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    Direct Thrombin Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Intravenous, direct thrombin inhibitor
    Used for thrombosis prophylaxis or treatment in patients with heparin-induced thrombocytopenia (HIT) and as an anticoagulant in patients with or at risk of HIT undergoing percutaneous coronary intervention (PCI)
    Hepatically eliminated, can use in end-stage renal disease without dosage adjustment

    COMMON BRAND NAMES

    Argatroban

    HOW SUPPLIED

    Argatroban/Argatroban, Sodium Chloride Intravenous Inj Sol: 1mg, 1mL, 100mg, 1-0.9%

    DOSAGE & INDICATIONS

    For use as an anticoagulant in the treatment of thrombosis (i.e., deep venous thrombosis (DVT), pulmonary embolism) or for venous thromboembolism (VTE) prophylaxis (i.e., deep venous thrombosis (DVT) prophylaxis, pulmonary embolism prophylaxis) in patients with heparin-induced thrombocytopenia (HIT).
    NOTE: Before administering argatroban, discontinue heparin therapy and obtain a baseline aPTT.
    For conversion to oral anticoagulant therapy in patients receiving argatroban.
    NOTE: Initiate warfarin therapy using the expected daily dose of warfarin; a loading dose of warfarin should not be used.
    NOTE: There is potential for combined effects on the INR with coadministration of argatroban and warfarin. The relationship between the INR obtained on combined therapy and the INR obtained on warfarin alone is dependent on both the dose of argatroban and the thromboplastin reagent used.
    Intravenous dosage (argatroban at doses up to 2 mcg/kg/minute with warfarin)
    Adults

    Measure INR daily while argatroban and warfarin are coadministered. In general, with doses of argatroban up to 2 mcg/kg/minute, argatroban can be discontinued when the INR is more than 4 on combined therapy. After argatroban is discontinued, repeat the INR measurement in 4 to 6 hours. If the repeat INR is below the desired therapeutic range, resume the infusion of argatroban and repeat the process daily until the desired therapeutic range on warfarin alone is reached. Clinical practice guidelines recommend allowing the platelet count to substantially recover (i.e., 150 x 109/L or more) before initiating warfarin; the initial warfarin dose should not exceed 5 mg/day. Overlap argatroban with warfarin for at least 5 days and until the INR is within the desired range.[49183]

    Intravenous dosage (argatroban at doses greater than 2 mcg/kg/minute with warfarin)
    Adults

    The relationship of INR on warfarin alone to the INR on warfarin plus argatroban is less predictable for argatroban doses more than 2 mcg/kg/minute. In order to predict the INR on warfarin alone, temporarily reduce the argatroban dose to 2 mcg/kg/minute. Repeat the INR 4 to 6 hours after reduction of the argatroban dose. In general, with doses of argatroban up to 2 mcg/kg/minute, argatroban can be discontinued when the INR is more than 4 on combined therapy. After argatroban is discontinued, repeat the INR measurement in 4 to 6 hours. If the repeat INR is below the desired therapeutic range, resume the infusion of argatroban and repeat the process daily until the desired therapeutic range on warfarin alone is reached. Clinical practice guidelines recommend allowing the platelet count to substantially recover (i.e., 150 x 109/L or more) before initiating warfarin; the initial warfarin dose should not exceed 5 mg/day. Overlap argatroban with warfarin for at least 5 days and until the INR is within the desired range.[49183]

    Intravenous dosage
    Adults

    2 mcg/kg/minute continuous IV infusion. Clinical practice guidelines recommend 0.5 to 1.2 mcg/kg/minute for patients with heart failure, multiple organ system failure, severe anasarca, or those who are post-cardiac surgery. Steady-state anticoagulant effects (including the aPTT) are typically attained within 1 to 3 hours. The steady-state aPTT should be 1.5 to 3 times the initial baseline value (not to exceed 100 seconds). Monitor aPTT 2 hours after initiation of therapy to confirm that the aPTT is within the desired therapeutic range. Dose adjustments (not to exceed 10 mcg/kg/minute) may be required to attain the target aPTT. In clinical studies, doses have ranged from 15 to 25 mg/hour continuous IV infusion. Adjustments in dose were based on maintaining an activated partial thromboplastin time (aPTT) of 1.5 to 2.5 times control and/or a plasma argatroban concentration of approximately 2 mcg/mL. Clinical practice guidelines recommend use of nonheparin anticoagulants, including argatroban, over further use of heparin, low-molecular weight heparin, or vitamin K antagonist. Argatroban is preferred over other nonheparin anticoagulants in patients with renal insufficiency.

    Infants†, Children†, and Adolescents†

    Safety and efficacy have not been established. Pharmacokinetic/pharmacodynamic models suggest an initial infusion rate of 0.75 mcg/kg/minute IV may have comparable aPTT responses to a standard adult initiation rate (2 mcg/kg/minute), based on a goal aPTT of 1.5 to 3 times the baseline value and avoidance of an aPTT more than 100 seconds. Based on aPTT evaluation every 2 hours, increasing the infusion rate by 0.1 to 0.25 mcg/kg/minute could achieve additional aPTT responses. However, this dosing regimen has not been adequately assessed and did not take into account multiple factors (e.g., current aPTT, target aPTT, clinical status).

    For coronary artery thrombosis prophylaxis or treatment during percutaneous coronary intervention (PCI) in patients who have or who are at risk of developing heparin-induced thrombocytopenia.
    Intravenous dosage
    Adults

    350 mcg/kg IV bolus over 3 to 5 minutes then 25 mcg/kg/minute continuous IV infusion. Activated clotting time (ACT) should be measured 5 to 10 minutes later. The procedure may proceed if the ACT is more than 300 seconds. If the ACT is less than 300 seconds, an additional 150 mcg/kg IV bolus should be administered, the infusion rate increased to 30 mcg/kg/minute, and the ACT repeated 5 to 10 minutes later. If the ACT is more than 450 seconds, the infusion rate should be decreased to 15 mcg/kg/minute, and the ACT repeated 5 to 10 minutes later. Once a therapeutic ACT (between 300 to 450 seconds) has been achieved, this infusion rate should be continued for the duration of the procedure. In case of dissection, impending abrupt closure, thrombus formation during the procedure, or inability to achieve or maintain an ACT more than 300 seconds, additional bolus doses of 150 mcg/kg may be administered and the infusion rate increased to 40 mcg/kg/minute. The ACT should be monitored after each additional bolus, change in infusion rate, and at the end of the procedure. In addition, during prolonged procedures, monitor ACT every 20 to 30 minutes. If a patient requires continued anticoagulation after completion of the procedure, argatroban may be continued at 2 mcg/kg/minute and adjusted as needed to maintain desired aPTT. Clinical practice guidelines recommend argatroban or bivalirudin over other nonheparin anticoagulants in patients with heparin-induced thrombocytopenia who require percutaneous coronary intervention.

    For use as adjunctive therapy to thrombolytic agents in the treatment of ST-elevation myocardial infarction (STEMI)† (i.e., acute myocardial infarction†).
    Intravenous dosage
    Adults

    100 mcg/kg IV bolus followed by either low-dose (1 mcg/kg/minute continuous IV infusion) or high-dose (3 mcg/kg/minute continuous IV infusion) argatroban was compared to heparin 70 units/kg IV bolus followed by 15 units/kg/hour continuous IV infusion; argatroban or heparin were administered as adjunctive therapy to alteplase and adjusted to maintain an aPTT of 50 to 70 seconds after the first 6 hours. Patients continued heparin or argatroban for 48 to 72 hours or until angioplasty, at which point patients receiving argatroban were switched to heparin. TIMI grade 3 blood flow at 90 minutes trended towards improvement with argatroban; however, these differences were not statistically different. Bleeding rates were lower, but not significantly, in patients receiving argatroban (10% for heparin vs. 2.6% for low-dose argatroban and 4.3% for high-dose argatroban).[26106]

    For the treatment of disseminated intravascular coagulation (DIC)†.
    Intravenous dosage
    Adults

    0.7 mcg/kg/minute continuous IV infusion with response to therapy defined as an increase in platelet count to more than 120,000 platelets/mm3, a decrease in fibrin or fibrinogen degradation products to less than 20 mcg/mL, and no significant decrease in antithrombin III concentrations.[26111]

    †Indicates off-label use

    MAXIMUM DOSAGE

    The maximum dosage is individualized based on aPTT or ACT monitoring and assessment of efficacy and safety parameters.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    In patients with HIT:
    Adults with moderate to severe hepatic impairment: decrease the initial dose to 0.5 mcg/kg/minute; adjust the dose as clinically indicated.
    Pediatric patients with hepatic impairment: pharmacokinetic/pharmacodynamic models suggest an initial infusion rate of 0.2 mcg/kg/minute, adjusted in increasing increments of 0.05 mcg/kg/minute, may have comparable argatroban exposure as expected with adults doses.
    In patients undergoing PCI:
    Carefully titrate to desired level of anticoagulation in patients with hepatic impairment.
    Avoid use in patients with clinically significant hepatic disease or AST/ALT levels 3 times or more the upper limit of normal.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
     
    Intermittent hemodialysis
    When argatroban is administered as a continuous infusion (2 mcg/kg/minute) prior to and during a 4-hour hemodialysis session with high-flux membranes, systemic clearance increases by approximately 20%; however, activated clotting times (ACTs) remain stable during dialysis and dosage adjustment is not necessary.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Premixed solution (1 mg/mL)
    Dilution is not required.
    Vial may be inverted for use with medical infusion set.
     
    Dilution of concentrated injection (100 mg/mL vial)
    Each 2.5 mL vial should be diluted in 0.9% Sodium Chloride Injection, 5% Dextrose Injection, or Lactated Ringer's Injection to a final concentration of 1 mg/mL.
    ASHP Recommended Standard Concentrations for Adult Continuous Infusions: 1 mg/mL.
    Each 2.5 mL vial should be diluted 100-fold by mixing with 250 mL of diluent. Use 250 mg (2.5 mL) per 250 mL of diluent or 500 mg (5 mL) per 500 mL of diluent. Use of diluent at room temperature is recommended.
    Mix with repeated inversion of the diluent bag for 1 minute. The diluted solution may show slight but brief haziness due to the formation of microprecipitates that rapidly dissolve upon mixing. The final solution must be clear before use. The pH of the diluted solution prepared as recommended is 3.2 to 7.5.
    Storage: Diluted solutions are stable for 24 hours at 25 degrees C (77 degrees F) in ambient indoor light. Solutions are physically and chemically stable for up to 96 hours when protected from light and stored at room temperature, 20 to 25 degrees C (68 to 77 degreed F) or in the refrigerator, 2 to 8 degrees C (36 to 46 degrees F). Do not expose prepared solution to direct sunlight.
    Storage after dilution (GlaxoSmithKline): Dilutions in 0.9% Sodium Chloride Injection, 5% Dextrose Injection, or Lactated Ringer's Injection are stable for 24 hours at controlled room temperature of 20 to 25 degrees C (68 to 77 degrees F) in ambient indoor light. Solutions are physically and chemically stable for up to 96 hours when protected from light and stored at controlled room temperature of 20 to 25 degrees C (68 to 77 degrees F) or under refrigeration at 2 to 8 degrees C (36 to 46 degrees F). Do not expose prepared solution to direct sunlight.
    Storage after dilution (Fresenius): Dilutions in 0.9% Sodium Chloride Injection are physically and chemically stable for up to 96 hours when protected from light and stored at controlled room temperature of 20 to 25 degrees C (68 to 77 degrees F) or under refrigeration at 2 to 8 degrees C (36 to 46 degrees F). Argatroban diluted in 5% Dextrose Injection or Lactated Ringer's Injection is physically and chemically stable for up to 4 hours when protected from light and stored at controlled room temperature of 20 to 25 degrees C (68 to 77 degrees F) or under refrigeration at 2 to 8 degrees C (36 to 46 degrees F). Do not expose prepared solution to direct sunlight.
     
    IV Infusion
    The rate of administration should be individualized based on patient weight.
    Standard infusion rates based on 1 mg/mL concentration and recommended initial dose in adult patients without hepatic impairment (2 mcg/kg/minute):
    Adults weighing 50 kg: 6 mL/hour
    Adults weighing 60 kg: 7 mL/hour
    Adults weighing 70 kg: 8 mL/hour
    Adults weighing 80 kg: 10 mL/hour
    Adults weighing 90 kg: 11 mL/hour
    Adults weighing 100 kg: 12 mL/hour
    Adults weighing 110 kg: 13 mL/hour
    Adults weighing 120 kg: 14 mL/hour
    Adults weighing 130 kg: 16 mL/hour
    Adults weighing 140 kg: 17 mL/hour

    STORAGE

    Argatroban:
    - Avoid extreme temperatures
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not dilute the product
    - Do not freeze
    - Protect from direct sunlight
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in a cool, dry place
    - Store in the original carton to protect from light

    CONTRAINDICATIONS / PRECAUTIONS

    Hepatic disease

    Start with a lower dose and carefully titrate argatroban in patients with hepatic disease. Achievement of steady-state aPTT concentrations may take longer and require more dosage adjustments in patients with hepatic impairment compared to patients with normal hepatic function. Upon argatroban discontinuation, full reversal of anticoagulant effects may require longer than 4 hours due to decreased clearance and increased elimination half-life. Avoid high doses of argatroban in patients undergoing PCI who have clinically significant hepatic disease or AST/ALT concentrations 3 times the upper limit of normal or more.[56982]

    Aneurysm, bleeding, coagulopathy, diverticulitis, endocarditis, GI bleeding, hemophilia, hypertension, inflammatory bowel disease, intracranial bleeding, intramuscular injections, lumbar puncture, menstruation, peptic ulcer disease, renal disease, retroperitoneal bleeding, spinal anesthesia, stroke, surgery, trauma

    Bleeding can be a major risk associated with use of argatroban; therefore, argatroban is contraindicated in patients with overt major bleeding. Coagulopathy should be ruled out before initiation of therapy. Blood coagulation tests should be performed before and regularly during therapy. Argatroban should not be initiated in patients with a baseline aPTT ratio of 2.5 or more. For patients at increased risk of bleeding, a careful assessment must be made weighing the risk of argatroban administration versus its anticipated benefit. Conditions which increase the risk of bleeding include: a recent stroke; severe uncontrolled hypertension; infective endocarditis; advanced renal disease; dissecting aortic aneurysm; peptic ulcer disease; diverticulitis; inflammatory bowel disease; hemophilia; menstruation; recent major surgery or trauma, including eye, brain, or spinal cord surgery; lumbar puncture; spinal anesthesia; recent puncture of large vessels or organ biopsy; an anomaly of vessels or organs; or recent major bleeding (including intracranial bleeding, GI bleeding, intraocular bleeding, retroperitoneal bleeding, or pulmonary bleeding). Argatroban should not be used in patients with uncontrollable bleeding. If possible, intramuscular injections should be avoided in patients receiving argatroban. Patients should be monitored closely for signs and/or symptoms of bleeding.

    Abrupt discontinuation, angina

    Patients with unstable angina have been reported to have a recurrence of rest angina following abrupt discontinuation of infusions of argatroban. Angina appears to occur after administration of higher doses of argatroban and is associated with greater prolongations of aPTT and evidence of rebound thrombin generation. Significant increases in thrombin-antithrombin III complex concentrations were observed within a few hours following infusion. Infusions of argatroban should be gradually tapered in patients with unstable angina following initiation of aspirin or other antiplatelet agents.

    Labor, obstetric delivery, pregnancy

    If argatroban is used during pregnancy, monitor neonates for bleeding and pregnant women for evidence of excessive bleeding or unexpected changes in coagulation parameters during labor or obstetric delivery. The use of argatroban during pregnancy may increase the risk of bleeding. Limited data from postmarketing reports and published literature do not suggest an association between the use of argatroban and adverse fetal developmental outcomes. In animal reproduction studies with argatroban doses up to 0.2- and 0.3-times the maximum recommended human dose (based on body surface area), there was no evidence of adverse developmental outcomes.

    Breast-feeding

    It is not known if argatroban is excreted in human milk; however, it is present in the milk of lactating rats. There are no data on the effects of argatroban on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for argatroban and any potential adverse effects on the breast-fed infant from argatroban or the underlying maternal condition. If pharmacotherapy is necessary in the nursing mother, previous American Academy of Pediatrics (AAP) recommendations considered warfarin to be usually compatible with breast-feeding.

    Children, infants, neonates

    A 30-day study evaluating argatroban (usual starting dose 1 mcg/kg/minute IV, titrated to achieve an aPTT of 1.5 to 3 times baseline) in 18 seriously ill pediatric patients did not establish safe and effective use in neonates, infants, children, and adolescents. During the study period, thrombotic events occurred during argatroban infusion in 2 patients and after argatroban discontinuation in 3 other patients. Major bleeding occurred in 2 patients; 1 patient with sepsis and thrombocytopenia experienced an intracranial hemorrhage after 4 days of argatroban therapy and another experienced intracranial hemorrhage after receiving argatroban for more than 14 days. All patients had serious underlying conditions and were receiving multiple concomitant medications.

    ADVERSE REACTIONS

    Severe

    GI bleeding / Delayed / 0.9-14.4
    cardiac arrest / Early / 5.8-5.8
    bleeding / Early / 1.8-5.3
    ventricular tachycardia / Early / 4.8-4.8
    bradycardia / Rapid / 4.5-4.5
    intracranial bleeding / Delayed / 1.0-4.3
    myocardial infarction / Delayed / 3.6-3.6
    atrial fibrillation / Early / 3.0-3.0
    hematemesis / Delayed / 2.6-2.6
    thrombosis / Delayed / 0.9-1.8
    hematuria / Delayed / 0.9-0.9
    retroperitoneal bleeding / Delayed / 0.9-0.9
    pulmonary edema / Early / 0.9-0.9

    Moderate

    chest pain (unspecified) / Early / 0.9-15.2
    hypotension / Rapid / 7.2-10.7
    bullous rash / Early / 0-10.0
    peripheral vasodilation / Rapid / 1.0-10.0
    hematoma / Early / 3.6-5.4
    hemoptysis / Delayed / 0.9-2.9
    angina / Early / 1.8-1.8
    dyspnea / Early / 10.0

    Mild

    rash / Early / 0-10.0
    back pain / Delayed / 8.0-8.0
    nausea / Early / 4.8-7.1
    fever / Early / 0.9-6.9
    vomiting / Early / 4.2-6.3
    diarrhea / Early / 6.2-6.2
    infection / Delayed / 3.3-6.0
    headache / Early / 5.4-5.4
    abdominal pain / Early / 2.6-3.6
    gastroesophageal reflux / Delayed / 0.9-0.9
    cough / Delayed / 2.8

    DRUG INTERACTIONS

    Abciximab: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., clopidogrel, platelet glycoprotein IIb/IIIa inhibitors, ticlopidine, etc.) in combination with argatroban.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) An additive risk of bleeding may be seen in patients receiving salicylates (e.g. aspirin, ASA) in combination with thrombin inhibitors. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Nonsteroidal antiinflammatory drugs (NSAIDs) may also increase bleeding risk when given with argatroban because of their potential to cause GI bleeding or inhibit platelet aggregation.
    Acetaminophen; Aspirin: (Moderate) An additive risk of bleeding may be seen in patients receiving salicylates (e.g. aspirin, ASA) in combination with thrombin inhibitors. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Nonsteroidal antiinflammatory drugs (NSAIDs) may also increase bleeding risk when given with argatroban because of their potential to cause GI bleeding or inhibit platelet aggregation.
    Acetaminophen; Aspirin; Diphenhydramine: (Moderate) An additive risk of bleeding may be seen in patients receiving salicylates (e.g. aspirin, ASA) in combination with thrombin inhibitors. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Nonsteroidal antiinflammatory drugs (NSAIDs) may also increase bleeding risk when given with argatroban because of their potential to cause GI bleeding or inhibit platelet aggregation.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) An additive risk of bleeding may be seen in patients receiving salicylates (e.g. aspirin, ASA) in combination with thrombin inhibitors. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Nonsteroidal antiinflammatory drugs (NSAIDs) may also increase bleeding risk when given with argatroban because of their potential to cause GI bleeding or inhibit platelet aggregation.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) An additive risk of bleeding may be seen in patients receiving salicylates (e.g. aspirin, ASA) in combination with thrombin inhibitors. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Nonsteroidal antiinflammatory drugs (NSAIDs) may also increase bleeding risk when given with argatroban because of their potential to cause GI bleeding or inhibit platelet aggregation.
    Ado-Trastuzumab emtansine: (Moderate) Use caution if coadministration of anticoagulants with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
    Altretamine: (Moderate) Due to the thrombocytopenic effects of altretamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Aminosalicylate sodium, Aminosalicylic acid: (Moderate) An additive risk of bleeding may be seen in patients receiving salicylates (e.g. aspirin, ASA) in combination with thrombin inhibitors. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Nonsteroidal antiinflammatory drugs (NSAIDs) may also increase bleeding risk when given with argatroban because of their potential to cause GI bleeding or inhibit platelet aggregation.
    Amlodipine; Celecoxib: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Anagrelide: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., clopidogrel, platelet glycoprotein IIb/IIIa inhibitors, ticlopidine, etc.) in combination with argatroban.
    Antithrombin III: (Major) An additive risk of bleeding may be seen in patients receiving argatroban and antithrombin III (AT III) concomitantly. In addition, the half-life of AT III may be altered during concomitant administration with anticoagulants. Coagulation tests (aPTT and anti-Factor Xa, when appropriate) should be performed regularly and especially in the first hours following the start or withdrawal of AT III therapy to ensure appropriate anticoagulation.
    Apixaban: (Major) Avoid concomitant use of apixaban and thrombin inhibitors due to the increased risk for bleeding. Short-term overlaps in anticoagulation therapy may be necessary for patients transitioning from one anticoagulant to another. Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if the use of multiple anticoagulants is necessary.
    Aspirin, ASA: (Moderate) An additive risk of bleeding may be seen in patients receiving salicylates (e.g. aspirin, ASA) in combination with thrombin inhibitors. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Nonsteroidal antiinflammatory drugs (NSAIDs) may also increase bleeding risk when given with argatroban because of their potential to cause GI bleeding or inhibit platelet aggregation.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) An additive risk of bleeding may be seen in patients receiving salicylates (e.g. aspirin, ASA) in combination with thrombin inhibitors. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Nonsteroidal antiinflammatory drugs (NSAIDs) may also increase bleeding risk when given with argatroban because of their potential to cause GI bleeding or inhibit platelet aggregation.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) An additive risk of bleeding may be seen in patients receiving salicylates (e.g. aspirin, ASA) in combination with thrombin inhibitors. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Nonsteroidal antiinflammatory drugs (NSAIDs) may also increase bleeding risk when given with argatroban because of their potential to cause GI bleeding or inhibit platelet aggregation.
    Aspirin, ASA; Caffeine: (Moderate) An additive risk of bleeding may be seen in patients receiving salicylates (e.g. aspirin, ASA) in combination with thrombin inhibitors. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Nonsteroidal antiinflammatory drugs (NSAIDs) may also increase bleeding risk when given with argatroban because of their potential to cause GI bleeding or inhibit platelet aggregation.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) An additive risk of bleeding may be seen in patients receiving salicylates (e.g. aspirin, ASA) in combination with thrombin inhibitors. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Nonsteroidal antiinflammatory drugs (NSAIDs) may also increase bleeding risk when given with argatroban because of their potential to cause GI bleeding or inhibit platelet aggregation.
    Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) An additive risk of bleeding may be seen in patients receiving salicylates (e.g. aspirin, ASA) in combination with thrombin inhibitors. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Nonsteroidal antiinflammatory drugs (NSAIDs) may also increase bleeding risk when given with argatroban because of their potential to cause GI bleeding or inhibit platelet aggregation.
    Aspirin, ASA; Carisoprodol: (Moderate) An additive risk of bleeding may be seen in patients receiving salicylates (e.g. aspirin, ASA) in combination with thrombin inhibitors. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Nonsteroidal antiinflammatory drugs (NSAIDs) may also increase bleeding risk when given with argatroban because of their potential to cause GI bleeding or inhibit platelet aggregation.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) An additive risk of bleeding may be seen in patients receiving salicylates (e.g. aspirin, ASA) in combination with thrombin inhibitors. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Nonsteroidal antiinflammatory drugs (NSAIDs) may also increase bleeding risk when given with argatroban because of their potential to cause GI bleeding or inhibit platelet aggregation.
    Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) An additive risk of bleeding may be seen in patients receiving salicylates (e.g. aspirin, ASA) in combination with thrombin inhibitors. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Nonsteroidal antiinflammatory drugs (NSAIDs) may also increase bleeding risk when given with argatroban because of their potential to cause GI bleeding or inhibit platelet aggregation.
    Aspirin, ASA; Dipyridamole: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., clopidogrel, platelet glycoprotein IIb/IIIa inhibitors, ticlopidine, etc.) in combination with argatroban. (Moderate) An additive risk of bleeding may be seen in patients receiving salicylates (e.g. aspirin, ASA) in combination with thrombin inhibitors. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Nonsteroidal antiinflammatory drugs (NSAIDs) may also increase bleeding risk when given with argatroban because of their potential to cause GI bleeding or inhibit platelet aggregation.
    Aspirin, ASA; Omeprazole: (Moderate) An additive risk of bleeding may be seen in patients receiving salicylates (e.g. aspirin, ASA) in combination with thrombin inhibitors. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Nonsteroidal antiinflammatory drugs (NSAIDs) may also increase bleeding risk when given with argatroban because of their potential to cause GI bleeding or inhibit platelet aggregation.
    Aspirin, ASA; Oxycodone: (Moderate) An additive risk of bleeding may be seen in patients receiving salicylates (e.g. aspirin, ASA) in combination with thrombin inhibitors. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Nonsteroidal antiinflammatory drugs (NSAIDs) may also increase bleeding risk when given with argatroban because of their potential to cause GI bleeding or inhibit platelet aggregation.
    Aspirin, ASA; Pravastatin: (Moderate) An additive risk of bleeding may be seen in patients receiving salicylates (e.g. aspirin, ASA) in combination with thrombin inhibitors. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Nonsteroidal antiinflammatory drugs (NSAIDs) may also increase bleeding risk when given with argatroban because of their potential to cause GI bleeding or inhibit platelet aggregation.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) An additive risk of bleeding may be seen in patients receiving salicylates (e.g. aspirin, ASA) in combination with thrombin inhibitors. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Nonsteroidal antiinflammatory drugs (NSAIDs) may also increase bleeding risk when given with argatroban because of their potential to cause GI bleeding or inhibit platelet aggregation.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) An additive risk of bleeding may be seen in patients receiving salicylates (e.g. aspirin, ASA) in combination with thrombin inhibitors. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Nonsteroidal antiinflammatory drugs (NSAIDs) may also increase bleeding risk when given with argatroban because of their potential to cause GI bleeding or inhibit platelet aggregation.
    Betrixaban: (Major) Avoid use of betrixaban with thrombin inhibitors due to the increased bleeding risk. Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if betrixaban and other anticoagulants are used concomitantly. Coadministration of betrixaban and other anticoagulants may increase the risk of bleeding. Long-term concomitant treatment with betrixaban and other anticoagulants is not recommended; short-term use may be necessary for patients transitioning to or from betrixaban.
    Bismuth Subsalicylate: (Moderate) An additive risk of bleeding may be seen in patients receiving salicylates (e.g. aspirin, ASA) in combination with thrombin inhibitors. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Nonsteroidal antiinflammatory drugs (NSAIDs) may also increase bleeding risk when given with argatroban because of their potential to cause GI bleeding or inhibit platelet aggregation.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) An additive risk of bleeding may be seen in patients receiving salicylates (e.g. aspirin, ASA) in combination with thrombin inhibitors. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Nonsteroidal antiinflammatory drugs (NSAIDs) may also increase bleeding risk when given with argatroban because of their potential to cause GI bleeding or inhibit platelet aggregation.
    Bivalirudin: (Major) An additive risk of bleeding may be seen in patients receiving bivalirudin with argatroban.
    Bupivacaine; Meloxicam: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Caplacizumab: (Major) Avoid concomitant use of caplacizumab and anticoagulants when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
    Carbenicillin: (Moderate) Some penicillins (e.g., carbenicillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Celecoxib: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Celecoxib; Tramadol: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Chlorambucil: (Moderate) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Choline Salicylate; Magnesium Salicylate: (Moderate) An additive risk of bleeding may be seen in patients receiving salicylates (e.g. aspirin, ASA) in combination with thrombin inhibitors. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Nonsteroidal antiinflammatory drugs (NSAIDs) may also increase bleeding risk when given with argatroban because of their potential to cause GI bleeding or inhibit platelet aggregation.
    Cilostazol: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., clopidogrel, platelet glycoprotein IIb/IIIa inhibitors, ticlopidine, etc.) in combination with argatroban.
    Citalopram: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and other drugs that affect coagulation like thrombin inhibitors. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
    Clofarabine: (Moderate) Due to the thrombocytopenic effects of clofarabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Clopidogrel: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., clopidogrel, platelet glycoprotein IIb/IIIa inhibitors, ticlopidine, etc.) in combination with argatroban.
    Collagenase: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Cytarabine, ARA-C: (Moderate) Due to the thrombocytopenic effects of pyrimidine analogs, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Dabigatran: (Major) Avoid use of dabigatran with argatroban due to the increased bleeding risk. Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if dabigatran and other anticoagulants are used concomitantly. Coadministration of dabigatran and other anticoagulants may increase the risk of bleeding. Long-term concomitant treatment with dabigatran and other anticoagulants is not recommended; short-term use may be necessary for patients transitioning to or from dabigatran.
    Dalteparin: (Major) An additive risk of bleeding may be seen in patients receiving dalteparin in combination with other anticoagulants. If coadministration of 2 or more anticoagulants is necessary, patients should be closely monitored for evidence of bleeding.
    Dasatinib: (Moderate) Monitor for evidence of bleeding if coadministration of dasatinib and anticoagulants is necessary. Dasatinib can cause serious and fatal bleeding. Concomitant anticoagulants may increase the risk of hemorrhage.
    Deferasirox: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including anticoagulants.
    Defibrotide: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like anticoagulants is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue systemic antithrombotic agents (not including use for routine maintenance or reopening of central venous catheters) prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
    Desirudin: (Major) Any agent which may enhance the risk of hemorrhage, including other anticoagulants, should generally be discontinued before initiating desirudin therapy. If coadministration cannot be avoided, close clinical and laboratory monitoring should be conducted.
    Dextran: (Moderate) Because of the potential effects of certain dextran formulations on bleeding time, use with caution in patients on anticoagulants concurrently.
    Diclofenac: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Diclofenac; Misoprostol: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Diflunisal: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Diphenhydramine; Ibuprofen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Diphenhydramine; Naproxen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Dipyridamole: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., clopidogrel, platelet glycoprotein IIb/IIIa inhibitors, ticlopidine, etc.) in combination with argatroban.
    Drotrecogin Alfa: (Major) Treatment with drotrecogin alfa should be carefully considered in patients who are receiving or have received any anticoagulants. There is an additive risk of beeding.
    Edoxaban: (Major) Avoid concurrent use of edoxaban with thrombin inhibitors due to the increased bleeding risk. Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if edoxaban and other anticoagulants are used concomitantly. Coadministration of edoxaban and other anticoagulants may increase the risk of bleeding. Long-term concomitant treatment with edoxaban and other anticoagulants is not recommended; short-term use may be necessary for patients transitioning to or from edoxaban.
    Eltrombopag: (Moderate) Use caution when discontinuing eltrombopag in patients receiving anticoagulants (e.g., warfarin, enoxaparin, dabigatran, rivaroxaban). The risk of bleeding and recurrent thrombocytopenia is increased in patients receiving these drugs when eltrombopag is discontinued.
    Enoxaparin: (Moderate) An additive risk of bleeding may be seen in patients receiving enoxaparin in combination with other anticoagulants. If coadministration of 2 or more anticoagulants is necessary, patients should be closely monitored for evidence of bleeding.
    Epoprostenol: (Moderate) When used concurrently with anticoagulants, epoprostenol may increase the risk of bleeding.
    Eptifibatide: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., clopidogrel, platelet glycoprotein IIb/IIIa inhibitors, ticlopidine, etc.) in combination with argatroban.
    Escitalopram: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and other drugs that affect coagulation like thrombin inhibitors. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
    Esterified Estrogens; Methyltestosterone: (Moderate) Methyltestosterone can increase the effects of anticoagulants through reduction of procoagulant factor. Patients receiving oral anticoagulant therapy should be closely monitored, especially when methyltestosterone treatment is initiated or discontinued.
    Etodolac: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Fenoprofen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): (Moderate) Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3-6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Fluoxetine: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and other drugs that affect coagulation like thrombin inhibitors. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
    Flurbiprofen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Fluvoxamine: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and other drugs that affect coagulation like thrombin inhibitors. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
    Fondaparinux: (Major) Discontinue thrombin inhibitors before starting fondaparinux due to the increased bleeding risk, unless these agents are essential. If coadministration is necessary, monitor patients closely and promptly evaluate any signs or symptoms of bleeding.
    Garlic, Allium sativum: (Moderate) Garlic produces clinically significant antiplatelet effects so additive risk of bleeding may occur if anticoagulants are given in combination. Avoid concurrent use of herbs which interact with anticoagulants when possible. If garlic dietary supplements are taken, monitor the INR or other appropriate parameters to attain clinical and anticoagulant endpoints. In regard to warfarin, published data are limited to a random case report; however, the product labeling for warfarin includes garlic as having potential for interaction due to additive pharmacologic activity. A case of spontaneous spinal epidural hematoma, attributed to dysfunctional platelets from excessive garlic use in a patient not receiving concomitant anticoagulation, has been reported.
    Ginger, Zingiber officinale: (Moderate) Additive bleeding may occur if anticoagulants are given in combination with ginger, zingiber officinale. Ginger inhibits thromboxane synthetase (platelet aggregation inducer) and is a prostacyclin agonist. Patients taking ginger and an anticoagulant should be monitored closely for bleeding.
    Ginkgo, Ginkgo biloba: (Moderate) Monitor for signs or symptoms of bleeding with coadministration of ginkgo biloba and thrombin inhibitors as an increased bleeding risk may occur. Although data are mixed, ginkgo biloba is reported to inhibit platelet aggregation and several case reports describe bleeding complications with ginkgo biloba, with or without concomitant drug therapy.
    Green Tea: (Moderate) Green tea has demonstrated antiplatelet and fibrinolytic actions in animals. It is possible that the use of green tea may increase the risk of bleeding if co-administered with anticoagulants (e.g., enoxaparin, heparin, warfarin, and others) thrombolytic agents, or platelet inhibitors (e.g., aspirin, clopidogrel, cilostazol and others). Caution and careful monitoring of clinical and/or laboratory parameters are warranted if green tea is coadministered with any of these agents. Exogenous administration or occult sources of vitamin K may decrease or reverse the activity of warfarin; stability of the diet can be an important factor in maintaining anticoagulation goals. Occult sources of vitamin K include green tea and green tea dietary supplements. Published data are limited in regard to this interaction. A patient with previous INRs of 3.2. and 3.79 on a dose of 7.5mg daily of warfarin (goal INR 2.5 to 3.5) had an INR of 1.37. One month later, the patient's INR was 1.14. The patient admitted that he had started consuming 0.51 gallon of green tea daily approximately one week prior to the INR of 1.37. The patient denied noncompliance and other changes in diet, medications, or health. The patient discontinued green tea and one week later his INR was 2.55. While the amount of vitamin K in a single cup of brewed green tea may not be high (0.03 mcg/100 g), the actual amount may vary from cup to cup depending on the amount of tea leaves used, the length of time the tea bags are allowed to brew, and the volume of tea consumed. Additionally, if a patient drinks multiple cups of tea per day, the amount of vitamin K could reach significance. It is recommended that patients on warfarin maintain a stable intake of green tea.
    Hemin: (Major) Because hemin has exhibited transient, mild anticoagulant effects during clinical studies, concurrent use of anticoagulants should be avoided. The extent and duration of the hypocoagulable state induced by hemin has not been established.
    Heparin: (Major) An additive risk of bleeding may be seen in patients receiving other anticoagulants in combination with heparin.
    Hydrocodone; Ibuprofen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) An additive risk of bleeding may be seen in patients receiving salicylates (e.g. aspirin, ASA) in combination with thrombin inhibitors. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Nonsteroidal antiinflammatory drugs (NSAIDs) may also increase bleeding risk when given with argatroban because of their potential to cause GI bleeding or inhibit platelet aggregation.
    Ibritumomab Tiuxetan: (Major) During and after therapy, avoid the concomitant use of Yttrium (Y)-90 ibrutumomab tiuxetan with drugs that interfere with coagulation such as anticoagulants; the risk of bleeding may be increased. If coadministration with anticoagulants is necessary, monitor platelet counts more frequently for evidence of thrombocytopenia.
    Ibrutinib: (Moderate) The concomitant use of ibrutinib and anticoagulant agents such as argatroban may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
    Ibuprofen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Ibuprofen; Famotidine: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Ibuprofen; Oxycodone: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Ibuprofen; Pseudoephedrine: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Icosapent ethyl: (Moderate) Icosapent ethyl is an ethyl ester of the omega-3 fatty acid eicosapentaenoic acid (EPA). Because omega-3 fatty acids inhibit platelet aggregation, caution is advised when icosapent ethyl is used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 36 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant icosapent ethyl therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Iloprost: (Moderate) When used concurrently with anticoagulants, inhaled iloprost may increase the risk of bleeding.
    Indomethacin: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Inotersen: (Moderate) Use caution with concomitant use of inotersen and anticoagulants due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of anticoagulants in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
    Intravenous Lipid Emulsions: (Moderate) Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3-6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Ketoprofen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Ketorolac: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Lansoprazole; Naproxen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Lepirudin: (Major) An additive risk of bleeding may be seen in patients receiving argatroban in combination with lepirudin.
    Lithium: (Moderate) Moderate to significant dietary sodium changes, or changes in sodium and fluid intake, may affect lithium excretion. Systemic sodium chloride administration may result in increased lithium excretion and therefore, decreased serum lithium concentrations. In addition, high fluid intake may increase lithium excretion. For patients receiving sodium-containing intravenous fluids, symptom control and lithium concentrations should be carefully monitored. It is recommended that patients taking lithium maintain consistent dietary sodium consumption and adequate fluid intake during the initial stabilization period and throughout lithium treatment. Supplemental oral sodium and fluid should be only be administered under careful medical supervision.
    Lomustine, CCNU: (Moderate) Due to the bone marrow suppressive and thrombocytopenic effects of lomustine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Magnesium Salicylate: (Moderate) An additive risk of bleeding may be seen in patients receiving salicylates (e.g. aspirin, ASA) in combination with thrombin inhibitors. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Nonsteroidal antiinflammatory drugs (NSAIDs) may also increase bleeding risk when given with argatroban because of their potential to cause GI bleeding or inhibit platelet aggregation.
    Meclofenamate Sodium: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Mefenamic Acid: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Meloxicam: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Methenamine; Sodium Salicylate: (Moderate) An additive risk of bleeding may be seen in patients receiving salicylates (e.g. aspirin, ASA) in combination with thrombin inhibitors. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Nonsteroidal antiinflammatory drugs (NSAIDs) may also increase bleeding risk when given with argatroban because of their potential to cause GI bleeding or inhibit platelet aggregation.
    Methoxsalen: (Minor) Agents, such as anticoagulants, that decrease clotting could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
    Methylsulfonylmethane, MSM: (Moderate) Increased effects from concomitant anticoagulant drugs such as increased bruising or blood in the stool have been reported in patients taking methylsulfonylmethane, MSM. Although these effects have not been confirmed in published medical literature or during clinical studies, clinicians should consider using methylsulfonylmethane, MSM with caution in patients who are taking anticoagulants such as warfarin until data confirming the safety of MSM in patients taking these drugs are available. During one of the available, published clinical trials in patients with osteoarthritis, those patients with bleeding disorders or using anticoagulants or antiplatelets were excluded from enrollment. Patients who choose to consume methylsulfonylmethane, MSM while receiving warfarin should be observed for increased bleeding.
    Methyltestosterone: (Moderate) Methyltestosterone can increase the effects of anticoagulants through reduction of procoagulant factor. Patients receiving oral anticoagulant therapy should be closely monitored, especially when methyltestosterone treatment is initiated or discontinued.
    Mifepristone: (Contraindicated) When mifepristone is used for the termination of pregnancy, concurrent use of anticoagulants is contraindicated due to the risk of serious bleeding.
    Miltefosine: (Moderate) Caution is advised when administering miltefosine with anticoagulants, as use of these drugs together may increase risk for bleeding. Miltefosine, when administered for the treatment of visceral leishmaniasis, has been associated with thrombocytopenia; monitor platelet counts in patients receiving treatment for this indication. In addition, monitor closely for increased bleeding if use in combination with an anticoagulant.
    Mycophenolate: (Moderate) Mycophenolate may causes thrombocytopenia and increase the risk for bleeding. Agents which may lead to an increased incidence of bleeding in patients with thrombocytopenia include anticoagulants.
    Nabumetone: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Nandrolone Decanoate: (Moderate) Androgens can enhance the effects of anticoagulants. Dosage of the anticoagulant may have to be decreased in order to maintain prothrombin time at the desired therapeutic level. When anabolic steroid or androgen therapy is started or stopped in patients on anticoagulant therapy, close monitoring is required. Additionally, nandrolone decanoate may generate a pharmacodynamic interaction with warfarin by independently affecting the activity of circulating coagulation proteins. Androgens reduce the amount or activity of circulating coagulant proteins thereby enhancing the anticoagulant effect of warfarin.
    Naproxen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Naproxen; Esomeprazole: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Naproxen; Pseudoephedrine: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Nelarabine: (Moderate) Due to the thrombocytopenic effects of nelarabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Nintedanib: (Moderate) Nintedanib is a VEGFR inhibitor and may increase the risk of bleeding. Monitor patients who are taking anticoagulants closely and adjust anticoagulation therapy as necessary. Use nintedanib in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk.
    Nonsteroidal antiinflammatory drugs: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Obinutuzumab: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    Olanzapine; Fluoxetine: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and other drugs that affect coagulation like thrombin inhibitors. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
    Omacetaxine: (Major) Avoid the concomitant use of omacetaxine and anticoagulants when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
    Oxandrolone: (Moderate) An increased effect of anticoagulants may occur with oxandrolone; the anticoagulant dosage may need adjustment downward with oxandrolone initiation or adjustment upward with oxandrolone discontinuation to maintain the desired clinical effect. Oxandrolone suppresses clotting factors II, V, VII, and X, which results in an increased prothrombin time. An increase in plasminogen-activator activity, and serum concentrations of plasminogen, protein C, and antithrombin III have occurred with several 17-alpha-alkylated androgens. For example, concurrent use of oxandrolone and warfarin may result in unexpectedly large increases in the INR or prothrombin time (PT). A multidose study of oxandrolone (5 or 10 mg PO twice daily) in 15 healthy individuals concurrently treated with warfarin resulted in significant increases in warfarin half-life and AUC; a 5.5-fold decrease in the mean warfarin dosage from 6.13 mg/day to 1.13 mg/day (approximately 80 to 85% dose reduction) was necessary to maintain a target INR of 1.5. According to the manufacturer, if oxandrolone therapy is initiated in a patient already receiving warfarin, the dose of warfarin may need to be decreased significantly to reduce the potential for excessive INR elevations and associated risk of serious bleeding events. The patient should be closely monitored with frequent evaluation of the INR and clinical parameter, and the dosage of warfarin should be adjusted as necessary until a stable target INR is achieved. Careful monitoring of the INR and necessary adjustment of the warfarin dosage are also recommended when the androgen therapy is changed or discontinued.
    Oxaprozin: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Paroxetine: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and other drugs that affect coagulation like thrombin inhibitors. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
    Pentosan: (Major) Pentosan is a weak anticoagulant. Pentosan has 1/15 the anticoagulant activity of heparin. An additive risk of bleeding may be seen in patients receiving other anticoagulants in combination with pentosan.
    Piperacillin: (Moderate) Some penicillins (e.g., piperacillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Piperacillin; Tazobactam: (Moderate) Some penicillins (e.g., piperacillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Piroxicam: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Platelet Inhibitors: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., clopidogrel, platelet glycoprotein IIb/IIIa inhibitors, ticlopidine, etc.) in combination with argatroban.
    Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Major) Prasterone (DHEA) is contraindicated for use in patients with active deep vein thrombosis, pulmonary embolism or history of these conditions. Prasterone is also contraindicated in patients with active arterial thromboembolic disease (for example, stroke and myocardial infarction), or a history of these conditions. Thus, patients receiving anticoagulation due to a history of these conditions are not candidates for prasterone treatment. DHEA is converted to androgens and estrogens within the human body and thus may affect hemostasis via androgenic or estrogenic effects. Estrogens increase the production of clotting factors VII, VIII, IX, and X. Androgens, such as testosterone, increase the synthesis of several anticoagulant and fibrinolytic proteins. Because of the potential effects on coagulation, patients receiving prasterone or DHEA concurrently with preventative anticoagulants (e.g., warfarin or heparin) or other platelet inhibitors, including aspirin, ASA should be monitored for side effects or the need for dosage adjustments.
    Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Major) Prasterone (DHEA) is contraindicated for use in patients with active deep vein thrombosis, pulmonary embolism or history of these conditions. Prasterone is also contraindicated in patients with active arterial thromboembolic disease (for example, stroke and myocardial infarction), or a history of these conditions. Thus, patients receiving anticoagulation due to a history of these conditions are not candidates for prasterone treatment. DHEA is converted to androgens and estrogens within the human body and thus may affect hemostasis via androgenic or estrogenic effects. Estrogens increase the production of clotting factors VII, VIII, IX, and X. Androgens, such as testosterone, increase the synthesis of several anticoagulant and fibrinolytic proteins. Because of the potential effects on coagulation, patients receiving prasterone or DHEA concurrently with preventative anticoagulants (e.g., warfarin or heparin) or other platelet inhibitors, including aspirin, ASA should be monitored for side effects or the need for dosage adjustments.
    Prasugrel: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., clopidogrel, platelet glycoprotein IIb/IIIa inhibitors, ticlopidine, etc.) in combination with argatroban.
    Rivaroxaban: (Major) Due to the increased bleeding risk, avoid concurrent use of rivaroxaban with thrombin inhibitors; the safety of concomitant use has not been studied. If a thrombin inhibitor is used during therapeutic transition periods, closely observe patients and promptly evaluate any signs or symptoms of blood loss.
    Rofecoxib: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Salicylates: (Moderate) An additive risk of bleeding may be seen in patients receiving salicylates (e.g. aspirin, ASA) in combination with thrombin inhibitors. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Nonsteroidal antiinflammatory drugs (NSAIDs) may also increase bleeding risk when given with argatroban because of their potential to cause GI bleeding or inhibit platelet aggregation.
    Salsalate: (Moderate) An additive risk of bleeding may be seen in patients receiving salicylates (e.g. aspirin, ASA) in combination with thrombin inhibitors. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Nonsteroidal antiinflammatory drugs (NSAIDs) may also increase bleeding risk when given with argatroban because of their potential to cause GI bleeding or inhibit platelet aggregation.
    Selective serotonin reuptake inhibitors: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and other drugs that affect coagulation like thrombin inhibitors. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
    Serotonin norepinephrine reuptake inhibitors: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like argatroban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
    Sertraline: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and other drugs that affect coagulation like thrombin inhibitors. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
    Sodium Iodide: (Moderate) Anticoagulants may alter sodium iodide I-131 pharmacokinetics and dynamics for up to 1 week after administrations.
    Sulfinpyrazone: (Major) Sulfinpyrazone should be avoided when possible with concurrent anticoagulants, thrombin inhibitors, and thrombolytic agents due to potential for increased bleeding risk. Alternative uricosuric agents may be considered. Sulfinpyrazone is a platelet inhibitor and exhibits antithrombotic actions in addition to its uricosuric effects. Additive hematological effects are possible as a result of the platelet inhibitory effects of sulfinpyrazone; the sulfide metabolite of sulfinpyrazone appears responsible for this effect. Sulfinpyrazone is also known to markedly potentiate the effect of warfarin. Sulfinpyrazone may inhibit CYP2C9, leading to a decrease in the clearance of S-warfarin. If concurrent therapy is warranted, significant initial dosage reductions (e.g., 50%) of warfarin may be necessary, with further dosage adjusted based on INR values. The INR should be closely monitored during concurrent therapy with warfarin, particularly during the initiation or termination phases of sulfinpyrazone treatment.
    Sulindac: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Sumatriptan; Naproxen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Telavancin: (Moderate) Telavancin has no effect on coagulation or platelet aggregation; however, caution is advised when administering telavancin concurrently with anticoagulants as telavancin may interfere with laboratory tests used in monitoring these medications. The coagulation tests affected by telavancin include prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (aPTT), activated clotting time, and coagulation based factor Xa tests. When measured shortly after completion of a telavancin infusion, the results of these tests are increased; however, the effects of telavancin on these tests dissipate over time as plasma concentrations of telavancin decrease. Therefore, when administering telavancin in conjunction with anticoagulants ensure that blood samples for these coagulation tests are collected as close as possible to the patient's next telavancin dose.
    Thrombolytic Agents: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents with thrombin inhibitors.
    Ticagrelor: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., clopidogrel, platelet glycoprotein IIb/IIIa inhibitors, ticlopidine, etc.) in combination with argatroban.
    Ticarcillin: (Moderate) Some penicillins (e.g., ticarcillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Ticarcillin; Clavulanic Acid: (Moderate) Some penicillins (e.g., ticarcillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Ticlopidine: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., clopidogrel, platelet glycoprotein IIb/IIIa inhibitors, ticlopidine, etc.) in combination with argatroban.
    Tinzaparin: (Major) An additive risk of bleeding may be seen in patients receiving tinzaparin in combination with other anticoagulants. If coadministration of 2 or more anticoagulants is necessary, patients should be closely monitored for evidence of bleeding.
    Tipranavir: (Moderate) Caution should be used when administering tipranavir to patients receiving anticoagulants or platelet inhibitors. In clinical trials, there have been 14 reports of intracranial bleeding (intracranial hemorrhage, ICH), including 8 fatalities, in 13 out of 6,840 HIV infected patients receiving tipranavir as part of combination antiretroviral therapy. In many of these reports, the patients had other medical conditions (CNS lesions, head trauma, recent neurosurgery, coagulopathy, hypertension, or alcoholism/alcohol abuse) or were receiving concomitant medications, including anticoagulants and antiplatelet agents, that may have caused or contributed to these events. The median time to onset of an ICH event was 525 days on tipranavir treatment. In general, there have been no reported patterns of abnormal coagulation parameters in patients receiving tipranavir, or preceding the development of ICH. Routine measurement of coagulation parameters does not appear to be indicated. An increased risk of ICH has previously been observed in patients with advanced HIV disease or AIDS; further investigations are ongoing to assess the role of tipranavir in ICH. While coadministration with warfarin does not result in altered warfarin concentrations, alterations in INR may still occur; close monitoring of the patient's INR is recommended. Patients should be advised to promptly report any signs or symptoms of bleeding.
    Tirofiban: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., clopidogrel, platelet glycoprotein IIb/IIIa inhibitors, ticlopidine, etc.) in combination with argatroban.
    Tolmetin: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Tolvaptan: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Trazodone: (Moderate) Patients should be instructed to monitor for signs and symptoms of bleeding while taking trazodone concurrently with anticoagulants and to promptly report any bleeding events to the practitioner. Serotonergic agents may increase the risk of bleeding when combined with anticoagulants via inhibition of serotonin uptake by platelets; however, the absolute risk is not known. It would be prudent for clinicians to monitor the INR and patient's clinical status closely if trazodone is added to or removed from the regimen of a patient stabilized on anticoagulant therapy.
    Treprostinil: (Moderate) When used concurrently with anticoagulants, treprostinil may increase the risk of bleeding.
    Valdecoxib: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Verteporfin: (Moderate) Use caution if coadministration of verteporfin with anticoagulants is necessary due to the risk of decreased verteporfin efficacy. Verteporfin is a light-activated drug. Once activated, local damage to neovascular endothelium results in a release of procoagulant and vasoactive factors resulting in platelet aggregation, fibrin clot formation, and vasoconstriction. Concomitant use of drugs that decrease clotting could decrease the efficacy of verteporfin therapy.
    Vilazodone: (Moderate) Patients should be instructed to monitor for signs and symptoms of bleeding while taking vilazodone concurrently with anticoagulants and to promptly report any bleeding events to the practitioner. Serotonergic agents may increase the risk of bleeding when combined with anticoagulants via inhibition of serotonin uptake by platelets; however, the absolute risk is not known. In addition, both vilazodone and warfarin are highly protein bound, which may result in displacement of warfarin from protein binding sites and an increased anticoagulant effect. It would be prudent for clinicians to monitor the INR and clinical status of the patient closely if vilazodone is added to or removed from the regimen of a patient stabilized on warfarin.
    Vorapaxar: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., clopidogrel, platelet glycoprotein IIb/IIIa inhibitors, ticlopidine, etc.) in combination with argatroban.
    Vortioxetine: (Moderate) Platelet aggregation may be impaired by vortioxetine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving anticoagulants. Bleeding events related to drugs that inhibit serotonin reuptake have ranged from ecchymosis to life-threatening hemorrhages. Patients should be instructed to monitor for signs and symptoms of bleeding while taking vortioxetine concurrently with anticoagulants and to promptly report any bleeding events to the practitioner. Co-administration of vortioxetine and warfarin has not been shown to significantly affect the pharmacokinetics of either agent.
    Warfarin: (Major) An additive risk of bleeding may be seen in patients receiving other anticoagulants (e.g., heparin, warfarin) in combination with argatroban.

    PREGNANCY AND LACTATION

    Pregnancy

    If argatroban is used during pregnancy, monitor neonates for bleeding and pregnant women for evidence of excessive bleeding or unexpected changes in coagulation parameters during labor or obstetric delivery. The use of argatroban during pregnancy may increase the risk of bleeding. Limited data from postmarketing reports and published literature do not suggest an association between the use of argatroban and adverse fetal developmental outcomes. In animal reproduction studies with argatroban doses up to 0.2- and 0.3-times the maximum recommended human dose (based on body surface area), there was no evidence of adverse developmental outcomes.

    MECHANISM OF ACTION

    Argatroban is a selective direct thrombin inhibitor similar to bivalirudin, desirudin, and lepirudin, recombinant forms of the natural anticoagulant hirudin. Argatroban reversibly inhibits the catalytic site of thrombin, neutralizing the actions of thrombin, including thrombin entrapped within established clots. It ultimately interferes with fibrin generation, platelet aggregation, factor XII activation, and other related biologic activities. Because all thrombin-dependent coagulation assays are affected, thrombin times are not helpful in monitoring argatroban activity. Argatroban is very short-acting due to its reversible binding to thrombin whereas lepirudin binds irreversibly to thrombin. Unlike heparin, neither argatroban nor lepirudin require antithrombin III for activity nor are these agents inhibited by platelet factor IV. No antagonists to direct thrombin inhibitors are known. Argatroban increases in a dose-dependent manner, the activated partial thromboplastin time (aPTT), the activated clotting time (ACT), the prothrombin time (PT), the International Normalized Ratio (INR), and the thrombin time in healthy volunteers and cardiac patients.

    PHARMACOKINETICS

    Argatroban is administered by intravenous infusion. The distribution of argatroban is mainly within the extracellular fluid. Protein binding is about 54%, with 20% bound to albumin and 34% to alpha1-acid glycoprotein. In healthy volunteers, peak plasma concentrations occur within 3 to 4 hours. Anticoagulant effects are produced immediately upon initiation of argatroban infusion. Steady-state plasma concentrations are typically attained within 1 to 3 hours and increase proportionally with dose. Steady-state anticoagulant effects are well correlated with steady-state plasma concentrations. Argatroban is metabolized by hydroxylation and aromatization of the quinoline ring. The anticoagulant effects of the primary metabolite (M1) are 3 to 5-fold weaker than those of argatroban. Plasma concentrations of the M1 range between 0% to 20% of that of the parent drug. The other metabolites (M2 to M4) have not been detected in plasma or feces and are found only in very low amounts in the urine. Argatroban excretion is primarily via the biliary tract. In radiolabeled studies, approximately 16% and 14% of an administered dose were excreted as unchanged drug in the urine and feces, respectively. Total body clearance is approximately 5.1 mL/kg/minute for infusion doses up to 40 mcg/kg/minute. The terminal elimination half-life is about 39 to 51 minutes.[56982]
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4/5
    The formation of argatroban metabolites is catalyzed by CYP3A4/5. Lack of effect of erythromycin, a potent CYP3A4/5 inhibitor, on argatroban pharmacokinetics suggests that CYP3A4/5-mediated metabolism is not an important elimination pathway.[56982]