Elmiron (pentosan polysulfate sodium)

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Pentosan polysulfate sodium is administered orally with water at least 1 hour before or 2 hours after meals.

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There is no enhanced messaging for this drug.

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

Anticoagulant;Antiplatelet;Thrombolytic/Alipogene Tiparvovec

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

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

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

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

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

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

Anticoagulants/Hemin

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

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

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

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

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

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

Anticoagulants/Iv And Im Diclofenac

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

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

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

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

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

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

Anticoagulants; Antiplatelets/Mifepristone

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

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

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

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

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

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

Gpis;Heparin;Thrombolytics;Warfarin/Bivalirudin; Desirudin

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

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

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

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

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

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

Oral Anticoagulants; Warfarin/Tenecteplase

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

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

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

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

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

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

Selected Anticoagulants; Thrombolytics/Defibrotide

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

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

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

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

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

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

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

Anticoagulants/Donanemab

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

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

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

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

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

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

Anticoagulants/Ketorolac

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

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

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

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

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

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

Anticoagulants/Lecanemab

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

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

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

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

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

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

Anticoagulants; Antiplatelets/Inotersen

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

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

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

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

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

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

Anticoagulants; Antiplatelets/Tipranavir

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

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

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

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

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

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

Anticoagulants; Antiplatelets; Thrombolytics/Caplacizumab

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

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

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

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

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

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

Anticoagulants; Fibrinolytics/Aducanumab

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

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

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

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

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

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

Anticoagulants; Thrombolytics/Urokinase

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

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

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

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

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

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

Slt Anticoagulants (Vitamin K Antag); Heparins/Abciximab

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

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

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

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

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

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

Slt Anticoagulants (Vitamin K Antag); Heparins/Alteplase

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

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

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

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

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

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

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

Anticoagulant;Antiplatelet;Thrombolytic/Icosapent Ethyl

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

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

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

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

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

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

Anticoagulants/Corticosteroids

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

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

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

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

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

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

Anticoagulants/Lifileucel

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

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

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

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

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

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

Anticoagulants; Antiplatelets/Fruquintinib; Surufatinib

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

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

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

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

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

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

Anticoagulants; Antiplatelets/Mifepristone (Cushing)

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

MECHANISM OF ACTION: Mifepristone is an antagonist at the progesterone receptor which can result in endometrium thickening, cystic dilatation of endometrial glands, or excessive vaginal bleeding. Concurrent use with anticoagulants or antiplatelets may further increase risk.

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

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

PATIENT MANAGEMENT: The manufacturer of mifepristone states that mifepristone should be used with caution in patients receiving concurrent anticoagulant or antiplatelet therapy.(1) If concurrent therapy is deemed medically necessary, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. Women experiencing vaginal bleeding during concurrent use should be referred to a gynecologist for further evaluation.

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

Anticoagulants; Antiplatelets/Obinutuzumab

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

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

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

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

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

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

Anticoagulants; Antiplatelets/Plasminogen

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

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

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

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

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

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

Anticoagulants; Antiplatelets/Tisotumab

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

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

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

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

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

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

Anticoagulants; Antiplatelets; Thrombolytics/Drotrecogin

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Heparin/Selected Salicylates

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

MECHANISM OF ACTION: Additive prolongation of bleeding time.

CLINICAL EFFECTS: Increased risk of bleeding which may extend for several days beyond discontinuation of salicylates.

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

PATIENT MANAGEMENT: Avoid concomitant administration of these drugs. If this combination is used, monitor patients for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. A non-acetylated salicylate may be used to avoid antiplatelet activity. 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. Single ingredient aspirin or buffered aspirin products with strengths < or = 325 mg and combination aspirin products which are used to treat cardiovascular disease (e.g. aspirin+statins, aspirin+dipyridamole) are not included in this interaction.

DISCUSSION: This interaction is likely to occur.

Heparins/Nsaids

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

MECHANISM OF ACTION: Heparin inhibits thrombosis by inactivating activated Factor X and inhibiting the conversion of prothrombin to thrombin.(1) NSAIDs inhibit coagulation by interfering with platelet-aggregation, while inhibition of prostaglandin synthesis increases the risk for gastrointestinal bleeding.

CLINICAL EFFECTS: Concurrent use of heparin and an NSAID may increase the risk for bleeding.(1,2)

PREDISPOSING FACTORS: 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: Manufacturers recommend caution and monitoring when using this combination of drugs.(1,2) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: Based upon drug mechanisms of action, careful monitoring would be prudent.

Heparins/Slt Anticoagulants (Vitamin K Antagonists); Citrate

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

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

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

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

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

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

Heparins/Sulfinpyrazone

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

MECHANISM OF ACTION: Sulfinpyrazone and its metabolite inhibit platelet aggregation induced by sodium arachidonate.(1)

CLINICAL EFFECTS: Concurrent use of heparin derivatives and sulfinpyrazone may result in bleeding.

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

PATIENT MANAGEMENT: Unless really needed, agents which may increase the risk of hemorrhage, such as sulfinpyrazone, should be discontinued prior to the initiation of heparin derivatives.(2) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs or risks for blood loss, including platelet count, 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: Sulfinpyrazone and its metabolite inhibit platelet aggregation induced by sodium arachidonate.(1) Unless really needed, agents which may increase the risk of hemorrhage, such as sulfinpyrazone, should be discontinued prior to the initiation of heparin derivatives.(2) Periodic complete blood counts, including platelet count, and stool occult blood tests are recommended during therapy.(2)

Pentosan/Heparins

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 heparin may result in additive effects.(1)

CLINICAL EFFECTS: Concurrent use of pentosan and heparin 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 heparin 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)

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)

Selected Anticoagulants; Antiplatelets/Ibrutinib

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

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

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

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

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

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

Selected Anticoagulants; Thrombolytics/Platelet Inhibitors

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

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

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

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

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

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

Slt Anticoagulants (Vitamin K Antag); Heparins/Reteplase

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

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

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

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

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

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

Slt Anticoagulants;Antiplatelets;Thrombolytics/Fluvoxamine

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) Fluvoxamine may cause a decrease in serotonin reuptake by platelets, resulting in an additive risk of bleeding with anticoagulants, antiplatelets, and thrombolytics.

CLINICAL EFFECTS: Concurrent use of fluvoxamine and agents that affect coagulation may result in bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Renal impairment has been associated with an elevated risk of GI bleed in patients on SSRIs.(2) Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Concurrent therapy of fluvoxamine and agents that affect coagulation should be undertaken 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, anti Factor Xa inhibition) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: 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.(3) 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.(4) In a case-control study conducted in users of acenocoumarol or phenprocoumon, 1,848 patients who had been hospitalized with abnormal bleeding were each matched to 4 control patients. When patients took both a SSRI and a coumarin, an increased risk of hospitalization due to major non-gastrointestinal bleeding was observed (adjusted OR 1.7), but not due to gastrointestinal bleeding (adjusted OR 0.8).(5) 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).(6) 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.(7) 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).(8)

Slt Anticoagulants;Antiplatelets;Thrombolytics/Ssris;Snris

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

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

CLINICAL EFFECTS: Concurrent use of a selective serotonin reuptake inhibitor(1-6) or a serotonin-norepinephrine reuptake inhibitor(7-9) and agents that affect coagulation may result in bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Renal impairment has been associated with an elevated risk of GI bleed in patients on SSRIs.(15) Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Selective serotonin reuptake inhibitors(1-6) or serotonin-norepinephrine reuptake inhibitors(7-9) and agents that affect coagulation should be used concurrently with caution. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: In a retrospective review of 5 years of data from the Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper gastro-intestinal bleeding in antidepressant users were compared to those in non-antidepressant users. The risk of a bleed in a patient using an NSAID only based on an observed-expected ration was 4.5 and in a patient using low-dose aspirin only was 2.5. Concurrent use of a selective serotonin reuptake inhibitor with NSAIDs or low-dose aspirin increased the risk of bleeding to 12.2 and 5.2, respectively.(10) In another study, there were 16 cases of upper gastrointestinal bleeding in patients receiving concurrent therapy with selective serotonin reuptake inhibitors and NSAIDs. Adjusted relative risk of bleeding with NSAIDs, selective serotonin reuptake inhibitors, or both were 3.7, 2.6, or 15.6, respectively.(11) In a case-control study conducted in users of acenocoumarol or phenprocoumon, 1848 patients who had been hospitalized with abnormal bleeding were each matched to 4 control patients. When patients took both a SSRI and a coumarin, an increased risk of hospitalization due to major non-gastrointestinal bleeding was observed (adjusted OR 1.7), but not due to gastrointestinal bleeding (adjusted OR 0.8).(12) A retrospective review examined patients discharged from a hospital with antiplatelet therapy following a myocardial infarction. When compared to aspirin therapy alone, both aspirin therapy with a SSRI and aspirin, clopidogrel, and SSRI therapy were associated with an increased risk of bleeding (hazard ratios 1.42 and 2.35, respectively.) Compared with dual antiplatelet therapy (aspirin and clopidogrel), use of aspirin and clopidogrel and a SSRI was also associated with increased risk of bleeding (hazard ratio 1.57).(13) In The Rotterdam Study, fluvoxamine increased the risk of over anticoagulation (hazard ratio 2.63). Paroxetine was not associated with an increased risk. There were insufficient numbers of patients taking other SSRIs to assess increased risk.(14) A self-controlled case study of 1,622 oral anticoagulant-precipitant drug pairs were reviewed and found 14% of drug pairs were associated with a statistically significant elevated risk of thromboembolism. Concurrent use of dabigatran and citalopram resulted in a ratio of rate ratios (95% CI) of 1.69 (1.11-2.57).(16) A systematic review and meta-analysis of 22 cohort and case-controlled studies including over 1 million patients found 1.55-fold higher odds of upper gastrointestinal (GI) bleeding in SSRI users compared with non-SSRI users (95% CI, 1.35-1.78). In subgroup analyses, the risk was found to be greatest among participants taking SSRIs concurrently with NSAIDs or antiplatelet medications.(17)

Pentosan polysulfate sodium is contraindicated in patients with known hypersensitivity to the drug, structurally related compounds, or any ingredient in the formulation.

There are no contraindication contraindications for this drug.

• Arterial aneurysm
• Diverticulitis of gastrointestinal tract
• Gastrointestinal ulcer
• Hemophilia
• Hemorrhage
• Increased risk of bleeding
• Invasive surgical procedure
• Thrombocytopenic disorder

• Disease of liver
• Heparin-induced thrombocytopenia
• Maculopathy
• Pigmentary retinopathy

The most common adverse effects of pentosan polysulfate sodium include rectal hemorrhage, alopecia, diarrhea, nausea, headache, blood in stool, rash, dyspepsia, abdominal pain, abnormal liver function tests, dizziness, and bruising.

Less Frequent

• Abnormal hepatic function tests
• Ecchymosis
• Infection
• Influenza
• Rectal bleeding

Rare or Very Rare

• Accommodation disorder
• Anemia
• Colitis
• Dyspnea
• Leukopenia
• Optic neuritis
• Pigmentary maculopathy
• Pigmentary retinopathy
• Retinal hemorrhage
• Thrombocytopenic disorder
• Urticaria
• Visual changes

Less Frequent

• Abdominal distension
• Acute abdominal pain
• Alopecia
• Diarrhea
• Dizziness
• Headache disorder
• Nausea
• Skin rash

Rare or Very Rare

• Anorexia
• Aphthous stomatitis
• Conjunctivitis
• Constipation
• Dyspepsia
• Epistaxis
• Esophagitis
• Flatulence
• Gastritis
• Gingival bleeding
• Pharyngitis
• Pruritus of skin
• Rhinitis
• Skin photosensitivity
• Tinnitus
• Toxic amblyopia
• Vomiting

No enhanced messaging available.

Safety and efficacy of pentosan polysulfate sodium in pediatric patients younger than 16 years of age have not been established.

Category B. (See Users Guide.)

It is not known whether pentosan polysulfate sodium is distributed into milk. The drug should be used with caution in nursing women.

No enhanced messaging available.