremity |
| I82.5Z1 | Chronic embolism and thrombosis of unspecified deep veins of right distal lower extremity |
| I82.5Z2 | Chronic embolism and thrombosis of unspecified deep veins of left distal lower extremity |
| I82.5Z3 | Chronic embolism and thrombosis of unspecified deep veins of distal lower extremity, bilateral |
| I82.5Z9 | Chronic embolism and thrombosis of unspecified deep veins of unspecified distal lower extremity |
| I82.62 | Acute embolism and thrombosis of deep veins of upper extremity |
| I82.621 | Acute embolism and thrombosis of deep veins of right upper extremity |
| I82.622 | Acute embolism and thrombosis of deep veins of left upper extremity |
| I82.623 | Acute embolism and thrombosis of deep veins of upper extremity, bilateral |
| I82.629 | Acute embolism and thrombosis of deep veins of unspecified upper extremity |
| I82.72 | Chronic embolism and thrombosis of deep veins of upper extremity |
| I82.721 | Chronic embolism and thrombosis of deep veins of right upper extremity |
| I82.722 | Chronic embolism and thrombosis of deep veins of left upper extremity |
| I82.723 | Chronic embolism and thrombosis of deep veins of upper extremity, bilateral |
| I82.729 | Chronic embolism and thrombosis of deep veins of unspecified upper extremity |
| I82.A | Embolism and thrombosis of axillary vein |
| I82.A1 | Acute embolism and thrombosis of axillary vein |
| I82.A11 | Acute embolism and thrombosis of right axillary vein |
| I82.A12 | Acute embolism and thrombosis of left axillary vein |
| I82.A13 | Acute embolism and thrombosis of axillary vein, bilateral |
| I82.A19 | Acute embolism and thrombosis of unspecified axillary vein |
| I82.A2 | Chronic embolism and thrombosis of axillary vein |
| I82.A21 | Chronic embolism and thrombosis of right axillary vein |
| I82.A22 | Chronic embolism and thrombosis of left axillary vein |
| I82.A23 | Chronic embolism and thrombosis of axillary vein, bilateral |
| I82.A29 | Chronic embolism and thrombosis of unspecified axillary vein |
| I82.B | Embolism and thrombosis of subclavian vein |
| I82.B1 | Acute embolism and thrombosis of subclavian vein |
| I82.B11 | Acute embolism and thrombosis of right subclavian vein |
| I82.B12 | Acute embolism and thrombosis of left subclavian vein |
| I82.B13 | Acute embolism and thrombosis of subclavian vein, bilateral |
| I82.B19 | Acute embolism and thrombosis of unspecified subclavian vein |
| I82.B2 | Chronic embolism and thrombosis of subclavian vein |
| I82.B21 | Chronic embolism and thrombosis of right subclavian vein |
| I82.B22 | Chronic embolism and thrombosis of left subclavian vein |
| I82.B23 | Chronic embolism and thrombosis of subclavian vein, bilateral |
| I82.B29 | Chronic embolism and thrombosis of unspecified subclavian vein |
| I82.C | Embolism and thrombosis of internal jugular vein |
| I82.C1 | Acute embolism and thrombosis of internal jugular vein |
| I82.C11 | Acute embolism and thrombosis of right internal jugular vein |
| I82.C12 | Acute embolism and thrombosis of left internal jugular vein |
| I82.C13 | Acute embolism and thrombosis of internal jugular vein, bilateral |
| I82.C19 | Acute embolism and thrombosis of unspecified internal jugular vein |
| I82.C2 | Chronic embolism and thrombosis of internal jugular vein |
| I82.C21 | Chronic embolism and thrombosis of right internal jugular vein |
| I82.C22 | Chronic embolism and thrombosis of left internal jugular vein |
| I82.C23 | Chronic embolism and thrombosis of internal jugular vein, bilateral |
| I82.C29 | Chronic embolism and thrombosis of unspecified internal jugular vein |
| T82.897 | Other specified complication of cardiac prosthetic devices, implants and grafts |
| Prevent thromboembolism in chronic atrial fibrillation | |
| I48.2 | Chronic atrial fibrillation |
| I48.20 | Chronic atrial fibrillation, unspecified |
| I48.21 | Permanent atrial fibrillation |
| Pulmonary thromboembolism | |
| I26 | Pulmonary embolism |
| I26.0 | Pulmonary embolism with acute cor pulmonale |
| I26.02 | Saddle embolus of pulmonary artery with acute cor pulmonale |
| I26.09 | Other pulmonary embolism with acute cor pulmonale |
| I26.9 | Pulmonary embolism without acute cor pulmonale |
| I26.92 | Saddle embolus of pulmonary artery without acute cor pulmonale |
| I26.93 | Single subsegmental thrombotic pulmonary embolism without acute cor pulmonale |
| I26.94 | Multiple subsegmental thrombotic pulmonary emboli without acute cor pulmonale |
| I26.99 | Other pulmonary embolism without acute cor pulmonale |
| I27.82 | Chronic pulmonary embolism |
Formulary Reference Tool